A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design.

PubMed

Staley, James R; Jones, Edmund; Kaptoge, Stephen; Butterworth, Adam S; Sweeting, Michael J; Wood, Angela M; Howson, Joanna M M

2017-06-01

Logistic regression is often used instead of Cox regression to analyse genome-wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP-disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease.

Scaling of the surface vasculature on the human placenta

NASA Astrophysics Data System (ADS)

Leonard, A. S.; Lee, J.; Schubert, D.; Croen, L. A.; Fallin, M. D.; Newschaffer, C. J.; Walker, C. K.; Salafia, C. M.; Morgan, S. P.; Vvedensky, D. D.

2017-10-01

The networks of veins and arteries on the chorionic plate of the human placenta are analyzed in terms of Voronoi cells derived from these networks. Two groups of placentas from the United States are studied: a population cohort with no prescreening, and a cohort from newborns with an elevated risk of developing autistic spectrum disorder. Scaled distributions of the Voronoi cell areas in the two cohorts collapse onto a single distribution, indicating common mechanisms for the formation of the complete vasculatures, but which have different levels of activity in the two cohorts.

Urgent and Elective Robotic Single-Site Cholecystectomy: Analysis and Learning Curve of 150 Consecutive Cases.

PubMed

Kubat, Eric; Hansen, Nathan; Nguyen, Huy; Wren, Sherry M; Eisenberg, Dan

2016-03-01

The use of robotic single-site cholecystectomy has increased exponentially. There are few reports describing the safety, efficacy, and operative learning curve of robotic single-site cholecystectomy either in the community setting or with nonelective surgery. We performed a retrospective review of a prospective database of our initial experience with robotic single-site cholecystectomy. Demographics and perioperative outcomes were evaluated for both urgent and elective cholecystectomy. Cumulative sum analysis was performed to determine the surgeon's learning curve. One hundred fifty patients underwent robotic single-site cholecystectomy. Seventy-four (49.3%) patients underwent urgent robotic single-site cholecystectomy, and 76 (50.7%) underwent elective robotic single-site cholecystectomy. Mean total operative time for robotic single-site cholecystectomy was 83.3 ± 2.7 minutes. Mean operative time for the urgent cohort was significantly longer than for the elective cohort (95.0 ± 4.4 versus 71.9 ± 2.6 minutes; P < .001). There was one conversion in the urgent cohort and none in the elective cohort. There was one bile duct injury (0.7%) in the urgent cohort. Perioperative complications occurred in 8.7% of patients, and most consisted of superficial surgical-site infections. There were no incisional hernias detected. The surgeon's learning curve, inclusive of urgent and elective cases, was 48 operations. Robotic single-site cholecystectomy can be performed safely and effectively in both elective and urgent cholecystectomy with a reasonable learning curve and acceptable perioperative outcomes.

Plasma and Dietary Antioxidant Status as Cardiovascular Disease Risk Factors: A Review of Human Studies

PubMed Central

Wang, Ying; Chun, Ock K.; Song, Won O.

2013-01-01

Extensive evidence has demonstrated that many antioxidants such as vitamin C, vitamin E, carotenoids and polyphenols have protective effects in preventing cardiovascular disease (CVD), a chronic disease that is mediated by oxidative stress and inflammation. This review focuses on evidence from prospective cohort studies and clinical trials in regard to the associations between plasma/dietary antioxidants and cardiovascular events. Long-term, large-scale, population-based cohort studies have found that higher levels of serum albumin, bilirubin, glutathione, vitamin E, vitamin C, and carotenoids were associated with a lower risk of CVD. Evidence from the cohort studies in regard to dietary antioxidants also supported the protective effects of dietary vitamin E, vitamin C, carotenoids, and polyphenols on CVD risk. However, results from large randomized controlled trials did not support long-term use of single antioxidant supplements for CVD prevention due to their null or even adverse effects on major cardiovascular events or cancer. Diet quality indexes that consider overall diet quality rather than single nutrients have been drawing increasing attention. Cohort studies and intervention studies that focused on diet patterns such as high total antioxidant capacity have documented protective effects on CVD risk. This review provides a perspective for future studies that investigate antioxidant intake and risk of CVD. PMID:23912327

Single-Anesthetic Versus Staged Bilateral Total Hip Arthroplasty: A Matched Cohort Study.

PubMed

Houdek, Matthew T; Wyles, Cody C; Watts, Chad D; Wagner, Eric R; Sierra, Rafael J; Trousdale, Robert T; Taunton, Michael J

2017-01-04

There is debate regarding the role of single-anesthetic versus staged bilateral total hip arthroplasty (THA) for patients with end-stage bilateral osteoarthritis. Studies have shown that single-anesthetic bilateral THA is associated with systemic complications, but there are limited data comparing patient outcomes in a matched setting of bilateral THA. We identified 94 patients (188 hips) who underwent single-anesthetic bilateral THA. Fifty-seven percent of the patients were male. Patients had a mean age of 52.2 years and body mass index of 27.1 kg/m. They were matched 1:1 on the basis of sex, age (±1 year), and year of surgery (±3 years) to a cohort of patients undergoing staged bilateral THA. In the staged group, there was <1 year between procedures (range, 5 days to 10 months). Mean follow-up was 4 years for each group. Patients in the single-anesthetic group experienced shorter total operating room time and length of stay. There was no difference (hazard ratio [HR] = 0.73, p = 0.50) in the overall revision-free survival in patients undergoing single-anesthetic or staged bilateral THA. The risks of reoperation (HR = 0.69, p = 0.40), complications (HR = 0.83, p = 0.48), and mortality (HR = 0.47, p = 0.10) were similar. Single-anesthetic bilateral THA reduced the total cost of care (by 27%, p = 0.0001). In this matched cohort analysis, single-anesthetic bilateral THA was not associated with an increased risk of revision, reoperation, or postoperative complications, while decreasing cost. In our experience, single-anesthetic bilateral THA is a safe procedure that, for certain patients, offers an excellent means to deal with bilateral hip osteoarthritis. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Opportunities and Challenges in Using Studies without a Control Group in Comparative Effectiveness Reviews

ERIC Educational Resources Information Center

Paulus, Jessica K.; Dahabreh, Issa J.; Balk, Ethan M.; Avendano, Esther E.; Lau, Joseph; Ip, Stanley

2014-01-01

When examining the evidence on therapeutic interventions to answer a comparative effectiveness research question, one should consider all studies that are informative on the interventions' causal effects. "Single group studies" evaluate outcomes longitudinally in cohorts of subjects who are managed with a single treatment strategy.…

The peroxisome proliferator-activated receptor agonist pioglitazone and 5-lipoxygenase inhibitor zileuton have no effect on lung inflammation in healthy volunteers by positron emission tomography in a single-blind placebo-controlled cohort study.

PubMed

Chen, Delphine L; Huang, Howard J; Byers, Derek E; Shifren, Adrian; Belikoff, Bryan; Engle, Jacquelyn T; Arentson, Elizabeth; Kemp, Debra; Phillips, Sharon; Scherrer, David E; Fujiwara, Hideji; Spayd, Katherine J; Brooks, Frank J; Pierce, Richard A; Castro, Mario; Isakow, Warren

2018-01-01

Anti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation. For this single center, single-blind, placebo-controlled cohort study, we enrolled healthy volunteers sequentially into the following treatment cohorts (N = 6 per cohort): pioglitazone plus placebo, zileuton plus placebo, or dual placebo prior to bronchoscopic endotoxin instillation. 18F-FDG uptake pre- and post-endotoxin was quantified as the Patlak graphical analysis-determined Ki (primary outcome measure). Secondary outcome measures included the mean standard uptake value (SUVmean), post-endotoxin bronchoalveolar lavage (BAL) cell counts and differentials and blood adiponectin and urinary leukotriene E4 (LTE4) levels, determined by enzyme-linked immunosorbent assay, to verify treatment compliance. One- or two-way analysis of variance assessed for differences among cohorts in the outcome measures (expressed as mean ± standard deviation). Ten females and eight males (29±6 years of age) completed all study procedures except for one volunteer who did not complete the post-endotoxin BAL. Ki and SUVmean increased in all cohorts after endotoxin instillation (Ki increased by 0.0021±0.0019, 0.0023±0.0017, and 0.0024±0.0020 and SUVmean by 0.47±0.14, 0.55±0.15, and 0.54±0.38 in placebo, pioglitazone, and zileuton cohorts, respectively, p<0.001) with no differences among treatment cohorts (p = 0.933). Adiponectin levels increased as expected with pioglitazone treatment but not urinary LTE4 levels as expected with zileuton treatment. BAL cell counts (p = 0.442) and neutrophil percentage (p = 0.773) were similar among the treatment cohorts. Endotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans. ClinicalTrials.gov NCT01174056.

The peroxisome proliferator-activated receptor agonist pioglitazone and 5-lipoxygenase inhibitor zileuton have no effect on lung inflammation in healthy volunteers by positron emission tomography in a single-blind placebo-controlled cohort study

PubMed Central

Huang, Howard J.; Byers, Derek E.; Shifren, Adrian; Belikoff, Bryan; Engle, Jacquelyn T.; Arentson, Elizabeth; Kemp, Debra; Phillips, Sharon; Scherrer, David E.; Fujiwara, Hideji; Spayd, Katherine J.; Brooks, Frank J.; Pierce, Richard A.; Castro, Mario; Isakow, Warren

2018-01-01

Background Anti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation. Methods For this single center, single-blind, placebo-controlled cohort study, we enrolled healthy volunteers sequentially into the following treatment cohorts (N = 6 per cohort): pioglitazone plus placebo, zileuton plus placebo, or dual placebo prior to bronchoscopic endotoxin instillation. 18F-FDG uptake pre- and post-endotoxin was quantified as the Patlak graphical analysis-determined Ki (primary outcome measure). Secondary outcome measures included the mean standard uptake value (SUVmean), post-endotoxin bronchoalveolar lavage (BAL) cell counts and differentials and blood adiponectin and urinary leukotriene E4 (LTE4) levels, determined by enzyme-linked immunosorbent assay, to verify treatment compliance. One- or two-way analysis of variance assessed for differences among cohorts in the outcome measures (expressed as mean ± standard deviation). Results Ten females and eight males (29±6 years of age) completed all study procedures except for one volunteer who did not complete the post-endotoxin BAL. Ki and SUVmean increased in all cohorts after endotoxin instillation (Ki increased by 0.0021±0.0019, 0.0023±0.0017, and 0.0024±0.0020 and SUVmean by 0.47±0.14, 0.55±0.15, and 0.54±0.38 in placebo, pioglitazone, and zileuton cohorts, respectively, p<0.001) with no differences among treatment cohorts (p = 0.933). Adiponectin levels increased as expected with pioglitazone treatment but not urinary LTE4 levels as expected with zileuton treatment. BAL cell counts (p = 0.442) and neutrophil percentage (p = 0.773) were similar among the treatment cohorts. Conclusions Endotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans. Trial registration ClinicalTrials.gov NCT01174056. PMID:29414995

Secondary depression in severe anxiety disorders: a population-based cohort study in Denmark

PubMed Central

Meier, Sandra M; Petersen, Liselotte; Mattheisen, Manuel; Mors, Ole; Mortensen, Preben B; Laursen, Thomas M

2016-01-01

Summary Background Depression and anxiety disorders are highly comorbid conditions and a worldwide disease burden; however, large-scale studies delineating their association are scarce. In this retrospective study, we aimed to assess the effect of severe anxiety disorders on the risk and course of depression. Methods We did a population-based cohort study with prospectively gathered data in Denmark using data from three Danish population registers: The Danish Civil Registration System, the Danish Psychiatric Central Register, and the Danish National Hospital Registry. We selected the cohort from people born in Denmark between Jan 1, 1955, and Dec 31, 2002, who we followed up from Jan 1, 1994, to Dec 31, 2012. The cohort was restricted to individuals with known parents. First, we investigated the effect of specific anxiety diagnoses on risk of single depressive episodes and recurrent depressive disorder. Second, we investigated the effect of comorbid anxiety on risk of readmission for depression, adjusting for sex, age, calendar year, parental age, place at residence at time of birth, and the interaction of age with sex. Findings We included 3 380 059 individuals in our study cohort. The adjusted incidence rate ratio (IRR) for single depressive episodes was 3·0 (95% CI 2·8–3·1, p<0·0001) and for recurrent depressive disorder was 5·0 (4·8–5·2) in patients with severe anxiety disorders compared with the general population. Compared with control individuals, the offspring of parents with anxiety disorders were more likely to be diagnosed with single depressive episodes (1·9, 1·8–2·0) or recurrent depressive disorder (2·1, 1·9–2·2). Comorbid anxiety increased the readmission rates in both patients with single depressive episodes and patients with recurrent depressive disorder. Interpretation Severe anxiety constitutes a significant risk factor for depression. Focusing on specific anxiety disorders might help to identify individuals at risk of depression, thereby providing new insights for prevention and treatment. Funding The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). PMID:26360447

Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.

PubMed

Khong, Jwu Jin; Burdon, Kathryn P; Lu, Yi; Laurie, Kate; Leonardos, Lefta; Baird, Paul N; Sahebjada, Srujana; Walsh, John P; Gajdatsy, Adam; Ebeling, Peter R; Hamblin, Peter Shane; Wong, Rosemary; Forehan, Simon P; Fourlanos, Spiros; Roberts, Anthony P; Doogue, Matthew; Selva, Dinesh; Montgomery, Grant W; Macgregor, Stuart; Craig, Jamie E

2016-11-18

Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10 -8 ). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10 -4 . Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.

Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants.

PubMed

Hartnett, M Elizabeth; Morrison, Margaux A; Smith, Silvia; Yanovitch, Tammy L; Young, Terri L; Colaizy, Tarah; Momany, Allison; Dagle, John; Carlo, Waldemar A; Clark, Erin A S; Page, Grier; Murray, Jeff; DeAngelis, Margaret M; Cotten, C Michael

2014-08-12

To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants. Preterm infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory, and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables. Single nucleotide polymorphisms significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis. Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 × 10(-5)) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P = 2.9 × 10(-7)). Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Toward standardized reporting for a cohort study on functioning: The Swiss Spinal Cord Injury Cohort Study.

PubMed

Prodinger, Birgit; Ballert, Carolina S; Brach, Mirjam; Brinkhof, Martin W G; Cieza, Alarcos; Hug, Kerstin; Jordan, Xavier; Post, Marcel W M; Scheel-Sailer, Anke; Schubert, Martin; Tennant, Alan; Stucki, Gerold

2016-02-01

Functioning is an important outcome to measure in cohort studies. Clear and operational outcomes are needed to judge the quality of a cohort study. This paper outlines guiding principles for reporting functioning in cohort studies and addresses some outstanding issues. Principles of how to standardize reporting of data from a cohort study on functioning, by deriving scores that are most useful for further statistical analysis and reporting, are outlined. The Swiss Spinal Cord Injury Cohort Study Community Survey serves as a case in point to provide a practical application of these principles. Development of reporting scores must be conceptually coherent and metrically sound. The International Classification of Functioning, Disability and Health (ICF) can serve as the frame of reference for this, with its categories serving as reference units for reporting. To derive a score for further statistical analysis and reporting, items measuring a single latent trait must be invariant across groups. The Rasch measurement model is well suited to test these assumptions. Our approach is a valuable guide for researchers and clinicians, as it fosters comparability of data, strengthens the comprehensiveness of scope, and provides invariant, interval-scaled data for further statistical analyses of functioning.

Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort.

PubMed

Hu, Danqing; Flick, Randall P; Zaccariello, Michael J; Colligan, Robert C; Katusic, Slavica K; Schroeder, Darrell R; Hanson, Andrew C; Buenvenida, Shonie L; Gleich, Stephen J; Wilder, Robert T; Sprung, Juraj; Warner, David O

2017-08-01

Exposure of young animals to general anesthesia causes neurodegeneration and lasting behavioral abnormalities; whether these findings translate to children remains unclear. This study used a population-based birth cohort to test the hypothesis that multiple, but not single, exposures to procedures requiring general anesthesia before age 3 yr are associated with adverse neurodevelopmental outcomes. A retrospective study cohort was assembled from children born in Olmsted County, Minnesota, from 1996 to 2000 (inclusive). Propensity matching selected children exposed and not exposed to general anesthesia before age 3 yr. Outcomes ascertained via medical and school records included learning disabilities, attention-deficit/hyperactivity disorder, and group-administered ability and achievement tests. Analysis methods included proportional hazard regression models and mixed linear models. For the 116 multiply exposed, 457 singly exposed, and 463 unexposed children analyzed, multiple, but not single, exposures were associated with an increased frequency of both learning disabilities and attention-deficit/hyperactivity disorder (hazard ratio for learning disabilities = 2.17 [95% CI, 1.32 to 3.59], unexposed as reference). Multiple exposures were associated with decreases in both cognitive ability and academic achievement. Single exposures were associated with modest decreases in reading and language achievement but not cognitive ability. These findings in children anesthetized with modern techniques largely confirm those found in an older birth cohort and provide additional evidence that children with multiple exposures are more likely to develop adverse outcomes related to learning and attention. Although a robust association was observed, these data do not determine whether anesthesia per se is causal.

GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects.

PubMed

Spreen, William; Ford, Susan L; Chen, Shuguang; Wilfret, David; Margolis, David; Gould, Elizabeth; Piscitelli, Stephen

2014-12-15

GSK1265744 (744) is an HIV-1 integrase inhibitor in clinical development as a long-acting (LA) injectable formulation. This study evaluated plasma and tissue pharmacokinetics after single-dose administration of 744 LA administered by intramuscular (IM) or subcutaneous injections. This was a phase I, open-label, 9-cohort, parallel study of 744 in healthy subjects. 744 was administered as a 200 mg/mL nanosuspension at doses of 100-800 mg IM and 100-400 mg subcutaneous. Eight (6 active and 2 placebo) male and female subjects participated in each of the first 7 cohorts. All 8 subjects, 4 males and 4 females, received active 744 LA in cohorts 8 and 9 and underwent rectal and cervicovaginal tissue sampling, respectively. Plasma pharmacokinetic sampling was performed for a minimum of 12 weeks or until 744 concentrations were ≤0.1 μg/mL. Rectal and cervicovaginal tissue biopsies were performed at weeks 2 and 8 (cohort 8) and weeks 4 and 12 (cohort 9). 744 LA was generally safe and well tolerated after single injections. A majority of subjects reported injection site reactions, all graded as mild in intensity. Plasma concentration-time profiles were prolonged with measureable concentrations up to 52 weeks after dosing. 744 LA 800 mg IM achieved mean concentrations above protein adjusted-IC90 for approximately 16 weeks. Rectal and cervicovaginal tissue concentrations ranged from <8% to 28% of corresponding plasma concentrations. These data suggest 744 LA injection has potential application as a monthly or less frequent HIV treatment or prevention agent.

A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated With Development of Erectile Dysfunction Following Radiation Therapy for Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kerns, Sarah L.; Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York; Stock, Richard

2013-01-01

Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. Results: Twelve SNPs identified in the discovery cohort and validated in themore » replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 Multiplication-Sign 10{sup -5} to 6.2 Multiplication-Sign 10{sup -4}). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value = 1.7 Multiplication-Sign 10{sup -29}). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 Multiplication-Sign 10{sup -19}). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.« less

The Relationship of Cohabitation and Mental Health: A Study of a Young Adult Cohort.

ERIC Educational Resources Information Center

Horwitz, Allan V.; White, Helene Raskin

1998-01-01

Uses a cohort of unmarried young adults who were sampled when they were 18, 21, or 24 years old and resampled seven years later. Results indicate no differences between cohabitators and married couples in levels of depression. Cohabitating men report more alcohol problems than married and single men; cohabitating women reported more alcohol…

Cost-Utility Analysis of Anterior Cervical Discectomy and Fusion With Plating (ACDFP) Versus Posterior Cervical Foraminotomy (PCF) for Patients With Single-level Cervical Radiculopathy at 1-Year Follow-up.

PubMed

Alvin, Matthew D; Lubelski, Daniel; Abdullah, Kalil G; Whitmore, Robert G; Benzel, Edward C; Mroz, Thomas E

2016-03-01

A retrospective 1-year cost-utility analysis. To determine the cost-effectiveness of anterior cervical discectomy and fusion with plating (ACDFP) in comparison with posterior cervical foraminotomy (PCF) for patients with single-level cervical radiculopathy. Cervical radiculopathy due to cervical spondylosis is commonly treated by either PCF or ACDFP for patients who are refractory to nonsurgical treatment. Although some have suggested superior outcomes with ACDFP as compared with PCF, the former is also associated with greater costs. The present study analyzes the cost-effectiveness of ACDFP versus PCF for patients with single-level cervical radiculopathy. Forty-five patients who underwent ACDFP and 25 patients who underwent PCF for single-level cervical radiculopathy were analyzed. One-year postoperative health outcomes were assessed based on Visual Analogue Scale, Pain Disability Questionnaire, Patient Health Questionnaire, and EuroQOL-5 Dimensions questionnaires to analyze the comparative effectiveness of each procedure. Direct medical costs were estimated using Medicare national payment amounts and indirect costs were based on patient missed work days and patient income. Postoperative 1-year cost/utility ratios and the incremental cost-effectiveness ratio (ICER) were calculated to assess for cost-effectiveness using a threshold of $100,000/QALY gained. The 1-year cost-utility ratio for the PCF cohort was significantly lower ($79,856/QALY gained) than that for the ACDFP cohort ($131,951/QALY gained) (P<0.01). In calculating the 1-year ICER, as the ACDFP cohort showed lower QALY gained than the PCF cohort, the ICER was negative and is not reported, meaning that ACDFP was dominated by PCF. Statistically significant and clinically relevant improvements (through minimum clinically important differences) were seen in both cohorts. Although both cohorts showed improved health outcomes, ACDFP was not cost-effective relative to the threshold of $100,000/QALY gained at 1-year postoperatively, whereas PCF was. The durability of these results must be analyzed with long-term cost-utility analysis studies.

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity in Relapsed and Refractory Non-Hodgkin’s Lymphoma

PubMed Central

Jones, Jeffrey A.; Rupert, Amy S.; Poi, Ming; Phelps, Mitch A.; Andritsos, Leslie; Baiocchi, Robert; Benson, Don M.; Blum, Kristie A.; Christian, Beth; Flynn, Joseph; Penza, Sam; Porcu, Pierluigi; Grever, Michael R.; Byrd, John C.

2014-01-01

Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. PMID:23959599

Systemic effects of low-dose dopamine during administration of cytarabine.

PubMed

Connelly, James; Benani, Dina J; Newman, Matthew; Burton, Bradley; Crow, Jessica; Levis, Mark

2017-09-01

Purpose Low-dose dopamine has been utilized to improve renal blood flow, urine output, and reduce drug-induced nephrotoxicity. The purpose of this study was to assess changes in renal function, cardiovascular adverse events, and neurologic toxicity in patients receiving cytarabine with or without low-dose dopamine. Methods A retrospective, single-center, cohort study of patients receiving cytarabine at 667 mg/m 2 /dose or greater, with or without dopamine at ≤5 mcg/kg/min. Cohorts were based upon initiation or absence of low-dose dopamine; cytarabine only, cytarabine + pre- and day of low-dose dopamine, and cytarabine + post-low-dose dopamine. Renal outcomes (urine output, serum creatinine, and creatinine clearance) were compared with baseline and between cohorts. Safety endpoints (arrhythmias, tachycardia, and neurotoxicity) were compared between cohorts based on low-dose dopamine exposure. Results There was no difference in urine output from baseline in all cohorts. Comparing cytarabine only and pre- and day of low-dose dopamine cohorts, there was no difference in urine output. In those receiving low-dose dopamine, there was no difference in serum creatinine and creatinine clearance from baseline. No arrhythmias were documented during the study period, and there was no difference in the incidence of tachycardia between groups (P = 0.66). Neurotoxicity was reported in three patients who were on low-dose dopamine. Conclusion Though variation existed in individual patients administered low-dose dopamine, the use of low-dose dopamine did not significantly impact renal function in this small sample at a single institution. In addition, low-dose dopamine did not negatively impact cardiovascular function.

Effects of Single-Sex and Coeducational Schooling on the Gender Gap in Educational Achievement

ERIC Educational Resources Information Center

Gibb, Sheree J.; Fergusson, David M.; Horwood, L. John

2008-01-01

This study examined the effects of single-sex and coeducational schooling on the gender gap in educational achievement to age 25. Data were drawn from the Christchurch Health and Development Study, a longitudinal study of a birth cohort of 1265 individuals born in 1977 in Christchurch, New Zealand. After adjustment for a series of covariates…

Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy.

PubMed

Kasteleijn-Nolst Trenité, Dorotheé G A; Biton, Victor; French, Jacqueline A; Abou-Khalil, Bassel; Rosenfeld, William E; Diventura, Bree; Moore, Elizabeth L; Hetherington, Seth V; Rigdon, Greg C

2013-08-01

To assess the effects of ICA-105665, an agonist of neuronal Kv7 potassium channels, on epileptiform EEG discharges, evoked by intermittent photic stimulation (IPS), the so-called photoparoxysmal responses (PPRs) in patients with epilepsy. Male and female patients aged 18-60 years with reproducible PPRs were eligible for enrollment. The study was conducted as a single-blind, single-dose, multiple-cohort study. Four patients were enrolled in each of the first three cohorts. Six patients were enrolled in the fourth cohort and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS frequencies (steps) were used to determine the standard photosensitivity range (SPR) following placebo on day 1 and ICA-105665 on day 2. The SPR was quantified for three eye conditions (eyes closing, eyes closed, and eyes open), and the most sensitive condition was used for assessment of efficacy. A partial response was defined as a reduction in the SPR of at least three units at three separate time points following ICA-105665 compared to the same time points following placebo with no time points with more than three units of increase. Complete suppression was defined by no PPRs in any eye condition at one or more time points. Six individual patients participated in the first three cohorts (100, 200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred in one patient at 100 mg, two patients receiving 400 mg ICA-105665 (complete abolishment of SPR occurred in one patient at 400 mg), and in four of six patients receiving 500 mg. The most common adverse events (AEs) were those related to the nervous system, and dizziness appeared to be the first emerging AE. The single patient in the 600 mg cohort developed a brief generalized seizure within 1 h of dosing, leading to the discontinuation of additional patients at this dose, per the predefined protocol stopping rules. ICA-105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Confounder summary scores when comparing the effects of multiple drug exposures.

PubMed

Cadarette, Suzanne M; Gagne, Joshua J; Solomon, Daniel H; Katz, Jeffrey N; Stürmer, Til

2010-01-01

Little information is available comparing methods to adjust for confounding when considering multiple drug exposures. We compared three analytic strategies to control for confounding based on measured variables: conventional multivariable, exposure propensity score (EPS), and disease risk score (DRS). Each method was applied to a dataset (2000-2006) recently used to examine the comparative effectiveness of four drugs. The relative effectiveness of risedronate, nasal calcitonin, and raloxifene in preventing non-vertebral fracture, were each compared to alendronate. EPSs were derived both by using multinomial logistic regression (single model EPS) and by three separate logistic regression models (separate model EPS). DRSs were derived and event rates compared using Cox proportional hazard models. DRSs derived among the entire cohort (full cohort DRS) was compared to DRSs derived only among the referent alendronate (unexposed cohort DRS). Less than 8% deviation from the base estimate (conventional multivariable) was observed applying single model EPS, separate model EPS or full cohort DRS. Applying the unexposed cohort DRS when background risk for fracture differed between comparison drug exposure cohorts resulted in -7 to + 13% deviation from our base estimate. With sufficient numbers of exposed and outcomes, either conventional multivariable, EPS or full cohort DRS may be used to adjust for confounding to compare the effects of multiple drug exposures. However, our data also suggest that unexposed cohort DRS may be problematic when background risks differ between referent and exposed groups. Further empirical and simulation studies will help to clarify the generalizability of our findings.

Use of age-period-cohort models to estimate effects of vehicle age, year of crash and year of vehicle manufacture on driver injury and fatality rates in single vehicle crashes in New South Wales, 2003-2010.

PubMed

Anderson, R W G; Searson, D J

2015-02-01

A novel application of age-period-cohort methods are used to explain changes in vehicle based crash rates in New South Wales, Australia over the period 2003-2010. Models are developed using vehicle age, crash period and vehicle cohort to explain changes in the rate of single vehicle driver fatalities and injuries in vehicles less than 13 years of age. Large declines in risk are associated with vehicle cohorts built after about 1996. The decline in risk appears to have accelerated to 12 percent per vehicle cohort year for cohorts since 2004. Within each cohort, the risk of crashing appears to be a minimum at two years of age and increases as the vehicle ages beyond this. Period effects (i.e., other road safety measures) between 2003 and 2010 appear to have contributed to declines of up to about two percent per annum to the driver-fatality single vehicle crash rate, and possibly only negligible improvements to the driver-injury single vehicle crash rate. Vehicle improvements appear to have been responsible for a decline in per-vehicle crash risk of at least three percent per calendar year for both severity levels over the same period. Given the decline in risk associated with more recent vehicle cohorts and the dynamics of fleet turnover, continued declines in per-vehicle crash risk over coming years are almost certain. Copyright © 2014. Published by Elsevier Ltd.

Through Increasing "Information Literacy" Capital and Habitus (Agency): The Complementary Impact on Composition Skills When Appropriately Sequenced

ERIC Educational Resources Information Center

Karas, Timothy

2017-01-01

Through a case study approach of a cohort of community college students at a single community college, the impact on success rates in composition courses was analyzed based on the sequence of completing an information literacy course. Two student cohorts were sampled based on completing an information literacy course prior to, or concurrently with…

Assessing adult mortality in HIV-1-afflicted Zimbabwe (1998 -2003).

PubMed Central

Lopman, Ben A.; Barnabas, Ruanne; Hallett, Timothy B.; Nyamukapa, Constance; Mundandi, Costa; Mushati, Phyllis; Garnett, Geoff P.; Gregson, Simon

2006-01-01

OBJECTIVE: To compare alternative methods to vital registration systems for estimating adult mortality, and describe patterns of mortality in Manicaland, Zimbabwe, which has been severely affected by HIV. METHODS: We compared estimates of adult mortality from (1) a single question on household mortality, (2) repeated household censuses, and (3) an adult cohort study with linked HIV testing from Manicaland, with a mathematical model fitted to local age-specific HIV prevalence (1998 -2000). FINDINGS: The crude death rate from the single question (29 per 1000 person-years) was roughly consistent with that from the mathematical model (22 -25 per 1000 person-years), but much higher than that from the household censuses (12 per 1000 person-years). Adult mortality in the household censuses (males 0.65; females 0.51) was lower than in the cohort study (males 0.77; females 0.57), while mathematical models gave a much higher estimate, especially for females (males 0.80 -0.83; females 0.75 -0.80). The population attributable fraction of adult deaths due to HIV was 0.61 for men and 0.70 for women, with life expectancy estimated to be 34.3 years for males and 38.2 years for females. CONCLUSION: Each method for estimating adult mortality had limitations in terms of loss to follow-up (cohort study), under-ascertainment (household censuses), transparency of underlying processes (single question), and sensitivity to parameterization (mathematical model). However, these analyses make clear the advantages of longitudinal cohort data, which provide more complete ascertainment than household censuses, highlight possible inaccuracies in model assumptions, and allow direct quantification of the impact of HIV. PMID:16583077

Screening for carcinoma in situ in the contralateral testicle in patients with testicular cancer: a population-based study.

PubMed

Kier, M G G; Lauritsen, J; Almstrup, K; Mortensen, M S; Toft, B G; Rajpert-De Meyts, E; Skakkebaek, N E; Rørth, M; von der Maase, H; Agerbaek, M; Holm, N V; Andersen, K K; Dalton, S O; Johansen, C; Daugaard, G

2015-04-01

Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation-wide, population-based study. A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984-2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984-1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS-negative biopsies in patients with metachronous GCC were revised according to today's standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model. In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS-negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design. Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration

PubMed Central

Baas, Dominique C.; Ho, Lintje; Tanck, Michael W.T.; Fritsche, Lars G.; Merriam, Joanna E.; van het Slot, Ruben; Koeleman, Bobby P.C.; Gorgels, Theo G.M.F.; van Duijn, Cornelia M.; Uitterlinden, André G.; de Jong, Paulus T.V.M.; Hofman, Albert; ten Brink, Jacoline B.; Vingerling, Johannes R.; Klaver, Caroline C.W.; Dean, Michael; Weber, Bernhard H. F.; Allikmets, Rando; Hageman, Gregory S.

2012-01-01

Purpose Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress–mediated AMD pathology. Methods Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Würzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed. Results In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies. Conclusions No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists. PMID:22509097

Academic Self-Concept, Gender and Single-Sex Schooling

ERIC Educational Resources Information Center

Sullivan, Alice

2009-01-01

This article assesses gender differences in academic self-concept for a cohort of children born in 1958 (the National Child Development Study). It addresses the question of whether attending single-sex or co-educational schools affected students' perceptions of their own academic abilities (academic self-concept). Academic self-concept was found…

Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria.

PubMed

White, Nicholas J; Duong, Tran T; Uthaisin, Chirapong; Nosten, François; Phyo, Aung P; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon; Jittamala, Podjanee; Chuthasmit, Kittiphum; Cheung, Ming S; Feng, Yiyan; Li, Ruobing; Magnusson, Baldur; Sultan, Marc; Wieser, Daniela; Xun, Xiaolei; Zhao, Rong; Diagana, Thierry T; Pertel, Peter; Leong, F Joel

2016-09-22

KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg). Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts. KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01753323 .).

Effectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study.

PubMed

Azman, Andrew S; Parker, Lucy A; Rumunu, John; Tadesse, Fisseha; Grandesso, Francesco; Deng, Lul L; Lino, Richard Laku; Bior, Bior K; Lasuba, Michael; Page, Anne-Laure; Ontweka, Lameck; Llosa, Augusto E; Cohuet, Sandra; Pezzoli, Lorenzo; Sodjinou, Dossou Vincent; Abubakar, Abdinasir; Debes, Amanda K; Mpairwe, Allan M; Wamala, Joseph F; Jamet, Christine; Lessler, Justin; Sack, David A; Quilici, Marie-Laure; Ciglenecki, Iza; Luquero, Francisco J

2016-11-01

Oral cholera vaccines represent a new effective tool to fight cholera and are licensed as two-dose regimens with 2-4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Médecins Sans Frontières, and partners engaged in the first field deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine effectiveness study in conjunction with this large public health intervention. We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the first day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confirmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classified as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine effectiveness was 80·2% (95% CI 61·5-100·0) and after adjusting for potential confounders was 87·3% (70·2-100·0). One dose of Shanchol was effective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological settings. Médecins Sans Frontières. Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.

A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort.

PubMed

Werner, Theresa L; Wade, Mark L; Agarwal, Neeraj; Boucher, Kenneth; Patel, Jesal; Luebke, Aaron; Sharma, Sunil

2015-12-01

JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the first clinical study assessing anti-tumor activity of JI-101 in a combinatorial regimen. In the PK cohort, four patients received single agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8, and single agent 200 mg JI-101 on day 15. In the PD cohort, eleven patients received single agent JI-101 at 200 mg twice daily for 28 day treatment cycles. JI-101 was well tolerated as a single agent and in combination with everolimus. No serious adverse events were observed. Common adverse events were hypertension, nausea, and abdominal pain. JI-101 increased exposure of everolimus by approximately 22%, suggestive of drug-drug interaction. The majority of patients had stable disease at their first set of restaging scans (two months), although no patients demonstrated a response to the drug per RECIST criteria. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent may be pursued in a less refractory patient population or in combination with cytotoxic chemotherapy.

Single-dose pharmacokinetics and safety of azilsartan medoxomil in children and adolescents with hypertension as compared to healthy adults.

PubMed

Webb, Nicholas J A; Wells, Thomas; Tsai, Max; Zhao, Zhen; Juhasz, Attila; Dudkowski, Caroline

2016-04-01

This open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12-16 years [cohort 1a; n = 9]; 6-11 years [cohort 2; n = 8]; 4-5 years [cohort 3; n = 3]). Model-based simulations were performed to guide dosing, especially in 1-5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20-60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg. Exposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized C max and AUC0-∞, was ∼15-30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8-25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25-50-kg subjects require half the adult dose (10-40 mg), whereas 50-100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine). This dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).

Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis.

PubMed

Cheong, Jae-Ho; Yang, Han-Kwang; Kim, Hyunki; Kim, Woo Ho; Kim, Young-Woo; Kook, Myeong-Cherl; Park, Young-Kyu; Kim, Hyung-Ho; Lee, Hye Seung; Lee, Kyung Hee; Gu, Mi Jin; Kim, Ha Yan; Lee, Jinae; Choi, Seung Ho; Hong, Soonwon; Kim, Jong Won; Choi, Yoon Young; Hyung, Woo Jin; Jang, Eunji; Kim, Hyeseon; Huh, Yong-Min; Noh, Sung Hoon

2018-05-01

Adjuvant chemotherapy after surgery improves survival of patients with stage II-III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II-III gastric cancer. In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II-III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival. We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2-92·0), 74·8% (69·9-80·1), and 66·0% (60·1-72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73·5-87·1] vs 64·5% [56·8-73·3]; univariate hazard ratio 0·47 [95% CI 0·30-0·75], p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% [66·5-79·9] in patients who received chemotherapy plus surgery vs 72·5% [65·8-79·9] in patients who only had surgery; 0·93 [0·62-1·38], p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (p interaction =0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort. The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II-III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted. Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare. Copyright © 2018 Elsevier Ltd. All rights reserved.

Comparing the cohort design and the nested case–control design in the presence of both time-invariant and time-dependent treatment and competing risks: bias and precision

PubMed Central

Austin, Peter C; Anderson, Geoffrey M; Cigsar, Candemir; Gruneir, Andrea

2012-01-01

Purpose Observational studies using electronic administrative healthcare databases are often used to estimate the effects of treatments and exposures. Traditionally, a cohort design has been used to estimate these effects, but increasingly, studies are using a nested case–control (NCC) design. The relative statistical efficiency of these two designs has not been examined in detail. Methods We used Monte Carlo simulations to compare these two designs in terms of the bias and precision of effect estimates. We examined three different settings: (A) treatment occurred at baseline, and there was a single outcome of interest; (B) treatment was time varying, and there was a single outcome; and C treatment occurred at baseline, and there was a secondary event that competed with the primary event of interest. Comparisons were made of percentage bias, length of 95% confidence interval, and mean squared error (MSE) as a combined measure of bias and precision. Results In Setting A, bias was similar between designs, but the cohort design was more precise and had a lower MSE in all scenarios. In Settings B and C, the cohort design was more precise and had a lower MSE in all scenarios. In both Settings B and C, the NCC design tended to result in estimates with greater bias compared with the cohort design. Conclusions We conclude that in a range of settings and scenarios, the cohort design is superior in terms of precision and MSE. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22653805

Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

PubMed

Wach, Achim; Dembowsky, Klaus; Dale, Glenn E

2018-04-01

Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. Copyright © 2018 American Society for Microbiology.

The value of the UK Clinical Aptitude Test in predicting pre-clinical performance: a prospective cohort study at Nottingham Medical School.

PubMed

Yates, Janet; James, David

2010-07-28

The UK Clinical Aptitude Test (UKCAT) was introduced in 2006 as an additional tool for the selection of medical students. It tests mental ability in four distinct domains (Quantitative Reasoning, Verbal Reasoning, Abstract Reasoning, and Decision Analysis), and the results are available to students and admissions panels in advance of the selection process. As yet the predictive validity of the test against course performance is largely unknown.The study objective was to determine whether UKCAT scores predict performance during the first two years of the 5-year undergraduate medical course at Nottingham. We studied a single cohort of students, who entered Nottingham Medical School in October 2007 and had taken the UKCAT. We used linear regression analysis to identify independent predictors of marks for different parts of the 2-year preclinical course. Data were available for 204/260 (78%) of the entry cohort. The UKCAT total score had little predictive value. Quantitative Reasoning was a significant independent predictor of course marks in Theme A ('The Cell'), (p = 0.005), and Verbal Reasoning predicted Theme C ('The Community') (p < 0.001), but otherwise the effects were slight or non-existent. This limited study from a single entry cohort at one medical school suggests that the predictive value of the UKCAT, particularly the total score, is low. Section scores may predict success in specific types of course assessment.The ultimate test of validity will not be available for some years, when current cohorts of students graduate. However, if this test of mental ability does not predict preclinical performance, it is arguably less likely to predict the outcome in the clinical years. Further research from medical schools with different types of curriculum and assessment is needed, with longitudinal studies throughout the course.

Coeducational or Single-Sex School: Does It Make a Difference on High School Girls' Academic Motivation?

ERIC Educational Resources Information Center

Chouinard, Roch; Vezeau, Carole; Bouffard, Therese

2008-01-01

The aim of the present study was to further examine the impact over time of single-sex and coeducational school environments on girls' motivation in language arts and mathematics. Two cohorts comprising 340 girls (7th to 9th grade; 9th to 11th grade) from eight coeducational and two single-sex schools were followed during a period of three…

Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians.

PubMed

Kaiser, Rachel; Taylor, Kimberly E; Deng, Yun; Zhao, Jian; Li, Yonghong; Nititham, Joanne; Chang, Monica; Catanese, Joseph; Begovich, Ann B; Brown, Elizabeth E; Edberg, Jeffrey C; McGwin, Gerald; Alarcón, Graciela S; Ramsey-Goldman, Rosalind; Reveille, John D; Vila, Luis M; Petri, Michelle; Kimberly, Robert P; Feng, Xuebing; Sun, Lingyun; Shen, Nan; Li, Wei; Lu, Jian-Xin; Wakeland, Edward K; Li, Quan-Zhen; Yang, Wanling; Lau, Yu-Lung; Liu, Fei-Lan; Chang, Deh-Ming; Yu, Chack-Yung; Song, Yeong W; Tsao, Betty P; Criswell, Lindsey A

2013-01-01

The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects. Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort. Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032. Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis. Copyright © 2013 by the American College of Rheumatology.

Family structure and child food insecurity.

PubMed

Miller, Daniel P; Nepomnyaschy, Lenna; Ibarra, Gabriel Lara; Garasky, Steven

2014-07-01

We examined whether food insecurity was different for children in cohabiting or repartnered families versus those in single-mother or married-parent (biological) families. We compared probabilities of child food insecurity (CFI) across different family structures in 4 national data sets: the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B), the Fragile Families and Child Wellbeing Study (FFCWS), the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K), and the Panel Study of Income Dynamics-Child Development Supplement (PSID-CDS). Unadjusted probabilities of CFI in cohabiting or repartnered families were generally higher than in married-biological-parent families and often statistically indistinguishable from those of single-mother families. However, after adjustment for sociodemographic factors, most differences between family types were attenuated and most were no longer statistically significant. Although children whose biological parents are cohabiting or whose biological mothers have repartnered have risks for food insecurity comparable to those in single-mother families, the probability of CFI does not differ by family structure when household income, family size, and maternal race, ethnicity, education, and age were held at mean levels.

Effects of Preoperative Simulation on Minimally Invasive Hybrid Lumbar Interbody Fusion.

PubMed

Rieger, Bernhard; Jiang, Hongzhen; Reinshagen, Clemens; Molcanyi, Marek; Zivcak, Jozef; Grönemeyer, Dietrich; Bosche, Bert; Schackert, Gabriele; Ruess, Daniel

2017-10-01

The main focus of this study was to evaluate how preoperative simulation affects the surgical work flow, radiation exposure, and outcome of minimally invasive hybrid lumbar interbody fusion (MIS-HLIF). A total of 132 patients who underwent single-level MIS-HLIF were enrolled in a cohort study design. Dose area product was analyzed in addition to surgical data. Once preoperative simulation was established, 66 cases (SIM cohort) were compared with 66 patients who had previously undergone MIS-HLIF without preoperative simulation (NO-SIM cohort). Dose area product was reduced considerably in the SIM cohort (320 cGy·cm 2 NO-SIM cohort: 470 cGy·cm 2 ; P < 0.01). Surgical time was shorter for the SIM cohort (155 minutes; NO-SIM cohort, 182 minutes; P < 0.05). SIM cohort had a better outcome in Numeric Rating Scale back at 6 months follow-up compared with the NO-SIM cohort (P < 0.05). Preoperative simulation reduced radiation exposure and resulted in less back pain at the 6 months follow-up time point. Preoperative simulation provided guidance in determining the correct cage height. Outcome controls enabled the surgeon to improve the procedure and the software algorithm. Copyright © 2017 Elsevier Inc. All rights reserved.

Validation of a patient-level medication regimen complexity index as a possible tool to identify patients for medication therapy management intervention.

PubMed

Hirsch, Jan D; Metz, Kelli R; Hosokawa, Patrick W; Libby, Anne M

2014-08-01

The Medication Regimen Complexity Index (MRCI) is a 65-item instrument that can be used to quantify medication regimen complexity at the patient level, capturing all prescribed and over-the-counter medications. Although the MRCI has been used in several studies, the narrow scope of the initial validation limits application at a population or clinical practice level. To conduct a MRCI validation pertinent to the desired clinical use to identify patients for medication therapy management interventions. An expert panel of clinical pharmacists ranked medication regimen complexity for two samples of cases: a single-disease cohort (diabetes mellitus) and a multiple-disease cohort (diabetes mellitus, hypertension, human immunodeficiency virus infection, geriatric depression). Cases for expert panel review were selected from 400 ambulatory clinic patients, and each case description included data that were available via claims or electronic medical records (EMRs). Construct validity was assessed using patient-level MRCI scores, medication count, and additional patient data. Concordance was evaluated using weighted κ agreement statistic, and correlations were determined using Spearman rank-order correlation coefficient (ρ) or Kendall τ. Moderate to good concordance between patient-level MRCI scores and expert medication regimen complexity ranking was observed (claims data, consensus ranking: single-disease cohort 0.55, multiple disease cohort 0.63). In contrast, only fair to moderate concordance was observed for medication count (single-disease cohort 0.33, multiple-disease cohort 0.48). Adding more-detailed administration directions from EMR data did not improve concordance. MRCI convergent validity was supported by strong correlations with medication count (all cohorts 0.90) and moderate correlations with morbidity measures (e.g., all cohorts; number of comorbidities 0.46, Chronic Disease Score 0.46). Nonsignificant correlation of MRCI scores with age and gender (all cohorts 0.08 and 0.06, respectively) supported MRCI divergent validity. This study used cross-sectional, retrospective patient data for a small number of patients and clinical pharmacists from only two universities; therefore, results may have limited generalizability. The patient-level MRCI is a valid tool for assessing medication regimen complexity that can be applied by using data commonly found in claims and EMR databases and could be useful to identify patients who may benefit from medication therapy management. © 2014 The Authors Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

A retrospective analysis of episodes of single tooth extraction under general anaesthesia for adults.

PubMed

Hong, B; Birnie, A

2016-01-15

To investigate the provision of adult dental extraction under general anaesthesia (DGA) at the Royal Cornwall Hospitals NHS Trust (RCHT)-- specifically adult single tooth DGA episodes in regards to numbers, demographics, justifications, and appropriateness regarding the use of resources. Data were collected retrospectively from the patient case notes and electronic records for the complete study cohort. This study included all episodes of adult single tooth DGA in all RCHT sites during 2014, except for mandibular third molar and impacted teeth. Each case was tested against the DGA case selection criteria empirically devised for this study. In 2014, 106 episodes of adult single tooth DGA were carried out in RCHT that met the inclusion criteria. Younger females from more socio-economically deprived areas of Cornwall were increasingly likely to have this procedure. Mental disorders were the most prevalent co-morbidity (21.7%) in this cohort. The vast majority of patients (93.4%) had previously tolerated dental treatment without the need for general anaesthesia (GA). Many referrals (46.2%) and listings (30.2%) specifically stated patient demand-driven reasons. None of the cohort had DGA due to failure of sedation. There were potentially 11 episodes that met the DGA case selection criteria. Patients waited for 126 days (median) from the referral date for an operation which took seven minutes (median) to complete. The majority (83%) of the cases were simple exodontia. Twenty patients (18.9%) had previous DGA. Potentially a considerable proportion of GA prescription appeared to be driven by patient demand rather than clinical need. This study poses a fundamental question--what drives the demand for DGA? National data collection and specific DGA case selection criteria are recommended.

Outpatient and Inpatient Single-Level Cervical Total Disc Replacement: A Comparison of 30-day Outcomes.

PubMed

Segal, Dale N; Wilson, Jacob M; Staley, Christopher; Yoon, Tim S

2018-06-11

Retrospective cohort study. To compare 30-day postoperative outcomes between patients undergoing outpatient and inpatient single-level cervical total disc replacement surgery. Cervical total disc replacement (TDR) is a motion sparing treatment for cervical radiculopathy and myelopathy. It is an alternative to anterior cervical discectomy and fusion (ACDF) with a similar complication rate. Like ACDF, it may be performed in the inpatient or outpatient setting. Efforts to reduce healthcare costs are driving spine surgery to be performed in the outpatient setting. As cervical total disc replacement surgery continues to gain popularity, the safety of treating patients on an outpatient basis needs to be validated. The National Surgical Quality Improvement Program (NSQIP) database was queried for patients who underwent single-level cervical disc replacement surgery between 2006-2015. Complication data including 30-day complications, reoperation rate, readmission rate, and length of stay data was compared between the inpatient and outpatient cohort using univariate analysis. There were 531 (34.2%) patients treated as outpatients and 1,022 (65.8%) were treated on an inpatient basis. The two groups had similar baseline characteristics. The overall 30-day complication rate was 1.4% for inpatients and 0.6% for outpatients. Reoperation rate was 0.6% for inpatient and 0.4% for outpatients. Readmission rate was 0.9% and 0.8% for inpatient and outpatient, respectively. There were no statistical differences identified in rates of readmission, reoperation, or complication between the inpatient and outpatient cohorts. There was no difference between 30-day complications, readmission and reoperation rates between inpatients and outpatients who underwent a single-level cervical total disc replacement. Furthermore, the overall 30-day complication rates were low. This study supports that single-level cervical TDR can be performed safely in an outpatient setting. 3.

Optimal timing of autologous cranioplasty after decompressive craniectomy in children.

PubMed

Piedra, Mark P; Thompson, Eric M; Selden, Nathan R; Ragel, Brian T; Guillaume, Daniel J

2012-10-01

The object of this study was to determine if early cranioplasty after decompressive craniectomy for elevated intracranial pressure in children reduces complications. Sixty-one consecutive cases involving pediatric patients who underwent autologous cranioplasty after decompressive craniectomy for raised intracranial pressure at a single academic children's hospital over 15 years were studied retrospectively. Sixty-one patients were divided into early (< 6 weeks; 28 patients) and late (≥ 6 weeks; 33 patients) cranioplasty cohorts. The cohorts were similar except for slightly lower age in the early (8.03 years) than the late (10.8 years) cranioplasty cohort (p < 0.05). Bone resorption after cranioplasty was significantly more common in the late (42%) than the early (14%) cranioplasty cohort (p < 0.05; OR 5.4). No other complication differed in incidence between the cohorts. After decompressive craniectomy for raised intracranial pressure in children, early (< 6 weeks) cranioplasty reduces the occurrence of reoperation for bone resorption, without altering the incidence of other complications.

Radiographic outcomes of single versus dual plate fixation of acute mid-shaft clavicle fractures.

PubMed

Chen, Xiaobin; Shannon, Steven F; Torchia, Michael; Schoch, Bradley

2017-06-01

The clavicle exhibits considerable movement in three planes making rigid fixation challenging. The addition of a second plate may be considered to improve fixation rigidity, but risks compromising the blood supply to the fracture site. The purpose of this study is to assess if extraperiosteal dual plate fixation increases the rate of non-union, reoperation, and complications at 1 year for surgically treated acute mid-shaft clavicle fractures. Between June 1998 and June 2013, surgically treated mid-shaft clavicle fractures undergoing open reduction internal fixation within 4 weeks of injury were retrospectively reviewed. Patients undergoing single plate fixation were compared to dual plate fixation. Patients were followed for a minimum of 1 year. Charts were reviewed to assess union rates, reoperation, and complications. One hundred and sixty-three clavicles (125 single plates, 34 dual plates) were evaluated. All patients (100%) in dual plating group and one hundred and fourteen (91%) in single plating group obtained bony union by 1 year (p = 0.13). Six patients (4.8%) experienced a non-union in the single plating cohort compared to the dual plating cohort who had a 100% union rate. Seven patients required reoperation in the single plate cohort due to implant failure (N = 4), infection (N = 2), and non-union (N = 1). This limited series of patients demonstrates dual plate fixation is a reliable option for acute mid-shaft clavicle fractures, with excellent union rates and low complication rates. Compared to single plate fixation, no significant differences in outcomes were identified. In the case of more complex fracture patterns, application of a second extraperiosteal plate may be utilized without compromising healing or increasing complication rates.

Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: a cohort study in Medawachchiya, Sri Lanka.

PubMed

Senevirathna, Lalantha; Abeysekera, Tilak; Nanayakkara, Shanika; Chandrajith, Rohana; Ratnatunga, Neelakanthi; Harada, Kouji H; Hitomi, Toshiaki; Komiya, Toshiyuki; Muso, Eri; Koizumi, Akio

2012-05-01

The alarming rise in the prevalence of chronic kidney disease of uncertain etiology (CKDu) among the low socioeconomic farming community in the North Central Province of Sri Lanka has been recognized as an emerging public health issue in the country. This study sought to determine the possible factors associated with the progression and mortality of CKDu. The study utilized a single-center cohort registered in 2003 and followed up until 2009 in a regional clinic in the endemic region, and used a Cox proportional hazards model. We repeatedly found an association between disease progression and hypertension. Men were at higher risk of CKDu than women. A significant proportion of the patients in this cohort were underweight, which emphasized the need for future studies on the nutritional status of these patients. Compared with findings in western countries and other regions of Asia, we identified hypertension as a major risk factor for progression of CKDu in this cohort.

Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers.

PubMed

Rice, David; Heil, Justin W; Biernat, Lukasz

2017-03-01

Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia. The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers. Healthy adults were assigned to receive liposomal bupivacaine via subcutaneous infiltration in a single 266 mg dose (cohort 1) or in two 266 mg doses, with the second dose given immediately, 24, 48, or 72 h after the first dose (cohorts 2-5). Pharmacokinetic parameters were estimated from blood samples collected up to day 14. Subjects were monitored for adverse events and assessed for neurologic function, cardiac function, and infiltration area abnormalities. Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (C max ) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean C max after the second dose was higher, but always less than double the C max for cohort 1. The highest individual C max (589 ng/mL) was observed in a subject who received the second dose 24 h after the first dose (cohort 4), but was well below the reported thresholds for neurotoxicity and cardiac toxicity (2000 and 4000 ng/mL, respectively). A single and repeated dose were well-tolerated, and there were no clinically meaningful findings regarding neurologic examinations and electrocardiography. The mean C max following a repeated dose of liposomal bupivacaine remained well below accepted values for central nervous system and cardiac toxicity. Liposomal bupivacaine was well-tolerated and revealed no clinically important safety signals. CLINICALTRIALS. NCT02210247.

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

PubMed

Zillikens, M Carola; Demissie, Serkalem; Hsu, Yi-Hsiang; Yerges-Armstrong, Laura M; Chou, Wen-Chi; Stolk, Lisette; Livshits, Gregory; Broer, Linda; Johnson, Toby; Koller, Daniel L; Kutalik, Zoltán; Luan, Jian'an; Malkin, Ida; Ried, Janina S; Smith, Albert V; Thorleifsson, Gudmar; Vandenput, Liesbeth; Hua Zhao, Jing; Zhang, Weihua; Aghdassi, Ali; Åkesson, Kristina; Amin, Najaf; Baier, Leslie J; Barroso, Inês; Bennett, David A; Bertram, Lars; Biffar, Rainer; Bochud, Murielle; Boehnke, Michael; Borecki, Ingrid B; Buchman, Aron S; Byberg, Liisa; Campbell, Harry; Campos Obanda, Natalia; Cauley, Jane A; Cawthon, Peggy M; Cederberg, Henna; Chen, Zhao; Cho, Nam H; Jin Choi, Hyung; Claussnitzer, Melina; Collins, Francis; Cummings, Steven R; De Jager, Philip L; Demuth, Ilja; Dhonukshe-Rutten, Rosalie A M; Diatchenko, Luda; Eiriksdottir, Gudny; Enneman, Anke W; Erdos, Mike; Eriksson, Johan G; Eriksson, Joel; Estrada, Karol; Evans, Daniel S; Feitosa, Mary F; Fu, Mao; Garcia, Melissa; Gieger, Christian; Girke, Thomas; Glazer, Nicole L; Grallert, Harald; Grewal, Jagvir; Han, Bok-Ghee; Hanson, Robert L; Hayward, Caroline; Hofman, Albert; Hoffman, Eric P; Homuth, Georg; Hsueh, Wen-Chi; Hubal, Monica J; Hubbard, Alan; Huffman, Kim M; Husted, Lise B; Illig, Thomas; Ingelsson, Erik; Ittermann, Till; Jansson, John-Olov; Jordan, Joanne M; Jula, Antti; Karlsson, Magnus; Khaw, Kay-Tee; Kilpeläinen, Tuomas O; Klopp, Norman; Kloth, Jacqueline S L; Koistinen, Heikki A; Kraus, William E; Kritchevsky, Stephen; Kuulasmaa, Teemu; Kuusisto, Johanna; Laakso, Markku; Lahti, Jari; Lang, Thomas; Langdahl, Bente L; Launer, Lenore J; Lee, Jong-Young; Lerch, Markus M; Lewis, Joshua R; Lind, Lars; Lindgren, Cecilia; Liu, Yongmei; Liu, Tian; Liu, Youfang; Ljunggren, Östen; Lorentzon, Mattias; Luben, Robert N; Maixner, William; McGuigan, Fiona E; Medina-Gomez, Carolina; Meitinger, Thomas; Melhus, Håkan; Mellström, Dan; Melov, Simon; Michaëlsson, Karl; Mitchell, Braxton D; Morris, Andrew P; Mosekilde, Leif; Newman, Anne; Nielson, Carrie M; O'Connell, Jeffrey R; Oostra, Ben A; Orwoll, Eric S; Palotie, Aarno; Parker, Stephen C J; Peacock, Munro; Perola, Markus; Peters, Annette; Polasek, Ozren; Prince, Richard L; Räikkönen, Katri; Ralston, Stuart H; Ripatti, Samuli; Robbins, John A; Rotter, Jerome I; Rudan, Igor; Salomaa, Veikko; Satterfield, Suzanne; Schadt, Eric E; Schipf, Sabine; Scott, Laura; Sehmi, Joban; Shen, Jian; Soo Shin, Chan; Sigurdsson, Gunnar; Smith, Shad; Soranzo, Nicole; Stančáková, Alena; Steinhagen-Thiessen, Elisabeth; Streeten, Elizabeth A; Styrkarsdottir, Unnur; Swart, Karin M A; Tan, Sian-Tsung; Tarnopolsky, Mark A; Thompson, Patricia; Thomson, Cynthia A; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Tranah, Gregory J; Tuomilehto, Jaakko; van Schoor, Natasja M; Verma, Arjun; Vollenweider, Peter; Völzke, Henry; Wactawski-Wende, Jean; Walker, Mark; Weedon, Michael N; Welch, Ryan; Wichmann, H-Erich; Widen, Elisabeth; Williams, Frances M K; Wilson, James F; Wright, Nicole C; Xie, Weijia; Yu, Lei; Zhou, Yanhua; Chambers, John C; Döring, Angela; van Duijn, Cornelia M; Econs, Michael J; Gudnason, Vilmundur; Kooner, Jaspal S; Psaty, Bruce M; Spector, Timothy D; Stefansson, Kari; Rivadeneira, Fernando; Uitterlinden, André G; Wareham, Nicholas J; Ossowski, Vicky; Waterworth, Dawn; Loos, Ruth J F; Karasik, David; Harris, Tamara B; Ohlsson, Claes; Kiel, Douglas P

2017-07-19

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10 -8 ) or suggestively genome wide (p < 2.3 × 10 -6 ). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Lung function comparison between two decades in cystic fibrosis children: A single centre study.

PubMed

Tridello, Gloria; Volpi, Sonia; Assael, Baroukh M; Meneghelli, Ilaria; Passiu, Marianna; Circelli, Maria

2015-12-01

The purpose of this study was to compare two cohorts of cystic fibrosis (CF) patients born and treated in two different decades, diagnosed through a CF neonatal screening program. We compared pulmonary function decline from 10 to 15 years of age in patients with cystic fibrosis born between 1979 and 1984 (Cohort 1) and between 1991 and 1996 (Cohort 2). Forced expiratory volume in 1 sec (FEV1%) and forced expiratory flow from 25% to 75% (FEF 25-75%) were analyzed by a linear mixed model approach. The differences between the two cohorts were estimated and the overall cohort effect was tested. Ninety-two patients (51 males, 41 females) fulfilled the selection criteria. Pancreatic insufficiency and CF related diabetes were present in 91% and 20% of patients, respectively. The mean absolute decrement of FEV1% was 9.2 (standard deviation [SD] 11.2) in Cohort 1 and 0.6 (SD 10.4) in Cohort 2 (P < 0.001). The mean decrement of FEF 25-75% was 16.3 (SD 19.5) in Cohort 1 and 1.3 (SD 16.8) in Cohort 2 (P < 0.001) and the Pseudomonas aeruginosa (Pa) colonization was 28% and 15% respectively (P = 0.1). Our results show that pulmonary function has clearly ameliorated over a decade in young CF patients, in a period during which several significant therapeutic changes have been introduced, such as dornase alfa, tobramycin and hypertonic saline. To our knowledge this is the first study showing a cohort effect in patients diagnosed after neonatal screening. © 2015 Wiley Periodicals, Inc.

Stand and cohort structures of old-growth Pinus resinosa-dominated forests of northern Minnesota, USA

Treesearch

Shawn Fraver; Brian J. Palik

2012-01-01

The wide range of stand and age-cohort structures in these old-growth P. resinosa stands depicts pre-settlement forests more complex than those of the single-cohort, post-stand-replacing-fire model that has guided regional forest management. Within-stand patchiness of cohort age structures implies disturbances operating at scales smaller than...

The course of work absenteeism involving neck pain: a cohort study of Ontario lost-time claimants.

PubMed

Van Eerd, Dwayne; Côté, Pierre; Kristman, Vicki; Rezai, Mana; Hogg-Johnson, Sheilah; Vidmar, Marjan; Beaton, Dorcas

2011-05-20

Cohort study. To describe the course of lost-time claims involving neck pain in workers compensated by the Ontario Workplace Safety and Insurance Board (WSIB). The prevalence of neck pain in workers varies from 27.1% to 47.8%. Very little is known about the course of work absenteeism related to neck pain. Our cohort included 5761 injured workers with an incident lost-time claim to the WSIB in 1997 and 1998. Claimants were followed for 2 years. We measured the cumulative time on lost-time benefits using the Kaplan-Meier method and described the number and duration of episodes on benefits. The median cumulative time-on-benefits for the cohort was 13 days (95% CI: 13-14). The cumulative time on benefits was shorter for men than women and for younger than older workers. 14.2% of claimants experienced multiple episodes of work absenteeism during the 2 years after the initial claim. The median time on benefits for claimants with a single episode was 11 days (95% CI: 10-11). The median length of the first episode on benefits was longer for claimants with multiple episodes (19-22 days) compared with those with a single episode (11 days). Age was positively associated with longer time-on-benefits in claimants with a single episode of work absenteeism. Most injured workers who make a workers' compensation claim that involves neck pain do not make a second claim in the subsequent 2 years. However, an important minority (14.2%) experience multiple episodes of work absenteeism and these workers accrue 40.4% of all lost-time days. Recurrent claims involving neck pain represent a significant burden of disability in Ontario.

Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

PubMed

Beuschlein, Felix; Weigel, Jens; Saeger, Wolfgang; Kroiss, Matthias; Wild, Vanessa; Daffara, Fulvia; Libé, Rosella; Ardito, Arianna; Al Ghuzlan, Abir; Quinkler, Marcus; Oßwald, Andrea; Ronchi, Cristina L; de Krijger, Ronald; Feelders, Richard A; Waldmann, Jens; Willenberg, Holger S; Deutschbein, Timo; Stell, Anthony; Reincke, Martin; Papotti, Mauro; Baudin, Eric; Tissier, Frédérique; Haak, Harm R; Loli, Paola; Terzolo, Massimo; Allolio, Bruno; Müller, Hans-Helge; Fassnacht, Martin

2015-03-01

Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. The aim of this study was to identify markers with prognostic value for patients in this clinical setting. From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

Single-site Laparoscopic Colorectal Surgery Provides Similar Clinical Outcomes Compared to Standard Laparoscopic Surgery: An Analysis of 626 Patients

PubMed Central

Sangster, William; Messaris, Evangelos; Berg, Arthur S.; Stewart, David B.

2015-01-01

BACKGROUND Compared to standard laparoscopy, single-site laparoscopic colorectal surgerymay potentially offer advantages by creating fewer surgical incisions and providing a multi-functional trocar. Previous comparisons, however, have been limited by small sample sizes and selection bias. OBJECTIVE To compare 60-day outcomes between standard laparoscopic and single-site laparoscopic colorectal surgery patients undergoing elective and urgent surgeries. DESIGN This was an unselected retrospective cohort study comparing patients who underwent elective and unplanned standard laparoscopic or single-site laparoscopic colorectal resections for benign and malignant disease between 2008 and 2014. Outcomes were compared using univariate analyses. SETTING This study was conducted at a single institution. PATIENTS A total of 626 consecutive patients undergoing laparoscopic colorectal surgery were included. MAIN OUTCOME MEASURES Morbidity and mortality within 60 postoperative days. RESULTS 318 (51%) and 308 (49%) patients underwent standard laparoscopic and single-site laparoscopic procedures, respectively. No significant difference was noted in mean operative time (Standard laparoscopy 182.1 ± 81.3 vs. Single-site laparoscopy 177±86.5, p=0.30) and postoperative length of stay (Standard laparoscopy 4.8±3.4 vs. Single-site laparoscopy 5.5 ± 6.9, p=0.14). Conversions to laparotomy and 60-day readmissions were also similar for both cohorts across all procedures performed. A significant difference was identified in the number of patients who developed postoperative complications (Standard laparoscopy 19.2% vs. Single-site laparoscopy 10.7%, p=0.004), especially with respect to surgical-site infections (Standard laparoscopy 11.3% vs. Single-site laparoscopy 5.8%, p=0.02). LIMITATIONS This was a retrospective, single institution study. CONCLUSIONS Single-site laparoscopic colorectal surgery demonstrates similar results to standard laparoscopic colorectal surgery in regards to operative time, length of stay and readmissions. Single-site laparoscopic colorectal surgery may provide advantages in limiting the development of certain complications such as superficial surgical-site infections. PMID:26252848

Canary TMA — EDRN Public Portal

Cancer.gov

This protocol describes a multi-center, retrospective, case-cohort tissue microarray (TMA) study to evaluate tissue biomarkers for their ability to predict recurrent prostate cancer at the time of radical prostatectomy (RP). Candidate biomarkers will be assessed by performing tissue localization studies on TMAs containing recurrent prostate cancer and non-recurrent prostate cancer. De-identified data will be transferred to a central repository for statistical analysis. Participating institutions will use a variation of case-cohort sampling to randomly select a subset of patients from a retrospectively constructed RP cohort and/or perform selected assays on the cohort. The study endpoint is time to recurrence; of primary interest is five year recurrence free survival. Recurrent prostate cancer is defined by 1) a single serum prostate-specific antigen (PSA) level greater than 0.2 ng/mL after RP and/or 2) receipt of salvage or secondary therapy after RP and/or 3) clinical or radiological evidence of metastatic disease. Non-recurrent prostate cancer is defined as disease with no evidence of recurrence.

The effectiveness of wellness coaching for improving quality of life.

PubMed

Clark, Matthew M; Bradley, Karleah L; Jenkins, Sarah M; Mettler, Emily A; Larson, Brent G; Preston, Heather R; Liesinger, Juliette T; Werneburg, Brooke L; Hagen, Philip T; Harris, Ann M; Riley, Beth A; Olsen, Kerry D; Vickers Douglas, Kristin S

2014-11-01

To learn more about the potential psychosocial benefits of wellness coaching. Although wellness coaching is increasing in popularity, there are few published outcome studies. In a single-cohort study design, 100 employees who completed the 12-week wellness coaching program were of a mean age of 42 years, 90% were women, and most were overweight or obese. Three areas of psychosocial functioning were assessed: quality of life (QOL; 5 domains and overall), depressive symptoms (Patient Health Questionnaire-9), and perceived stress level (Perceived Stress Scale-10). Participants were recruited from January 1, 2011, through December 31, 2011; data were collected up to July 31, 2012, and were analyzed from August 1, 2012, through October 31, 2013. These 100 wellness coaching completers exhibited significant improvements in all 5 domains of QOL and overall QOL (P<.0001), reduced their level of depressive symptoms (P<.0001), and reduced their perceived stress level (P<.001) after 12 weeks of in-person wellness coaching, and they maintained these improvements at the 24-week follow-up. In this single-arm cohort study (level 2b evidence), participating in wellness coaching was associated with improvement in 3 key areas of psychosocial functioning: QOL, mood, and perceived stress level. The results from this single prospective cohort study suggest that these areas of functioning improve after participating in wellness coaching; however, randomized clinical trials involving large samples of diverse individuals are needed to establish level 1 evidence for wellness coaching. Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

A Comparison of Health Care Resource Utilization and Costs for Patients with Allergic Rhinitis on Single-Product or Free-Combination Therapy of Intranasal Steroids and Intranasal Antihistamines.

PubMed

Harrow, Brooke; Sedaghat, Ahmad R; Caldwell-Tarr, Amanda; Dufour, Robert

2016-12-01

Allergic rhinitis (AR) is a common condition that can be treated with a number of different therapies. Treatments such as intranasal antihistamines (INAs) and intranasal steroids (INSs) are widely used by AR patients. For some allergy sufferers, a combination of therapies, specifically an INA and an INS, is required to address their symptoms. A new treatment, the formulation of azelastine hydrochloride and fluticasone pro-pionate used as a single spray (MP-AzeFlu), has become available for AR patients who need both types of treatment. In this regard, the comparison with the alternative concomitant use of INAs and INSs is of interest. The current study examines the health care resource utilization and costs for each cohort. To examine the resource utilization and costs associated with AR for patients treated with MP-AzeFlu or concurrent therapy with single-ingredient INA and INS sprays (free-combination therapy). A retrospective administrative claims study for commercially insured patients from a large U.S. health plan was performed. Patients with an AR diagnosis and a prescription claim for MP-AzeFlu or free-combination therapy between September 1, 2012, and September 30, 2013, were identified. Patients were aged at least 12 years at index date (first prescription fill for intranasal therapy) and were required to have 12 months pre-index and 6 months post-index of continuous enrollment. Health care resource utilization and costs were assessed for the post-index period. The cohorts were adjusted on baseline demographic and clinical characteristics using inverse propensity treatment weights. Other covariates, prescriber specialty, product switching during the post-index period, and pre-index total costs were included in the regression models measuring outcomes. One clinical characteristic of interest was the presence of asthma as comorbidity. A subset analysis of AR patients with asthma was also performed. All-cause-related pharmacy fills as well as pharmacy, medical, and total costs were significantly reduced by using MP-AzeFlu (N = 810) instead of the free combination of drugs (N = 726). For AR-related health care resource utilization, the MP-AzeFlu cohort had significantly fewer pharmacy fills than the free-combination cohort (1.01 and 1.17, respectively; P < 0.001) with no significant difference in outpatient services and specialist visits (P = 0.139 and P = 0.117, respectively). Six-month AR-related pharmacy and total costs were significantly lower (P < 0.001 and P = 0.001) for the MP-AzeFlu cohort ($128 and $334, respectively) than the free-combination cohort ($268 and $458, respectively). There was no statistically significant difference in AR-related medical costs between the 2 cohorts (P = 0.454). For the subcohort of AR patients with asthma, the MP-AzeFlu cohort had lower 6-month asthma resource utilization and costs than the free-combination cohort. These findings suggest that, for AR patients needing INAs and INSs, the single-spray formulation MP-AzeFlu had better economic outcomes than for patients who rely on the free combination of these agents. MP-AzeFlu also appears to keep asthma-related utilization and costs down for those AR patients who also suffer from asthma. Potential explanations for these findings are explored. This study was funded by Meda Pharmaceuticals. Authors were either employed by Meda Pharmaceuticals or received consulting fees from Meda Pharmaceuticals. Comprehensive Health Insights and Sedaghat received funding from Meda Pharmaceuticals as a consultant to participate in this study. Dufour and Caldwell-Tarr are employees of Comprehensive Health Insights. Harrow is currently employed by TESARO. This study was conceived by Harrow, Dufour, and Caldwell-Tarr. All authors contributed to the design of the study. Dufour took the lead in data collection, along with Caldwell-Tarr, and data interpretion was performed by Harrow, along with the other authors. Analyses were performed by Dufour. The manuscript was written and revised by all authors.

Mortality Measurement at Advanced Ages: A Study of the Social Security Administration Death Master File

PubMed Central

Gavrilov, Leonid A.; Gavrilova, Natalia S.

2011-01-01

Accurate estimates of mortality at advanced ages are essential to improving forecasts of mortality and the population size of the oldest old age group. However, estimation of hazard rates at extremely old ages poses serious challenges to researchers: (1) The observed mortality deceleration may be at least partially an artifact of mixing different birth cohorts with different mortality (heterogeneity effect); (2) standard assumptions of hazard rate estimates may be invalid when risk of death is extremely high at old ages and (3) ages of very old people may be exaggerated. One way of obtaining estimates of mortality at extreme ages is to pool together international records of persons surviving to extreme ages with subsequent efforts of strict age validation. This approach helps researchers to resolve the third of the above-mentioned problems but does not resolve the first two problems because of inevitable data heterogeneity when data for people belonging to different birth cohorts and countries are pooled together. In this paper we propose an alternative approach, which gives an opportunity to resolve the first two problems by compiling data for more homogeneous single-year birth cohorts with hazard rates measured at narrow (monthly) age intervals. Possible ways of resolving the third problem of hazard rate estimation are elaborated. This approach is based on data from the Social Security Administration Death Master File (DMF). Some birth cohorts covered by DMF could be studied by the method of extinct generations. Availability of month of birth and month of death information provides a unique opportunity to obtain hazard rate estimates for every month of age. Study of several single-year extinct birth cohorts shows that mortality trajectory at advanced ages follows the Gompertz law up to the ages 102–105 years without a noticeable deceleration. Earlier reports of mortality deceleration (deviation of mortality from the Gompertz law) at ages below 100 appear to be artifacts of mixing together several birth cohorts with different mortality levels and using cross-sectional instead of cohort data. Age exaggeration and crude assumptions applied to mortality estimates at advanced ages may also contribute to mortality underestimation at very advanced ages. PMID:22308064

Development of Advanced Technologies for Complete Genomic and Proteomic Characterization of Quantized Human Tumor Cells

DTIC Science & Technology

2015-09-01

glioblastoma . We have successfully established several patient-derived cell lines from glioblastoma tumors and further established a number of...and single-cell technologies. Although the focus of this research is glioblastoma , the proposed tools are generally applicable to all cancer-based...studies. 15. SUBJECT TERMS Human cohorts, Glioblastoma , Genomic, Proteomic, Single-cell technologies, Hypothesis-driven, integrative systems approach

Single freeze per vein strategy with the second-generation cryoballoon for atrial fibrillation: a propensity score-matched study between 180- and 240-s application time in a large cohort of patients.

PubMed

De Regibus, Valentina; Abugattas, Juan-Pablo; Iacopino, Saverio; Mugnai, Giacomo; Storti, Cesare; Conte, Giulio; Auricchio, Angelo; Ströker, Erwin; Coutiño, Hugo-Enrique; Takarada, Ken; Salghetti, Francesca; Lusoc, Ian; Capulzini, Lucio; Brugada, Pedro; de Asmundis, Carlo; Chierchia, Gian-Battista

2017-11-02

The single-freeze strategy using the second-generation cryoballoon (CB-A, Arctic Front Advance, Medtronic, Minneapolis, MN, USA) has been reported to be as effective as the recommended double-freeze approach in several single-centre studies. In this retrospective, international, multicentre study, we compare the 3-min single-freeze strategy with the 4-min single-freeze strategy. Four hundred and thirty-two patients having undergone pulmonary vein isolation (PVI) by means of CB-A using a single-freeze strategy were considered for this analysis. A cohort of patients who were treated with a 3-min strategy (Group 1) was compared with a propensity score-matched cohort of patients who underwent a 4-min strategy (Group 2). Pulmonary vein isolation was successfully achieved in all the veins using the 28-mm CB-A. The procedural and fluoroscopy times were lower in Group 1 (67.8 ± 17 vs. 73.8 ± 26.3, P < 0.05; 14.9 ± 7.8 vs. 24.2 ± 10.6 min, P < 0.05). The most frequent complication was PNP, with no difference between the two groups (P = 0.67). After a mean follow-up of 13 ± 8 months, taking into consideration a blanking period of 3 months, 85.6% of patients in Group 1 and 87% of patients in Group 2 were free from arrhythmia recurrence at final follow-up (P = 0.67). There is no difference in acute success, rate of complications, and freedom from atrial fibrillation recurrences during the follow-up between 3-min and 4-min per vein freeze strategies. The procedural and fluoroscopy times were significantly shorter in 3-min per vein strategy. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.

Variants in TTC25 affect autistic trait in patients with autism spectrum disorder and general population.

PubMed

Vojinovic, Dina; Brison, Nathalie; Ahmad, Shahzad; Noens, Ilse; Pappa, Irene; Karssen, Lennart C; Tiemeier, Henning; van Duijn, Cornelia M; Peeters, Hilde; Amin, Najaf

2017-08-01

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder with a complex genetic architecture. To identify genetic variants underlying ASD, we performed single-variant and gene-based genome-wide association studies using a dense genotyping array containing over 2.3 million single-nucleotide variants in a discovery sample of 160 families with at least one child affected with non-syndromic ASD using a binary (ASD yes/no) phenotype and a quantitative autistic trait. Replication of the top findings was performed in Psychiatric Genomics Consortium and Erasmus Rucphen Family (ERF) cohort study. Significant association of quantitative autistic trait was observed with the TTC25 gene at 17q21.2 (effect size=10.2, P-value=3.4 × 10 -7 ) in the gene-based analysis. The gene also showed nominally significant association in the cohort-based ERF study (effect=1.75, P-value=0.05). Meta-analysis of discovery and replication improved the association signal (P-value meta =1.5 × 10 -8 ). No genome-wide significant signal was observed in the single-variant analysis of either the binary ASD phenotype or the quantitative autistic trait. Our study has identified a novel gene TTC25 to be associated with quantitative autistic trait in patients with ASD. The replication of association in a cohort-based study and the effect estimate suggest that variants in TTC25 may also be relevant for broader ASD phenotype in the general population. TTC25 is overexpressed in frontal cortex and testis and is known to be involved in cilium movement and thus an interesting candidate gene for autistic trait.

Impact of 5-HT(3) RA selection within triple antiemetic regimens on uncontrolled highly emetogenic chemotherapy-induced nausea/vomiting.

PubMed

Schwartzberg, Lee; Jackson, James; Jain, Gagan; Balu, Sanjeev; Buchner, Deborah

2011-08-01

It is recommended that patients initiate triple antiemetic therapy with one of the 5-hydroxytryptamine receptor antagonists (5-HT(3) RAs), aprepitant (or its intravenous prodrug fosaprepitant) and dexamethasone prior to the start of highly emetogenic chemotherapy (HEC). However, the impact of 5-HT(3) RA selection within triple antiemetic regimens on the risk of uncontrolled chemotherapy-induced nausea and vomiting (CINV) with HEC has not been well studied. To assess the likelihood of an uncontrolled CINV event following antiemetic prophylaxis with the 5-HT(3) RA palonosetron + aprepitant/fosaprepitant + dexamethasone (palonosetron cohort) versus any of the other 5-HT(3) RAs + aprepitant/fosaprepitant + dexamethasone (other 5-HT(3) RA cohort) among single-day HEC cycles. Single-day HEC cycles (a gap of at least 5 days between two administrations) among patients with a cancer diagnosis and receiving antiemetic prophylaxis with the aforementioned regimens between 1/1/2006 and 6/30/2010 were identified from the IMS LifeLink claims database. Uncontrolled CINV events were identified through ICD-9-CM codes (nausea and vomiting), Current Procedural Terminology codes (hydration), rescue medications and/or use of antiemetic therapy from days 2-5 following HEC administration. Risks for an uncontrolled CINV event among all patients, and within breast cancer and multiple cancer subpopulations, were analyzed at cycle level using logistic multivariate regression models. A total of 8018 cycles for the palonosetron cohort and 1926 cycles for the other 5-HT(3) RA cohort (3574 and 978 patients, respectively) were analyzed. Single-day HEC cycles received by the palonosetron cohort had a significantly lower unadjusted risk of an uncontrolled CINV event (17.5 vs 20.7% for the other 5-HT(3) RA cohort; p = 0.0010), with a 17% lower adjusted risk for palonosetron-administered cycles (odds ratio: 0.83; 95% CI: 0.73-0.94; p = 0.0042). Results in the breast cancer and multiple cancer subgroups were consistent with those for the overall population. In this retrospective claims data analysis, single-day HEC cycles administered with palonosetron + aprepitant/fosaprepitant + dexamethasone had a lower risk for an uncontrolled CINV event versus other 5-HT(3) RAs + aprepitant/fosaprepitant + dexamethasone.

SLC30A8 nonsynonymous variant is associated with recovery following exercise and skeletal muscle size and strength.

PubMed

Sprouse, Courtney; Gordish-Dressman, Heather; Orkunoglu-Suer, E Funda; Lipof, Jason S; Moeckel-Cole, Stephanie; Patel, Ronak R; Adham, Kasra; Larkin, Justin S; Hubal, Monica J; Kearns, Amy K; Clarkson, Priscilla M; Thompson, Paul D; Angelopoulos, Theodore J; Gordon, Paul M; Moyna, Niall M; Pescatello, Linda S; Visich, Paul S; Zoeller, Robert F; Hoffman, Eric P; Tosi, Laura L; Devaney, Joseph M

2014-01-01

Genome-wide association studies have identified thousands of variants that are associated with numerous phenotypes. One such variant, rs13266634, a nonsynonymous single nucleotide polymorphism in the solute carrier family 30 (zinc transporter) member eight gene, is associated with a 53% increase in the risk of developing type 2 diabetes (T2D). We hypothesized that individuals with the protective allele against T2D would show a positive response to short-term and long-term resistance exercise. Two cohorts of young adults-the Eccentric Muscle Damage (EMD; n = 156) cohort and the Functional Single Nucleotide Polymorphisms Associated with Muscle Size and Strength Study (FAMuSS; n = 874)-were tested for association of the rs13266634 variant with measures of skeletal muscle response to resistance exercise. Our results were sexually dimorphic in both cohorts. Men in the EMD study with two copies of the protective allele showed less post-exercise bout strength loss, less soreness, and lower creatine kinase values. In addition, men in the FAMuSS, homozygous for the protective allele, showed higher pre-exercise strength and larger arm skeletal muscle volume, but did not show a significant difference in skeletal muscle hypertrophy or strength with resistance training.

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

PubMed Central

Krishnan, Vyjayanthi; Andersen, Bo H.; Shoemaker, Christine; Sivko, Gloria S.; Tordoff, Kevin P.; Stark, Gregory V.; Zhang, Jianfeng; Feng, Tsungwei; Duchars, Matthew

2015-01-01

AdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 × 107, 1.5 × 109, or 3.5 × 1010 viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 × 1010 viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD50) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA. PMID:25673303

Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts.

PubMed

Goodarzi, Mark O; Jones, Michelle R; Li, Xiaohui; Chua, Angela K; Garcia, Obed A; Chen, Yii-Der I; Krauss, Ronald M; Rotter, Jerome I; Ankener, Wendy; Legro, Richard S; Azziz, Ricardo; Strauss, Jerome F; Dunaif, Andrea; Urbanek, Margrit

2012-02-01

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (p(combined cohorts)=10(-8)); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57-88%) for LHCGR at p=0.01. At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

PubMed Central

2012-01-01

Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies. PMID:22340283

The learning curve of laparoendoscopic single-Site (LESS) fundoplication: definable, short, and safe.

PubMed

Ross, Sharona B; Choung, Edward; Teta, Anthony F; Colibao, Lotiffa; Luberice, Kenneth; Paul, Harold; Rosemurgy, Alexander S

2013-01-01

This study of laparoendoscopic single-site (LESS) fundoplication for gastroesophageal reflux disease was undertaken to determine the "learning curve" for implementing LESS fundoplication. One hundred patients, 38% men, with a median age of 61 years and median body mass index of 26 kg/m(2) , underwent LESS fundoplications. The operative times, placement of additional trocars, conversions to "open" operations, and complications were compared among patient quartiles to establish a learning curve. Median data are reported. The median operative times and complications did not differ among 25-patient cohorts. Additional trocars were placed in 27% of patients, 67% of whom were in the first 25-patient cohort. Patients undergoing LESS fundoplication had a dramatic relief in the frequency and severity of all symptoms of reflux across all cohorts equally (P < .05), particularly for heartburn and regurgitation, without causing dysphagia. LESS fundoplication ameliorates symptoms of gastroesophageal reflux disease without apparent scarring. Notably, few operations required additional trocars after the first 25-patient cohort. Patient selection became more inclusive (eg, more "redo" fundoplications) with increasing experience, whereas operative times and complications remained relatively unchanged. The learning curve of LESS fundoplication is definable, short, and safe. We believe that patients will seek LESS fundoplication because of the efficacy and superior cosmetic outcomes; surgeons will need to meet this demand.

Single cell analysis of innate cytokine responses to pattern recognition receptor stimulation in children across four continents

PubMed Central

Smolen, Kinga K; Cai, Bing; Fortuno, Edgardo S; Gelinas, Laura; Larsen, Martin; Speert, David P; Chamekh, Mustapha; Kollmann, Tobias R

2014-01-01

Innate immunity instructs adaptive immunity, and suppression of innate immunity is associated with increased risk for infection. We had previously shown that whole blood cellular components from a cohort of South African children secreted significantly lower levels of most cytokines following stimulation of pattern recognition receptors (PRR) as compared to whole blood from cohorts of Ecuadorian, Belgian, or Canadian children. To begin dissecting the responsible molecular mechanisms, we now set out to identify the relevant cellular source of these differences. Across the four cohorts represented in our study, we identified significant variation in the cellular composition of whole blood; however, significant reduction of the intracellular cytokine production on the single cell level was only detected in South African childrens’ monocytes, cDC, and pDC. We also uncovered a marked reduction in polyfunctionality for each of these cellular compartments in South African children as compared to children from other continents. Together our data identify differences in cell composition as well as profoundly lower functional responses of innate cells in our cohort of South African children. A possible link between altered innate immunity and increased risk for infection or lower response to vaccines in South African infants needs to be explored. PMID:25135829

Frequency and co-prescription pattern of Chinese herbal products for hypertension in Taiwan: a Cohort study.

PubMed

Yang, Pei-Rung; Shih, Wei-Tai; Chu, Yen-Hua; Chen, Pau-Chung; Wu, Ching-Yuan

2015-06-06

Chinese herbal products (CHPs) have been frequently used among patients with chronic diseases including hypertension; however, the co-prescription pattern of herbal formulae and single herbs remain uncharacterized. Thus, this large-scale pharmacoepidemiological study evaluated the frequency and co-prescription pattern of CHPs for treating hypertension in Taiwan from 2003 to 2009. The database of traditional Chinese medicine (TCM) outpatient claims was obtained from the National Health Insurance in Taiwan. Patients with hypertension during study period were defined according to diagnostic codes in the International Classification of Disease Ninth Revision, Clinical Modification. The frequencies and percentages of herbal formula and single herb prescriptions for hypertension were analyzed. We also applied association rules to evaluate the CHPs co-prescription patterns. The hypertension cohort included 154,083 patients, 123,240 patients of which (approximately 80 %) had used TCM at least once. In total, 81,582 visits involving CHP prescriptions were hypertension related; Tian-Ma-Gou-Teng-Yin and Dan Shen (Radix Salvia Miltiorrhizae) were the most frequently prescribed herbal formula and single herb, respectively, for treating hypertension. This study elucidated the utilization pattern of CHPs for treating hypertension. Future studies on the efficacy and safety of these CHPs and on drug-herb interactions are warranted.

Comparison of outcomes after single or DOUBLE-CUFF artificial urinary sphincter insertion.

PubMed

O'Connor, R Corey; Gerber, Glenn S; Avila, Desiderio; Chen, Andrew A; Bales, Gregory T

2003-10-01

To assess the effectiveness and complications associated with single and double-cuff artificial urinary sphincter (AUS) implantation for postprostatectomy stress urinary incontinence. A retrospective study of 56 men with postprostatectomy stress urinary incontinence who underwent either single (28 patients) or double (28 patients) cuff AUS placement was performed. Patients in each cohort were matched on the basis of preoperative pad use, risk factors for complications, and age. Patient selection was blinded relative to outcome. Continence, quality of life, and complications were assessed using the Incontinence Impact Questionnaire Short Form (IIQ-7), postoperative pad use, and chart review. The mean age was 67 years for each group. Daily pad use decreased from 7.7 to 1.1 in patients treated with a single-cuff AUS and from 7.8 to 0.7 in patients with a double-cuff AUS (P = 0.25). Complete continence (0 pads daily) was reported in 3 (11%) of 28 men with single-cuff and 12 (43%) of 28 men with double-cuff sphincters (P = 0.008). The IIQ-7 scores improved from 14.8 to 3.1 after single-cuff placement and from 16.3 to 2.5 after double-cuff placement (P = 0.03). With an average follow-up of 41.3 and 21.2 months for the single and double-cuff cohorts, respectively, five complications were reported in the single-cuff recipients and four in the double-cuff patients. A significantly greater rate of complete continence and improvement in the IIQ-7 were seen in men with double-cuff AUS compared with single-cuff devices. Additional study is needed to confirm the relative advantages of double-cuff insertion.

Impact of singlehood during pregnancy on dietary intake and birth outcomes- a study in the Norwegian Mother and Child Cohort Study.

PubMed

Farbu, Jorunn; Haugen, Margaretha; Meltzer, Helle Margrete; Brantsæter, Anne Lise

2014-12-05

Little attention has been given to the impact of singlehood during pregnancy. The aim of this study was to examine the impact of marital status on diet during pregnancy and pregnancy outcome. The study population comprised 62,773 women participating in the Norwegian Mother and Child Cohort Study. Marital status was categorised into singles living alone, singles living with parents and married/cohabiting (reference group). Participants answered a general health questionnaire in gestational week 15-17 and a food frequency questionnaire in gestational week 22. We used nonparametric tests to compare dietary intakes by marital status, and multiple logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for infants being small for gestational age (SGA), large for gestational age (LGA), and preterm delivery (defined as delivery before gestational week 37). Single women living with parents had lower intakes of fruits and vegetables, higher intake of total energy, higher proportion of energy from added sugar, and lower intake of fibre than the reference group. Singles living alone also had a higher intake of added sugar. In both of the single groups, daily smoking was more prevalent than in women living with a partner. In analyses adjusted for maternal age, pre-pregnancy BMI, energy intake, energy contributed by protein, education, income, parity and nausea, single women living alone had increased risk of SGA with OR = 1.27 (95% CI: 1.05, 1.55). When smoking was included among the confounding variables, the association was no longer significant. Likewise, singles living alone had increased risk of preterm delivery, with OR = 1.32 (95% CI: 1.01, 1.72) in a partly adjusted model, but the association did not remain significant in a model fully adjusted for confounding variables. Single mothers had lower dietary quality and included more smokers than women who lived with a partner. Single mothers living alone had higher prevalence of SGA and preterm delivery, but the associations with adverse pregnancy outcomes were confounded by other variables. This study shows that single mothers should be given special attention during antenatal care and counselling.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

PubMed

Perera, Minoli A; Cavallari, Larisa H; Limdi, Nita A; Gamazon, Eric R; Konkashbaev, Anuar; Daneshjou, Roxana; Pluzhnikov, Anna; Crawford, Dana C; Wang, Jelai; Liu, Nianjun; Tatonetti, Nicholas; Bourgeois, Stephane; Takahashi, Harumi; Bradford, Yukiko; Burkley, Benjamin M; Desnick, Robert J; Halperin, Jonathan L; Khalifa, Sherief I; Langaee, Taimour Y; Lubitz, Steven A; Nutescu, Edith A; Oetjens, Matthew; Shahin, Mohamed H; Patel, Shitalben R; Sagreiya, Hersh; Tector, Matthew; Weck, Karen E; Rieder, Mark J; Scott, Stuart A; Wu, Alan H B; Burmester, James K; Wadelius, Mia; Deloukas, Panos; Wagner, Michael J; Mushiroda, Taisei; Kubo, Michiaki; Roden, Dan M; Cox, Nancy J; Altman, Russ B; Klein, Teri E; Nakamura, Yusuke; Johnson, Julie A

2013-08-31

VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10(-8) in the discovery cohort and p<0·0038 in the replication cohort. The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10(-8)). This association was confirmed in the replication cohort (p=5·04×10(-5)); analysis of the two cohorts together produced a p value of 4·5×10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust. Copyright © 2013 Elsevier Ltd. All rights reserved.

A Controlled, Randomized Double-Blind Study to Evaluate the Safety and Efficacy of Chitosan-N-Acetylcysteine for the Treatment of Dry Eye Syndrome.

PubMed

Schmidl, Doreen; Werkmeister, René; Kaya, Semira; Unterhuber, Angelika; Witkowska, Katarzyna J; Baumgartner, Renate; Höller, Sonja; O'Rourke, Maria; Peterson, Ward; Wolter, Annika; Prinz, Martin; Schmetterer, Leopold; Garhöfer, Gerhard

2017-06-01

This study was designed to evaluate the effect of chitosan-N-acetylcysteine (C-NAC) eye drops on tear film thickness (TFT) in patients with dry eye syndrome (DES). This was a controlled, randomized, double-blind clinical investigation with patients assigned to 2 cohorts. In Cohort I, 21 patients were randomized to receive 1 instillation of C-NAC eye drops in 1 eye and placebo (normal saline solution) in the contralateral eye. In Cohort II, 17 patients were randomized to receive C-NAC eye drops once (QD) or twice (BID) daily for 5 days. TFT was assessed with a custom-built ultrahigh-resolution optical coherence tomography system. In Cohort I, mean TFT increased from 3.9 ± 0.5 μm predose to 4.8 ± 1.1 μm 10 min postdose after treatment with C-NAC. The increase was significantly different from placebo over time (P < 0.0001) and remained stable until 24 h postdose. In Cohort II, TFT increased with QD and BID instillation, with no significant difference between regimens. In both groups, Ocular Surface Disease Index scores improved, fewer patients presented with corneal damage, and symptoms of ocular discomfort/conjunctival redness were reduced. A single instillation of C-NAC significantly increased mean TFT in patients with DES as early as 10 min after instillation and lasted for 24 h. The magnitude of the increase in TFT following a single instillation was comparable with that after instillation twice daily over 5 days. Corneal damage improved in >60% of patients. C-NAC could be a viable treatment option for DES.

Clinical Outcomes of a Pneumatic Unloader Brace for Kellgren-Lawrence Grades 3 to 4 Osteoarthritis: A Minimum 1-Year Follow-Up Study.

PubMed

Chughtai, Morad; Bhave, Anil; Khan, Sabahat Z; Khlopas, Anton; Ali, Osman; Harwin, Steven F; Mont, Michael A

2016-11-01

The use of a pneumatic unloader brace has been shown in pilot studies to decrease pain and increase muscle strength in patients with knee osteoarthritis (OA). Therefore, we analyzed patients who had knee OA, and either received a pneumatic unloader brace and conventional treatment or conventional treatment alone. Specifically, we assessed: (1) use of pain relieving injections; (2) opioid consumption; and (3) the eventual need for total knee arthroplasty (TKA) in the above-mentioned cohort. We performed an analysis of a longitudinally maintained database of patients from a prospective, randomized, single center study. This study randomized patients who had Kellgren-Lawrence grades 3 to 4 to receive either a pneumatic unloader brace and conventional treatment or conventional treatment alone. The brace cohort comprised 11 patients with a mean age of 55 years (range, 37-70 years). The final matched cohort comprised 25 patients with a mean age of 63 years (range, 41-86 years). The minimum follow-up was 1 year. There was a lower proportion of patients who underwent an eventual TKA in the bracing cohort as compared with the nonbracing cohort (18 vs. 36%). The mean time to TKA was longer in the bracing cohort as compared with the nonbracing cohort (482 vs. 389 days). The proportion of patients who used opioids was similar in both groups (27 vs. 22%). There was a significantly lower number of patients who received injections in the bracing cohort as compared with the nonbracing cohort (46 vs. 83%, p  = 0.026). The bracing cohort had received a significantly lower number of injections and a lower rate of subsequent TKA as compared with the nonbracing cohort. The mean time to TKA was also longer among the bracing cohort. These results may demonstrate the potential of this brace to reduce the need for and prolonging the time to TKA. Performing larger prospective randomized studies, with built-in compliance monitors is warranted. This brace may be a valuable adjunct to the current knee OA treatment armamentarium pending further investigation. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Muscle Fiber Size and Function in Elderly Humans: A Longitudinal Study

USDA-ARS?s Scientific Manuscript database

Cross-sectional studies are likely to underestimate age-related changes in skeletal muscle strength and mass. The purpose of this longitudinal study was to assess whole muscle and single muscle fiber alterations in the same cohort of 12 older (mean age: start of study=71.1+/-5.4 yrs and end of study...

Temporal trends in compliance with appropriateness criteria for stress single-photon emission computed tomography sestamibi studies in an academic medical center.

PubMed

Gibbons, Raymond J; Askew, J Wells; Hodge, David; Miller, Todd D

2010-03-01

The purpose of this study was to apply published appropriateness criteria for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in a single academic medical center to determine if the percentage of inappropriate studies was changing over time. In a previous study, we applied the American College of Cardiology Foundation/American Society of Nuclear Cardiology (ASNC) appropriateness criteria for stress SPECT MPI and reported that 14% of stress SPECT studies were performed for inappropriate reasons. Using similar methodology, we retrospectively examined 284 patients who underwent stress SPECT MPI in October 2006 and compared the findings to the previous cohort of 284 patients who underwent stress SPECT MPI in May 2005. The indications for testing in the 2 cohorts were very similar. The overall level of agreement in characterizing categories of appropriateness between 2 experienced cardiovascular nurse abstractors was good (kappa = 0.68), which represented an improvement from our previous study (kappa = 0.56). There was a significant change between May 2005 and October 2006 in the overall classification of categories for appropriateness (P = .024 by chi(2) statistic). There were modest, but insignificant, increases in the number of patients who were unclassified (15% in the current study vs 11% previously), appropriate (66% vs 64%), and uncertain (12% vs 11%). Only 7% of the studies in the current study were inappropriate, which represented a significant (P = .004) decrease from the 14% reported in the 2005 cohort. In the absence of any specific intervention, there was a significant change in the overall classification of SPECT appropriateness in an academic medical center over 17 months. The only significant difference in individual categories was a decrease in inappropriate studies. Additional measurements over time will be required to determine if this trend is sustainable or generalizable.

The association of variants in the FTO gene with longitudinal body mass index profiles in non-Hispanic white children and adolescents.

PubMed

Hallman, D M; Friedel, V C; Eissa, M A H; Boerwinkle, E; Huber, J C; Harrist, R B; Srinivasan, S R; Chen, W; Dai, S; Labarthe, D R; Berenson, G S

2012-01-01

To investigate possible age-related changes in associations between polymorphisms in the fat mass and obesity-associated (FTO) gene and higher body mass index (BMI). Multilevel mixed regression models were used to examine associations between four FTO variants and longitudinal BMI profiles in non-Hispanic white and African American children and adolescents 8-17 years of age from two different longitudinal cohort studies, the Bogalusa Heart Study (BHS) and Project HeartBeat! (PHB). In the BHS, there were 1551 examinations of 478 African Americans and 3210 examinations of 1081 non-Hispanic whites; in PHB, there were 971 examinations of 131 African Americans and 4458 examinations of 505 non-Hispanic whites. In African Americans, no significant FTO associations with BMI were found. In non-Hispanic whites, linkage disequilibrium among all four variants made haplotype analysis superfluous, so we focused on the single-nucleotide polymorphism, rs9939609. In longitudinal multilevel models, the A/A genotype of rs9939609 was associated with higher BMI in non-Hispanic whites in both cohorts at all ages. A significant age-by-genotype interaction found only in the BHS cohort predicted that in those with the A/A genotype, BMI would be ∼0.7 kg m(-2) higher at age 8 and ∼1.6 kg m(-2) higher at age 17 than in those with A/T or T/T genotypes. The design of PHB limited follow-up of any single individual to 4 years, and may have reduced the ability to detect any age-by-genotype interaction in this cohort. The A/A genotype of rs9939609 in the FTO gene is associated with higher longitudinal BMI profiles in non-Hispanic whites from two different cohorts. The association may change with age, with the A/A genotype being associated with a larger BMI difference in late adolescence than in childhood, though this was observed only in the BHS cohort and requires verification.

Clinical characteristics and laboratory findings of 252 Chinese patients with anti-phospholipid syndrome: comparison with Euro-Phospholipid cohort.

PubMed

Shi, Hui; Teng, Jia-Lin; Sun, Yue; Wu, Xin-Yao; Hu, Qiong-Yi; Liu, Hong-Lei; Cheng, Xiao-Bing; Yin, Yu-Feng; Ye, Jun-Na; Chen, Pojen P; Yang, Cheng-de

2017-03-01

This study aims to characterize the Chinese Han patients with anti-phospholipid syndrome (APS) and compare the data with those of the Euro-Phospholipid cohort. We conducted a single center study consisting of 252 patients with definite APS from 2000 to 2015. We analyzed the clinical and laboratory characteristics of our cohort and compared the data with those of the Euro-Phospholipid cohort. Our cohort consisted of 216 females and 36 males, with a mean age at entry into this study of 41 years (range 11-74 years). Of these patients, 69 (27.4%) patients had primary APS, and 183 (72.6%) had secondary APS (SAPS), including 163 (64.7%) patients had systemic lupus erythematosus (SLE). Thrombotic events occurred in 190 (75.4%) patients, and the most common ones were deep vein thrombosis (40.1%) and stroke (23.8%), which were similar to the reports of the Euro-Phospholipid cohort. In contrast, our cohort had less pulmonary embolism (6.7%). Among 93 females with 299 pregnancy episodes, the rates of early (<10 weeks) and late fetal loss (≥10 weeks) were, respectively, 37.8% and 24.4%. The latter was significantly higher than that of the Euro-Phospholipid cohort. Moreover, 7 APS nephropathy patients (characterized histopathologically by thrombotic microangiopathy) and 8 catastrophic APS patients were found in our cohort. Anti-cardiolipin antibodies (aCL) were detected in 169 (67.1%) patients, lupus anti-coagulant (LA) was detected in 83 (32.9%), and anti-β2 glycoprotein I antibodies (anti-β2GPI) in 148 (58.7%) patients. These results show that some clinical manifestations of APS may vary among different racial groups.

Environmental exposure assessment in European birth cohorts: results from the ENRIECO project

PubMed Central

2013-01-01

Environmental exposures during pregnancy and early life may have adverse health effects. Single birth cohort studies often lack statistical power to tease out such effects reliably. To improve the use of existing data and to facilitate collaboration among these studies, an inventory of the environmental exposure and health data in these studies was made as part of the ENRIECO (Environmental Health Risks in European Birth Cohorts) project. The focus with regard to exposure was on outdoor air pollution, water contamination, allergens and biological organisms, metals, pesticides, smoking and second hand tobacco smoke (SHS), persistent organic pollutants (POPs), noise, radiation, and occupational exposures. The review lists methods and data on environmental exposures in 37 European birth cohort studies. Most data is currently available for smoking and SHS (N=37 cohorts), occupational exposures (N=33), outdoor air pollution, and allergens and microbial agents (N=27). Exposure modeling is increasingly used for long-term air pollution exposure assessment; biomonitoring is used for assessment of exposure to metals, POPs and other chemicals; and environmental monitoring for house dust mite exposure assessment. Collaborative analyses with data from several birth cohorts have already been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and SHS. Key success factors for collaborative analyses are common definitions of main exposure and health variables. Our review emphasizes that such common definitions need ideally be arrived at in the study design phase. However, careful comparison of methods used in existing studies also offers excellent opportunities for collaborative analyses. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question. PMID:23343014

Comparative Assessment of a Single Dose and a 2-dose Vaccination Series of a Quadrivalent Meningococcal CRM-conjugate Vaccine (MenACWY-CRM) in Children 2-10 Years of Age.

PubMed

Johnston, William; Essink, Brandon; Kirstein, Judith; Forleo-Neto, Eduardo; Percell, Sandra; Han, Linda; Keshavan, Pavitra; Smolenov, Igor

2016-01-01

We compared the immunogenicity, safety and 1-year antibody persistence of a single-dose and a 2-dose series of a licensed meningococcal ACWY-CRM conjugate vaccine (MenACWY-CRM) in 2- to 10-year-old children. In this phase III, multicenter, observer-blind study, children aged 2-5 years (n = 359) and 6-10 years (n = 356) were randomized 1:1 to receive 2 doses of MenACWY-CRM (ACWY2) or 1 dose of placebo followed by 1 dose of MenACWY-CRM (ACWY1), 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement (hSBA). Primary outcomes were to assess the immunologic noninferiority and superiority of ACWY2 versus ACWY1. One-month after the second dose, the hSBA seroresponse in ACWY2 was noninferior to ACWY1 for all 4 serogroups, in both age cohorts, and was superior for serogroups C and Y in the 2- to 5-year-old age cohort and for serogroup Y in the 6- to 10-year-old age cohort. Overall, 90%-99% of subjects in ACWY2 and 65%-96% in ACWY1 had hSBA titers ≥ 8; geometric mean titers were 1.8- to 6.4-fold higher in ACWY2 than ACWY1 across serogroups. At 1 year postvaccination, geometric mean titers declined, and the differences between ACWY2 and ACWY1 remained significant for serogroups A and C in the 2- to 5-year-old age cohort and for serogroups C and Y in the 6- to 10-year-old age cohort. The safety profile of MenACWY-CRM was similar in both groups. The single dose and 2-dose MenACWY-CRM series were immunogenic and well tolerated. Although antibody responses were greater after 2 doses, especially in the 2- to 5-year-old age cohort, this difference was less pronounced at 1 year postvaccination.

Association of the Estrogen Receptor 1 (ESR1) Gene with Body Height in Adult Males from Two Swedish Population Cohorts

PubMed Central

Dahlgren, Andreas; Lundmark, Per; Axelsson, Tomas; Lind, Lars; Syvänen, Ann-Christine

2008-01-01

Human body height is a complex genetic trait with high heritability. We performed an association study of 17 candidate genes for height in the Uppsala Longitudinal Study of Adult Men (ULSAM) that consists of 1153 elderly men of age 70 born in the central region of Sweden. First we genotyped a panel of 137 single nucleotide polymorphism (SNPs) evenly distributed across the candidate genes in the ULSAM cohort. We identified 4 SNPs in the estrogen receptor gene (ESR1) on chromosome 6q25.1 with suggestive signals of association (p<0.05) with standing body height. This result was followed up by genotyping the same 25 SNPs in the ESR1 gene as in ULSAM in a second population cohort, the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort that consist of 507 males and 509 females of age 70 from the same geographical region as ULSAM. One SNP, rs2179922 located in intron 4 of ESR1 showed and association signal (p = 0.0056) in the male samples from the PIVUS cohort. Homozygote carriers of the G-allele of the SNP rs2179922 were on average 0.90 cm taller than individuals with the two other genotypes at this SNP in the ULSAM cohort and 2.3 cm taller in the PIVUS cohort. No association was observed for the females in the PIVUS cohort. PMID:18350145

Preparation of Single-cohort Colonies and Hormone Treatment of Worker Honeybees to Analyze Physiology Associated with Role and/or Endocrine System.

PubMed

Ueno, Takayuki; Kawasaki, Kiyoshi; Kubo, Takeo

2016-09-06

Honeybee workers are engaged in various tasks related to maintaining colony activity. The tasks of the workers change according to their age (age-related division of labor). Young workers are engaged in nursing the brood (nurse bees), while older workers are engaged in foraging for nectar and pollen (foragers). The physiology of the workers changes in association with this role shift. For example, the main function of the hypopharyngeal glands (HPGs) changes from the secretion of major royal jelly proteins (MRJPs) to the secretion of carbohydrate-metabolizing enzymes. Because worker tasks change as the workers age in typical colonies, it is difficult to discriminate the physiological changes that occur with aging from those that occur with the role shift. To study the physiological changes in worker tissues, including the HPGs, in association with the role shift, it would be useful to manipulate the honeybee colony population by preparing single-cohort colonies in which workers of almost the same age perform different tasks. Here we describe a detailed protocol for preparing single-cohort colonies for this analysis. Six to eight days after single-cohort colony preparation, precocious foragers that perform foraging tasks earlier than usual appear in the colony. Representative results indicated role-associated changes in HPG gene expression, suggesting role-associated HPG function. In addition to manipulating the colony population, analysis of the endocrine system is important for investigating role-associated physiology. Here, we also describe a detailed protocol for treating workers with 20-hydroxyecdysone (20E), an active form of ecdysone, and methoprene, a juvenile hormone analogue. The survival rate of treated bees was sufficient to examine gene expression in the HPGs. Gene expression changes were observed in response to 20E- and/or methoprene-treatment, suggesting that hormone treatments induce physiological changes of the HPGs. The protocol for hormone treatment described here is appropriate for examining hormonal effects on worker physiology.

The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: Reduced cervical cancer risk and decreased yield of precancer per screen.

PubMed

Silver, Michelle I; Schiffman, Mark; Fetterman, Barbara; Poitras, Nancy E; Gage, Julia C; Wentzensen, Nicolas; Lorey, Thomas; Kinney, Walter K; Castle, Philip E

2016-12-01

The objective of cervical screening is to detect and treat precancer to prevent cervical cancer mortality and morbidity while minimizing overtreatment of benign human papillomavirus (HPV) infections and related minor abnormalities. HPV/cytology cotesting at extended 5-year intervals currently is a recommended screening strategy in the United States, but the interval extension is controversial. In the current study, the authors examined the impact of a decade of an alternative, 3-year cotesting, on rates of precancer and cancer at Kaiser Permanente Northern California. The effect on screening efficiency, defined as numbers of cotests/colposcopy visits needed to detect a precancer, also was considered. Two cohorts were defined. The "open cohort" included all women screened at least once during the study period; > 1 million cotests were performed. In a fixed "long-term screening cohort," the authors considered the cumulative impact of repeated screening at 3-year intervals by restricting the cohort to women first cotested in 2003 through 2004 (ie, no women entering screening later were added to this group). Detection of cervical intraepithelial neoplasia 3/adenocarcinoma in situ (CIN3/AIS) increased in the open cohort (2004-2006: 82.0/100,000 women screened; 2007-2009: 140.6/100,000 women screened; and 2010-2012: 126.0/100,000 women screened); cancer diagnoses were unchanged. In the long-term screening cohort, the detection of CIN3/AIS increased and then decreased to the original level (2004-2006: 80.5/100,000 women screened; 2007-2009: 118.6/100,000 women screened; and 2010-2012: 84.9./100,000 women screened). The number of cancer diagnoses was found to decrease. When viewed in terms of screening efficiency, the number of colposcopies performed to detect a single case of CIN3/AIS increased in the cohort with repeat screening. Repeated cotesting at a 3-year interval eventually lowers population rates of precancer and cancer. However, a greater number of colposcopies are required to detect a single precancer. Cancer 2016;122:3682-6. © 2016 American Cancer Society. © 2016 American Cancer Society.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

PubMed

Palanca-Wessels, Maria Corinna A; Czuczman, Myron; Salles, Gilles; Assouline, Sarit; Sehn, Laurie H; Flinn, Ian; Patel, Manish R; Sangha, Randeep; Hagenbeek, Anton; Advani, Ranjana; Tilly, Herve; Casasnovas, Olivier; Press, Oliver W; Yalamanchili, Sreeni; Kahn, Robert; Dere, Randall C; Lu, Dan; Jones, Surai; Jones, Cheryl; Chu, Yu-Waye; Morschhauser, Franck

2015-06-01

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. All rights reserved.

First direct comparison of clinical outcomes between European and Asian cohorts in transcatheter aortic valve implantation: the Massy study group vs. the PREVAIL JAPAN trial.

PubMed

Watanabe, Yusuke; Hayashida, Kentaro; Takayama, Morimasa; Mitsudo, Kazuaki; Nanto, Shinsuke; Takanashi, Shuichiro; Komiya, Tatsuhiko; Kuratani, Toru; Tobaru, Tetsuya; Goto, Tsuyoshi; Lefèvre, Thierry; Sawa, Yoshiki; Morice, Marie-Claude

2015-02-01

The efficacy and safety of transcatheter aortic valve implantation (TAVI) in Asian populations were unknown. The purpose of this study was to compare directly the clinical outcomes of the first Japanese trial and a European single-center experience after TAVI. Between April 2010 and October 2011, 64 patients were included in the PREVAIL JAPAN multicenter trial which was set up to evaluate the safety and efficacy of the Edwards SAPIEN XT™ (Edwards Lifesciences, Irvine, CA, USA) in high-risk Japanese patients with severe aortic stenosis. Between March 2010 and January 2012, 237 consecutive patients treated with TAVI using the Edwards SAPIEN XT™ prosthesis at Institut Cardiovasculaire Paris Sud were prospectively included in the Massy cohort. We compared the clinical outcomes of these two cohorts. Patients were of similar age (83.4±6.6 years vs. 84.5±6.1 years, p=0.25), but logistic EuroSCORE was higher in the Massy cohort (20.2±11.7% vs. 15.6±8.0%, p<0.01). Body surface area was smaller in the PREVAIL JAPAN cohort (1.41±0.14m(2) vs. 1.72±0.18m(2); p<0.01) as was the annulus diameter (20.4±1.46mm vs. 22.0±1.84mm, p<0.01). The transfemoral approach was used in 57.8% in the Japanese cohort vs. 51.5% in the Massy cohort. Device success was similar (89.1% vs. 94.1%, p=0.21, respectively), as well as 30-day and 6-month survival rates (92.2% vs. 90.7% and 89.1% vs. 83.1%, p=0.71 and p=0.25, respectively). The incidence of major vascular complications was not significantly different between the two groups (9.4% vs. 5.9%, p=0.23, respectively). A higher post-procedural mean pressure gradient was observed in the PREVAIL JAPAN cohort (12.7±11.4mmHg vs. 10.1±3.6mmHg, p=0.01), but satisfactory improvement in 6-month functional status was obtained in both cohorts (76.5% vs. 77.2%, p=0.91). Clinical outcomes after TAVI in the patients included in the PREVAIL JAPAN trial were acceptable and as safe as that of a single-center European cohort. Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Creation of a pediatric mature B-cell non-Hodgkin lymphoma cohort within the Pediatric Health Information System Database.

PubMed

Citrin, Rebecca; Horowitz, Joseph P; Reilly, Anne F; Li, Yimei; Huang, Yuan-Shung; Getz, Kelly D; Seif, Alix E; Fisher, Brian T; Aplenc, Richard

2017-01-01

Mature B-cell non-Hodgkin lymphoma (B-NHL) constitutes a collection of relatively rare pediatric malignancies. In order to utilize administrative data to perform large-scale epidemiologic studies within this population, a two-step process was used to assemble a 12-year cohort of B-NHL patients treated between 2004 and 2015 within the Pediatric Health Information System database. Patients were identified by ICD-9 codes, and their chemotherapy data were then manually reviewed against standard B-NHL treatment regimens. A total of 1,409 patients were eligible for cohort inclusion. This process was validated at a single center, utilizing both an institutional tumor registry and medical record review as the gold standards. The validation demonstrated appropriate sensitivity (91.5%) and positive predictive value (95.1%) to allow for the future use of this cohort for epidemiologic and comparative effectiveness research.

Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial.

PubMed

Heier, Jeffrey S; Kherani, Saleema; Desai, Shilpa; Dugel, Pravin; Kaushal, Shalesh; Cheng, Seng H; Delacono, Cheryl; Purvis, Annie; Richards, Susan; Le-Halpere, Annaig; Connelly, John; Wadsworth, Samuel C; Varona, Rafael; Buggage, Ronald; Scaria, Abraham; Campochiaro, Peter A

2017-07-01

Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration. This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2 × 10 8 vector genomes (vg); cohort 2, 2 × 10 9 vg; cohort 3, 6 × 10 9 vg; and cohort 4, 2 × 10 10 vg, n=3 per cohort) and one maximum tolerated dose cohort (cohort 5, 2 × 10 10 vg, n=7) and followed up for 52 weeks. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, number NCT01024998. 19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-week trial period. Two patients in cohort 4 (2 × 10 10 vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2 × 10 10 vg had aqueous humour concentrations of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to a mean of 53·2 ng/mL at week 52 (SD 17·1). At baseline, four of these five patients were negative for anti-AAV2 serum antibodies and the fifth had a very low titre (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titres of 1:400 or greater. In 11 of 19 patients with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid reduction and improvement in vision, whereas five showed no fluid reduction. One patient in cohort 5 showed a large decrease in vision between weeks 26 and 52 that was not thought to be vector-related. Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Additional studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies. Sanofi Genzyme, Framingham, MA, USA. Copyright © 2017 Elsevier Ltd. All rights reserved.

Predicting the Necessity for Extracorporeal Circulation During Lung Transplantation: A Feasibility Study.

PubMed

Hinske, Ludwig Christian; Hoechter, Dominik Johannes; Schröeer, Eva; Kneidinger, Nikolaus; Schramm, René; Preissler, Gerhard; Tomasi, Roland; Sisic, Alma; Frey, Lorenz; von Dossow, Vera; Scheiermann, Patrick

2017-06-01

The factors leading to the implementation of unplanned extracorporeal circulation during lung transplantation are poorly defined. Consequently, the authors aimed to identify patients at risk for unplanned extracorporeal circulation during lung transplantation. Retrospective data analysis. Single-center university hospital. A development data set of 170 consecutive patients and an independent validation cohort of 52 patients undergoing lung transplantation. The authors investigated a cohort of 170 consecutive patients undergoing single or sequential bilateral lung transplantation without a priori indication for extracorporeal circulation and evaluated the predictive capability of distinct preoperative and intraoperative variables by using automated model building techniques at three clinically relevant time points (preoperatively, after endotracheal intubation, and after establishing single-lung ventilation). Preoperative mean pulmonary arterial pressure was the strongest predictor for unplanned extracorporeal circulation. A logistic regression model based on preoperative mean pulmonary arterial pressure and lung allocation score achieved an area under the receiver operating characteristic curve of 0.85. Consequently, the authors developed a novel 3-point scoring system based on preoperative mean pulmonary arterial pressure and lung allocation score, which identified patients at risk for unplanned extracorporeal circulation and validated this score in an independent cohort of 52 patients undergoing lung transplantation. The authors showed that patients at risk for unplanned extracorporeal circulation during lung transplantation could be identified by their novel 3-point score. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy of Negative Pressure Wound Treatment in Preventing Surgical Site Infections after Whipple Procedures.

PubMed

Gupta, Ryan; Darby, Geoffrey C; Imagawa, David K

2017-10-01

Surgical site infections (SSIs) occur at an average rate of 21.1 per cent after Whipple procedures per NSQIP data. In the setting of adherence to standard National Surgery Quality Improvement Program (NSQIP) Hepatopancreatobiliary recommendations including wound protector use and glove change before closing, this study seeks to evaluate the efficacy of using negative pressure wound treatment (NPWT) over closed incision sites after a Whipple procedure to prevent SSI formation. We retrospectively examined consecutive patients from January 2014 to July 2016 who met criteria of completing Whipple procedures with full primary incision closure performed by a single surgeon at a single institution. Sixty-one patients were included in the study between two cohorts: traditional dressing (TD) (n = 36) and NPWT dressing (n = 25). There was a statistically significant difference (P = 0.01) in SSI formation between the TD cohort (n = 15, SSI rate = 0.41) and the NPWT cohort (n = 3, SSI rate = 0.12). The adjusted odds ratio (OR) of SSI formation was significant for NPWT use [OR = 0.15, P = 0.036] and for hospital length of stay [OR = 1.21, P = 0.024]. Operative length, operative blood loss, units of perioperative blood transfusion, intraoperative gastrojejunal tube placement, preoperative stent placement, and postoperative antibiotic duration did not significantly impact SSI formation (P > 0.05).

Pteridine levels and head weights are correlated with age and colony task in the honey bee, Apis mellifera

PubMed Central

Rinkevich, Frank D.; Margotta, Joseph W.; Pittman, Jean M.; Ottea, James A.

2016-01-01

Background. The age of an insect strongly influences many aspects of behavior and reproduction. The interaction of age and behavior is epitomized in the temporal polyethism of honey bees in which young adult bees perform nurse and maintenance duties within the colony, while older bees forage for nectar and pollen. Task transition is dynamic and driven by colony needs. However, an abundance of precocious foragers or overage nurses may have detrimental effects on the colony. Additionally, honey bee age affects insecticide sensitivity. Therefore, determining the age of a set of individual honey bees would be an important measurement of colony health. Pteridines are purine-based pigment molecules found in many insect body parts. Pteridine levels correlate well with age, and wild caught insects may be accurately aged by measuring pteridine levels. The relationship between pteridines and age varies with a number of internal and external factors among many species. Thus far, no studies have investigated the relationship of pteridines with age in honey bees. Methods. We established single-cohort colonies to obtain age-matched nurse and forager bees. Bees of known ages were also sampled from colonies with normal demographics. Nurses and foragers were collected every 3–5 days for up to 42 days. Heads were removed and weighed before pteridines were purified and analyzed using previously established fluorometric methods. Results. Our analysis showed that pteridine levels significantly increased with age in a linear manner in both single cohort colonies and colonies with normal demography. Pteridine levels were higher in foragers than nurses of the same age in bees from single cohort colonies. Head weight significantly increased with age until approximately 28-days of age and then declined for both nurse and forager bees in single cohort colonies. A similar pattern of head weight in bees from colonies with normal demography was observed but head weight was highest in 8-day old nurse bees and there was no relationship of head weight with age of foragers. Discussion. Although the relationship between pteridine levels and age was significant, variation in the data yielded a +4-day range in age estimation. This allows an unambiguous method to determine whether a bee may be a young nurse or old forager in colonies with altered demographics as in the case of single cohort colonies. Pteridine levels in bees do not correlate with age as well as in other insects. However, most studies used insects reared under tightly controlled laboratory conditions, while we used free-living bees. The dynamics of head weight change with age is likely to be due to growth and atrophy of the hypopharyngeal glands. Taken together, these methods represent a useful tool for assessing the age of an insect. Future studies utilizing these methods will provide a more holistic view of colony health. PMID:27413635

The Effect of Foreign Language Study in Tennessee Middle Schools on Mathematics Achievement

ERIC Educational Resources Information Center

Tobias, Keith S.

2012-01-01

This quantitative method, quasi-experimental design study examined the possible effect of foreign language study in Tennessee middle schools on mathematics achievement. The population was 1,708 historical student test scores of a single cohort spanning 6th through 8th Grades from the same schools within a large urban public school district. NCLB…

Variation in Definition of Prolonged Mechanical Ventilation.

PubMed

Rose, Louise; McGinlay, Michael; Amin, Reshma; Burns, Karen Ea; Connolly, Bronwen; Hart, Nicholas; Jouvet, Philippe; Katz, Sherri; Leasa, David; Mawdsley, Cathy; McAuley, Danny F; Schultz, Marcus J; Blackwood, Bronagh

2017-10-01

Consistency of definitional criteria for terminology applied to describe subject cohorts receiving mechanical ventilation within ICU and post-acute care settings is important for understanding prevalence, risk stratification, effectiveness of interventions, and projections for resource allocation. Our objective was to quantify the application and definition of terms for prolonged mechanical ventilation. We conducted a scoping review of studies (all designs except single-case study) reporting a study population (adult and pediatric) using the term prolonged mechanical ventilation or a synonym. We screened 5,331 references, reviewed 539 full-text references, and excluded 120. Of the 419 studies (representing 38 countries) meeting inclusion criteria, 297 (71%) reported data on a heterogeneous subject cohort, and 66 (16%) included surgical subjects only (46 of those 66, 70% cardiac surgery). Other studies described COPD (16, 4%), trauma (22, 5%), neuromuscular (17, 4%), and sepsis (1, 0.2%) cohorts. A total of 741 terms were used to refer to the 419 study cohorts. The most common terms were: prolonged mechanical ventilation (253, 60%), admission to specialized unit (107, 26%), and long-term mechanical ventilation (79, 19%). Some authors (282, 67%) defined their cohorts based on duration of mechanical ventilation, with 154 studies (55%) using this as the sole criterion. We identified 37 different durations of ventilation ranging from 5 h to 1 y, with > 21 d being the most common (28 of 282, 7%). For studies describing a surgical cohort, minimum ventilation duration required for inclusion was ≥ 24 h for 20 of 66 studies (30%). More than half of all studies (237, 57%) did not provide a reason/rationale for definitional criteria used, with only 28 studies (7%) referring to a consensus definition. We conclude that substantial variation exists in the terminology and definitional criteria for cohorts of subjects receiving prolonged mechanical ventilation. Standardization of terminology and definitional criteria is required for study data to be maximally informative. Copyright © 2017 by Daedalus Enterprises.

Peer Attitudes Towards Adolescent Participants in Male- and Female-Oriented Sports

ERIC Educational Resources Information Center

Alley, Thomas R.; Hicks, Catherine M.

2005-01-01

This study examined gender stereotypes in peer ratings of femininity and masculinity for adolescent participants in three sports. Following a preliminary study of gender stereotyping of several sports, high school students rated unfamiliar cohorts each of whom was described in a single paragraph as either a male or female dedicated participant in…

Risk Factors for Rural Residential Fires

ERIC Educational Resources Information Center

Allareddy, Veerasathpurush; Peek-Asa, Corinne; Yang, Jingzhen; Zwerling, Craig

2007-01-01

Context and Purpose: Rural households report high fire-related mortality and injury rates, but few studies have examined the risk factors for fires. This study aims to identify occupant and household characteristics that are associated with residential fires in a rural cohort. Methods: Of 1,005 households contacted in a single rural county, 691…

Single drug biomarker prediction for ER- breast cancer outcome from chemotherapy.

PubMed

Chen, Yong-Zi; Kim, Youngchul; Soliman, Hatem H; Ying, GuoGuang; Lee, Jae K

2018-06-01

ER-negative breast cancer includes most aggressive subtypes of breast cancer such as triple negative (TN) breast cancer. Excluded from hormonal and targeted therapies effectively used for other subtypes of breast cancer, standard chemotherapy is one of the primary treatment options for these patients. However, as ER- patients have shown highly heterogeneous responses to different chemotherapies, it has been difficult to select most beneficial chemotherapy treatments for them. In this study, we have simultaneously developed single drug biomarker models for four standard chemotherapy agents: paclitaxel (T), 5-fluorouracil (F), doxorubicin (A) and cyclophosphamide (C) to predict responses and survival of ER- breast cancer patients treated with combination chemotherapies. We then flexibly combined these individual drug biomarkers for predicting patient outcomes of two independent cohorts of ER- breast cancer patients who were treated with different drug combinations of neoadjuvant chemotherapy. These individual and combined drug biomarker models significantly predicted chemotherapy response for 197 ER- patients in the Hatzis cohort (AUC = 0.637, P  = 0.002) and 69 ER- patients in the Hess cohort (AUC = 0.635, P  = 0.056). The prediction was also significant for the TN subgroup of both cohorts (AUC = 0.60, 0.72, P  = 0.043, 0.009). In survival analysis, our predicted responder patients showed significantly improved survival with a >17 months longer median PFS than the predicted non-responder patients for both ER- and TN subgroups (log-rank test P -value = 0.018 and 0.044). This flexible prediction capability based on single drug biomarkers may allow us to even select new drug combinations most beneficial to individual patients with ER- breast cancer. © 2018 The authors.

Validation and Refinement of Chronic Lung Allograft Dysfunction Phenotypes in Bilateral and Single Lung Recipients

PubMed Central

Todd, Jamie L.; Zhang, Alice; Li, Ning; Mayalall, Aradhna; Finlen Copeland, C. Ashley; Shino, Michael; Pavlisko, Elizabeth N.; Wallace, W. Dean; Gregson, Aric; Ross, David J.; Saggar, Rajan; Lynch, Joseph P.; Belperio, John; Snyder, Laurie D.; Palmer, Scott M.

2016-01-01

Rationale: The clinical course of chronic lung allograft dysfunction (CLAD) is heterogeneous. Forced vital capacity (FVC) loss at onset, which may suggest a restrictive phenotype, was associated with worse survival for bilateral lung transplant recipients in one previously published single-center study. Objectives: We sought to replicate the significance of FVC loss in an independent, retrospectively identified cohort of bilateral lung transplant recipients and to investigate extended application of this approach to single lung recipients. Methods: FVC loss and other potential predictors of survival after the onset of CLAD were assessed using Kaplan-Meier and Cox proportional hazards models. Measurements and Main Results: FVC loss at the onset of CLAD was associated with higher mortality in an independent cohort of bilateral lung transplant recipients (hazard ratio [HR], 2.75; 95% confidence interval [CI], 2.02–3.73; P < 0.0001) and in a multicenter cohort of single lung recipients (HR, 1.80; 95% CI, 1.09–2.98; P = 0.02). Including all subjects, the deleterious impact of FVC loss on survival persisted after adjustment for other relevant clinical variables (HR, 2.36; 95% CI, 1.77–3.15; P < 0.0001). In patients who develop CLAD without FVC loss, chest computed tomography features suggestive of pleural or parenchymal fibrosis also predicted worse survival in both bilateral (HR, 2.01; 95% CI, 1.16–5.20; P = 0.02) and single recipients (HR, 2.47; 95% CI, 1.24–10.57; P = 0.02). Conclusions: We independently validated the prognostic significance of FVC loss for bilateral lung recipients and demonstrated that this approach to CLAD classification also confers prognostic information for single lung transplant recipients. Improved understanding of these discrete phenotypes is critical to the development of effective therapies. PMID:27144793

The Minimum Data Set 3.0 Cognitive Function Scale.

PubMed

Thomas, Kali S; Dosa, David; Wysocki, Andrea; Mor, Vincent

2017-09-01

The Minimum Data Set (MDS) 3.0 introduced the Brief Interview for Mental Status (BIMS), a short performance-based cognitive screener for nursing home (NH) residents. Not all residents are able to complete the BIMS and are consequently assessed by staff. We designed a Cognitive Function Scale (CFS) integrating self-report and staff-report data and present evidence of the scale's construct validity. A retrospective cohort study. The subjects consisted of 3 cohorts: (1) long-stay NH residents (N=941,077) and (2) new admissions (N=2,066,580) during 2011-2012, and (3) residents with the older MDS 2.0 assessment in 2010 and the newer MDS 3.0 assessment (n=688,511). MDS 3.0 items were used to create a single, integrated 4-category hierarchical CFS that was compared with residents' prior MDS 2.0 Cognitive Performance Scale scores and other concurrent MDS 3.0 measures of construct validity. The new CFS suggests that 28% of the long-stay cohort in 2011-2012 were cognitively intact, 22% were mildly impaired, 33% were moderately impaired, and 17% were severely impaired. For the admission cohort, the CFS noted 56% as cognitively intact, 23% as mildly impaired, 17% as moderately impaired, and 4% as severely impaired. The CFS corresponded closely with residents' prior MDS 2.0 Cognitive Performance Scale scores and with performance of Activities of Daily Living, and nurses' judgments of function and behavior in both the admission and long-stay cohorts. The new CFS is valuable to researchers as it provides a single, integrated measure of NH residents' cognitive function, regardless of the mode of assessment.

Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma

PubMed Central

Wong, E T; Lok, E; Gautam, S; Swanson, K D

2015-01-01

Background: Patients with recurrent glioblastoma have a poor outcome. Data from the phase III registration trial comparing tumour-treating alternating electric fields (TTFields) vs chemotherapy provided a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy. Methods: Using an unsupervised binary partitioning algorithm, we segregated both cohorts of the trial based on the dexamethasone dose that yielded the greatest statistical difference in overall survival (OS). The results were validated in a separate cohort treated in a single institution with TTFields and their T lymphocytes were correlated with OS. Results: Patients who used dexamethasone doses >4.1 mg per day had a significant reduction in OS when compared with those who used ⩽4.1 mg per day, 4.8 vs 11.0 months respectively (χ2=34.6, P<0.0001) in the TTField-treated cohort and 6.0 vs 8.9 months respectively (χ2=10.0, P<0.0015) in the chemotherapy-treated cohort. In a single institution validation cohort treated with TTFields, the median OS of patients who used dexamethasone >4.1 mg per day was 3.2 months compared with those who used ⩽4.1 mg per day was 8.7 months (χ2=11.1, P=0.0009). There was a significant correlation between OS and T-lymphocyte counts. Conclusions: Dexamethasone exerted profound effects on both TTFields and chemotherapy efficacy resulting in lower patient OS. Therefore, global immunosuppression by dexamethasone likely interferes with immune functions that are necessary for the treatment of glioblastoma. PMID:26125449

Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.

PubMed

Smith, Nicholas L; Felix, Janine F; Morrison, Alanna C; Demissie, Serkalem; Glazer, Nicole L; Loehr, Laura R; Cupples, L Adrienne; Dehghan, Abbas; Lumley, Thomas; Rosamond, Wayne D; Lieb, Wolfgang; Rivadeneira, Fernando; Bis, Joshua C; Folsom, Aaron R; Benjamin, Emelia; Aulchenko, Yurii S; Haritunians, Talin; Couper, David; Murabito, Joanne; Wang, Ying A; Stricker, Bruno H; Gottdiener, John S; Chang, Patricia P; Wang, Thomas J; Rice, Kenneth M; Hofman, Albert; Heckbert, Susan R; Fox, Ervin R; O'Donnell, Christopher J; Uitterlinden, Andre G; Rotter, Jerome I; Willerson, James T; Levy, Daniel; van Duijn, Cornelia M; Psaty, Bruce M; Witteman, Jacqueline C M; Boerwinkle, Eric; Vasan, Ramachandran S

2010-06-01

Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3. We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination.

PubMed

Holler, Ernst; Rogler, Gerhard; Brenmoehl, Julia; Hahn, Joachim; Herfarth, Hans; Greinix, Hildegard; Dickinson, Anne M; Socié, Gerard; Wolff, Daniel; Fischer, Gottfried; Jackson, Graham; Rocha, Vanderson; Steiner, Beate; Eissner, Guenther; Marienhagen, Jeorg; Schoelmerich, Juergen; Andreesen, Reinhard

2006-05-15

To assess the role of NOD2/CARD15 variants on the long-term outcome of allogeneic stem cell transplantation in a genetically homogeneous group, we extended our previous study (cohort I, n = 78) and typed DNA for NOD2/CARD15 single nucleotide polymorphisms (SNPs) from an additional 225 recipients and their HLA-identical sibling donors (cohort II) treated at four other European centers. Results of genotyping were compared with clinical outcome. The strong association of NOD2/CARD15 variants with transplantation-related mortality (TRM) was confirmed in univariate and multivariate analysis; TRM increased from 20% in cohort I/22% in cohort II in recipient/donor pairs without any NOD2/CARD15 variants to 47% in cohort I/32% in cohort II in the presence of one variant in either donor or recipient and further to 57% in cohort I/74% in cohort II in the presence of 2 or more variants (P < .002 in both cohorts). NOD2/CARD15 SNPs were not associated with relapse rate but had a strong impact on overall survival. In an analysis of center effects, the type of gastrointestinal decontamination was the only factor interfering with the prognostic significance of NOD2/CARD15 SNPs. Our data further support an interaction between gastrointestinal defense mechanisms, activation of the innate immune system, and specific transplant-related complications.

Prediction of Waitlist Mortality in Adult Heart Transplant Candidates: The Candidate Risk Score.

PubMed

Jasseron, Carine; Legeai, Camille; Jacquelinet, Christian; Leprince, Pascal; Cantrelle, Christelle; Audry, Benoît; Porcher, Raphael; Bastien, Olivier; Dorent, Richard

2017-09-01

The cardiac allocation system in France is currently based on urgency and geography. Medical urgency is defined by therapies without considering objective patient mortality risk factors. This study aimed to develop a waitlist mortality risk score from commonly available candidate variables. The study included all patients, aged 16 years or older, registered on the national registry CRISTAL for first single-organ heart transplantation between January 2010 and December 2014. This population was randomly divided in a 2:1 ratio into derivation and validation cohorts. The association of variables at listing with 1-year waitlist death or delisting for worsening medical condition was assessed within the derivation cohort. The predictors were used to generate a candidate risk score (CRS). Validation of the CRS was performed in the validation cohort. Concordance probability estimation (CPE) was used to evaluate the discriminative capacity of the models. During the study period, 2333 patients were newly listed. The derivation (n =1 555) and the validation cohorts (n = 778) were similar. Short-term mechanical circulatory support, natriuretic peptide decile, glomerular filtration rate, and total bilirubin level were included in a simplified model and incorporated into the score. The Concordance probability estimation of the CRS was 0.73 in the derivation cohort and 0.71 in the validation cohort. The correlation between observed and expected 1-year waitlist mortality in the validation cohort was 0.87. The candidate risk score provides an accurate objective prediction of waitlist mortality. It is currently being used to develop a modified cardiac allocation system in France.

Lack of Association Between Maternal or Neonatal Vitamin D Status and Risk of Childhood Type 1 Diabetes: A Scandinavian Case-Cohort Study.

PubMed

Thorsen, Steffen U; Mårild, Karl; Olsen, Sjurdur F; Holst, Klaus K; Tapia, German; Granström, Charlotta; Halldorsson, Thorhallur I; Cohen, Arieh S; Haugen, Margaretha; Lundqvist, Marika; Skrivarhaug, Torild; Njølstad, Pål R; Joner, Geir; Magnus, Per; Størdal, Ketil; Svensson, Jannet; Stene, Lars C

2018-06-01

Studies on vitamin D status during pregnancy and risk of type 1 diabetes mellitus (T1D) lack consistency and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration, based on serial samples from the first trimester until delivery and on umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10-nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single-Ascending-Dose Study in Patients With Mild to Moderate Alzheimer Disease.

PubMed

Lu, Ming; Brashear, H Robert

2018-06-19

This study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending subcutaneous doses of bapineuzumab in patients with mild to moderate Alzheimer disease. Forty patients were randomized across 5 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 80 mg; 8 patients each [bapineuzumab 6; placebo 2]). The incidence of treatment-emergent adverse events (TEAEs) was higher in pooled bapineuzumab cohorts (83%) than in the pooled placebo group (27.7%). Most common TEAEs in the bapineuzumab group were gastrointestinal disorders and musculoskeletal and connective tissue disorders (bapineuzumab 17% each; placebo 0%). Serious TEAEs were observed in 7% of bapineuzumab-treated patients without any deaths or adverse event-related discontinuation. The median times to reach peak measurable concentration (C max ) of bapineuzumab were 14 days for 5-, 10-, and 20-mg cohorts, 11 days for 40-mg, and 7 days for 80-mg cohorts. The apparent volume of distribution of bapineuzumab was 134.29 to 204.68 mL/kg. The total body clearance was consistent at 10 to 80 mg. The average terminal half-life ranged from 26 to 46 days (5- to 80-mg groups). Exposure to bapineuzumab increased dose-proportionally from 10 to 80 mg. There was a positive correlation between C max and area under the concentration-time curve to the last measurable concentration (AUC last ) of plasma amyloid-β, and between the C max and AUC last of serum bapineuzumab. © 2018, The American College of Clinical Pharmacology.

Genome-wide association study of suicide attempts in mood disorder patients.

PubMed

Perlis, Roy H; Huang, Jie; Purcell, Shaun; Fava, Maurizio; Rush, A John; Sullivan, Patrick F; Hamilton, Steven P; McMahon, Francis J; Schulze, Thomas G; Schulze, Thomas; Potash, James B; Zandi, Peter P; Willour, Virginia L; Penninx, Brenda W; Boomsma, Dorret I; Vogelzangs, Nicole; Middeldorp, Christel M; Rietschel, Marcella; Nöthen, Markus; Cichon, Sven; Gurling, Hugh; Bass, Nick; McQuillin, Andrew; Hamshere, Marian; Craddock, Nick; Sklar, Pamela; Smoller, Jordan W

2010-12-01

Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.

Genome-Wide Association Study of Suicide Attempts in Mood Disorder Patients

PubMed Central

Perlis, Roy H.; Huang, Jie; Purcell, Shaun; Fava, Maurizio; Rush, A. John; Sullivan, Patrick F.; Hamilton, Steven P.; McMahon, Francis J.; Schulze, Thomas; Potash, James B.; Zandi, Peter P.; Willour, Virginia L.; Penninx, Brenda W.; Boomsma, Dorret I.; Vogelzangs, Nicole; Middeldorp, Christel M.; Rietschel, Marcella; Nöthen, Markus; Cichon, Sven; Gurling, Hugh; Bass, Nick; McQuillin, Andrew; Hamshere, Marian; Craddock, Nick; Sklar, Pamela; Smoller, Jordan W.

2013-01-01

Objective Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. PMID:21041247

Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers.

PubMed

Chandorkar, Gurudatt; Zhan, Qiao; Donovan, Julie; Rege, Shruta; Patino, Hernando

2017-03-28

Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models. Safety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies. Participants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [C max ]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6-12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (C max : 25.5, 37.6, and 93.5 ng/mL) than on day 1 (C max : 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 μg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate. Both SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea. NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016.

Evaluation of community-acquired sepsis by PIRO system in the emergency department.

PubMed

Chen, Yun-Xia; Li, Chun-Sheng

2013-09-01

The predisposition, infection/insult, response, and organ dysfunction (PIRO) staging system for septic patients allows grouping of heterogeneous patients into homogeneous subgroups. The purposes of this single-center, prospective, observational cohort study were to create a PIRO system for patients with community-acquired sepsis (CAS) presenting to the emergency department (ED) and assess its prognostic and stratification capabilities. Septic patients were enrolled and allocated to derivation (n = 831) or validation (n = 860) cohorts according to their enrollment dates. The derivation cohort was used to identify independent predictors of mortality and create a PIRO system by binary logistic regression analysis, and the prognostic performance of PIRO was investigated in the validation cohort by receiver operator characteristic (ROC) curve. Ten independent predictors of 28-day mortality were identified. The PIRO system combined the components of predisposition (age, chronic obstructive pulmonary disease, hypoalbuminemia), infection (central nervous system infection), response (temperature, procalcitonin), and organ dysfunction (brain natriuretic peptide, troponin I, mean arterial pressure, Glasgow coma scale score). The area under the ROC of PIRO was 0.833 for the derivation cohort and 0.813 for the validation cohort. There was a stepwise increase in 28-day mortality with increasing PIRO score and the differences between the low- (PIRO 0-10), intermediate- (11-20), and high- (>20) risk groups were very significant in both cohorts (p < 0.01). The present study demonstrates that this PIRO system is valuable for prognosis and risk stratification in patients with CAS in the ED.

PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in rheumatoid arthritis patients: a genetic study of six cohorts.

PubMed

Rodriguez-Rodriguez, Luis; Ivorra-Cortes, Jose; Carmona, F David; Martín, Javier; Balsa, Alejandro; van Steenbergen, Hanna W; van der Helm-van Mil, Annette H M; González-Álvaro, Isidoro; Fernandez-Gutiérrez, Benjamín

2015-11-05

Prostaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. The aim of this study was to analyze its role in radiological joint damage in rheumatoid arthritis (RA). Six independent cohorts of patients with RA of European or North American descent were included, comprising 1789 patients with 5083 sets of X-rays. The Hospital Clínico San Carlos Rheumatoid Arthritis, Princesa Early Arthritis Register Longitudinal study, and Hospital Universitario de La Paz early arthritis (Spain) cohorts were used as discovery cohorts, and the Leiden Early Arthritis Clinic (The Netherlands), Wichita (United States), and National Databank for Rheumatic Diseases (United States and Canada) cohorts as replication cohorts. First, the PTGER4 rs6896969 single-nucleotide polymorphism (SNP) was genotyped using TaqMan assays and available Illumina Immunochip data and studied in the discovery and replication cohorts. Second, the PTGER4 gene and adjacent regions were analyzed using Immunochip genotyping data in the discovery cohorts. On the basis of pooled p values, linkage disequilibrium structure of the region, and location in regions with transcriptional properties, SNPs were selected for replication. The results from discovery, replication, and overall cohorts were pooled using inverse-variance-weighted meta-analysis. Influence of the polymorphisms on the overall radiological damage (constant effect) and on damage progression over time (time-varying effect) was analyzed. The rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, although no significant association was observed in the replication cohorts or the overall pooled analysis. Regarding the analysis of the PTGER4 region, 976 variants were analyzed in the discovery cohorts. From the constant and time-varying effect analyses, 12 and 20 SNPs, respectively, were selected for replication. Only the rs76523431 variant showed a significant association with radiographic progression in the time-varying effect pooled analysis of the discovery, replication, and overall cohorts. The overall pooled effect size was 1.10 (95 % confidence interval 1.05-1.14, p = 2.10 × 10(-5)), meaning that radiographic yearly progression was 10 % greater for each copy of the minor allele. The PTGER4 gene is a candidate risk factor for radiological progression in RA.

Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer

PubMed Central

Allevi, G; Strina, C; Andreis, D; Zanoni, V; Bazzola, L; Bonardi, S; Foroni, C; Milani, M; Cappelletti, M R; Gussago, F; Aguggini, S; Giardini, R; Martinotti, M; Fox, S B; Harris, A L; Bottini, A; Berruti, A; Generali, D

2013-01-01

Background: The objective of this study was to determine the optimal scheduling of 2.5 mg daily letrozole in neoadjuvant breast cancer patients to obtain pathological complete response (pathCR) and assess Ki-67 expression as an early predictor of response. Patients and methods: This single institution study comprised 120 oestrogen receptor (ER)-positive postmenopausal women with primary breast cancer (clinical stage ⩾T2, N0–1), from three sequential cohorts (cohort A of 40, cohort B of 40 and cohort C of 40 patients, respectively) based on different duration of the neoadjuvant letrozole. Biological markers such as ER, progesterone receptor, HER2 and Ki-67 expression were tested at diagnosis and at definitive surgery. Results: A total of 89 patients (75.4%) achieved an objective response with 44 (37.3%) clinical CRs and 45 (38.1%) partial responses. The clinical CRs were significantly observed in cohort C (23 out of 40 patients, 57.5%) and B (16 out of 38 patients, 42.1%) compared with cohort A (5 out of 40 patients, 12.5%) (P-value for trend <0.001). Letrozole induced a similar significant reduction in Ki-67 index after treatment in all cohorts. The pathCR rate was significantly more frequent in cohort C (7 out of 40 patients, 17.5%) than in cohort A (1 out of 40 patients, 2.5%) and B (2 out of 40 patients, 5.0%) (P-value for trend <0.04). Conclusion: One-year neoadjuvant letrozole therapy leads to a higher pathCR rate and may be the optimal length of drug exposure. PMID:23579222

Evolution of deep gray matter volume across the human lifespan.

PubMed

Narvacan, Karl; Treit, Sarah; Camicioli, Richard; Martin, Wayne; Beaulieu, Christian

2017-08-01

Magnetic resonance imaging of subcortical gray matter structures, which mediate behavior, cognition and the pathophysiology of several diseases, is crucial for establishing typical maturation patterns across the human lifespan. This single site study examines T1-weighted MPRAGE images of 3 healthy cohorts: (i) a cross-sectional cohort of 406 subjects aged 5-83 years; (ii) a longitudinal neurodevelopment cohort of 84 subjects scanned twice approximately 4 years apart, aged 5-27 years at first scan; and (iii) a longitudinal aging cohort of 55 subjects scanned twice approximately 3 years apart, aged 46-83 years at first scan. First scans from longitudinal subjects were included in the cross-sectional analysis. Age-dependent changes in thalamus, caudate, putamen, globus pallidus, nucleus accumbens, hippocampus, and amygdala volumes were tested with Poisson, quadratic, and linear models in the cross-sectional cohort, and quadratic and linear models in the longitudinal cohorts. Most deep gray matter structures best fit to Poisson regressions in the cross-sectional cohort and quadratic curves in the young longitudinal cohort, whereas the volume of all structures except the caudate and globus pallidus decreased linearly in the longitudinal aging cohort. Males had larger volumes than females for all subcortical structures, but sex differences in trajectories of change with age were not significant. Within subject analysis showed that 65%-80% of 13-17 year olds underwent a longitudinal decrease in volume between scans (∼4 years apart) for the putamen, globus pallidus, and hippocampus, suggesting unique developmental processes during adolescence. This lifespan study of healthy participants will form a basis for comparison to neurological and psychiatric disorders. Hum Brain Mapp 38:3771-3790, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Adjuvant treatment of resectable biliary tract cancer with cisplatin plus gemcitabine: A prospective single center phase II study.

PubMed

Siebenhüner, Alexander R; Seifert, Heike; Bachmann, Helga; Seifert, Burkhardt; Winder, Thomas; Feilchenfeldt, Jonas; Breitenstein, Stefan; Clavien, Pierre-Alain; Stupp, Roger; Knuth, Alexander; Pestalozzi, Bernhard; Samaras, Panagiotis

2018-01-11

Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC. Patients initially received gemcitabine 1000 mg/m 2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m 2 and cisplatin 25 mg/m 2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed. Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3-100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50-100) for cisplatin and 100% (IQR 75-100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0-33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8-62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts. Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients. The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

Disrupted modular organization of resting-state cortical functional connectivity in U.S. military personnel following concussive ‘mild’ blast-related traumatic brain injury†

PubMed Central

Han, Kihwan; Mac Donald, Christine L.; Johnson, Ann M.; Barnes, Yolanda; Wierzechowski, Linda; Zonies, David; Oh, John; Flaherty, Stephen; Fang, Raymond; Raichle, Marcus E.; Brody, David L.

2013-01-01

Blast-related traumatic brain injury (TBI) has been one of the “signature injuries” of the wars in Iraq and Afghanistan. However, neuroimaging studies in concussive ‘mild’ blast-related TBI have been challenging due to the absence of abnormalities in computed tomography or conventional magnetic resonance imaging (MRI) and the heterogeneity of the blast-related injury mechanisms. The goal of this study was to address these challenges utilizing single-subject, module-based graph theoretic analysis of resting-state functional MRI (fMRI) data. We acquired 20 minutes of resting-state fMRI in 63 U.S. military personnel clinically diagnosed with concussive blast-related TBI and 21 U.S. military controls who had blast exposures but no diagnosis of TBI. All subjects underwent an initial scan within 90 days post-injury and 65 subjects underwent a follow-up scan 6 to 12 months later. A second independent cohort of 40 U.S. military personnel with concussive blast-related TBI patients served as a validation dataset. The second independent cohort underwent an initial scan within 30 days post-injury. 75% of scans were of good quality, with exclusions primarily due to excessive subject motion. Network analysis of the subset of these subjects in the first cohort with good quality scans revealed spatially localized reductions in participation coefficient, a measure of between-module connectivity, in the TBI patients relative to the controls at the time of the initial scan. These group differences were less prominent on the follow-up scans. The 15 brain areas with the most prominent reductions in participation coefficient were next used as regions of interest (ROIs) for single-subject analyses. In the first TBI cohort, more subjects than would be expected by chance (27/47 versus 2/47 expected, p < 0.0001) had 3 or more brain regions with abnormally low between-module connectivity relative to the controls on the initial scans. On the follow-up scans, more subjects than expected by chance (5/37, p = 0.044) but fewer subjects than on the initial scans had 3 or more brain regions with abnormally low between-module connectivity. Analysis of the second TBI cohort validation dataset with no free parameters provided a partial replication; again more subjects than expected by chance (8/31, p = 0.006) had 3 or more brain regions with abnormally low between-module connectivity on the initial scans, but the numbers were not significant (2/27, p = 0.276) on the follow-up scans. A single-subject, multivariate analysis by probabilistic principal component analysis of the between-module connectivity in the 15 identified ROIs, showed that 31/47 subjects in the first TBI cohort were found to be abnormal relative to the controls on the initial scans. In the second TBI cohort, 9/31 patients were found to be abnormal in identical multivariate analysis with no free parameters. Again, there were not substantial differences on the follow-up scans. Taken together, these results indicate that single-subject, module-based graph theoretic analysis of resting-state fMRI provides potentially useful information for concussive blast-related TBI if high quality scans can be obtained. The underlying biological mechanisms and consequences of disrupted between-module connectivity are unknown, thus further studies are required. PMID:23968735

Protective Role of BST2 Polymorphisms in Mother-to-Child Transmission of HIV-1 and Adult AIDS Progression.

PubMed

Kamada, Anselmo J; Bianco, Anna M; Zupin, Luisa; Girardelli, Martina; Matte, Maria C C; Medeiros, Rúbia Marília de; Almeida, Sabrina Esteves de Matos; Rocha, Marineide M; Segat, Ludovica; Chies, José A B; Kuhn, Louise; Crovella, Sergio

2016-07-01

Bone marrow stromal cell antigen-2 (BST-2)/Tetherin is a restriction factor that prevents Human immunodeficiency virus type 1 (HIV-1) release from infected cells and mediates pro-inflammatory cytokine production. This study investigated the risk conferred by single nucleotide polymorphisms (rs919266, rs9192677, and rs9576) at BST-2 coding gene (BST2) in HIV-1 mother-to-child transmission and in disease progression. Initially, 101 HIV-1+ pregnant women and 331 neonates exposed to HIV-1 from Zambia were enrolled. Additional BST2 single nucleotide polymorphism analyses were performed in 2 cohorts with acquired immunodeficiency syndrome (AIDS) progression: an adult Brazilian cohort (37 rapid, 30 chronic and 21 long-term non-progressors) and an Italian pediatric cohort (21 rapid and 67 slow progressors). The rs9576A allele was nominally associated with protection during breastfeeding (P = 0.019) and individuals carrying rs919266 GA showed slower progression to AIDS (P = 0.033). Despite the influence of rs919266 and rs9576 on BST2 expression being still undetermined, a preventive role by BST2 polymorphisms was found during HIV-1 infection.

Educating Chinese Nurses About Rehabilitation Nursing: Findings From a Single Cohort Quantitative Pilot Project.

PubMed

Mauk, Kristen L; Li, Pei Ying; Jin, Huilu; Rogers, Julie; Scalzitti, Kristina

The purpose of this study was to present results of a pilot program to educate nurses in China about rehabilitation nursing. A single cohort, pre- and posttest design with an educational intervention. A 3-day basic rehabilitation nursing education program was conducted in Shanghai and Hangzhou by a certified rehabilitation nurse specialist from the United States. The effect of the educational intervention was measured using pre- and posttests for six topic areas. Data were analyzed using descriptive statistics, correlations, and paired samples t tests. Paired samples t tests showed a significant improvement (p < .01) as a result of the educational intervention on all three tests covering the six basic topics. The knowledge of the nurses on topics of basic rehabilitation nursing significantly increased as a result of the educational program. Rehabilitation nurses interested in international travel and developing professional relationships with nurses in China can provide education to promote our specialty practice overseas.

Examining Part-Time Faculty Utilization and Its Impact on Student Retention at a Public Research University

ERIC Educational Resources Information Center

Johnson, Iryna Y.

2006-01-01

The important concern surrounding growing reliance on part-time faculty is its effect on student retention. Existing studies explored the relationship between part-time faculty utilization and retention of entering cohorts. The study herein assesses retention of the entire population of degree-seeking undergraduates at a single institution. The…

Introducing Engineering in Elementary Education: A 5-Year Study of Teachers and Students

ERIC Educational Resources Information Center

Diefes-Dux, Heidi A.

2015-01-01

Engineering, when integrated into K-12 education, may offer a number of potential student learning and future success benefits. In a 5-year study, four cohorts of elementary teachers of grades 2 to 4 in a single US school district were provided with teacher professional development with engineering education. Teachers were prepared to teach…

Adolescents' School Enrollment and Employment: Effect of State Welfare Policies. JCPR Working Paper.

ERIC Educational Resources Information Center

Hao, Lingxin; Astone, Nan M.; Cherlin, Andrew J.

This study hypothesizes that stringent welfare policies may promote school enrollment and reduce employment among adolescents from low-income, single parent, and welfare families. Using data from the National Longitudinal Survey of Youth, 1997 cohort, combined with state-level data sources, this analysis uses a dynamic model to study school and…

Do Asian women do as well as their Caucasian counterparts in IVF treatment: Cohort study.

PubMed

Kan, Andrew; Leung, Peter; Luo, Kehui; Fay, Louise; Tan, Chunyan Leeann

2015-06-01

To evaluate if there is a difference in pregnancy rate between Asian and Caucasian women when they undergo in vitro fertilization (IVF). This was a retrospective cohort study set in a private reproductive medicine clinic. The study consisted of a total of 2594 patients (Asian, n = 522; Caucasian, n = 2072) undergoing IVF managed by a single doctor over a 10 year period. The main outcome measures were clinical pregnancy rate and live birth rate. Logistic regression was used to control for confounding factors. Asian women achieved a significantly lower clinical pregnancy and live birth rate than their Caucasian counterparts, despite replacement of more embryos. This difference was not significant after controlling for age and duration of infertility. Despite higher doses of gonadotrophin, they achieved fewer oocytes and had resultant fewer embryos for transfer or cryopreservation. In a study designed to reduce the effect of confounding factors by looking at a large number of patients from a single IVF unit under the care of a single doctor, there does not appear to be a difference in IVF pregnancy rate as a result of race. Asian women tend to present for IVF treatment at a later age after having tried for a longer period of time and this contributes significantly to their lower pregnancy rate. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

Increased odds of patient-reported success at 2 years after anterior cruciate ligament reconstruction in patients without cartilage lesions: a cohort study from the Swedish National Knee Ligament Register.

PubMed

Hamrin Senorski, Eric; Alentorn-Geli, Eduard; Musahl, Volker; Fu, Freddie; Krupic, Ferid; Desai, Neel; Westin, Olof; Samuelsson, Kristian

2018-04-01

To investigate whether the surgical technique of single-bundle anterior cruciate ligament (ACL) reconstruction, the visualization of anatomic surgical factors and the presence or absence of concomitant injuries at primary ACL reconstruction are able to predict patient-reported success and failure. The hypothesis of this study was that anatomic single-bundle surgical procedures would be predictive of patient-reported success. This cohort study was based on data from the Swedish National Knee Ligament Register during the period of 1 January 2005 through 31 December 2014. Patients who underwent primary single-bundle ACL reconstruction with hamstring tendons were included. Details on surgical technique were collected using an online questionnaire comprising essential anatomic anterior cruciate ligament reconstruction scoring checklist items, defined as the utilization of accessory medial portal drilling, anatomic tunnel placement, the visualization of insertion sites and pertinent landmarks. A univariate logistic regression model adjusted for age and gender was used to determine predictors of patient-reported success and failure, i.e. 20th and 80th percentile, respectively, in the Knee injury and Osteoarthritis Outcome Score (KOOS), 2 years after ACL reconstruction. In the 6889 included patients, the surgical technique used for single-bundle ACL reconstruction did not predict the predefined patient-reported success or patient-reported failure in the KOOS 4 . Patient-reported success was predicted by the absence of concomitant injury to the meniscus (OR = 0.81 [95% CI, 0.72-0.92], p = 0.001) and articular cartilage (OR = 0.70 [95% CI, 0.61-0.81], p < 0.001). Patient-reported failure was predicted by the presence of a concomitant injury to the articular cartilage (OR = 1.27 [95% CI, 1.11-1.44], p < 0.001). Surgical techniques used in primary single-bundle ACL reconstruction did not predict the KOOS 2 years after the reconstruction. However, the absence of concomitant injuries at index surgery predicted patient-reported success in the KOOS. The results provide further evidence that concomitant injuries at ACL reconstruction affect subjective knee function and a detailed knowledge of the treatment of these concomitant injuries is needed. Retrospective cohort study, Level III.

ESTIMATION OF INTERNAL EXPOSURE TO URANIUM WITH UNCERTAINTY FROM URINALYSIS DATA USING THE InDEP COMPUTER CODE

PubMed Central

Anderson, Jeri L.; Apostoaei, A. Iulian; Thomas, Brian A.

2015-01-01

The National Institute for Occupational Safety and Health (NIOSH) is currently studying mortality in a cohort of 6409 workers at a former uranium processing facility. As part of this study, over 220 000 urine samples were used to reconstruct organ doses due to internal exposure to uranium. Most of the available computational programs designed for analysis of bioassay data handle a single case at a time, and thus require a significant outlay of time and resources for the exposure assessment of a large cohort. NIOSH is currently supporting the development of a computer program, InDEP (Internal Dose Evaluation Program), to facilitate internal radiation exposure assessment as part of epidemiological studies of both uranium- and plutonium-exposed cohorts. A novel feature of InDEP is its batch processing capability which allows for the evaluation of multiple study subjects simultaneously. InDEP analyses bioassay data and derives intakes and organ doses with uncertainty estimates using least-squares regression techniques or using the Bayes’ Theorem as applied to internal dosimetry (Bayesian method). This paper describes the application of the current version of InDEP to formulate assumptions about the characteristics of exposure at the study facility that were used in a detailed retrospective intake and organ dose assessment of the cohort. PMID:22683620

Genetic associations with childhood brain growth, defined in two longitudinal cohorts.

PubMed

Szekely, Eszter; Schwantes-An, Tae-Hwi Linus; Justice, Cristina M; Sabourin, Jeremy A; Jansen, Philip R; Muetzel, Ryan L; Sharp, Wendy; Tiemeier, Henning; Sung, Heejong; White, Tonya J; Wilson, Alexander F; Shaw, Philip

2018-06-01

Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10 -9 ), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

An Automatic Approach for Analyzing Treatment Effectiveness Based on Medication Hierarchy - The Myocardial Infarction Case Study.

PubMed

Li, Yingxue; Hu, Yiying; Yang, Jingang; Li, Xiang; Liu, Haifeng; Xie, Guotong; Xu, Meilin; Hu, Jingyi; Yang, Yuejin

2017-01-01

Treatment effectiveness plays a fundamental role in patient therapies. In most observational studies, researchers often design an analysis pipeline for a specific treatment based on the study cohort. To evaluate other treatments in the data set, much repeated and multifarious work including cohort construction, statistical analysis need to be done. In addition, as treatments are often with an intrinsic hierarchical relationship, many rational comparable treatment pairs can be derived as new treatment variables besides the original single treatment one from the original cohort data set. In this paper, we propose an automatic treatment effectiveness analysis approach to solve this problem. With our approach, clinicians can assess the effect of treatments not only more conveniently but also more thoroughly and comprehensively. We applied this method to a real world case of estimating the drug effectiveness on Chinese Acute Myocardial Infarction (CAMI) data set and some meaningful results are obtained for potential improvement of patient treatments.

Efficacy and immunogenicity of single-dose AdVAV intranasal anthrax vaccine compared to anthrax vaccine absorbed in an aerosolized spore rabbit challenge model.

PubMed

Krishnan, Vyjayanthi; Andersen, Bo H; Shoemaker, Christine; Sivko, Gloria S; Tordoff, Kevin P; Stark, Gregory V; Zhang, Jianfeng; Feng, Tsungwei; Duchars, Matthew; Roberts, M Scot

2015-04-01

AdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 × 10(7), 1.5 × 10(9), or 3.5 × 10(10) viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 × 10(10) viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD50) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.

PubMed

Coyle, T E; Reding, M T; Lin, J C; Michaels, L A; Shah, A; Powell, J

2014-04-01

BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A. This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses. BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed. This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

Time-saving impact of an algorithm to identify potential surgical site infections.

PubMed

Knepper, B C; Young, H; Jenkins, T C; Price, C S

2013-10-01

To develop and validate a partially automated algorithm to identify surgical site infections (SSIs) using commonly available electronic data to reduce manual chart review. Retrospective cohort study of patients undergoing specific surgical procedures over a 4-year period from 2007 through 2010 (algorithm development cohort) or over a 3-month period from January 2011 through March 2011 (algorithm validation cohort). A single academic safety-net hospital in a major metropolitan area. Patients undergoing at least 1 included surgical procedure during the study period. Procedures were identified in the National Healthcare Safety Network; SSIs were identified by manual chart review. Commonly available electronic data, including microbiologic, laboratory, and administrative data, were identified via a clinical data warehouse. Algorithms using combinations of these electronic variables were constructed and assessed for their ability to identify SSIs and reduce chart review. The most efficient algorithm identified in the development cohort combined microbiologic data with postoperative procedure and diagnosis codes. This algorithm resulted in 100% sensitivity and 85% specificity. Time savings from the algorithm was almost 600 person-hours of chart review. The algorithm demonstrated similar sensitivity on application to the validation cohort. A partially automated algorithm to identify potential SSIs was highly sensitive and dramatically reduced the amount of manual chart review required of infection control personnel during SSI surveillance.

Literacy Outcomes for Primary School Children Who Are Deaf and Hard of Hearing: A Cohort Comparison Study.

PubMed

Harris, Margaret; Terlektsi, Emmanouela; Kyle, Fiona E

2017-03-01

In this study, we compared the language and literacy of two cohorts of children with severe-profound hearing loss, recruited 10 years apart, to determine if outcomes had improved in line with the introduction of newborn hearing screening and access to improved hearing aid technology. Forty-two children with deafness, aged 5-7 years with a mean unaided loss of 102 DB, were assessed on language, reading, and phonological skills. Their performance was compared with that of a similar group of 32 children with deafness assessed 10 years earlier and also a group of 40 children with normal hearing of similar single word reading ability. English vocabulary was significantly higher in the new cohort although it was still below chronological age. Phonological awareness and reading ability had not significantly changed over time. In both cohorts, English vocabulary predicted reading, but phonological awareness was only a significant predictor for the new cohort. The current results show that vocabulary knowledge of children with severe-profound hearing loss has improved over time, but there has not been a commensurate improvement in phonological skills or reading. They suggest that children with severe-profound hearing loss will require continued support to develop robust phonological coding skills to underpin reading.

Rapid Rule-Out of Acute Myocardial Injury Using a Single High-Sensitivity Cardiac Troponin I Measurement.

PubMed

Sandoval, Yader; Smith, Stephen W; Shah, Anoop S V; Anand, Atul; Chapman, Andrew R; Love, Sara A; Schulz, Karen; Cao, Jing; Mills, Nicholas L; Apple, Fred S

2017-01-01

Rapid rule-out strategies using high-sensitivity cardiac troponin assays are largely supported by studies performed outside the US in selected cohorts of patients with chest pain that are atypical of US practice, and focused exclusively on ruling out acute myocardial infarction (AMI), rather than acute myocardial injury, which is more common and associated with a poor prognosis. Prospective, observational study of consecutive patients presenting to emergency departments [derivation (n = 1647) and validation (n = 2198) cohorts], where high-sensitivity cardiac troponin I (hs-cTnI) was measured on clinical indication. The negative predictive value (NPV) and diagnostic sensitivity of an hs-cTnI concentration

The largest survivorship and clinical outcomes study of the fixed bearing Stryker Triathlon Partial Knee Replacement - A multi-surgeon, single centre cohort study with a minimum of two years of follow-up.

PubMed

Middleton, S W F; Schranz, P J; Mandalia, V I; Toms, A D

2018-05-03

The surgical management of isolated medial compartment degenerative disease of the knee causes debate. Unicompartmental arthroplasty options include fixed and mobile bearing implant designs with fixed bearing becoming increasingly popular. We present the largest cohort of a fixed bearing single radius design, Stryker Triathlon Partial Knee Replacement (PKR). We prospectively collected demographic data and patient reported outcome measures (PROMs) on our cohort of PKR implants since its adoption in our unit, 2009 until March 2015. A total of 129 implants in 115 patients with a mean follow-up of 5.5 years (2.5 to 8.5 years) were included. There were 11 revisions at an average of 1.7 years (0.6-4.1 years), two for infection, two for mal-alignment, five for progression of disease and two for loosening. The survivorship of the implants at five years is 90%. The PKR provides good survivorship at five years and PROM scores that are equal to the largest and most popular comparable implants. There is an associated learning curve with this implant, as there is with all systems and this is reflected in our results. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Selective serotonin reuptake inhibitors and risk of major congenital anomalies for pregnancies in Japan: A nationwide birth cohort study of the Japan Environment and Children's Study.

PubMed

Nishigori, Hidekazu; Obara, Taku; Nishigori, Toshie; Mizuno, Satoshi; Metoki, Hirohito; Hoshiai, Tetsuro; Watanabe, Zen; Sakurai, Kasumi; Ishikuro, Mami; Tatsuta, Nozomi; Nishijima, Ichiko; Fujiwara, Ikuma; Kuriyama, Shinichi; Arima, Takahiro; Nakai, Kunihiko; Yaegashi, Nobuo

2017-05-01

We analyzed data from the Japan Environment and Children's Study (JECS), on the association between selective serotonin reuptake inhibitors (SSRI) use during pregnancy and the risk of developing of major congenital anomalies in Japan. JECS is an ongoing nationwide birth cohort study. The study includes 95 994 single pregnant women and their offspring. Among them, 172 used any SSRI up to the 12 th gestational week. Crude analyses show a significantly increased incidence of upper limb, abdominal, and urogenital abnormalities. In particular, the incidence of microcephaly, hydrencephalus, esophageal atresia, small intestinal atresia, and achondroplasia was significantly higher with than without exposure to these substances. On multivariate analyses, urogenital abnormality was significant (odds ratio 3.227; 95% confidence interval: 1.460-7.134). This Japanese nationwide birth cohort survey clarified that the use of any SSRI until the 12 th gestational week was associated with urogenital abnormality in children. The survey for association with minor classification abnormality needs further examination in Japan. © 2016 Japanese Teratology Society.

Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts.

PubMed

Marioni, Riccardo E; Deary, Ian J; Murray, Gordon D; Lowe, Gordon D O; Strachan, Mark W J; Luciano, Michelle; Houlihan, Lorna M; Gow, Alan J; Harris, Sarah E; Rumley, Ann; Stewart, Marlene C; Fowkes, F Gerry R; Price, Jackie F

2011-09-01

There is increasing evidence to suggest that elevated plasma levels of fibrinogen are associated with late-life cognitive performance. This study tested the association of single nucleotide polymorphisms in the fibrinogen α (FGA) and β (FGB) genes with cognitive performance. Data were analysed from three community-dwelling populations of older persons (>50 years) in central Scotland: the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial (n = 2,091), the Edinburgh Type 2 Diabetes Study (ET2DS, n = 1,066), and the Lothian Birth Cohort 1936 (LBC1936, n = 1,091). Cognition was assessed using a battery of five, seven, and four psychometric tests, respectively. This information was used to derive a general cognitive factor. Weakly significant associations were found between the rs4220 (FGB), and rs2227412 (FGB) SNPs and a single test of cognitive performance in the AAA Trial (p < 0.05). These findings did not replicate in the LBC1936 or ET2DS cohorts, except for the rs2227412 SNP, which was significantly associated with the general cognitive factor in the ET2DS (p = 3.3 × 10(-4)). A summary term that combined results from all three studies suggested that the rs2227412 genotype associated with reduced cognitive ability also associated with higher plasma fibrinogen levels. These findings suggest a tentative role for fibrinogen as a determinant of late-life cognitive performance and justify further attempts at replication in older persons.

Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.

PubMed

Halbritter, Jan; Porath, Jonathan D; Diaz, Katrina A; Braun, Daniela A; Kohl, Stefan; Chaki, Moumita; Allen, Susan J; Soliman, Neveen A; Hildebrandt, Friedhelm; Otto, Edgar A

2013-08-01

Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes (NPHP1-NPHP13) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7. This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide.

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects.

PubMed

Luo, Rosa; Bozigian, Haig; Jimenez, Roland; Loewen, Gordon; O'Brien, Christopher F

2017-08-01

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 C max and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 C max and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%-30% that of VBZ based on molar ratios. In the first study, the maximum-tolerated dose was not achieved; headache (2 events) was the only treatment-emergent adverse event (TEAE) reported by more than one subject. In the second study, fatigue (4 events) was the only TEAE reported by more than one subject following SD VBZ. Following QD VBZ, the TEAEs of fatigue, insomnia, disturbance in attention, and nervousness were dose-dependent; the latter three TEAEs were considered dose-limiting. Subject withdrawals due to TEAEs were 1 each for PBO and 50 mg VBZ QD, and 3 for 100 mg VBZ QD. Clinically relevant effects on laboratory parameters, vital signs or ECGs were limited to increased CPK (SD: 1 each for 5 mg VBZ and PBO), ALT (QD: 1 each for 50 and 100 mg VBZ and PBO), and triglycerides (QD: 1 each for 50 mg VBZ and PBO). VBZ has an acceptable safety profile and predictable pharmacokinetics that result in stable concentrations of active compounds with low peak-to-trough fluctuation following once-daily dosing.

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects

PubMed Central

Luo, Rosa; Bozigian, Haig; Jimenez, Roland; Loewen, Gordon; O’Brien, Christopher F.

2017-01-01

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 Cmax and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 Cmax and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%–30% that of VBZ based on molar ratios. In the first study, the maximum-tolerated dose was not achieved; headache (2 events) was the only treatment-emergent adverse event (TEAE) reported by more than one subject. In the second study, fatigue (4 events) was the only TEAE reported by more than one subject following SD VBZ. Following QD VBZ, the TEAEs of fatigue, insomnia, disturbance in attention, and nervousness were dose-dependent; the latter three TEAEs were considered dose-limiting. Subject withdrawals due to TEAEs were 1 each for PBO and 50 mg VBZ QD, and 3 for 100 mg VBZ QD. Clinically relevant effects on laboratory parameters, vital signs or ECGs were limited to increased CPK (SD: 1 each for 5 mg VBZ and PBO), ALT (QD: 1 each for 50 and 100 mg VBZ and PBO), and triglycerides (QD: 1 each for 50 mg VBZ and PBO). VBZ has an acceptable safety profile and predictable pharmacokinetics that result in stable concentrations of active compounds with low peak-to-trough fluctuation following once-daily dosing. PMID:28839339

Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study.

PubMed

Parsa, Afshin; Kanetsky, Peter A; Xiao, Rui; Gupta, Jayanta; Mitra, Nandita; Limou, Sophie; Xie, Dawei; Xu, Huichun; Anderson, Amanda Hyre; Ojo, Akinlolu; Kusek, John W; Lora, Claudia M; Hamm, L Lee; He, Jiang; Sandholm, Niina; Jeff, Janina; Raj, Dominic E; Böger, Carsten A; Bottinger, Erwin; Salimi, Shabnam; Parekh, Rulan S; Adler, Sharon G; Langefeld, Carl D; Bowden, Donald W; Groop, Per-Henrik; Forsblom, Carol; Freedman, Barry I; Lipkowitz, Michael; Fox, Caroline S; Winkler, Cheryl A; Feldman, Harold I

2017-03-01

The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of P <1×10 -6 for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in LINC00923 replicated in the African American Study of Kidney Disease and Hypertension cohort (discovery P =5.42×10 -7 ; replication P =0.039; combined P =7.42×10 -9 ). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); P =4.90×10 -6 ). Similarly, rs931891 in LINC00923 associated with eGFR decline ( P =1.44×10 -4 ) in white patients without diabetes. In summary, SNPs in LINC00923 , an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted. Copyright © 2017 by the American Society of Nephrology.

Evaluation of Planned Treatment Breaks During Radiation Therapy for Anal Cancer: Update of RTOG 92-08

DOE Office of Scientific and Technical Information (OSTI.GOV)

Konski, Andre; Garcia, Miguel; John, Madhu

2008-09-01

Purpose: Radiation Therapy Oncology Group (RTOG) 92-08 began as a single arm, Phase II trial for patients with anal cancer consisting of radiation (RT) + 5-flourouracil + mitomycin-C with a mandatory 2-week break and was amended after completion to evaluate the same treatment regimen without a treatment break. Long-term efficacy and late toxicity reporting are the specific aims of this study. Methods and Materials: Survivals were estimated with the Kaplan-Meier method. Overall survival (OS) was compared with RTOG 87-04 with the log-rank test. Time to local failure, regional failure, locoregional failure (LRF), distant metastases, second primary, and colostomy failure weremore » estimated by the cumulative incidence method. LRF was compared with RTOG 87-04 using the Gray's test. Results: Forty-seven patients entered in the mandatory treatment break cohort. The study was reopened in 1995 to the no mandatory treatment break cohort completing accrual with 20 patients in 1996. Of 67 total patients, 1 patient in the mandatory treatment break portion of the study did not receive any protocol treatment and is excluded from analyses. After adjusting for tumor size, neither cohort showed a statistically significant difference in OS or LRF compared with the RTOG 87-04 mitomycin-C arm. No patient in either cohort experienced a Grade 3 or higher late toxicity. Conclusions: No statistically significant differences were seen in OS or LRF when compared to the mitomycin-C arm of RTOG 87-04, but the sample sizes for the mandatory break cohort and the no mandatory break cohort are small. Late toxicity was low and similar for the treatment cohorts.« less

Restless Leg Syndrome in Different Types of Demyelinating Neuropathies: A Single-Center Pilot Study

PubMed Central

Luigetti, Marco; Del Grande, Alessandra; Testani, Elisa; Bisogni, Giulia; Losurdo, Anna; Giannantoni, Nadia Mariagrazia; Mazza, Salvatore; Sabatelli, Mario; Della Marca, Giacomo

2013-01-01

Objective: to determine the prevalence of restless legs syndrome (RLS) in a cohort of patients with demyelinating neuropathies. Methods: Patients were retrospectively recruited from our cohort of different forms of demyelinating neuropathies, including chronic inflammatory demyelinating neuropathy (CIDP), Charcot-Marie-Tooth 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP) referred to our Department of Neurology in a 10-year period. The validated 4-item RLS questionnaire was used for diagnosis of RLS. All patients with RLS who fulfilled criteria underwent a suggested immobilization test to confirm the diagnosis. A group of outpatients referred to the sleep disorders unit and data from published literature were used as controls. Results: Prevalence of RLS in demyelinating neuropathy group was higher than prevalence observed in control population (p = 0.0142) or in the literature data (p = 0.0007). In particular, in comparison with both control population and literature data, prevalence of RLS was higher in CIDP group (p = 0.0266 and p = 0.0063, respectively) and in CMT1A group (p = 0.0312 and p = 0.0105, respectively), but not in HNPP (p = 1.000 and p = 0.9320, respectively). Conclusions: our study confirms a high prevalence of RLS in inflammatory neuropathies as CIDP and, among inherited neuropathies, in CMT1A but not in HNPP. Considering that this is only a small cohort from a single-center retrospective experience, the link between RLS and neuropathy remains uncertain, and larger multicenter studies are probably needed to clarify the real meaning of the association between RLS and neuropathy. Citation: Luigetti M; Del Grande A; Testani E; Bisogni G; Losurdo A; Giannantoni NM; Mazza S; Sabatelli M; Della Marca G. Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study. J Clin Sleep Med 2013;9(9):945-949. PMID:23997707

Navvus FFR to reduce CONTRAst, Cost and radiaTion (CONTRACT); insights from a single-centre clinical and economical evaluation with the RXi Rapid-Exchange FFR device.

PubMed

Masdjedi, Kaneshka; Van Mieghem, Nicolas M; Diletti, Roberto; van Geuns, Robert-Jan; de Jaegere, Peter; Regar, Evelyn; Zijlstra, Felix; van Domburg, Ron T; Daemen, Joost

2017-04-15

To assess whether the RXi Navvus system compared to the use of standard Fractional Flow Reserve (FFR) wires reduces total contrast volume, radiation and overall study cost in a real world patient population referred for coronary angiography or percutaneous coronary intervention. FFR is the mainstay of functional hemodynamic assessment of coronary artery lesions. The RXi Navvus system (ACIST Medical Systems, Eden Prairie, MN) is a monorail microcatheter with FFR-measurement capability through optical pressure sensor technology. This is an investigator-initiated, prospective, single-center, observational cohort study. A total of 238 patients were enrolled, 97 patients with Navvus and 141 with conventional pressure-wire based FFR (PW-FFR). Final analyses were performed on the cohort in which only 1 device was used (82 Navvus procedures vs. 136 PW-FFR procedures). No significant differences were found in the total amount of contrast used (150±77 vs 147±79ml; p=0.81), radiation use (6200±4601 vs. 5076±4655 centiG∗cm 2 ; p=0.09) or costs (€1994,- vs. €1930,-; p=0.32) in the Navvus vs. PW-FFR groups respectively. No significant differences were found in the amount of contrast used, total procedural costs or radiation when the Navvus system was used as compared to conventional FFR wires. CONTRACT is an investigator-initiated, prospective, single-center, observational cohort study that evaluated whether the RXi Navvus system compared to the use of standard Fractional Flow Reserve (FFR) wires reduces total contrast volume, radiation and overall study cost in a real world patient population referred for coronary angiography or percutaneous coronary intervention. Use of the RXi Navvus system was associated with comparable procedural costs, amount of radiation and contrast used as compared to PW-FFR systems. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Genome-wide analysis of epistasis in body mass index using multiple human populations.

PubMed

Wei, Wen-Hua; Hemani, Gib; Gyenesei, Attila; Vitart, Veronique; Navarro, Pau; Hayward, Caroline; Cabrera, Claudia P; Huffman, Jennifer E; Knott, Sara A; Hicks, Andrew A; Rudan, Igor; Pramstaller, Peter P; Wild, Sarah H; Wilson, James F; Campbell, Harry; Hastie, Nicholas D; Wright, Alan F; Haley, Chris S

2012-08-01

We surveyed gene-gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E-08) and a Bonferroni corrected threshold (P=1.1E-12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E-08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E-08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

N-of-1-pathways MixEnrich: advancing precision medicine via single-subject analysis in discovering dynamic changes of transcriptomes.

PubMed

Li, Qike; Schissler, A Grant; Gardeux, Vincent; Achour, Ikbel; Kenost, Colleen; Berghout, Joanne; Li, Haiquan; Zhang, Hao Helen; Lussier, Yves A

2017-05-24

Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate and individualized treatment decisions, these methods are not designed to address single-patient transcriptome analyses. We previously developed and validated the N-of-1-pathways framework using two methods, Wilcoxon and Mahalanobis Distance (MD), for personal transcriptome analysis derived from a pair of samples of a single patient. Although, both methods uncover concordantly dysregulated pathways, they are not designed to detect dysregulated pathways with up- and down-regulated genes (bidirectional dysregulation) that are ubiquitous in biological systems. We developed N-of-1-pathways MixEnrich, a mixture model followed by a gene set enrichment test, to uncover bidirectional and concordantly dysregulated pathways one patient at a time. We assess its accuracy in a comprehensive simulation study and in a RNA-Seq data analysis of head and neck squamous cell carcinomas (HNSCCs). In presence of bidirectionally dysregulated genes in the pathway or in presence of high background noise, MixEnrich substantially outperforms previous single-subject transcriptome analysis methods, both in the simulation study and the HNSCCs data analysis (ROC Curves; higher true positive rates; lower false positive rates). Bidirectional and concordant dysregulated pathways uncovered by MixEnrich in each patient largely overlapped with the quasi-gold standard compared to other single-subject and cohort-based transcriptome analyses. The greater performance of MixEnrich presents an advantage over previous methods to meet the promise of providing accurate personal transcriptome analysis to support precision medicine at point of care.

Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult Chinese subjects.

PubMed

Gummesson, Anders; Li, Haiyan; Gillen, Michael; Xu, John; Niazi, Mohammad; Hirshberg, Boaz

2014-11-01

As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the potential for increased patient compliance with the convenience of once daily dosing. The aim of the present study was to show that the FDC of saxagliptin and metformin XR is bioequivalent to co-administration of the individual components when given to Chinese subjects residing in China. This was a randomized, open-label, single-dose, two-period, cross-over pharmacokinetic study in two cohorts of healthy adult Chinese male subjects (n = 32 in each cohort) under fed conditions. In cohort 1, the pharmacokinetic properties of a saxagliptin/metformin XR 5/500 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and a 500 mg metformin XR tablet. In cohort 2, the pharmacokinetic properties of a saxagliptin/metformin XR 5/1,000 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and 2 × 500 mg metformin XR tablets. The two cohorts were independent of each other with respect to treatment and results. The pharmacokinetic properties of the active metabolite of saxagliptin (5-hydroxy-saxagliptin), as well as the safety and tolerability of each treatment, were also evaluated. For both cohorts, saxagliptin and metformin in the FDCs were bioequivalent to the individual components, as the limits of the 90 % confidence intervals of the geometric least squares mean ratios were contained within the 80-125 % bioequivalence limits for the area under the plasma concentration-time curve parameters and within the 70-143 % bioequivalence limits for the maximum plasma concentration. Similar exposures of 5-hydroxy-saxagliptin were observed with the two treatment regimens within each cohort. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. Saxagliptin/metformin XR 5/500 mg and saxagliptin/metformin XR 5/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin XR of the same strengths and were generally well tolerated. These results in healthy Chinese subjects are consistent with those of previous assessments of saxagliptin/metformin XR FDC in the saxagliptin clinical development programme.

End-Stage Liver Disease in Patients with Intracranial Hemorrhage Is Associated with Increased Mortality: A Cohort Study.

PubMed

Lagman, Carlito; Nagasawa, Daniel T; Sheppard, John P; Jacky Chen, Cheng Hao; Nguyen, Thien; Prashant, Giyarpuram N; Niu, Tianyi; Tucker, Alexander M; Kim, Won; Pouratian, Nader; Kaldas, Fady M; Busuttil, Ronald W; Yang, Isaac

2018-05-01

To determine if end-stage liver disease (ESLD) in patients with intracranial hemorrhage (ICH) is associated with increased mortality. This single-center, retrospective cohort study included 53 patients (33 in ESLD cohort and 20 in non-ESLD cohort) who received neurosurgical care between 2006 and 2017. ESLD was defined clinically as severely impaired liver function and at least 1 major complication of liver failure. The primary outcome was mortality. Overall, in-hospital, and 30-day mortality rates were higher in the ESLD cohort versus the non-ESLD cohort (79 vs. 30%, 79 vs. 20%, and 64 vs. 25%, all P ≤ 0.01). We identified a significant difference in overall survival between ESLD and non-ESLD cohorts on Kaplan-Meier analysis (P = 0.004 with log-rank and Wilcoxon tests). Odds of overall, in-hospital, and 30-day mortality in the ESLD cohort were 8.67 (95% confidence interval [CI], 2.44-30.84), 14.86 (95% CI, 3.75-58.90), and 5.25 (95% CI, 1.53-18.08). Other predictors of overall mortality included primary admission diagnosis of liver disease (odds ratio [OR] = 9.60; 95% CI, 3.75-58.90), higher Child-Pugh (OR = 1.64; 95% CI, 2.66-34.67) and Model for End-Stage Liver Disease (OR = 1.12; 95% CI, 1.04-1.20) scores, lower Glasgow Coma Scale score (OR = 0.73; 95% CI, 0.61-0.88), ICH that developed in the hospital (OR = 4.11; 95% CI, 1.21-13.98), and intraparenchymal hemorrhage (OR = 9.23; 95% CI, 1.72-49.56). ESLD in patients with ICH is associated with increased mortality. Copyright © 2018 Elsevier Inc. All rights reserved.

Influence of timing of sexual debut and first marriage on sexual behaviour in later life: findings from four survey rounds in the Kisesa cohort in northern Tanzania

PubMed Central

Żaba, B; Isingo, R; Wringe, A; Marston, M; Slaymaker, E; Urassa, M

2009-01-01

Objectives: To evaluate quality of sexual debut and first marriage data, measure trends and study the association of risky sexual behaviour in youth with adult risk behaviour. Methods: Reports on age at first sex (AFS) and age at first marriage (AFM) from the Kisesa cohort study, 1994–2004, were evaluated for consistency and used to describe trends in median age-at-event and time spent single but sexually active in different birth cohorts. The association of these variables with marital stability and numbers of partners at later ages was explored using statistical regression techniques. Results: AFS and AFM were inconsistently reported by 32% and 33% of respondents, respectively, but there was no general tendency to report lower or higher ages at a later report date. In 10-year birth cohorts born between 1950–9 and 1980–9, male median AFS declined from 18.1 to 17.0 years and female median AFM rose from 16.2 to 16.6 years. Young people of both sexes currently spend longer sexually active but unmarried than previously. Early marriage is statistically associated with remarriage and polygamy; longer time between sexual debut and marriage is associated with higher numbers of partners at later stages of life. Conclusion: Inconsistent reporting of age-at-event introduces noise but does not bias estimates of population level indicators. Lengthening time spent single and sexually active suggests that men and women entering first marriage will have been exposed to increased numbers of non-marital partners. Successful youth interventions may also influence adult behaviour. PMID:19307336

Pathway-based discovery of genetic interactions in breast cancer

PubMed Central

Xu, Zack Z.; Boone, Charles; Lange, Carol A.

2017-01-01

Breast cancer is the second largest cause of cancer death among U.S. women and the leading cause of cancer death among women worldwide. Genome-wide association studies (GWAS) have identified several genetic variants associated with susceptibility to breast cancer, but these still explain less than half of the estimated genetic contribution to the disease. Combinations of variants (i.e. genetic interactions) may play an important role in breast cancer susceptibility. However, due to a lack of statistical power, the current tests for genetic interactions from GWAS data mainly leverage prior knowledge to focus on small sets of genes or SNPs that are known to have an association with breast cancer. Thus, many genetic interactions, particularly among novel variants, remain understudied. Reverse-genetic interaction screens in model organisms have shown that genetic interactions frequently cluster into highly structured motifs, where members of the same pathway share similar patterns of genetic interactions. Based on this key observation, we recently developed a method called BridGE to search for such structured motifs in genetic networks derived from GWAS studies and identify pathway-level genetic interactions in human populations. We applied BridGE to six independent breast cancer cohorts and identified significant pathway-level interactions in five cohorts. Joint analysis across all five cohorts revealed a high confidence consensus set of genetic interactions with support in multiple cohorts. The discovered interactions implicated the glutathione conjugation, vitamin D receptor, purine metabolism, mitotic prometaphase, and steroid hormone biosynthesis pathways as major modifiers of breast cancer risk. Notably, while many of the pathways identified by BridGE show clear relevance to breast cancer, variants in these pathways had not been previously discovered by traditional single variant association tests, or single pathway enrichment analysis that does not consider SNP-SNP interactions. PMID:28957314

Voice Loudness and Gender Effects on Jitter and Shimmer in Healthy Adults

ERIC Educational Resources Information Center

Brockmann, Meike; Storck, Claudio; Carding, Paul N.; Drinnan, Michael J.

2008-01-01

Purpose: The aim of this study was to investigate voice loudness and gender effects on jitter and shimmer in healthy young adults because previous descriptions have been inconsistent. Method: Fifty-seven healthy adults (28 women, 29 men) aged 20-40 years were included in this cross-sectional single-cohort study. Three phonations of /a/ at soft,…

Repeatability of Mice Consumption Discrimination of Wheat (Triticum aestivum L.) Varieties across Field Experiments and Mouse Cohorts.

PubMed

Kiszonas, Alecia M; Fuerst, E Patrick; Morris, Craig F

2015-07-01

Whole grain wheat (Triticum aestivum L.) foods can provide critical nutrients for health and nutrition in the human diet. Potential flavor differences among varieties can be examined using consumption discrimination of the house mouse (Mus musculus L.) as a model system. This study examines consistency and repeatability of the mouse model and potentially, wheat grain flavor. A single elimination tournament design was used to measure relative consumption preference for hard red spring and hard white spring varieties across all 3 experiments in combination with 2 mouse cohorts. Fifteen replicate mice were used in 24-h trials to examine differences in preference among paired wheat varieties until an overall "winner" was established as the most highly preferred variety of wheat. In all 3 experiment-cohort combinations, the same varieties were preferred as the "winner" of both the hard red spring and hard white spring wheat varieties, Hollis and BR 7030, respectively. Despite the consistent preference for these varieties across experiments, the degree (magnitude) to which the mice preferred these varieties varied across experiments. For the hard white spring wheat varieties, the small number of varieties and confounding effects of experiment and cohort limited our ability to accurately gauge repeatability. Conversely, for the hard red spring wheat varieties, consumption preferences were consistent across experiments and mice cohorts. The single-elimination tournament model was effective in providing repeatable results in an effort to more fully understand the mouse model system and possible flavor differences among wheat varieties. The mouse model system used here is effective in identifying wheat varieties that may be more or less desirable to humans in whole wheat foods. The system identifies consistent differences across different mouse cohorts and crop years. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Characterizing the genetic risk for Type 2 diabetes in a Malaysian multi-ethnic cohort.

PubMed

Abdullah, N; Abdul Murad, N A; Attia, J; Oldmeadow, C; Mohd Haniff, E A; Syafruddin, S E; Abd Jalal, N; Ismail, N; Ishak, M; Jamal, R; Scott, R J; Holliday, E G

2015-10-01

To characterize the association with Type 2 diabetes of known Type 2 diabetes risk variants in people in Malaysia of Malay, Chinese and Indian ancestry who participated in the Malaysian Cohort project. We genotyped 1604 people of Malay ancestry (722 cases, 882 controls), 1654 of Chinese ancestry (819 cases, 835 controls) and 1728 of Indian ancestry (851 cases, 877 controls). First, 62 candidate single-nucleotide polymorphisms previously associated with Type 2 diabetes were assessed for association via logistic regression within ancestral groups and then across ancestral groups using a meta-analysis. Second, estimated odds ratios were assessed for excess directional concordance with previously studied populations. Third, a genetic risk score aggregating allele dosage across the candidate single-nucleotide polymorphisms was tested for association within and across ancestral groups. After Bonferroni correction, seven individual single-nucleotide polymorphisms were associated with Type 2 diabetes in the combined Malaysian sample. We observed a highly significant excess in concordance of effect directions between Malaysian and previously studied populations. The genetic risk score was strongly associated with Type 2 diabetes in all Malaysian groups, explaining from 1.0 to 1.7% of total Type 2 diabetes risk variance. This study suggests there is substantial overlap of the genetic risk alleles underlying Type 2 diabetes in Malaysian and other populations. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

Cryostorage duration does not affect pregnancy and neonatal outcomes: a retrospective single-centre cohort study of vitrified-warmed blastocysts.

PubMed

Ueno, Satoshi; Uchiyama, Kazuo; Kuroda, Tomoko; Yabuuchi, Akiko; Ezoe, Kenji; Okimura, Tadashi; Okuno, Takashi; Kobayashi, Tamotsu; Kato, Keiichi

2018-06-01

A retrospective cohort study of 8736 autologous single vitrified-warmed blastocyst transfer cycles was conducted in a single centre to investigate the effect of cryostorage on clinical and neonatal outcomes. Cryostorage duration was classified into three groups: (A) 0-2 months (n = 4702); (B) 2-13 months (n = 2853) and (C) 13-97 months (n = 1181). Blastocysts were vitrified using the Cryotop method. No significant differences were observed in live birth rates: (A) 37.3%; (B) 34.9%; (C) (35.2%). Gestational period was significantly shorter in group C: (A) 38.7 ± 1.8; (B) 38.6 ± 1.6; (C) 38.1 ± 1.7; P < 0.05. This was clinically unimportant as the average gestational age was more than 38 weeks. No significant differences between groups were observed in birth weight: (A) 3060 ± 455 g; (B) 3052 ± 449 g; (C) 2992 ± 445 g, or congenital malformation rates: (A) 2.2%; (B) 1.9%; (C) 1.8%. The limitation of this study was that maximum storage duration was 8 years; most blastocysts were in cryostorage for much shorter periods. Long-term storage of blastocysts that are vitrified using an open device vitrification system has no negative effect on pregnancy and neonatal outcomes. Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

PubMed

Mahlangu, J N; Coetzee, M J; Laffan, M; Windyga, J; Yee, T T; Schroeder, J; Haaning, J; Siegel, J E; Lemm, G

2012-05-01

BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 μg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. © 2012 International Society on Thrombosis and Haemostasis.

Minimally Invasive Lateral Access Surgery and Reoperation Rates: A Multi-Institution Retrospective Review of 2060 Patients.

PubMed

Nayar, Gautam; Wang, Timothy; Sankey, Eric W; Berry-Candelario, John; Elsamadicy, Aladine A; Back, Adam; Karikari, Isaac; Isaacs, Robert

2018-05-19

Risk factors for surgical revision remain important because of additional readmission, anesthesia, and morbidity for the patient and significant cost for health care systems. Although the rate of reoperation (RRO) is well described for traditional open posterior (OP) approaches, the RRO in minimally invasive lateral (MIL) surgery remains poorly characterized. This study compares the RRO in patients undergoing decompressive lumbar spine surgery via MIL versus OP approaches. Patient demographics and comorbidities were retrospectively collected for 2060 patients undergoing single-stage elective lumbar spinal surgery at multiple institutions. A subset of 1484 patients had long-term data (long-term cohort [LT cohort]). The RRO was compared between approaches through univariate and multivariate analysis. There were 1292 patients (62.7%) who underwent lateral access surgery, whereas 768 patients (37.3%) underwent OP surgery. The MIL cohort was significantly older, had a higher proportion of men, and had more comorbidities than the OP cohort. In the LT cohort, lateral patients were significantly older and had more comorbidities, with a lower body mass index and a lower proportion of men and smokers. Surgical complications between the groups trended to be similar. The MIL cohort had a significantly lower RRO at both 30 days (approximately 57% lower, MIL cohort: 1.01% vs. OP cohort: 2.36%, P = 0.02) and 2 years (approximately 61% lower, MIL cohort: 2.09% vs. OP cohort: 5.37%, P < 0.01) after surgery. On multivariate analysis, surgical approach was the only significant predictor for the RRO at both 30 days (open posterior approach odds ratio [OR], 4.47; 95% confidence interval [CI], 1.33-15.09; P = 0.02) and 2 years (open posterior approach OR, 3.26; 95% CI, 1.26-8.42; P = 0.01). This study shows that MIL surgical approaches, compared with OP approaches, have a significantly lower RRO after lumbar spine surgery. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of Social Support and Marital Status on Perceived Surgical Effectiveness and 30-Day Hospital Readmission.

PubMed

Adogwa, Owoicho; Elsamadicy, Aladine A; Vuong, Victoria D; Mehta, Ankit I; Vasquez, Raul A; Cheng, Joseph; Bagley, Carlos A; Karikari, Isaac O

2017-12-01

Retrospective cohort review. To determine whether higher levels of social support are associated with improved surgical outcomes after elective spine surgery. The medical records of 430 patients (married, n = 313; divorced/separated/widowed, n = 71; single, n = 46) undergoing elective spine surgery at a major academic medical center were reviewed. Patients were categorized by their marital status at the time of surgery. Patient demographics, comorbidities, and postoperative complication rates were collected. All patients had prospectively collected outcomes measures and a minimum of 1-year follow-up. Patient reported outcomes instruments (Oswestry Disability Index, Short Form-36, and visual analog scale-back pain/leg pain) were completed before surgery, then at 1 year after surgery. Baseline characteristics were similar in all cohorts. There was no statistically significant difference in the length of hospital stay across all 3 cohorts, although "single patients" had longer duration of in-hospital stays that trended toward significance (single 6.24 days vs married 4.53 days vs divorced/separated/widowed 4.55 days, P = .05). Thirty-day readmission rates were similar across all cohorts (married 7.03% vs divorced/separated/widowed 7.04% vs single 6.52%, P = .99). Additionally, there were no significant differences in baseline and 1-year patient reported outcomes measures between all groups. Increased social support did not appear to be associated with superior short and long-term clinical outcomes after spine surgery; however, it was associated with a shorter duration of in-hospital stay with no increase in 30-day readmission rates.

Association of prediabetes-associated single nucleotide polymorphisms with microalbuminuria.

PubMed

Choi, Jong Wook; Moon, Shinje; Jang, Eun Jung; Lee, Chang Hwa; Park, Joon-Sung

2017-01-01

Increased glycemic exposure, even below the diagnostic criteria for diabetes mellitus, is crucial in the pathogenesis of diabetic microvascular complications represented by microalbuminuria. Nonetheless, there is limited evidence regarding which single nucleotide polymorphisms (SNPs) are associated with prediabetes and whether genetic predisposition to prediabetes is related to microalbuminuria, especially in the general population. Our objective was to answer these questions. We conducted a genomewide association study (GWAS) separately on two population-based cohorts, Ansung and Ansan, in the Korean Genome and Epidemiology Study (KoGES). The initial GWAS was carried out on the Ansung cohort, followed by a replication study on the Ansan cohort. A total of 5682 native Korean participants without a significant medical illness were classified into either control group (n = 3153) or prediabetic group (n = 2529). In the GWAS, we identified two susceptibility loci associated with prediabetes, one at 17p15.3-p15.1 in the GCK gene and another at 7p15.1 in YKT6. When variations in GCK and YKT6 were used as a model of prediabetes, this genetically determined prediabetes increased microalbuminuria. Multiple logistic regression analyses revealed that fasting glucose concentration in plasma and SNP rs2908289 in GCK were associated with microalbuminuria, and adjustment for age, gender, smoking history, systolic blood pressure, waist circumference, and serum triglyceride levels did not attenuate this association. Our results suggest that prediabetes and the associated SNPs may predispose to microalbuminuria before the diagnosis of diabetes mellitus. Further studies are needed to explore the details of the physiological and molecular mechanisms underlying this genetic association.

Association of prediabetes-associated single nucleotide polymorphisms with microalbuminuria

PubMed Central

Choi, Jong Wook; Moon, Shinje; Jang, Eun Jung; Lee, Chang Hwa; Park, Joon-Sung

2017-01-01

Increased glycemic exposure, even below the diagnostic criteria for diabetes mellitus, is crucial in the pathogenesis of diabetic microvascular complications represented by microalbuminuria. Nonetheless, there is limited evidence regarding which single nucleotide polymorphisms (SNPs) are associated with prediabetes and whether genetic predisposition to prediabetes is related to microalbuminuria, especially in the general population. Our objective was to answer these questions. We conducted a genomewide association study (GWAS) separately on two population-based cohorts, Ansung and Ansan, in the Korean Genome and Epidemiology Study (KoGES). The initial GWAS was carried out on the Ansung cohort, followed by a replication study on the Ansan cohort. A total of 5682 native Korean participants without a significant medical illness were classified into either control group (n = 3153) or prediabetic group (n = 2529). In the GWAS, we identified two susceptibility loci associated with prediabetes, one at 17p15.3-p15.1 in the GCK gene and another at 7p15.1 in YKT6. When variations in GCK and YKT6 were used as a model of prediabetes, this genetically determined prediabetes increased microalbuminuria. Multiple logistic regression analyses revealed that fasting glucose concentration in plasma and SNP rs2908289 in GCK were associated with microalbuminuria, and adjustment for age, gender, smoking history, systolic blood pressure, waist circumference, and serum triglyceride levels did not attenuate this association. Our results suggest that prediabetes and the associated SNPs may predispose to microalbuminuria before the diagnosis of diabetes mellitus. Further studies are needed to explore the details of the physiological and molecular mechanisms underlying this genetic association. PMID:28158221

Estimation of Genetic Relationships Between Individuals Across Cohorts and Platforms: Application to Childhood Height.

PubMed

Fedko, Iryna O; Hottenga, Jouke-Jan; Medina-Gomez, Carolina; Pappa, Irene; van Beijsterveldt, Catharina E M; Ehli, Erik A; Davies, Gareth E; Rivadeneira, Fernando; Tiemeier, Henning; Swertz, Morris A; Middeldorp, Christel M; Bartels, Meike; Boomsma, Dorret I

2015-09-01

Combining genotype data across cohorts increases power to estimate the heritability due to common single nucleotide polymorphisms (SNPs), based on analyzing a Genetic Relationship Matrix (GRM). However, the combination of SNP data across multiple cohorts may lead to stratification, when for example, different genotyping platforms are used. In the current study, we address issues of combining SNP data from different cohorts, the Netherlands Twin Register (NTR) and the Generation R (GENR) study. Both cohorts include children of Northern European Dutch background (N = 3102 + 2826, respectively) who were genotyped on different platforms. We explore imputation and phasing as a tool and compare three GRM-building strategies, when data from two cohorts are (1) just combined, (2) pre-combined and cross-platform imputed and (3) cross-platform imputed and post-combined. We test these three strategies with data on childhood height for unrelated individuals (N = 3124, average age 6.7 years) to explore their effect on SNP-heritability estimates and compare results to those obtained from the independent studies. All combination strategies result in SNP-heritability estimates with a standard error smaller than those of the independent studies. We did not observe significant difference in estimates of SNP-heritability based on various cross-platform imputed GRMs. SNP-heritability of childhood height was on average estimated as 0.50 (SE = 0.10). Introducing cohort as a covariate resulted in ≈2 % drop. Principal components (PCs) adjustment resulted in SNP-heritability estimates of about 0.39 (SE = 0.11). Strikingly, we did not find significant difference between cross-platform imputed and combined GRMs. All estimates were significant regardless the use of PCs adjustment. Based on these analyses we conclude that imputation with a reference set helps to increase power to estimate SNP-heritability by combining cohorts of the same ethnicity genotyped on different platforms. However, important factors should be taken into account such as remaining cohort stratification after imputation and/or phenotypic heterogeneity between and within cohorts. Whether one should use imputation, or just combine the genotype data, depends on the number of overlapping SNPs in relation to the total number of genotyped SNPs for both cohorts, and their ability to tag all the genetic variance related to the specific trait of interest.

Soft tissue contour changes at immediate postextraction single-tooth implants with immediate restoration: a 12-month prospective cohort study.

PubMed

Cardaropoli, Daniele; Tamagnone, Lorenzo; Roffredo, Alessandro; Gaveglio, Lorena

2015-01-01

In the maxillary arch from premolar to premolar, 26 single dental implants were inserted in fresh extraction sockets and immediately provisionalized. The bone-to-implant gap was grafted with a bovine bone mineral. After 3 months, definitive ceramic crowns were placed. At baseline and after 1 year, the soft tissue horizontal width, mesiodistal papillary level, midfacial gingival level, and pink esthetic score were evaluated. No statistical differences were found between baseline and 1 year for all parameters. Immediate single-tooth implants, with immediate restoration, are capable of maintaining the soft tissue contour and esthetics compared to the pretreatment status.

Development of the Ovarian Cancer Cohort Consortium: Risk Factor Associations by Heterogeneity of Disease

DTIC Science & Technology

2013-10-01

10 cohorts have collected pathology reports – we currently are working with these cohorts to have personnel from the DCC either train on- site staff...for abstraction or to travel to the site and conduct the abstraction directly. Due to the difficulties in obtaining the appropriate permissions to...REPRODUCTIVE HISTORY PREG Number of pregnancies lasting > 6 months Twins count as a single birth; 999=unknown AGEFIRST Age at first birth

An exclusively human milk diet reduces necrotizing enterocolitis.

PubMed

Herrmann, Kenneth; Carroll, Katherine

2014-05-01

This study tested the hypothesis that feeding an exclusively human milk (EHM) diet to premature infants reduces the incidence of necrotizing enterocolitis (NEC) associated with enteral feeding. An observational study for infants born at less than 33 weeks of gestational age was performed in a single neonatal intensive care unit. An EHM diet prospectively eliminated bovine-based artificial milk, including bovine-based fortifier, through 33 weeks postmenstrual age (PMA). The clinical data from a 2.5-year interval of the EHM diet were compared with data from the previous 6.5 years for similar infants who received bovine-based milk products before 33 weeks PMA. In the EHM diet cohort, 148 of 162 infants (91%) received EHM through 33 weeks PMA. In order to achieve an EHM diet, 140 of 162 infants (86%) received their own mother's milk, and 98 of 162 infants (60%) received donor human milk. The EHM cohort was also fed a human milk-based fortifier to truly eliminate bovine products. The distribution of NEC onset in the EHM cohort was significantly different from that in the control cohort for the day of onset (p=0.042) and the PMA at onset (p=0.011). In the control cohort, NEC onset after Day 7 of life occurred in 15 of 443 infants (3.4%), significantly more than in the EHM cohort where NEC occurred in two of 199 infants (1%) (p=0.009). Changing to an EHM milk diet through 33 weeks PMA reduced the incidence of NEC associated with enteral feeding.

Does Manipulation under Anesthesia Increase the Risk of Revision Total Knee Arthroplasty? A Matched Case Control Study.

PubMed

Pierce, Todd P; Issa, Kimona; Festa, Anthony; Scillia, Anthony J; McInerney, Vincent K; Mont, Michael A

2017-09-01

Manipulation under anesthesia (MUA) can help patients regain an adequate range of motion (ROM) following total knee arthroplasty (TKA). Although there are studies reporting that MUA can assist in improving ROM, there is a paucity of studies regarding whether requiring an MUA is associated with an increased risk of revision. The purpose of this study was to assess the: (1) incidence of revision TKA and (2) outcomes of those undergoing MUA and compare it with a matched cohort who did not require MUA. A prospectively collected database of two high-volume institutions was assessed for patients who required a single MUA following TKA between 2005 and 2011. We found a total of 138 knees with a mean 8.5-year follow-up post-MUA. We compared this with a matched cohort (1:1) who underwent TKA during this same time period but did not require an MUA. Incidence of revision surgery and clinical outcomes were compared between the two cohorts. Within the MUA cohort, nine knees underwent revision, which was similar to the matched cohort that had seven revisions (93 vs. 95%; p  = 0.6). The mean KSS-functional (88 vs. 90 points; p  = 0.15) and clinical scores (87 vs. 89 points; p  = 0.1) were similar between the two cohorts. Undergoing an MUA was not associated with an increased risk of revision TKA. If patients require MUA, they may still achieve satisfactory outcomes. This information can be used in educating patients so they may be able to formulate their expectations following their MUA. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Global Developmental Delay and Its Relationship to Cognitive Skills

ERIC Educational Resources Information Center

Riou, Emilie M.; Ghosh, Shuvo; Francoeur, Emmett; Shevell, Michael I.

2009-01-01

Global developmental delay (GDD) is defined as evidence of significant delays in two or more developmental domains. Our study determined the cognitive skills of a cohort of young children with GDD. A retrospective chart review of all children diagnosed with GDD within a single developmental clinic was carried out. Scores on fine motor (Peabody…

Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings.

PubMed

King, C; Beard, J; Crampin, A C; Costello, A; Mwansambo, C; Cunliffe, N A; Heyderman, R S; French, N; Bar-Zeev, N

2015-09-11

Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings

PubMed Central

King, C.; Beard, J.; Crampin, A.C.; Costello, A.; Mwansambo, C.; Cunliffe, N.A.; Heyderman, R.S.; French, N.; Bar-Zeev, N.

2015-01-01

Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality. PMID:26235370

The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding.

PubMed

Bucklin, Mason H; Acquisto, Nicole M; Nelson, Catherine

2014-05-01

Previous studies have suggested the used of off-label recombinant factor VII (rFVIIa) increases the risk of thromboembolic events, but the effect of the dose of rFVIIa is not well described in the literature. All adult patients that received off-label rFVIIa from 2005-2012 were included in this single-center, retrospective cohort study. The primary endpoint was the incidence of a thromboembolic event in the low dose (<50 mcg/kg) compared to the high dose (≥50 mcg/kg) cohort. Secondary endpoints compared time to thromboembolic event, incidence of arterial compared to venous events, and mortality. There were 152 patients that received rFVIIa during the study period with 66 in the low dose cohort and 86 in the high dose cohort. Mean total dose of rFVIIa was 30.2 mcg/kg (SD ± 9.5 mcg/kg) in the low dose and 99.8 mcg/kg (SD ± 64.7 mcg/kg) in the high dose cohort (p=0.0001). The overall incidence of thromboembolic events was 12.5%. There were 12 (14%) events in the low dose cohort and seven (10.6%) in the high dose cohort, RR=0.76 (95% CI 0.31-1.82). There were no differences in any of the secondary outcomes. A higher incidence of thromboembolic events in cardiothoracic surgery (20.8%) and penetrating trauma patients (21.4%) was seen compared to the remaining cohort (6.7%). No significant difference in the incidence of thromboembolic events was seen between low dose versus high dose rFVIIa over a seven year period at our institution. However, due to the relatively low overall incidence and a small sample size, type II error may be present. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prognostic Implications of Single-Sample Confirmatory Testing for Undiagnosed Diabetes: A Prospective Cohort Study.

PubMed

Selvin, Elizabeth; Wang, Dan; Matsushita, Kunihiro; Grams, Morgan E; Coresh, Josef

2018-06-19

Current clinical definitions of diabetes require repeated blood work to confirm elevated levels of glucose or hemoglobin A1c (HbA1c) to reduce the possibility of a false-positive diagnosis. Whether 2 different tests from a single blood sample provide adequate confirmation is uncertain. To examine the prognostic performance of a single-sample confirmatory definition of undiagnosed diabetes. Prospective cohort study. The ARIC (Atherosclerosis Risk in Communities) study. 13 346 ARIC participants (12 268 without diagnosed diabetes) with 25 years of follow-up for incident diabetes, cardiovascular outcomes, kidney disease, and mortality. Confirmed undiagnosed diabetes was defined as elevated levels of fasting glucose (≥7.0 mmol/L [≥126 mg/dL]) and HbA1c (≥6.5%) from a single blood sample. Among 12 268 participants without diagnosed diabetes, 978 had elevated levels of fasting glucose or HbA1c at baseline (1990 to 1992). Among these, 39% had both (confirmed undiagnosed diabetes), whereas 61% had only 1 elevated measure (unconfirmed undiagnosed diabetes). The confirmatory definition had moderate sensitivity (54.9%) but high specificity (98.1%) for identification of diabetes cases diagnosed during the first 5 years of follow-up, with specificity increasing to 99.6% by 15 years. The 15-year positive predictive value was 88.7% compared with 71.1% for unconfirmed cases. Confirmed undiagnosed diabetes was significantly associated with cardiovascular and kidney disease and mortality, with stronger associations than unconfirmed diabetes. Lack of repeated measurements of fasting glucose and HbA1c. A single-sample confirmatory definition of diabetes had a high positive predictive value for subsequent diagnosis and was strongly associated with clinical end points. Our results support the clinical utility of using a combination of elevated fasting glucose and HbA1c levels from a single blood sample to identify undiagnosed diabetes in the population. National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute.

The learning curve of laparoendoscopic single-site (LESS) cholecystectomy: definable, short, and safe.

PubMed

Hernandez, Jonathan; Ross, Sharona; Morton, Connor; McFarlin, Kellie; Dahal, Sujat; Golkar, Farhaad; Albrink, Michael; Rosemurgy, Alexander

2010-11-01

The applications of laparoendoscopic single-site (LESS) surgery, including cholecystectomy, are occurring quickly, although little is generally known about issues associated with the learning curve of this new technique including operative time, conversion rates, and safety. We prospectively followed all patients undergoing LESS cholecystectomy, and compared operations undertaken at our institutions in cohorts of 25 patients with respect to operative times, conversion rates, and complications. One-hundred fifty patients of mean age 46 years underwent LESS cholecystectomy. No significant differences in operative times were demonstrable between any of the 25-patient cohorts operated on at our institution. A significant reduction in operative times (p < 0.001) after completion of 75 LESS procedures was, however, identified with the experience of a single surgeon. No significant reduction in the number of procedures requiring an additional trocar(s) or conversion to open operations was observed after completion of 25 LESS cholecystectomies. Complication rates were low, and not significantly different between any 25-patient cohorts. For surgeons proficient with multi-incision laparoscopic cholecystectomy, the learning curve for LESS cholecystectomy begins near proficiency. Operative complications and conversions were infrequent and unchanged across successive 25-patient cohorts, and were similar to those reported for multi-incision laparoscopic cholecystectomy after the learning curve. Copyright © 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Profiles of rural longitudinal integrated clerkship students: a descriptive study of six consecutive student cohorts *.

PubMed

Brooks, Kathleen D; Eley, Diann S; Zink, Therese

2014-02-01

Medical schools worldwide are challenged to address the rural primary care workforce shortage by creating community-engaged curricula to nurture student interest in rural practice. To examine the personal characteristics of six consecutive rural longitudinal integrated clerkship student cohorts to understand whom the programs attract and select and thus inform the development of such programs. A cross-sectional cohort design was used. Six cohorts (2007-2012) completed a survey on demographics and factors that influenced their choice of rural primary care. The Temperament and Character Inventory was used to measure personality. Analysis was mainly descriptive. Where appropriate univariate analysis compared variables between groups. Sample size was 205 with the majority female (61%), between 25 and 29 years (64%), single (60%) and lived longest in rural communities with populations less than 20,000 (60%). Rural lifestyle, background and desire to work in underserved areas were noted to impact rural medicine interest. Professional satisfaction, personal and professional goals and family needs had the highest impact on career decisions, and financial concerns lowest. The stability of students' personal characteristics across cohorts and the workforce outcomes of this program suggest the recruitment process successfully nurtures students who will fit well into future rural practice.

Retrieval of the Leadless Cardiac Pacemaker: A Multicenter Experience.

PubMed

Reddy, Vivek Y; Miller, Marc A; Knops, Reinoud E; Neuzil, Petr; Defaye, Pascal; Jung, Werner; Doshi, Rahul; Castellani, Mark; Strickberger, Adam; Mead, R Hardwin; Doppalapudi, Harish; Lakkireddy, Dhanunjaya; Bennett, Matthew; Sperzel, Johannes

2016-12-01

Leadless cardiac pacemakers have emerged as a safe and effective alternative to conventional transvenous single-chamber ventricular pacemakers. Herein, we report a multicenter experience on the feasibility and safety of acute retrieval (<6 weeks) and chronic retrieval (>6 weeks) of the leadless cardiac pacemaker in humans. This study included patients enrolled in 3 multicenter trials, who received a leadless cardiac pacemaker implant and who subsequently underwent a device removal attempt. The overall leadless pacemaker retrieval success rate was 94%: for patients whose leadless cardiac pacemaker had been implanted for <6 weeks (acute retrieval cohort), complete retrieval was achieved in 100% (n=5/5); for those implanted for ≥ 6 weeks (chronic retrieval cohort), retrieval was achieved in 91% (n=10/11) of patients. The mean duration of time from implant to retrieval attempt was 346 days (range, 88-1188 days) in the chronic retrieval cohort, and nearly two thirds (n=7; 63%) had been implanted for >6 months before the retrieval attempt. There were no procedure-related adverse events at 30 days post retrieval procedure. This multicenter experience demonstrated the feasibility and safety of retrieving a chronically implanted single-chamber (right ventricle) active fixation leadless pacemaker. URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02051972, NCT02030418, and NCT01700244. © 2016 American Heart Association, Inc.

Risk of neurological diseases among survivors of electric shocks: a nationwide cohort study, Denmark, 1968-2008.

PubMed

Grell, Kathrine; Meersohn, Andrea; Schüz, Joachim; Johansen, Christoffer

2012-09-01

Several studies suggest a link between electric injuries and neurological diseases, where electric shocks may explain elevated risks for neuronal degeneration and, subsequently, neurological diseases. We conducted a retrospective cohort study on the risk of neurological diseases among people in Denmark who had survived an electric accident in 1968-2008. The cohort included 3,133 people and occurrences of neurological diseases were determined by linkage to the nationwide population-based Danish National Register of Patients. The numbers of cases observed at first hospital contact in the cohort were compared with the respective rates of first hospital contacts for neurological diseases in the general population. We observed significantly increased risks for peripheral nerve diseases (standardized hospitalization ratio (SHR), 1.66; 95% confidence interval (CI), 1.22-2.22), for migraine (SHR, 1.80; 95% CI, 1.23-2.54), for vertigo (SHR, 1.60; 95% CI, 1.22-2.05), and for epilepsy (SHR, 1.45; 95% CI, 1.11-1.85). Only small numbers of cases of other neurological diseases were found, making the risk estimates unstable. These findings suggest an association between a single electric shock and increased risks for peripheral nerve diseases, migraines, vertigo, and epilepsy, but confirmation of these observations is needed. Copyright © 2012 Wiley Periodicals, Inc.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PubMed

Bauer, M; Glenn, T; Alda, M; Andreassen, O A; Angelopoulos, E; Ardau, R; Baethge, C; Bauer, R; Bellivier, F; Belmaker, R H; Berk, M; Bjella, T D; Bossini, L; Bersudsky, Y; Cheung, E Y W; Conell, J; Del Zompo, M; Dodd, S; Etain, B; Fagiolini, A; Frye, M A; Fountoulakis, K N; Garneau-Fournier, J; Gonzalez-Pinto, A; Harima, H; Hassel, S; Henry, C; Iacovides, A; Isometsä, E T; Kapczinski, F; Kliwicki, S; König, B; Krogh, R; Kunz, M; Lafer, B; Larsen, E R; Lewitzka, U; Lopez-Jaramillo, C; MacQueen, G; Manchia, M; Marsh, W; Martinez-Cengotitabengoa, M; Melle, I; Monteith, S; Morken, G; Munoz, R; Nery, F G; O'Donovan, C; Osher, Y; Pfennig, A; Quiroz, D; Ramesar, R; Rasgon, N; Reif, A; Ritter, P; Rybakowski, J K; Sagduyu, K; Scippa, A M; Severus, E; Simhandl, C; Stein, D J; Strejilevich, S; Hatim Sulaiman, A; Suominen, K; Tagata, H; Tatebayashi, Y; Torrent, C; Vieta, E; Viswanath, B; Wanchoo, M J; Zetin, M; Whybrow, P C

2015-01-01

Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The Community Mentoring REU: A Novel Paradigm for Research Experiences for Undergraduates Programs

NASA Astrophysics Data System (ADS)

Kobulnicky, Henry; Maierhofer, Lara; Kobulnicky, Carol; Dale, Daniel A.

2018-01-01

Research Experience for Undergraduates programs were conceived to promote entry of college students into STEM disciplines. Evidence suggests that participating in REUs increases interest in STEM, conveys skills leading to STEM jobs and graduate study, increases science self-efficacy, builds professional networks for young scientists, and cultivates identity as a scientist. Nevertheless, the factors that mediate desired outcomes are still poorly understood, and persistence of negative mentoring experiences among REU participants motivates the design and study of novel approaches to preparing future STEM professionals. During five summers spanning 2012-2016 we implemented a "Community Mentoring" paradigm at the University of Wyoming's 10-week Astronomy REU program. In contrast to "traditional model (TM)" REUs that pair a single senior scientist mentor with a single junior mentee, community mentoring (CM) unites 6-8 undergraduates with 3-5 faculty (perhaps assisted by a graduate student or postdoc) on a collaborative team addressing a single science goal. In CM, students have access to a pool of mentors and a peer group reading the same literature, working in a common location, sharing equipment (in this case the WIRO 2.3 meter telescope), sharing data, and learning the same analysis skills. The community interacts daily, modeling the highly collaborative nature of modern scientific teams. Our study used an electronic survey consisting of 24 questions to compare a cohort of 28 CM students to a national control group of 77 students who conducted REUs elsewhere during the same period, typically under the TM. CM students report a significantly higher level of "learning from their peers", "learning to work on a science team", and "sense of community" compared to the TM cohort. The CM cohort also reports a higher overall level of satisfaction with the REU and a lower level of negative experiences, such as finding it difficult to get time with a mentor. This talk will review other lessons learned in five years of community mentoring as it describes an alternative paradigm for REUs.

Psychometric evaluation of the Chinese version of the Subjective Happiness Scale: evidence from the Hong Kong FAMILY Cohort.

PubMed

Nan, Hairong; Ni, Michael Y; Lee, Paul H; Tam, Wilson W S; Lam, Tai Hing; Leung, Gabriel M; McDowell, Ian

2014-08-01

With China's rapid economic growth in the past few decades, there is currently an emerging focus on happiness. Cross-cultural validity studies have indicated that the four-item Subjective Happiness Scale (SHS) has high internal consistency and stable reliability. However, the psychometric characteristics of the SHS in broader Chinese community samples are unknown. We evaluated the factor structure and psychometric properties of the SHS in the Hong Kong general population. The Chinese SHS was derived using forward-backward translation. Of the Cantonese-speaking participants aged ≥15 years, 2,635 were randomly selected from the random sample component of the FAMILY Cohort, a territory-wide cohort study in Hong Kong. In addition to the SHS, a single-item overall happiness scale, the Patient Health Questionnaire-9 (PHQ-9), the Family Adaptation, Partnership, Growth, Affection, Resolve (APGAR) scale, and the Medical Outcomes Study 12-item short-form version 2 (SF-12) mental and physical health scales were administered. Exploratory and confirmatory factor analyses supported a single factor with high loadings for the four SHS items. Multiple group analyses indicated factor invariance across sex and age groups. Cronbach's alpha was 0.82, and 2-week test-retest reliability (n = 191) was 0.70. The SHS correlated significantly with single-item overall happiness (Spearman's rho [ρ] = 0.57), Family APGAR (ρ = 0.26), PHQ-9 (ρ = -0.34), and mental health-related quality of life (ρ = 0.40) but showed a lower correlation with physical health (ρ = 0.15). A regression model that included the PHQ-9 and Family APGAR scores explained 37% of the variance in SF-12 mental health scores; adding the SHS raised the variance explained to 41 %. Our results support the reliability and validity of the SHS as a relevant component in the measurement battery for mental well-being in a Chinese general population.

Preparation For Medical School via an Intensive Summer Program for Future Doctors: A Pilot Study of Student Confidence and Reasoning Skills

ERIC Educational Resources Information Center

Musick, David W.; Ray, Richard H.

2016-01-01

A medical school conducted a summer pre-matriculation program. The program provided basic sciences content comparable to first year medical student instruction along with clinical and other learning experiences. The study purpose was to examine self-confidence levels and reasoning skills of a single cohort of students. We examined the association…

Rare copy number variants in patients with congenital conotruncal heart defects.

PubMed

Xie, Hongbo M; Werner, Petra; Stambolian, Dwight; Bailey-Wilson, Joan E; Hakonarson, Hakon; White, Peter S; Taylor, Deanne M; Goldmuntz, Elizabeth

2017-03-01

Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome. Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls. Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development. Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Selective versus routine patch metal allergy testing to select bar material for the Nuss procedure in 932 patients over 10years.

PubMed

Obermeyer, Robert J; Gaffar, Sheema; Kelly, Robert E; Kuhn, M Ann; Frantz, Frazier W; McGuire, Margaret M; Paulson, James F; Kelly, Cynthia S

2018-02-01

The aim of the study was to determine the role of patch metal allergy testing to select bar material for the Nuss procedure. An IRB-approved (11-04-WC-0098) single institution retrospective, cohort study comparing selective versus routine patch metal allergy testing to select stainless steel or titanium bars for Nuss repair was performed. In Cohort A (9/2004-1/2011), selective patch testing was performed based on clinical risk factors. In Cohort B (2/2011-9/2014), all patients were patch tested. The cohorts were compared for incidence of bar allergy and resultant premature bar loss. Risk factors for stainless steel allergy or positive patch test were evaluated. Cohort A had 628 patients with 63 (10.0%) selected for patch testing, while all 304 patients in Cohort B were tested. Over 10years, 15 (1.8%) of the 842 stainless steel Nuss repairs resulted in a bar allergy, and 5 had a negative preoperative patch test. The incidence of stainless steel bar allergy (1.8% vs 1.7%, p=0.57) and resultant bar loss (0.5% vs 1.3%, p=0.23) was not statistically different between cohorts. An allergic reaction to a stainless steel bar or a positive patch test was more common in females (OR=2.3, p<0.001) and patients with a personal (OR=24.8, p<0.001) or family history (OR=3.1, p<0.001) of metal sensitivity. Stainless steel bar allergies occur at a low incidence with either routine or selective patch metal allergy testing. If selective testing is performed, it is advisable in females and patients with a personal or family history of metal sensitivity. A negative preoperative patch metal allergy test does not preclude the possibility of a postoperative stainless steel bar allergy. Level III Treatment Study and Study of Diagnostic Test. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of Long-term Differences in Dysphagia: Cervical Arthroplasty and Anterior Cervical Fusion.

PubMed

Smucker, Joseph D; Bassuener, Scott R; Sasso, Rick C; Riew, K Daniel

2017-10-01

Retrospective cohort study. This study investigates the incidence of long-term dysphagia in cervical disc arthroplasty, and anterior cervical discectomy and fusion (ACDF) patients. No long-term comparison of dysphagia between cervical arthroplasty and fusion patients has been published. Widely variable short-term postsurgical dysphagia rates have been reported. Cohorts for this study are patients with single-level cervical degenerative disc disease previously enrolled in a randomized clinical trial comparing cervical arthroplasty and ACDF. Subjective modified Bazaz Dysphagia Severity questionnaires were distributed to each patient at a minimum of 5 years postoperative for the long-term assessment. Dysphagia severity data were pooled to compare the rate of patients with dysphagia (grade>1) to asymptomatic (grade=1). In the arthroplasty cohort, 15 of 22 (68%) patients completed long-term swallowing questionnaires with no reports of dysphagia. Eighteen of 25 (72%) ACDF patients completed questionnaires, with 5 of 18 (28%) reporting dysphagia. This is a statistically significant difference (P=0.042) favoring lower rates of long-term dysphagia after cervical arthroplasty at an average interval of 7 years postoperative (range, 5.5-8.5 y). No significant difference between rates of self-reported short-term dysphagia was noted with 12% (3/25) and 9% (2/22) in the ACDF and arthroplasty groups, respectively (P=0.56). All short-term dysphagia cases in the arthroplasty cohort reported complete resolution of symptoms within 12 months postoperative. In the ACDF cohort, persistent symptoms at 7 years were noted in all responding patients. Three ACDF patients reported new late-onset, which was not noted in the arthroplasty cohort. To date, these findings represent the longest reported follow-up interval comparing rates of dysphagia between randomized cohorts of cervical arthroplasty and fusion patients. Our study suggests that cervical arthroplasty is less likely than ACDF to cause sustained long-term or late-presenting dysphagia.

Multimorbidity and the risk of restless legs syndrome in 2 prospective cohort studies.

PubMed

Szentkirályi, András; Völzke, Henry; Hoffmann, Wolfgang; Trenkwalder, Claudia; Berger, Klaus

2014-06-03

Our aim was to evaluate the association between the cumulative effect of comorbidity and the risk of restless legs syndrome (RLS) in 2 population-based German cohort studies. The Dortmund Health Study (DHS) (n = 1,312; median follow-up time: 2.1 years) and the Study of Health in Pomerania (SHIP) (n = 4,308; median follow-up time: 5.0 years) were used for the analyses. RLS was assessed at baseline and follow-up according to the RLS minimal criteria. A comorbidity index was calculated as a sum of the following conditions: diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine. The relationship between comorbidity and incident RLS was analyzed with multivariate logistic regression models. An increase in the number of comorbid conditions at baseline predicted prevalent RLS (DHS: trend odds ratio [OR] = 1.24, 95% confidence interval [CI] 0.99-1.56; SHIP: trend OR = 1.34, 95% CI 1.18-1.52) and incident RLS (DHS: trend OR = 1.32, 95% CI 1.04-1.68; SHIP: trend OR = 1.59, 95% CI 1.37-1.85) after adjustment for several covariates. The ORs for incident RLS associated with 3 or more comorbid diseases (DHS: OR = 2.51, 95% CI 1.18-5.34; SHIP: OR = 4.30, 95% CI 2.60-7.11) were higher than the ORs for any single disease. Multimorbidity was a strong risk factor for RLS in these 2 population-based cohort studies. The results support the hypothesis that cumulative disease burden is more important than the presence of a specific single disease in the pathophysiology of RLS. © 2014 American Academy of Neurology.

Preeclampsia does not share common risk alleles in 9p21 with coronary artery disease and type 2 diabetes.

PubMed

Kaartokallio, Tea; Lokki, A Inkeri; Peterson, Hanna; Kivinen, Katja; Hiltunen, Leena; Salmela, Elina; Lappalainen, Tuuli; Maanselkä, Paula; Heino, Sanna; Knuutila, Sakari; Sayed, Ayat; Poston, Lucilla; Brennecke, Shaun P; Johnson, Matthew P; Morgan, Linda; Moses, Eric K; Kere, Juha; Laivuori, Hannele

2016-08-01

Preeclampsia is a common and partially genetic pregnancy complication characterized by hypertension and proteinuria. Association with cardiovascular disease and type 2 diabetes has been reported in 9p21 by several genome-wide association studies. It has been hypothesized that cardiometabolic diseases may share common etiology with preeclampsia. We tested association with the 9p21 region to preeclampsia in the Finnish population by genotyping 23 tagging single nucleotide polymorphisms (SNPs) in 15 extended preeclampsia families and in a nationwide cohort consisting of 281 cases and 349 matched controls. Replication was conducted in additional datasets. Four SNPs (rs7044859, rs496892, rs564398 and rs7865618) showed nominal association (p ≤ 0.024 uncorrected) with preeclampsia in the case-control cohort. To increase power, we genotyped two SNPs in additional 388 cases and 341 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort. Partial replication was also attempted in a UK cohort (237 cases and 199 controls) and in 74 preeclamptic families from Australia/New Zealand. We were unable to replicate the initial association in the extended Finnish dataset or in the two international cohorts. Our study did not find evidence for the involvement of the 9p21 region in the risk of preeclampsia. Key Message Chromosome 9p21 is not associated with preeclampsia.

Comparing the rubella seronegativity in pregnant women who received one dose of rubella vaccine at different ages in Taiwan.

PubMed

Shih, Ching-Tang; Chang, Yuan-Chun; Wang, Huey-Lan; Lin, Ching-Chiang

2016-09-14

Vaccination is the best strategy to prevent rubella and congenital rubella. The aim of our study was to assess the immunity to rubella and determine rubella virus antibody titers in pregnant women who were offered a single dose of rubella vaccine at different ages of their lives. A total 15,067 rubella IgG antibody test results for Taiwanese pregnant women who received routine prenatal checkup at Fooyin University Hospital from 1999 to 2014 were analyzed in this study. The women were divided into five birth cohorts in order to compare their rubella seronegativities and antibody titers according to the different period of rubella vaccination policy in Taiwan. The total rubella seronegativity rate was 11.2% (95% CI: 10.7-11.7%) and the mean rubella antibody titers was 51.0IU/mL (SD=54.7IU/mL). The junior school cohort has the lowest rubella seronegativity of 7.6% (95% CI: 6.9-8.2%). The seronegativities were significantly high in the preschool cohort and in the 15-month-old cohort, 14.9% (95% CI: 13.2-16.6%) and 14.8% (95% CI: 11.5-18.1%), respectively. The OR values were 2.1 (95% CI: 1.8-2.5, p<0.001) in the preschool cohort and 2.2 (95% CI: 1.6-2.8, p<0.001) in the 15-month-old cohort, respectively, against the junior school cohort. Women in the 15-month-old cohort have lowest average rubella IgG titer, 25.4IU/mL. The total rubella seronegativity rate was 11.2% in all native pregnant women. Women who received one dose rubella vaccine at preschool and 15-month-old have highest seronegativities. The 15-month-old cohort has the lowest average rubella IgG titer. We recommend a revised catch-up immunization policy to women who received one dose rubella vaccine at a younger age. Copyright © 2016 Elsevier Ltd. All rights reserved.

Early Prediction of Intensive Care Unit-Acquired Weakness: A Multicenter External Validation Study.

PubMed

Witteveen, Esther; Wieske, Luuk; Sommers, Juultje; Spijkstra, Jan-Jaap; de Waard, Monique C; Endeman, Henrik; Rijkenberg, Saskia; de Ruijter, Wouter; Sleeswijk, Mengalvio; Verhamme, Camiel; Schultz, Marcus J; van Schaik, Ivo N; Horn, Janneke

2018-01-01

An early diagnosis of intensive care unit-acquired weakness (ICU-AW) is often not possible due to impaired consciousness. To avoid a diagnostic delay, we previously developed a prediction model, based on single-center data from 212 patients (development cohort), to predict ICU-AW at 2 days after ICU admission. The objective of this study was to investigate the external validity of the original prediction model in a new, multicenter cohort and, if necessary, to update the model. Newly admitted ICU patients who were mechanically ventilated at 48 hours after ICU admission were included. Predictors were prospectively recorded, and the outcome ICU-AW was defined by an average Medical Research Council score <4. In the validation cohort, consisting of 349 patients, we analyzed performance of the original prediction model by assessment of calibration and discrimination. Additionally, we updated the model in this validation cohort. Finally, we evaluated a new prediction model based on all patients of the development and validation cohort. Of 349 analyzed patients in the validation cohort, 190 (54%) developed ICU-AW. Both model calibration and discrimination of the original model were poor in the validation cohort. The area under the receiver operating characteristics curve (AUC-ROC) was 0.60 (95% confidence interval [CI]: 0.54-0.66). Model updating methods improved calibration but not discrimination. The new prediction model, based on all patients of the development and validation cohort (total of 536 patients) had a fair discrimination, AUC-ROC: 0.70 (95% CI: 0.66-0.75). The previously developed prediction model for ICU-AW showed poor performance in a new independent multicenter validation cohort. Model updating methods improved calibration but not discrimination. The newly derived prediction model showed fair discrimination. This indicates that early prediction of ICU-AW is still challenging and needs further attention.

Focal Cryotherapy for Localized Prostate Cancer.

PubMed

Tay, K J; Polascik, T J

2016-07-01

To systematically review the oncological and functional outcomes of contemporary primary prostate focal cryotherapy for localized prostate cancer in the context of current developments in prostate focal therapy. We performed a systematic search of the Pubmed, Cochrane and Embase databases to identify studies where primary prostate focal cryotherapy was performed to treat prostate cancer. These included reports on focal/ lesion/ sector ablation, hemi-ablation and partial prostate ablation. We excluded salvage focal therapy studies. Where multiple reports were published over time from a single cohort, the latest one was used. Our search yielded 290 publications, including 17 primary reports on eight single-center cohort studies and one multi-center registry report. Of 1,595 men identified, mean age was 60.5-69.5 years and mean PSA 5.1-7.8 ng/ml. When stratified by D'Amico risk criteria, 52% of the aggregate total number of men were low-risk, 38% intermediate-risk and 10% high-risk. Besides 12-core TRUS biopsy, 3 cohorts reported using TTMB and one included mpMRI to select men for focal treatment. Median follow-up ranged from 13-63 months. BPFS ranged from 71-98%. The overall post-treatment positive biopsy rate was 8-25%. Among 5 cohorts with a mandatory 6-12 month posttreatment biopsy, 216 of 272 men (79%) did undergo biopsy, with 47 positive (21.8%). Of these, 15 were infield, 26 outfield, 2 bilateral and 4 undeclared. Ten upgraded to Gleason≥7. Overall, two men had metastatic disease and none died of prostate cancer. Post-treatment continence rates were 96-100% and rates of erectile dysfunction ranged from 0-42%. The rate of post-treatment urinary retention ranged from 0-15%. The rate of recto-urethral fistula was 0-0.1%. Focal cryotherapy for localized prostate cancer is a safe and provides good preservation of sexual and urinary function. Accurate cancer localization and risk stratification is key to patient selection. In highly selected patients, focal therapy has good short to medium term oncological efficacy.

Early life socioeconomic determinants of dietary score and pattern trajectories across six waves of the Longitudinal Study of Australian Children.

PubMed

Gasser, Constantine E; Mensah, Fiona K; Kerr, Jessica A; Wake, Melissa

2017-12-01

Social patterning of dietary-related diseases may partly be explained by population disparities in children's diets. This study aimed to determine which early life socioeconomic factors best predict dietary trajectories across childhood. For waves 2-6 of the Baby (B) Cohort (ages 2-3 to 10-11 years) and waves 1-6 of the Kindergarten (K) Cohort (ages 4-5 to 14-15 years) of the Longitudinal Study of Australian Children, we constructed trajectories of dietary scores and of empirically derived dietary patterns. Dietary scores, based on the Australian Dietary Guidelines, summed children's consumption frequencies of seven groups of foods or drinks over the last 24 hours. Dietary patterns at each wave were derived using factor analyses of 12-16 food or drink items. Using multinomial logistic regression analyses, we examined associations of baseline single (parental education, remoteness area, parental employment, income, food security and home ownership) and composite (socioeconomic position and neighbourhood disadvantage) factors with adherence to dietary trajectories. All dietary trajectory outcomes across both cohorts showed profound gradients by composite socioeconomic position but not by neighbourhood disadvantage. For example, odds for children in the lowest relative to highest socioeconomic position quintile being in the 'never healthy' relative to the 'always healthy' score trajectory were OR=16.40, 95% CI 9.40 to 28.61 (B Cohort). Among the single variables, only parental education consistently predicted dietary trajectories. Child dietary trajectories vary profoundly by family socioeconomic position. If causal, reducing dietary inequities may require researching underlying pathways, tackling socioeconomic inequities and targeting health promoting interventions to less educated families. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

World Hip Trauma Evaluation (WHiTE): framework for embedded comprehensive cohort studies.

PubMed

Costa, Matthew L; Griffin, Xavier L; Achten, Juul; Metcalfe, David; Judge, Andrew; Pinedo-Villanueva, Rafael; Parsons, Nicholas

2016-10-21

Osteoporotic hip fractures present a significant global challenge to patients, clinicians and healthcare systems. It is estimated that hip fracture accounts for 1.4% of total social and healthcare costs in the established market economies. The World Hip Trauma Evaluation (WHiTE) was set up to measure outcome in a comprehensive cohort of UK patients with hip fracture. All patients in the cohort are treated under a single comprehensive treatment pathway. A core outcome set, including health-related quality of life, is collected on all the patients. This protocol describes the current multicentre project that will be used as a vehicle to deliver a series of embedded observational studies. Research Ethics Committee approval was granted (Rec reference 11/LO/0927, approved 18/8/2011) and each hospital trust provided National Health Service (NHS) approvals. The study is registered with National Institute of Health Research Portfolio (UKCRN ID 12351) and the ISRCTN registry (ISRCTN63982700). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The child health exposure analysis resource as a vehicle to measure environment in the environmental influences on child health outcomes program.

PubMed

Wright, Robert O; Teitelbaum, Susan; Thompson, Claudia; Balshaw, David

2018-04-01

Demonstrate the role of environment as a predictor of child health. The children's health exposure analysis resource (CHEAR) assists the Environmental influences on child health outcomes (ECHO) program in understanding the time sensitive and dynamic nature of perinatal and childhood environment on developmental trajectories by providing a central infrastructure for the analysis of biological samples from the ECHO cohort awards. CHEAR will assist ECHO cohorts in defining the critical or sensitive period for effects associated with environmental exposures. Effective incorporation of these principles into multiple existing cohorts requires extensive multidisciplinary expertise, creativity, and flexibility. The pursuit of life course - informed research within the CHEAR/ECHO structure represents a shift in focus from single exposure inquiries to one that addresses multiple environmental risk factors linked through shared vulnerabilities. CHEAR provides ECHO both targeted analyses of inorganic and organic toxicants, nutrients, and social-stress markers and untargeted analyses to assess the exposome and discovery of exposure-outcome relationships. Utilization of CHEAR as a single site for characterization of environmental exposures within the ECHO cohorts will not only support the investigation of the influence of environment on children's health but also support the harmonization of data across the disparate cohorts that comprise ECHO.

Segmenting a general practitioner market to improve recruitment outcomes.

PubMed

Hemphill, Elizabeth; Kulik, Carol T

2011-05-01

Recruitment is an ongoing challenge in the health industry with general practitioner (GP) shortages in many areas beyond rural and Indigenous communities. This paper suggests a marketing solution that identifies different segments of the GP market for recruitment strategy development. In February 2008, 96 GPs in Australia responded to a mail questionnaire (of which 85 questionnaires were useable). A total of 350 GPs were sent the questionnaire. Respondents considered small sets of attributes in the decision to accept a new job at a general practice and selected the most and least important attribute from each set. We identified latent class clusters (cohorts) of GPs from the most-least important data. Three cohorts were found in the GP market, distinguishing practitioners who emphasised job, family or practice attributes in their decision to join a practice. Few significant demographic differences exist between the cohorts. A segmented GP market suggests two alternative recruitment strategies. One option is for general practices to target members of a single cohort (family-, job-, or practice-focussed GPs). The other option is for general practices to diversify their recruitment strategies to target all three cohorts (family-, job- and practice-focussed GPs). A single brand (practice) can have multiple advertising strategies with each strategy involving advertising activities targeting a particular consumer segment.

[The cardiovascular mortality in Tiumen' cohort depending on social gradient].

PubMed

Akimova, E V; Smaznov, V Iu; Kaiumova, M M; Gafarov, V V; Kuznetsov, V A

2008-01-01

The study was carried out on two representative samples from electoral roll of citizen aged from 25 to 64 years of the Central administrative okrug of the city of Tyumen. The procedures of mail survey and cardiological screening were applied. In the process of prospective monitoring of the mentioned investigated cohort during the last seven years the detection of cases of death from cardiovascular diseases on the basis of Tyumen administration registry office was analyzed. The relative risk of death from cardiovascular causes had unilateral increase in males and females paralleled by the increase of education level. The significant relationship of the relative risk of death from cardiovascular diseases with the professional involvement was established in the group of toil workers. Depending of the marital status relative risk of death from cardiovascular causes among persons of different gender had disdirectional trend. It increased among family status females as compared with single females and, on the contrary, significantly decreased among married males as compared with divorced, single and widowed males.

The role of gender in social network organization.

PubMed

Psylla, Ioanna; Sapiezynski, Piotr; Mones, Enys; Lehmann, Sune

2017-01-01

The digital traces we leave behind when engaging with the modern world offer an interesting lens through which we study behavioral patterns as expression of gender. Although gender differentiation has been observed in a number of settings, the majority of studies focus on a single data stream in isolation. Here we use a dataset of high resolution data collected using mobile phones, as well as detailed questionnaires, to study gender differences in a large cohort. We consider mobility behavior and individual personality traits among a group of more than 800 university students. We also investigate interactions among them expressed via person-to-person contacts, interactions on online social networks, and telecommunication. Thus, we are able to study the differences between male and female behavior captured through a multitude of channels for a single cohort. We find that while the two genders are similar in a number of aspects, there are robust deviations that include multiple facets of social interactions, suggesting the existence of inherent behavioral differences. Finally, we quantify how aspects of an individual's characteristics and social behavior reveals their gender by posing it as a classification problem. We ask: How well can we distinguish between male and female study participants based on behavior alone? Which behavioral features are most predictive?

Comparison of Clinicopathological Characteristics in the Patients with Cardiac Cancer with or without Esophagogastric Junctional Invasion: A Single-Center Retrospective Cohort Study

PubMed Central

Ito, Hiroaki; Inoue, Haruhiro; Odaka, Noriko; Satodate, Hitoshi; Suzuki, Michitaka; Mukai, Shumpei; Takehara, Yusuke; Omoto, Tomokatsu; Kudo, Shin-ei

2013-01-01

Background. This study addresses clinicopathological differences between patients with gastric cardia and subcardial cancer with and without esophagogastric junctional invasion. Methods. We performed a single-center, retrospective cohort study. We studied patients who underwent curative surgery for gastric cardia and subcardial cancers. Tumors centered in the proximal 5 cm of the stomach were classed into two types, according to whether they did (Ge) or did not (G) invade the esophagogastric junction. Results. A total of 80 patients were studied; 19 (73.1%) of 26 Ge tumors and 16 (29.6%) of 54 G tumors had lymph nodes metastases. Incidence of nodal metastasis in pT1 tumors was significantly higher in the Ge tumor group. No nodal metastasis in cervical lymph nodes was recognized. Only two patients with Ge tumors had mediastinal lymph node metastases. Incidence of perigastric lymph node metastasis was significantly higher in those with Ge tumors. Ge tumors tended to be staged as progressive disease using the esophageal cancer staging manual rather than the gastric cancer staging manual. Conclusion. Because there are some differences in clinicopathological characteristics, it is thought to be adequate to distinguish type Ge from type G tumor. PMID:23365732

The role of gender in social network organization

PubMed Central

Psylla, Ioanna; Mones, Enys; Lehmann, Sune

2017-01-01

The digital traces we leave behind when engaging with the modern world offer an interesting lens through which we study behavioral patterns as expression of gender. Although gender differentiation has been observed in a number of settings, the majority of studies focus on a single data stream in isolation. Here we use a dataset of high resolution data collected using mobile phones, as well as detailed questionnaires, to study gender differences in a large cohort. We consider mobility behavior and individual personality traits among a group of more than 800 university students. We also investigate interactions among them expressed via person-to-person contacts, interactions on online social networks, and telecommunication. Thus, we are able to study the differences between male and female behavior captured through a multitude of channels for a single cohort. We find that while the two genders are similar in a number of aspects, there are robust deviations that include multiple facets of social interactions, suggesting the existence of inherent behavioral differences. Finally, we quantify how aspects of an individual’s characteristics and social behavior reveals their gender by posing it as a classification problem. We ask: How well can we distinguish between male and female study participants based on behavior alone? Which behavioral features are most predictive? PMID:29261767

Work and retirement among a cohort of older men in the United States, 1966-1983.

PubMed

Hayward, M D; Grady, W R

1990-08-01

Multivariate increment-decrement working life tables are estimated for a cohort of older men in the United States for the period 1966-1983. The approach taken allows multiple processes to be simultaneously incorporated into a single model, resulting in a more realistic portrayal of a cohort's late-life labor force behavior. In addition, because the life table model is developed from multivariate hazard equations, we identify the effects of sociodemographic characteristics on the potentially complex process by which the labor force career is ended. In contrast to the assumed homogeneity of previous working life table analyses, the present study shows marked differences in labor force mobility and working and nonworking life expectancy according to occupation, class of worker, education, race, and marital status. We briefly discuss the implications of these findings for inequities of access to retirement, private and public pension consumption, and future changes in the retirement process.

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program

PubMed Central

Gwinn, Katrina; David, Karen K; Swanson-Fischer, Christine; Albin, Roger; Hillaire-Clarke, Coryse St; Sieber, Beth-Anne; Lungu, Codrin; Bowman, F DuBois; Alcalay, Roy N; Babcock, Debra; Dawson, Ted M; Dewey, Richard B; Foroud, Tatiana; German, Dwight; Huang, Xuemei; Petyuk, Vlad; Potashkin, Judith A; Saunders-Pullman, Rachel; Sutherland, Margaret; Walt, David R; West, Andrew B; Zhang, Jing; Chen-Plotkin, Alice; Scherzer, Clemens R; Vaillancourt, David E; Rosenthal, Liana S

2017-01-01

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset. PMID:28644039

Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study.

PubMed

Luigetti, Marco; Del Grande, Alessandra; Testani, Elisa; Bisogni, Giulia; Losurdo, Anna; Giannantoni, Nadia Mariagrazia; Mazza, Salvatore; Sabatelli, Mario; Della Marca, Giacomo

2013-09-15

to determine the prevalence of restless legs syndrome (RLS) in a cohort of patients with demyelinating neuropathies. Patients were retrospectively recruited from our cohort of different forms of demyelinating neuropathies, including chronic inflammatory demyelinating neuropathy (CIDP), Charcot-Marie-Tooth 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP) referred to our Department of Neurology in a 10-year period. The validated 4-item RLS questionnaire was used for diagnosis of RLS. All patients with RLS who fulfilled criteria underwent a suggested immobilization test to confirm the diagnosis. A group of outpatients referred to the sleep disorders unit and data from published literature were used as controls. Prevalence of RLS in demyelinating neuropathy group was higher than prevalence observed in control population (p = 0.0142) or in the literature data (p = 0.0007). In particular, in comparison with both control population and literature data, prevalence of RLS was higher in CIDP group (p = 0.0266 and p = 0.0063, respectively) and in CMT1A group (p = 0.0312 and p = 0.0105, respectively), but not in HNPP (p = 1.000 and p = 0.9320, respectively). our study confirms a high prevalence of RLS in inflammatory neuropathies as CIDP and, among inherited neuropathies, in CMT1A but not in HNPP. Considering that this is only a small cohort from a single-center retrospective experience, the link between RLS and neuropathy remains uncertain, and larger multicenter studies are probably needed to clarify the real meaning of the association between RLS and neuropathy.

COMPARISON OF BASELINE UROLOGIC SYMPTOMS IN MEN AND WOMEN IN THE MULTIDISCIPLINARY APPROACH TO THE STUDY OF CHRONIC PELVIC PAIN (MAPP) RESEARCH COHORT

PubMed Central

Clemens, J. Quentin; Clauw, Daniel J.; Kreder, Karl; Krieger, John N.; Kusek, John W.; Lai, H. Henry; Rodriguez, Larissa; Williams, David A.; Hou, Xiaoling; Stephens, Alisa; Landis, J Richard

2015-01-01

INTRODUCTION The clinical features of interstitial cystitis/ bladder pain syndrome (IC/BPS) are similar to those of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, no studies have directly compared the characteristics of these syndromes in men and women. METHODS The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network recruited 191 men and 233 women with IC/BPS or CP/CPPS. Baseline data included demographics, the Interstitial Cystitis Symptom Index (ICSI) and Problem Index (ICPI), the Genitourinary Pain Index (GUPI), the American Urological Association Symptom Index (AUASI), Likert scales to assess urinary urgency, frequency, pain and overall symptom severity, and a single question about the most bothersome pelvic symptom. RESULTS After adjustment for age, income and symptom duration, measures of pain severity were similar across genders. Mean scores for the ICSI, ICPI and AUASI were significantly higher in women than men, reflecting more bladder-focused symptoms in women. The most bothersome single symptom in both men and women was pain in the pubic/bladder area (34% of men, 58% of women). The characteristics of the men and women in the MAPP cohort were similar to those reported in other research cohorts of IC/BPS and CP/CPPS. CONCLUSIONS Our findings indicate that pain severity is similar in both sexes, and that bladder-focused symptoms (urgency, suprapubic pain, frequency) are more common in women. However, a substantial proportion of men also report these types of bladder symptoms. PMID:25463989

Molecular subgroups of adult medulloblastoma: a long-term single-institution study.

PubMed

Zhao, Fu; Ohgaki, Hiroko; Xu, Lei; Giangaspero, Felice; Li, Chunde; Li, Peng; Yang, Zhijun; Wang, Bo; Wang, Xingchao; Wang, Zhenmin; Ai, Lin; Zhang, Jing; Luo, Lin; Liu, Pinan

2016-07-01

Recent transcriptomic approaches have demonstrated that there are at least 4 distinct subgroups in medulloblastoma (MB); however, survival studies of molecular subgroups in adult MB have been inconclusive because of small sample sizes. The aim of this study is to investigate the molecular subgroups in adult MB and identify their clinical and prognostic implications in a large, single-institution cohort. We determined gene expression profiles for 13 primary adult MBs. Bioinformatics tools were used to establish distinct molecular subgroups based on the most informative genes in the dataset. Immunohistochemistry with subgroup-specific antibodies was then used for validation within an independent cohort of 201 formalin-fixed MB tumors, in conjunction with a systematic analysis of clinical and histological characteristics. Three distinct molecular variants of adult MB were identified: the SHH, WNT, and group 4 subgroups. Validation of these subgroups in the 201-tumor cohort by immunohistochemistry identified significant differences in subgroup-specific demographics, histology, and metastatic status. The SHH subgroup accounted for the majority of the tumors (62%), followed by the group 4 subgroup (28%) and the WNT subgroup (10%). Group 4 tumors had significantly worse progression-free and overall survival compared with tumors of the other molecular subtypes. We have identified 3 subgroups of adult MB, characterized by distinct expression profiles, clinical features, pathological features, and prognosis. Clinical variables incorporated with molecular subgroup are more significantly informative for predicting adult patient outcome. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

What Goes Around Can Come Around: An Unexpected Deleterious Effect of Using Mouse Running Wheels for Environmental Enrichment

PubMed Central

Leduc, Renee Y M; Rauw, Gail; Baker, Glen B; McDermid, Heather E

2017-01-01

Environmental enrichment items such as running wheels can promote the wellbeing of laboratory mice. Growing evidence suggests that wheel running simulates exercise effects in many mouse models of human conditions, but this activity also might change other aspects of mouse behavior. In this case study, we show that the presence of running wheels leads to pronounced and permanent circling behavior with route-tracing in a proportion of the male mice of a genetically distinct cohort. The genetic background of this cohort includes a mutation in Arhgap19, but genetic crosses showed that an unknown second-site mutation likely caused the induced circling behavior. Behavioral tests for inner-ear function indicated a normal sense of gravity in the circling mice. However, the levels of dopamine, serotonin, and some dopamine metabolites were lower in the brains of circling male mice than in mice of the same genetic background that were weaned without wheels. Circling was seen in both singly and socially housed male mice. The additional stress of fighting may have exacerbated the predisposition to circling in the socially housed animals. Singly and socially housed male mice without wheels did not circle. Our current findings highlight the importance and possibly confounding nature of the environmental and genetic background in mouse behavioral studies, given that the circling behavior and alterations in dopamine and serotonin levels in this mouse cohort occurred only when the male mice were housed with running wheels. PMID:28315651

Effects of etomidate on complications related to intubation and on mortality in septic shock patients treated with hydrocortisone: a propensity score analysis

PubMed Central

2012-01-01

Introduction Endotracheal intubation in the ICU is associated with a high incidence of complications. Etomidate use is debated in septic shock because it increases the risk of critical illness-related corticosteroid insufficiency, which may impact outcome. We hypothesized that hydrocortisone, administered in all septic shock cases in our ICU, may counteract some negative effects of etomidate. The aim of our study was to compare septic shock patients who received etomidate versus another induction drug both for short-term safety and for long-term outcomes. Methods A single-center observational study was carried out in septic shock patients, treated with hydrocortisone and intubated within the first 48 hours of septic shock. Co-primary end points were life-threatening complications incidence occurring within the first hour after intubation and mortality during the ICU stay. Statistical analyses included unmatched and matched cohorts using a propensity score analysis. P < 0.05 was considered significant. Results Sixty patients in the etomidate cohort and 42 patients in the non-etomidate cohort were included. Critical illness-related corticosteroid insufficiency was 79% in the etomidate cohort and 52% in the non-etomidate cohort (P = 0.01). After intubation, life-threatening complications occurred in 36% of the patients whatever the cohort. After adjustment with propensity score analysis, etomidate was a protective factor for death in the ICU both in unmatched (hazard ratio, 0.33 (0.15 to 0.75); P < 0.01)) and matched cohorts (hazard ratio, 0.33 (0.112 to 0.988); P = 0.04). Conclusion In septic shock patients treated with hydrocortisone, etomidate did not decrease life-threatening complications following intubation, but when associated with hydrocortisone it also did not impair outcome. PMID:23171852

Esophagus cancer and radiation exposure due to nuclear test fallout: an analysis based on the data of the Semipalatinsk historical cohort, 1960-1999.

PubMed

Bauer, S; Gusev, B I; Pivina, L M; Apsalikov, K N; Grosche, B

2006-01-01

This paper describes the Semipalatinsk historical cohort study and, in particular, examines the association between combined external and internal radiation exposure and esophagus cancer. Esophagus cancer is the most frequent single cancer site in the cause of death follow-up for the Semipalatinsk cohort. Set up in the 1960s, this historical cohort included 10 exposed settlements in the vicinity of the Semipalatinsk nuclear test site in East Kazakhstan as well as 6 comparison settlements in a low exposure area of the same region. The external and internal radiation doses to the population of the settlements under study were mainly due to local fallout from atmospheric nuclear testing (1949-1962). The database includes dosimetry and health information for 19.545 inhabitants of exposed and comparison villages in the Semipalatinsk region, comprising a total of 582.750 person-years of follow-up between 1960 and 1999. Cumulative effective dose estimates in this cohort range from 20 mSv to -4 Sv, with a mean dose of 634 mSv in the exposed group. Relative risks were calculated in terms of rate ratios, using a Poisson regression model for grouped person-time data. Esophagus cancer was found substantially elevated, with a statistically significant increase of the relative risk with dose and an ERR/Sv of 2.37 (1.45; 3.28) for the total cohort. If the data set was restricted to the exposed group only, the ERR/Sv was found considerably lower (0.18 (-0.16; 0.52)), whereas the dose-response remained significant only in women. Overall, our results based on the Semipalatinsk historical cohort indicate an association between fallout exposure and the risk of esophagus cancer that should be further investigated.

Blood-based NfL

PubMed Central

Janelidze, Shorena; Hall, Sara; Magdalinou, Nadia; Lees, Andrew J.; Andreasson, Ulf; Norgren, Niklas; Linder, Jan; Forsgren, Lars; Constantinescu, Radu; Zetterberg, Henrik; Blennow, Kaj

2017-01-01

Objective: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders. Methods: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated. Results: We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81). Conclusions: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics. Classification of evidence: This study provides Class III evidence that blood NfL levels discriminate between PD and APD. PMID:28179466

Contact Kinematic Differences Between Gap Balanced vs Measured Resection Techniques for Single Radius Posterior-Stabilized Total Knee Arthroplasty.

PubMed

Teeter, Matthew G; Perry, Kevin I; Yuan, Xunhua; Howard, James L; Lanting, Brent A

2017-06-01

Measured resection (MR) and gap balancing (GB) are common surgical techniques for total knee arthroplasty (TKA). Controversy has arisen as each conceptually differs in how the knee is balanced through bone and soft tissue management. The objective of the present study was to compare both the frequency of condylar liftoff and the location of femorotibial contact from extension through midflexion between patients undergoing GB or MR TKA. A total of 24 knees (23 patients) were randomly assigned at referral to either a surgeon performing MR or GB TKA with the same single radius, posterior-stabilized implant (12 per cohort). At 1-year postoperation, patients underwent biplanar radiographic imaging at 0°, 20°, 40°, and 60° of flexion. Condylar liftoff, contact location, and magnitude of excursion on each condyle were measured. Preoperative and postoperative clinical outcome scores were also collected. There was no difference (P = .41) in the frequency of liftoff between cohorts. The MR cohort had more posterior contact on the medial condyle (P < .01) and more anterior contact on the lateral condyle (P < .01) throughout flexion. Motion patterns were similar between cohorts, with similar medial (P = .48) and lateral (P = .44) excursion, which was equal in magnitude between condyles for both MR (P = .48) and GB (P = .73). There was no difference in clinical outcome scores between groups. For this particular implant system, GB and MR appear to produce similar kinematic and patient-reported outcome results. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of a Middle-Age and Geriatric Trauma Mortality Risk Score A Tool to Guide Palliative Care Consultations.

PubMed

Konda, Sanjit R; Seymour, Rachel; Manoli, Arthur; Gales, Jordan; Karunakar, Madhav A

2016-11-01

This study aimed to develop a tool to quantify risk of inpatient mortality among geriatric and middleaged trauma patients. This study sought to demonstrate the ability of the novel risk score in the early identification of high risk trauma patients for resource-sparing interventions, including referral to palliative medicine. This retrospective cohort study utilized data from a single level 1 trauma center. Regression analysis was used to create a novel risk of inpatient mortality score. A total of 2,387 low energy and 1,201 high-energy middle-aged (range: 55 to 64 years of age) and geriatric (65 years of age or odler) trauma patients comprised the study cohort. Model validation was performed using 37,474 lowenergy and 97,034 high-energy patients from the National Trauma Databank (NTDB). Potential hospital cost reduction was calculated for early referral of high risk trauma patients to palliative medicine services in comparison to no palliative medicine referral. Factors predictive of inpatient mortality among the study and validation patient cohorts included; age, Glasgow Coma Scale, and Abbreviated Injury Scale for the head and neck and chest. Within the validation cohort, the novel mortality risk score demonstrated greater predictive capacity than existing trauma scores [STTGMALE-AUROC: 0.83 vs. TRISS 0.80, (p < 0.01), STTGMAHE-AUROC: 0.86 vs. TRISS 0.85, (p < 0.01)]. Our model demonstrated early palliative medicine evaluation could produce $1,083,082 in net hospital savings per year. This novel risk score for older trauma patients has shown fidelity in prediction of inpatient mortality; in the study and validation cohorts. This tool may be used for early intervention in the care of patients at high risk of mortality and resource expenditure.

Genome-wide association study of sporadic brain arteriovenous malformations.

PubMed

Weinsheimer, Shantel; Bendjilali, Nasrine; Nelson, Jeffrey; Guo, Diana E; Zaroff, Jonathan G; Sidney, Stephen; McCulloch, Charles E; Al-Shahi Salman, Rustam; Berg, Jonathan N; Koeleman, Bobby P C; Simon, Matthias; Bostroem, Azize; Fontanella, Marco; Sturiale, Carmelo L; Pola, Roberto; Puca, Alfredo; Lawton, Michael T; Young, William L; Pawlikowska, Ludmila; Klijn, Catharina J M; Kim, Helen

2016-09-01

The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium. The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls. The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort. We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Medical Student Views of Substance Abuse Treatment, Policy and Training

ERIC Educational Resources Information Center

Agrawal, Shantanu; Everett, Worth W.; Sharma, Sonali

2010-01-01

Purpose: This study examined the impact of medical education on students' views of substance abuse treatment, public policy options and training. Method: A longitudinal survey was conducted on a single-class cohort of 101 students in a major American, urban medical school. The survey was administered in the Spring semesters of the first to third…

Preadmission Schooling Context Helps to Predict Examination Performance throughout Medical School

ERIC Educational Resources Information Center

Stringer, Neil; Chan, Michael; Bimpeh, Yaw; Chan, Philip

2017-01-01

This study investigates the effects of socioeconomic status and schooling on the academic attainment of a cohort of students at a single medical school (N = 240). Partial least squares structural equation modelling was used to explore how students' summative assessment scores over 4 years of medical school were affected by: attainment in secondary…

Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.

PubMed

Dehghan, Abbas; Köttgen, Anna; Yang, Qiong; Hwang, Shih-Jen; Kao, Wh Linda; Rivadeneira, Fernando; Boerwinkle, Eric; Levy, Daniel; Hofman, Albert; Astor, Brad C; Benjamin, Emelia J; van Duijn, Cornelia M; Witteman, Jacqueline C; Coresh, Josef; Fox, Caroline S

2008-12-06

Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.

Declining prevalence of HIV-1 drug resistance in treatment-failing patients: a clinical cohort study.

PubMed

Di Giambenedetto, Simona; Bracciale, Laura; Colafigli, Manuela; Colatigli, Manuela; Cattani, Paola; Pinnetti, Carmen; Pannetti, Carmen; Bacarelli, Alessandro; Prosperi, Mattia; Fadda, Giovanni; Cauda, Roberto; De Luca, Andrea

2007-01-01

A major barrier to successful viral suppression in HIV type 1 (HIV-1)-infected individuals is the emergence of virus resistant to antiretroviral drugs. We explored the evolution of genotypic drug resistance prevalence in treatment-failing patients from 1999 to 2005 in a clinical cohort. Prevalence of major International AIDS Society-USA HIV-1 drug resistance mutations was measured over calendar years in a population with treatment failure and undergoing resistance testing. Predictors of the presence of resistance mutations were analysed by logistic regression. Significant reductions of the prevalence of resistance to all three drug classes examined were observed. This was accompanied by a reduction in the proportion of treatment-failing patients. Independent predictors of drug resistance were the earlier calendar year, prior use of suboptimal nucleoside analogue therapy, male sex and higher CD4 levels at testing. In a single clinical cohort, we observed a decrease in the prevalence of resistance to all three examined antiretroviral drug classes over time. If this finding is confirmed in multicentre cohorts it may translate into reduced transmission of drug-resistant virus from treated patients.

China’s marriage squeeze: A decomposition into age and sex structure

PubMed Central

LI, Xiaomin; LI, Shuzhuo; FELDMAN, Marcus W.

2016-01-01

Most recent studies of marriage patterns in China have emphasized the male-biased sex ratio but have largely neglected age structure as a factor in China’s male marriage squeeze. In this paper we develop an index we call “spousal sex ratio” (SSR) to measure the marriage squeeze, and a method of decomposing the proportion of male surplus into age and sex structure effects within a small spousal age difference interval. We project that China’s marriage market will be confronted with a relatively severe male squeeze. For the decomposition of the cohort aged 30, from 2010 to 2020 age structure will be dominant, while from 2020 through 2034 the contribution of age structure will gradually decrease and that of sex structure will increase. From then on, sex structure will be dominant. The index and decomposition, concentrated on a specific female birth cohort, can distinguish spousal competition for single cohorts which may be covered by a summary index for the whole marriage market; these can also be used for consecutive cohorts to reflect the situation of the whole marriage market. PMID:27242390

China's marriage squeeze: A decomposition into age and sex structure.

PubMed

Jiang, Quanbao; Li, Xiaomin; Li, Shuzhuo; Feldman, Marcus W

2016-06-01

Most recent studies of marriage patterns in China have emphasized the male-biased sex ratio but have largely neglected age structure as a factor in China's male marriage squeeze. In this paper we develop an index we call "spousal sex ratio" (SSR) to measure the marriage squeeze, and a method of decomposing the proportion of male surplus into age and sex structure effects within a small spousal age difference interval. We project that China's marriage market will be confronted with a relatively severe male squeeze. For the decomposition of the cohort aged 30, from 2010 to 2020 age structure will be dominant, while from 2020 through 2034 the contribution of age structure will gradually decrease and that of sex structure will increase. From then on, sex structure will be dominant. The index and decomposition, concentrated on a specific female birth cohort, can distinguish spousal competition for single cohorts which may be covered by a summary index for the whole marriage market; these can also be used for consecutive cohorts to reflect the situation of the whole marriage market.

Single Motherhood, Alcohol Dependence, and Smoking During Pregnancy: A Propensity Score Analysis.

PubMed

Waldron, Mary; Bucholz, Kathleen K; Lian, Min; Lessov-Schlaggar, Christina N; Miller, Ruth Huang; Lynskey, Michael T; Knopik, Valerie S; Madden, Pamela A F; Heath, Andrew C

2017-09-01

Few studies linking single motherhood and maternal smoking during pregnancy consider correlated risk from problem substance use beyond history of smoking and concurrent use of alcohol. In the present study, we used propensity score methods to examine whether the risk of smoking during pregnancy associated with single motherhood is the result of potential confounders, including alcohol dependence. Data were drawn from mothers participating in a birth cohort study of their female like-sex twin offspring (n = 257 African ancestry; n = 1,711 European or other ancestry). We conducted standard logistic regression models predicting smoking during pregnancy from single motherhood at twins' birth, followed by propensity score analyses comparing single-mother and two-parent families stratified by predicted probability of single motherhood. In standard models, single motherhood predicted increased risk of smoking during pregnancy in European ancestry but not African ancestry families. In propensity score analyses, rates of smoking during pregnancy were elevated in single-mother relative to two-parent European ancestry families across much of the spectrum a priori risk of single motherhood. Among African ancestry families, within-strata comparisons of smoking during pregnancy by single-mother status were nonsignificant. These findings highlight single motherhood as a unique risk factor for smoking during pregnancy in European ancestry mothers, over and above alcohol dependence. Additional research is needed to identify risks, beyond single motherhood, associated with smoking during pregnancy in African ancestry mothers.

Treatment of Patients With Hepatitis C Virus Infection With Ledipasvir-Sofosbuvir in the Liver Transplant Setting.

PubMed

Abaalkhail, Faisal; Elsiesy, Hussein; Elbeshbeshy, Hany; Shawkat, Mohamed; Yousif, Sarra; Ullah, Waheed; Alabbad, Saleh; Al-Jedai, Ahmed; Ajlan, Aziza; Broering, Dieter; Saab, Sammy; Al Sebayel, Mohammed; Al-Hamoudi, Waleed

2017-11-01

Hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma and the leading indication for liver transplantation. In the Middle East, genotype 4 HCV infection is the most common genotype. However, limited data exists on the treatment of genotype-4 in the liver transplant setting. We evaluated the safety and efficacy of ledipasvir (LDV)-sofosbuvir (SOF) in treating HCV genotype-4 infected patients with cirrhosis or postliver transplantation. This prospective, single-arm, observational study includes cohort of patients with cirrhosis before liver transplantation (cohort A) and a cohort of postliver transplantation patients (cohort B). Patients received LDV/SOF (90-400 mg) once daily for 12 to 24 weeks with or without ribavirin (RBV). Patients with creatinine clearance below 30 were excluded. A total of 111 patients (61 cirrhotic; 50 postliver transplants) with HCV genotype 4 were treated in King Faisal Specialist Hospital and Research Center; 55% cohort A and 44% cohort B received RBV. Sustained virological response sustain virological response (SVR)12 was 91.8% and 86% of cohorts A and B, respectively. There were no treatment-related mortality or serious adverse effects. RBV dose reduction occurred in 25% without any treatment discontinuation. SVR12 rates in cohort A were significantly higher in patients with a viral load below 800 000 (100% vs 83.9%, P value = 0.022). Viral load did not impact SVR rates in cohort B. The use of RBV did not increase SVR12 and was associated with anemia. LDV/SOF without RBV is an effective and safe treatment option for patients with HCV genotype 4 infection in preliver and postliver transplant settings.

Gene-Lifestyle Interactions in Complex Diseases: Design and Description of the GLACIER and VIKING Studies

PubMed Central

Kurbasic, Azra; Poveda, Alaitz; Chen, Yan; Ågren, Åsa; Engberg, Elisabeth; Hu, Frank B.; Johansson, Ingegerd; Barroso, Ines; Brändström, Anders; Hallmans, Göran; Renström, Frida; Franks, Paul W.

2014-01-01

Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics. PMID:25396097

Gene-Lifestyle Interactions in Complex Diseases: Design and Description of the GLACIER and VIKING Studies.

PubMed

Kurbasic, Azra; Poveda, Alaitz; Chen, Yan; Agren, Asa; Engberg, Elisabeth; Hu, Frank B; Johansson, Ingegerd; Barroso, Ines; Brändström, Anders; Hallmans, Göran; Renström, Frida; Franks, Paul W

2014-12-01

Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics.

Ten‐Year Blood Pressure Trajectories, Cardiovascular Mortality, and Life Years Lost in 2 Extinction Cohorts: the Minnesota Business and Professional Men Study and the Zutphen Study

PubMed Central

Tielemans, Susanne M. A. J.; Geleijnse, Johanna M.; Menotti, Alessandro; Boshuizen, Hendriek C.; Soedamah‐Muthu, Sabita S.; Jacobs, David R.; Blackburn, Henry; Kromhout, Daan

2015-01-01

Background Blood pressure (BP) trajectories derived from measurements repeated over years have low measurement error and may improve cardiovascular disease prediction compared to single, average, and usual BP (single BP adjusted for regression dilution). We characterized 10‐year BP trajectories and examined their association with cardiovascular mortality, all‐cause mortality, and life years lost. Methods and Results Data from 2 prospective and nearly extinct cohorts of middle‐aged men—the Minnesota Business and Professional Men Study (n=261) and the Zutphen Study (n=632)—were used. BP was measured annually during 1947–1957 in Minnesota and 1960–1970 in Zutphen. BP trajectories were identified by latent mixture modeling. Cox proportional hazards and linear regression models examined BP trajectories with cardiovascular mortality, all‐cause mortality, and life years lost. Associations were adjusted for age, serum cholesterol, smoking, and diabetes mellitus. Mean initial age was about 50 years in both cohorts. After 10 years of BP measurements, men were followed until death on average 20 years later. All Minnesota men and 98% of Zutphen men died. Four BP trajectories were identified, in which mean systolic BP increased by 5 to 49 mm Hg in Minnesota and 5 to 20 mm Hg in Zutphen between age 50 and 60. The third systolic BP trajectories were associated with 2 to 4 times higher cardiovascular mortality risk, 2 times higher all‐cause mortality risk, and 4 to 8 life years lost, compared to the first trajectory. Conclusions Ten‐year BP trajectories were the strongest predictors, among different BP measures, of cardiovascular mortality, all‐cause mortality, and life years lost in Minnesota. However, average BP was the strongest predictor in Zutphen. PMID:25753924

Change of sleep quality from pre- to 3 years post-solid organ transplantation: The Swiss Transplant Cohort Study

PubMed Central

Denhaerynck, Kris; Huynh-Do, Uyen; Binet, Isabelle; Hadaya, Karine; De Geest, Sabina

2017-01-01

Background Poor sleep quality (SQ) is common after solid organ transplantation; however, very little is known about its natural history. We assessed the changes in SQ from pre- to 3 years post-transplant in adult heart, kidney, liver and lung recipients included in the prospective nation-wide Swiss Transplant Cohort Study. We explored associations with selected variables in patients suffering persistent poor SQ compared to those with good or variable SQ. Methods Adult single organ transplant recipients enrolled in the Swiss Transplant Cohort Study with pre-transplant and at least 3 post-transplant SQ assessment data were included. SQ was self-reported pre-transplant (at listing), then at 6, 12, 24 and 36 months post-transplant. A single SQ item was used to identify poor (0–5) and good sleepers (6–10). Between organ groups, SQ was compared via logistic regression analysis with generalized estimating equations. Within the group reporting persistently poor SQ, we used logistic regression or Kaplan-Meier analysis as appropriate to check for differences in global quality of life and survival. Results In a sample of 1173 transplant patients (age: 52.1±13.2 years; 65% males; 66% kidney, 17% liver, 10% lung, 7% heart) transplanted between 2008 and 2012, pre- transplant poor SQ was highest in liver (50%) and heart (49%) recipients. Overall, poor SQ decreased significantly from pre-transplant (38%) to 24 months post-transplant (26%) and remained stable at 3 years (29%). Patients reporting persistently poor SQ had significantly more depressive symptomatology and lower global quality of life. Conclusion Because self-reported poor SQ is related to poorer global quality of life, these results emphasize the need for further studies to find suitable treatment options for poor SQ in transplant recipients. PMID:29020112

Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

PubMed

Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

2016-01-01

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

Integrating health profile with survival for quality of life assessment.

PubMed

Hwang, Jing-Shiang; Wang, Jung-Der

2004-02-01

In cohort studies or clinical trials, measurements of quality of life (QoL) were averaged across available individuals for each group at given points in time to produce single measures for comparisons. However, estimates of these single measures may be severely biased if substantial mortality occurs over time. The objective of this study is to develop a method that integrates QoL measurement and survival for long-term evaluation of health services. We defined a mean QoL score function over time for an index population as the average QoL score of all individuals both alive and dead at each time point in the population. While a living subject's QoL can be assessed by asking one's subjective preference, the score of a decedent can be assigned a fixed value depending on the specific facet on health profile. The mean QoL score function over time is reduced to a single measure of expected cumulative QoL score, which is the area under the curve of mean QoL score function over a given time interval and can be estimated by taking a random sample from a cross-sectional survey. For the QoL score function to be extrapolated to life-long, it requires the assumption that the disease causes premature death or a long-term moderate impairment of QoL. We provided methods and computer programs for estimating mean QoL score functions and the reduced single measures for use in comparisons. A cohort of 779 breast cancer patients from Chiangmai, Thailand were followed for 12 years to demonstrate the proposed methods. The data included the 12-year complete survival records and QoL scores on 233 patients collected from a cross-sectional survey using WHOQOL questionnaire and standard gamble method. The expected cumulative QoL scores using utility and psychometric scales were compared among patients in four groups of clinical stages in this cohort for time from onset up to 12 years and life-long. We conclude that such an integration of QoL measurement with survival can be useful for the evaluation of health service and clinical decision.

Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies & methylation analysis of 3 studies in the Cohorts for Heart & Aging Research

USDA-ARS?s Scientific Manuscript database

Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression. Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation. Design: We selected 7 SNPs on the basis of predic...

A class of non-linear exposure-response models suitable for health impact assessment applicable to large cohort studies of ambient air pollution.

PubMed

Nasari, Masoud M; Szyszkowicz, Mieczysław; Chen, Hong; Crouse, Daniel; Turner, Michelle C; Jerrett, Michael; Pope, C Arden; Hubbell, Bryan; Fann, Neal; Cohen, Aaron; Gapstur, Susan M; Diver, W Ryan; Stieb, David; Forouzanfar, Mohammad H; Kim, Sun-Young; Olives, Casey; Krewski, Daniel; Burnett, Richard T

2016-01-01

The effectiveness of regulatory actions designed to improve air quality is often assessed by predicting changes in public health resulting from their implementation. Risk of premature mortality from long-term exposure to ambient air pollution is the single most important contributor to such assessments and is estimated from observational studies generally assuming a log-linear, no-threshold association between ambient concentrations and death. There has been only limited assessment of this assumption in part because of a lack of methods to estimate the shape of the exposure-response function in very large study populations. In this paper, we propose a new class of variable coefficient risk functions capable of capturing a variety of potentially non-linear associations which are suitable for health impact assessment. We construct the class by defining transformations of concentration as the product of either a linear or log-linear function of concentration multiplied by a logistic weighting function. These risk functions can be estimated using hazard regression survival models with currently available computer software and can accommodate large population-based cohorts which are increasingly being used for this purpose. We illustrate our modeling approach with two large cohort studies of long-term concentrations of ambient air pollution and mortality: the American Cancer Society Cancer Prevention Study II (CPS II) cohort and the Canadian Census Health and Environment Cohort (CanCHEC). We then estimate the number of deaths attributable to changes in fine particulate matter concentrations over the 2000 to 2010 time period in both Canada and the USA using both linear and non-linear hazard function models.

Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort

PubMed Central

Gambin, Tomasz; Akdemir, Zeynep C.; Yuan, Bo; Gu, Shen; Chiang, Theodore; Carvalho, Claudia M.B.; Shaw, Chad; Jhangiani, Shalini; Boone, Philip M.; Eldomery, Mohammad K.; Karaca, Ender; Bayram, Yavuz; Stray-Pedersen, Asbjørg; Muzny, Donna; Charng, Wu-Lin; Bahrambeigi, Vahid; Belmont, John W.; Boerwinkle, Eric; Beaudet, Arthur L.; Gibbs, Richard A.

2017-01-01

Abstract We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor–Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi-exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17–50% of pathogenic CNVs in different disease cohorts where 7.1–11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses. PMID:27980096

The PHF21B gene is associated with major depression and modulates the stress response.

PubMed

Wong, M-L; Arcos-Burgos, M; Liu, S; Vélez, J I; Yu, C; Baune, B T; Jawahar, M C; Arolt, V; Dannlowski, U; Chuah, A; Huttley, G A; Fogarty, R; Lewis, M D; Bornstein, S R; Licinio, J

2017-07-01

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.

Breastfeeding, Bottle Feeding Practices and Malocclusion in the Primary Dentition: A Systematic Review of Cohort Studies

PubMed Central

Hermont, Ana Paula; Martins, Carolina C.; Zina, Lívia G.; Auad, Sheyla M.; Paiva, Saul M.; Pordeus, Isabela A.

2015-01-01

The World Health Organization recommends exclusive breast feeding for at least six months. However, there is no scientific evidence of the benefits of breast feeding for oral health in children under primary dentition. This study aimed to search for scientific evidence regarding the following question: is bottle feeding associated with malocclusion in the primary dentition compared to children that are breastfed? An electronic search was performed in seven databases. The systematic review included 10 cohort studies. It was not possible to conduct meta-analysis; therefore a qualitative analysis was assessed. The majority of studies evaluated feeding habits by means of questionnaires and conducted a single examination. Three studies observed that bottle feeding was significantly associated with overjet and posterior crossbite. Studies reported several cut-off times for breastfeeding (varying from 1 month up to 3 years of age) and several types of malocclusion. Controlling for non-nutritive sucking habits was reported for only half of the studies and this may have led to biased results. The scientific evidence could not confirm a specific type of malocclusion associated with the feeding habits or an adequate time of breastfeeding to benefit the children against malocclusion. Further cohort studies are needed to confirm this evidence. PMID:25785498

Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort.

PubMed

Brookes, Keeley J; McConnell, George; Williams, Kirsty; Chaudhury, Sultan; Madhan, Gaganjit; Patel, Tulsi; Turley, Christopher; Guetta-Baranes, Tamar; Bras, Jose; Guerreiro, Rita; Hardy, John; Francis, Paul T; Morgan, Kevin

2018-06-08

The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOEɛ4 allele was identified (p = 3.99×10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.

Cost-Effectiveness of a Diabetes Pay-For-Performance Program in Diabetes Patients with Multiple Chronic Conditions.

PubMed

Hsieh, Hui-Min; Gu, Song-Mao; Shin, Shyi-Jang; Kao, Hao-Yun; Lin, Yi-Chieh; Chiu, Herng-Chia

2015-01-01

Pay for performance (P4P) has been used as a strategy to improve quality for patients with chronic illness. Little was known whether care provided to individuals with multiple chronic conditions in a P4P program were cost-effective. This study investigated cost effectiveness of a diabetes P4P program for caring patients with diabetes alone (DM alone) and diabetes with comorbid hypertension and hyperlipidemia (DMHH) from a single payer perspective in Taiwan. Analyzing data using population-based longitudinal databases, we compared costs and effectiveness between P4P and non-P4P diabetes patient groups in two cohorts. Propensity score matching (PSM) was used to match comparable control groups for intervention groups. Outcomes included life-years, quality-adjusted life-years (QALYs), program intervention costs, cost-savings and incremental cost-effectiveness ratios (ICERs). QALYs for P4P patients and non-P4P patients were 2.80 and 2.71 for the DM alone cohort and 2.74 and 2.66 for the DMHH patient cohort. The average incremental intervention costs per QALYs was TWD$167,251 in the DM alone cohort and TWD$145,474 in the DMHH cohort. The average incremental all-cause medical costs saved by the P4P program per QALYs were TWD$434,815 in DM alone cohort and TWD$506,199 in the DMHH cohort. The findings indicated that the P4P program for both cohorts were cost-effective and the resulting return on investment (ROI) was 2.60:1 in the DM alone cohort and 3.48:1 in the DMHH cohort. We conclude that the diabetes P4P program in both cohorts enabled the long-term cost-effective use of resources and cost-savings, especially for patients with multiple comorbid conditions.

Cost-Effectiveness of a Diabetes Pay-For-Performance Program in Diabetes Patients with Multiple Chronic Conditions

PubMed Central

Hsieh, Hui-Min; Gu, Song-Mao; Shin, Shyi-Jang; Kao, Hao-Yun; Lin, Yi-Chieh; Chiu, Herng-Chia

2015-01-01

Pay for performance (P4P) has been used as a strategy to improve quality for patients with chronic illness. Little was known whether care provided to individuals with multiple chronic conditions in a P4P program were cost-effective. This study investigated cost effectiveness of a diabetes P4P program for caring patients with diabetes alone (DM alone) and diabetes with comorbid hypertension and hyperlipidemia (DMHH) from a single payer perspective in Taiwan. Analyzing data using population-based longitudinal databases, we compared costs and effectiveness between P4P and non-P4P diabetes patient groups in two cohorts. Propensity score matching (PSM) was used to match comparable control groups for intervention groups. Outcomes included life-years, quality-adjusted life-years (QALYs), program intervention costs, cost-savings and incremental cost-effectiveness ratios (ICERs). QALYs for P4P patients and non-P4P patients were 2.80 and 2.71 for the DM alone cohort and 2.74 and 2.66 for the DMHH patient cohort. The average incremental intervention costs per QALYs was TWD$167,251 in the DM alone cohort and TWD$145,474 in the DMHH cohort. The average incremental all-cause medical costs saved by the P4P program per QALYs were TWD$434,815 in DM alone cohort and TWD$506,199 in the DMHH cohort. The findings indicated that the P4P program for both cohorts were cost-effective and the resulting return on investment (ROI) was 2.60:1 in the DM alone cohort and 3.48:1 in the DMHH cohort. We conclude that the diabetes P4P program in both cohorts enabled the long-term cost-effective use of resources and cost-savings, especially for patients with multiple comorbid conditions. PMID:26173086

Non-Cholesterol Sterol Levels Predict Hyperglycemia and Conversion to Type 2 Diabetes in Finnish Men

PubMed Central

Cederberg, Henna; Gylling, Helena; Miettinen, Tatu A.; Paananen, Jussi; Vangipurapu, Jagadish; Pihlajamäki, Jussi; Kuulasmaa, Teemu; Stančáková, Alena; Smith, Ulf; Kuusisto, Johanna; Laakso, Markku

2013-01-01

We investigated the levels of non-cholesterol sterols as predictors for the development of hyperglycemia (an increase in the glucose area under the curve in an oral glucose tolerance test) and incident type 2 diabetes in a 5-year follow-up study of a population-based cohort of Finnish men (METSIM Study, N = 1,050) having non-cholesterol sterols measured at baseline. Additionally we determined the association of 538,265 single nucleotide polymorphisms (SNP) with non-cholesterol sterol levels in a cross-sectional cohort of non-diabetic offspring of type 2 diabetes (the Kuopio cohort of the EUGENE2 Study, N = 273). We found that in a cross-sectional METSIM Study the levels of sterols indicating cholesterol absorption were reduced as a function of increasing fasting glucose levels, whereas the levels of sterols indicating cholesterol synthesis were increased as a function of increasing 2-hour glucose levels. A cholesterol synthesis marker desmosterol significantly predicted an increase, and two absorption markers (campesterol and avenasterol) a decrease in the risk of hyperglycemia and incident type 2 diabetes in a 5-year follow-up of the METSIM cohort, mainly attributable to insulin sensitivity. A SNP of ABCG8 was associated with fasting plasma glucose levels in a cross-sectional study but did not predict hyperglycemia or incident type 2 diabetes. In conclusion, the levels of some, but not all non-cholesterol sterols are markers of the worsening of hyperglycemia and type 2 diabetes. PMID:23840693

Developmental dysplasia of the hip: impact of sonographic newborn hip screening on the outcome of early treated decentered hip joints-a single center retrospective comparative cohort study based on Graf's method of hip ultrasonography.

PubMed

Tschauner, Christian; Fürntrath, Frank; Saba, Yasaman; Berghold, Andrea; Radl, Roman

2011-12-01

PURPOSE/BACKGROUND/INTRODUCTION: The aim of this study was to retrospectively evaluate the impact of neonatal sonographic hip screening using Graf's method for the management and outcome of orthopaedic treatment of decentered hip joints with developmental dysplasia of the hip (DDH), using three decades (1978-2007) of clinical information compiled in a medical database. Three representative cohorts of consecutive cases of decentered hip joints were selected according to different search criteria and inclusion and exclusion parameters: (1) cohort 1 (1978-1982; n = 80), without sonographic screening; (2) cohort 2.1 (1994-1996; n = 91), with nationwide established general sonographic screening according to the Graf-method; (3) cohort 2.2 (2003-2005; n = 91), with sonographic screening including referred cases for open reduction from non-screened populations. These three cohorts were compared for the following parameters: age at initial treatment, successful closed reduction, necessary overhead traction, necessary adductor-tenotomy, rate of open reduction, rate of avascular necrosis (AVN) and rate of secondary acetabuloplasty. The age at initial treatment was reduced from 5.5 months in the first cohort to 2 months in the two subsequent two cohorts and the rate of successful closed reduction increased from 88.7 to 98.9 and 95.6%, respectively. There was a statistically significant improvement in six out of seven parameters with sonographic hip screening; only the rate of secondary acetabuloplasty did not improve significantly. Compared to the era before the institution of a sonographic hip screening programme according to the Graf-method in Austria in 1992, ultrasound screening based-treatment of decentered hip joints has become safer, shorter and simpler: "safer" means lower rate of AVN, "shorter" means less treatment time due to earlier onset and "simpler" means that the devices are now less invasive and highly standardized.

Determinants of quality of life in adults with CHD: an Australian cohort.

PubMed

Eaton, Sarah L; Wang, QiFeng; Menahem, Samuel

2017-10-01

Following improved survival rates in children with CHD, their quality of life and its determinants have become increasingly important. As part of a multicentre study entitled "Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart Disease - International Study", this article reviews the relationships among quality of life, anxiety and depression, sense of coherence, and severity of disease in an Australian cohort of adults with CHD. Methods and results Adults with CHD were recruited from a single, community-based cardiology practice. All patients completed a self-reported questionnaire. A total of 135 patients, 71 males and 64 females, were recruited with a mean age of 26 years. The median quality of life in this cohort was 90; one-fifth of the patients experienced symptoms of anxiety. There was a significant negative correlation between quality of life and symptoms of anxiety and depression and a positive correlation between quality of life and sense of coherence. The quality of life of this cohort was generally excellent; however, one-fifth of them experienced symptoms of anxiety. Those with less anxiety and depression symptoms appeared to have a better quality of life, as did those who reported a higher sense of coherence. Interestingly, there was no significant relationship between complexity of CHD and quality of life.

Empirical performance of the calibrated self-controlled cohort analysis within temporal pattern discovery: lessons for developing a risk identification and analysis system.

PubMed

Norén, G Niklas; Bergvall, Tomas; Ryan, Patrick B; Juhlin, Kristina; Schuemie, Martijn J; Madigan, David

2013-10-01

Observational healthcare data offer the potential to identify adverse drug reactions that may be missed by spontaneous reporting. The self-controlled cohort analysis within the Temporal Pattern Discovery framework compares the observed-to-expected ratio of medical outcomes during post-exposure surveillance periods with those during a set of distinct pre-exposure control periods in the same patients. It utilizes an external control group to account for systematic differences between the different time periods, thus combining within- and between-patient confounder adjustment in a single measure. To evaluate the performance of the calibrated self-controlled cohort analysis within Temporal Pattern Discovery as a tool for risk identification in observational healthcare data. Different implementations of the calibrated self-controlled cohort analysis were applied to 399 drug-outcome pairs (165 positive and 234 negative test cases across 4 health outcomes of interest) in 5 real observational databases (four with administrative claims and one with electronic health records). Performance was evaluated on real data through sensitivity/specificity, the area under receiver operator characteristics curve (AUC), and bias. The calibrated self-controlled cohort analysis achieved good predictive accuracy across the outcomes and databases under study. The optimal design based on this reference set uses a 360 days surveillance period and a single control period 180 days prior to new prescriptions. It achieved an average AUC of 0.75 and AUC >0.70 in all but one scenario. A design with three separate control periods performed better for the electronic health records database and for acute renal failure across all data sets. The estimates for negative test cases were generally unbiased, but a minor negative bias of up to 0.2 on the RR-scale was observed with the configurations using multiple control periods, for acute liver injury and upper gastrointestinal bleeding. The calibrated self-controlled cohort analysis within Temporal Pattern Discovery shows promise as a tool for risk identification; it performs well at discriminating positive from negative test cases. The optimal parameter configuration may vary with the data set and medical outcome of interest.

Socio-demographic characteristics of participation in the opportunistic German cervical cancer screening programme: results from the EPIC-Heidelberg cohort.

PubMed

Seidel, David; Becker, Nikolaus; Rohrmann, Sabine; Nimptsch, Katharina; Linseisen, Jakob

2009-04-01

To analyse participation in the German cervical cancer screening programme by socio-demographic characteristics. In the EPIC-Heidelberg cohort study 13,612 women aged 35-65 years were recruited between 1994 and 1998. Follow-up questionnaires were used to analyse participation in cervical cancer screening. Subjects were categorised according to age (birth cohort), education, vocational training, employment status, marital status and household size. Associations between socio-demographic characteristics and participation in cervical cancer screening were analysed using multinomial logistic regression. Females of the oldest and middle birth cohort were less likely to be screened compared to the youngest birth cohort. Less-educated women and those with a low-level secondary school degree had a decreased likelihood of undergoing screening in comparison to better educated women. Married women and women living in households with four or more persons were more likely to participate in the screening programme than single women or women living alone. Employment status did not modify participation in cervical cancer screening. Knowledge on the characteristics of women with a lower attendance to cervical cancer screening could be used to improve the effectiveness of the current (opportunistic) programme by dedicated health promotion programmes. However, an organized screening programme with written invitation of all eligible women would be the preferred option.

Radiation dose in 320-slice multidetector cardiac CT: a single center experience of evolving dose minimization.

PubMed

Tung, Matthew K; Cameron, James D; Casan, Joshua M; Crossett, Marcus; Troupis, John M; Meredith, Ian T; Seneviratne, Sujith K

2013-01-01

Minimization of radiation exposure remains an important subject that occurs in parallel with advances in scanner technology. We report our experience of evolving radiation dose and its determinants after the introduction of 320-multidetector row cardiac CT within a single tertiary cardiology referral service. Four cohorts of consecutive patients (total 525 scans), who underwent cardiac CT at defined time points as early as 2008, are described. These include a cohort just after scanner installation, after 2 upgrades of the operating system, and after introduction of an adaptive iterative image reconstruction algorithm. The proportions of nondiagnostic coronary artery segments and studies with nondiagnostic segments were compared between cohorts. Significant reductions were observed in median radiation doses in all cohorts compared with the initial cohort (P < .001). Median dose-length product fell from 944 mGy · cm (interquartile range [IQR], 567.3-1426.5 mGy · cm) to 156 mGy · cm (IQR, 99.2-265.0 mGy · cm). Although the proportion of prospectively triggered scans has increased, reductions in radiation dose have occurred independently of distribution of scan formats. In multiple regression that combined all groups, determinants of dose-length product were tube output, the number of cardiac cycles scanned, tube voltage, scan length, scan format, body mass index, phase width, and heart rate (adjusted R(2) = 0.85, P < .001). The proportion of nondiagnostic coronary artery segments was slightly increased in group 4 (2.9%; P < .01). While maintaining diagnostic quality in 320-multidetector row cardiac CT, the radiation dose has decreased substantially because of a combination of dose-reduction protocols and technical improvements. Continued minimization of radiation dose will increase the potential for cardiac CT to expand as a cardiac imaging modality. Copyright © 2013 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.

Analysis of Formant Frequencies in Patients with Oral or Oropharyngeal Cancers Treated by Glossectomy

ERIC Educational Resources Information Center

Kazi, Rehan; Prasad, Vyas M. N.; Kanagalingam, Jeeve; Georgalas, Christos; Venkitaraman, Ramachandran; Nutting, Christopher M.; Clarke, Peter; Rhys-Evans, Peter; Harrington, Kevin J.

2007-01-01

Aims: To compare voice quality as defined by formant analysis using a sustained vowel in patients who have undergone a partial glossectomy with a group of normal subjects. Methods & Procedures: The design consisted of a single centre, cross-sectional cohort study. The setting was an Adult Tertiary Referral Unit. A total of 26 patients (19…

Infant Mortality in Washington, D.C.: A Study of Risk Factors among Black Residents.

ERIC Educational Resources Information Center

Ahmed, Feroz

This report examines the determinants of the high level of infant mortality in Washington, D.C. Data were analyzed for 36,872 black resident single-delivery births occurring in the years 1980 through 1984, and 762 infant deaths occurring to these birth cohorts from 1980 to 1985. Findings were the following: (1) poor birthweight distribution among…

The Relative Benefits and Cost of Medicaid Home- and Community-Based Services in Florida

ERIC Educational Resources Information Center

Mitchell, Glenn, II; Salmon, Jennifer R.; Polivka, Larry; Soberon-Ferrer, Horacio

2006-01-01

Purpose: We compared inpatient days, nursing home days, and total Medicaid claims for five Medicaid-funded home- and community-based services (HCBS) programs for in-home and assisted living services in Florida. Design and Methods: We studied a single cohort of Medicaid enrollees in Florida aged 60 and older, who were enrolled for the first time in…

Determinants of establishment survival for residential trees in Sacramento County, CA

Treesearch

Lara A. Roman; John J. Battles; Joe R. McBride

2014-01-01

Urban forests can provide ecosystem services that motivate tree planting campaigns, and tree survival is a key element of program success and projected benefits. We studied survival in a shade tree give-away program in Sacramento, CA, monitoring a cohort of young trees for five years on single-family residential properties. We used conditional inference trees to...

Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors in a single-center cohort.

PubMed

Kander, Elizabeth M; Raza, Sania; Zhou, Zheng; Gao, Juehua; Zakarija, Anaadriana; McMahon, Brandon J; Stein, Brady L

2015-11-01

The BCR-ABL1-negative myeloproliferative neoplasms (MPN) share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhage are less well defined than those for thrombosis. Because patients with CALR mutations have higher platelet counts compared to JAK2 V617F-mutated patients, bleeding rates may be increased in this group. Our aim was to retrospectively evaluate whether acquired von Willebrand disease (AvWD), thrombocytosis, mutational status, or treatment history are associated with bleeding in a cohort of MPN patients. Using an electronic database, MPN patients seen between 2005 and 2013 were retrospectively identified using ICD-9 codes and billing records. A bleeding event was defined as one that was identified in the medical record and graded based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0. Among 351 MPN patients, 15.6 % experienced 64 bleeding event types. There was no association of bleeding with mutational status, gender, MPN subtype, aspirin use, prior thrombosis, or platelet count at presentation. There was an association between bleeding and older age at diagnosis. aVWD was identified in six patients. In this single-center retrospective study, bleeding events were identified in 15 % of patients, and associated with older age at diagnosis. aVWD was rarely tested for in this cohort.

Criminal victimization in childhood and adolescence according to official records: the Pelotas (Brazil) birth cohort study

PubMed Central

Giraldo Gallo, Erika Alejandra; Menezes, Ana Maria B.; Murray, Joseph; Duarte da Silva, Luciana Anselmi; Wehrmeister, Fernando César; Gonçalves, Helen; Barros, Fernando

2016-01-01

This article describes different types of officially recorded victimization among 5,249 children in the 1993 birth cohort in the city of Pelotas, Rio Grande do Sul State, Brazil. Official data were obtained from the Secretariat for Public Security and the Special Court for Children and Youth. Victimization was registered for in 1,150 cohort members, with 1,396 incidents recorded as of December 31, 2012. The total incidence of victimization was 15.7 ocorrences per 1,000 person-years, with the majority involving violent victimization (12.7 per 1,000 person-years). Victimization increased gradually in childhood and rapidly throughout adolescence. The highest incidence rates were among females (p < 0.05), the poor (p < 0.05), children of adolescent mothers (p < 0.001), and children of single mothers (p < 0.05). The most common violent victimization types were physical injuries, robbery, and crimes against personal freedom; non-violent victimization mainly involved theft. Studies like this help identify lifetime risk and protective factors for victimization, highlighting the importance of surveillance and control measures against violence. PMID:27580232

Clinical Profile and Early Complications after Single and Dual Chamber Permanent Pacemaker Implantation at Manmohan Cardiothoracic Vascular and Transplant Centre, Kathmandu, Nepal.

PubMed

Khanal, J; Poudyal, R R; Devkota, S; Thapa, S; Dhungana, R R

2015-01-01

Permanent pacemaker implantation is a minimally invasive surgical procedure in the management of patients with cardiac problems. However, complications during and after implantation are not uncommon. There is lack of evidences in rate of complications with the selection of pacemakers in Nepal. Therefore, this study was performed to compare the frequency of implantation and complication rate between single chamber and dual chamber pacemaker. The present study is based on all consecutive pacemaker implantations in a single centre between April 2014 and May 2015. A total of 116 patients were categorized into two cohorts according to the type of pacemaker implanted- single chamber or dual chamber. All patients had regular 2-weeks follow-up intervals with standardized documentation of all relevant patient data till 6-week after implantation. Data were presented as means ± standard deviation (SD) for continuous variables and as proportions for categorical variables. Comparison of continuous variables between the groups was made with independent Student's t-test. For discrete variables distribution between groups were compared with Chi-square test. The mean age (±SD) of total population at implant was 64.08 (± 15.09) years. Dual chamber units were implanted in 44 (37.93%) of patients, single chamber in 72 (62.06%). Only 14 women (31.81%) received dual chamber compared with 42 women (58.33%) who received single chamber (Chi-square=18, DF=1, P = 0.0084). Complete atrioventricular block was the commonest (56.03%) indication for permanent pacemaker insertion followed by sick sinus syndrome (33.62%), symptomatic high-grade AV block (11.20%). Hypertension (dual chamber 21.55%, single chamber 40.51%) was the most common comorbidity in both cohorts. Complications occurred in 11 (9.48%) patients. More proportion of complication occurred in single chamber group (9 patients, 12.50%) than in dual chamber (2 patients, 4.54%). Complications occurring in dual chamber group include pocket hematoma 1 patient (2.27%) and arrhythmia in 1 patient (2.27%). Similarly, complications occurring in single chamber include RV perforation in two patients (2.77%) and one each (1.38%) had pocket hematoma, pneumothorax, infection, swelling at pocket site, arrhythmia in the form of NSVT, leads displacement, DVT and mortality. Women were more likely to receive single chamber systems than men. More proportion of complication occurred in single chamber group than in dual chamber. Future prospective studies on larger number of patients are needed to confirm and support our findings.

Neighbourhood Ethnic Density Effects on Behavioural and Cognitive Problems Among Young Racial/Ethnic Minority Children in the US and England: A Cross-National Comparison.

PubMed

Zhang, Nan; Beauregard, Jennifer L; Kramer, Michael R; Bécares, Laia

2017-01-01

Studies on adult racial/ethnic minority populations show that the increased concentration of racial/ethnic minorities in a neighbourhood-a so-called ethnic density effect-is associated with improved health of racial/ethnic minority residents when adjusting for area deprivation. However, this literature has focused mainly on adult populations, individual racial/ethnic groups, and single countries, with no studies focusing on children of different racial/ethnic groups or comparing across nations. This study aims to compare neighbourhood ethnic density effects on young children's cognitive and behavioural outcomes in the US and in England. We used data from two nationally representative birth cohort studies, the US Early Childhood Longitudinal Study-Birth Cohort and the UK Millennium Cohort Study, to estimate the association between own ethnic density and behavioural and cognitive development at 5 years of age. Findings show substantial heterogeneity in ethnic density effects on child outcomes within and between the two countries, suggesting that ethnic density effects may reflect the wider social and economic context. We argue that researchers should take area deprivation into account when estimating ethnic density effects and when developing policy initiatives targeted at strengthening and improving the health and development of racial and ethnic minority children.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiely, J Blanco; Olszanski, A; Both, S

Purpose: To develop a quantitative decision making metric for automatically detecting irregular breathing using a large patient population that received phase-sorted 4DCT. Methods: This study employed two patient cohorts. Cohort#1 contained 256 patients who received a phasesorted 4DCT. Cohort#2 contained 86 patients who received three weekly phase-sorted 4DCT scans. A previously published technique used a single abdominal surrogate to calculate the ratio of extreme inhalation tidal volume to normal inhalation tidal volume, referred to as the κ metric. Since a single surrogate is standard for phase-sorted 4DCT in radiation oncology clinical practice, tidal volume was not quantified. Without tidal volume,more » the absolute κ metric could not be determined, so a relative κ (κrel) metric was defined based on the measured surrogate amplitude instead of tidal volume. Receiver operator characteristic (ROC) curves were used to quantitatively determine the optimal cutoff value (jk) and efficiency cutoff value (τk) of κrel to automatically identify irregular breathing that would reduce the image quality of phase-sorted 4DCT. Discriminatory accuracy (area under the ROC curve) of κrel was calculated by a trapezoidal numeric integration technique. Results: The discriminatory accuracy of ?rel was found to be 0.746. The key values of jk and tk were calculated to be 1.45 and 1.72 respectively. For values of ?rel such that jk≤κrel≤τk, the decision to reacquire the 4DCT would be at the discretion of the physician. This accounted for only 11.9% of the patients in this study. The magnitude of κrel held consistent over 3 weeks for 73% of the patients in cohort#3. Conclusion: The decision making metric, ?rel, was shown to be an accurate classifier of irregular breathing patients in a large patient population. This work provided an automatic quantitative decision making metric to quickly and accurately assess the extent to which irregular breathing is occurring during phase-sorted 4DCT.« less

The population impact of HPV/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen

PubMed Central

Silver, Michelle I.; Schiffman, Mark; Fetterman, Barbara; Poitras, Nancy; Gage, Julia C.; Wentzensen, Nicolas; Lorey, Thomas; Kinney, Walter; Castle, Philip E.

2016-01-01

Background Cervical screening aims to detect and treat precancer to prevent cervical cancer mortality and morbidity, while minimizing overtreatment of benign human papillomavirus (HPV) infections and related minor abnormalities. HPV/cytology cotesting at extended 5-year intervals is now a recommended screening strategy in the US, but the interval extension is controversial. We studied the impact of a decade of an alternative, 3-year cotesting, on rates of precancer and cancer at Kaiser Permanente Northern California. We also considered the effect on screening efficiency, defined as numbers of cotests/colposcopy visits needed to detect a precancer. Methods Two cohorts were defined. The “open cohort” included all women screened at least once during the study period; >1 million cotests were performed. In a fixed “long-term screening cohort”, we considered the cumulative impact of repeated screening at 3-year intervals by restricting to women first cotested in 2003–4 (i.e., no women entering screening later were added to this group). Results Detection of CIN3/AIS increased in the open cohort (2004–6, 82.0/100,000 women screened; 2007–9, 140.6/100,000; and 2010–12, 126.0/100,000); cancer diagnoses were unchanged. In the long-term screening cohort, detection of CIN3/AIS increased then decreased to the original level (2004–6, 80.5/100,000; 2007–9, 118.6/100,000; and 2010–2, 84.9/100,000). Cancer diagnoses decreased. Seen in terms of screening efficiency, the number of colposcopies performed todetect a single CIN3/AIS increased in the cohort with repeat screening. Conclusion Repeated cotesting at a 3-year interval eventually lowers population rates of precancer and cancer; however, a greater number of colposcopies is required to detect a single precancer. PMID:27657992

Multiple sclerosis and pregnancy: a single-centre prospective comparative study.

PubMed

Cuello, J P; Martínez Ginés, M L; Martin Barriga, M L; de Andrés, C

2017-03-01

Multiple sclerosis (MS) is a autoimmune disorder which preferentially affects young women of childbearing age. During pregnancy, the annualized relapse rate (AAR) is modified, but pregnancy has no harm effect on the long-term course of the disease. We aimed to study the clinical course of our MS patients during pregnancy, and compare their obstetrics outcomes with a control group of non-MS patients. A single centre prospective observational study was conducted. We assessed the reproductive history, MS history, pregnancy course and new-born outcome of a cohort of MS patients who had had a pregnancy between january 2007 and july 2012. We compared the global outcomes with a control cohort of 58 age-matched healthy pregnancies. Complete data from 35 consecutive women were analyzed, 40 deliveries. Control groups: 58 patients, 60 deliveries. EDSS at pregnancy 0,7. ARR before pregnancy 0,5. During pregnancy 0,3, after pregnancy 0,4. Twelve patients were on disease-modifying drugs (DMD) before pregnancy, 4 prenatal exposure occurs. The comparison between relapse rate and EDSS before, during and after delivery showed no statistically significant difference. In addition, compared to control group, there were also no differences in the obstetric outcomes. In MS cohort, we found a higher incidence of assisted reproductive treatments and lower breastfeeding rate, both statistically significant. Our series confirms that pregnancy has no negative long term impact on the progression of MS and also suggest that there is no additional morbidity in the pregnancy, comparing to the rest of the population. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Does cemented or cementless single-stage exchange arthroplasty of chronic periprosthetic hip infections provide similar infection rates to a two-stage? A systematic review.

PubMed

George, D A; Logoluso, N; Castellini, G; Gianola, S; Scarponi, S; Haddad, F S; Drago, L; Romano, C L

2016-10-10

The best surgical modality for treating chronic periprosthetic hip infections remains controversial, with a lack of randomised controlled studies. The aim of this systematic review is to compare the infection recurrence rate after a single-stage versus a two-stage exchange arthroplasty, and the rate of cemented versus cementless single-stage exchange arthroplasty for chronic periprosthetic hip infections. We searched for eligible studies published up to December 2015. Full text or abstract in English were reviewed. We included studies reporting the infection recurrence rate as the outcome of interest following single- or two-stage exchange arthroplasty, or both, with a minimum follow-up of 12 months. Two reviewers independently abstracted data and appraised quality assessment. After study selection, 90 observational studies were included. The majority of studies were focused on a two-stage hip exchange arthroplasty (65 %), 18 % on a single-stage exchange, and only a 17 % were comparative studies. There was no statistically significant difference between a single-stage versus a two-stage exchange in terms of recurrence of infection in controlled studies (pooled odds ratio of 1.37 [95 % CI = 0.68-2.74, I 2  = 45.5 %]). Similarly, the recurrence infection rate in cementless versus cemented single-stage hip exchanges failed to demonstrate a significant difference, due to the substantial heterogeneity among the studies. Despite the methodological limitations and the heterogeneity between single cohorts studies, if we considered only the available controlled studies no superiority was demonstrated between a single- and two-stage exchange at a minimum of 12 months follow-up. The overalapping of confidence intervals related to single-stage cementless and cemented hip exchanges, showed no superiority of either technique.

Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry: results of a genome-wide association study.

PubMed

Yazar, Seyhan; Mishra, Aniket; Ang, Wei; Kearns, Lisa S; Mountain, Jenny A; Pennell, Craig; Montgomery, Grant W; Young, Terri L; Hammond, Christopher J; Macgregor, Stuart; Mackey, David A; Hewitt, Alex W

2013-01-01

Corneal astigmatism is a common eye disorder characterized by irregularities in corneal curvature. Recently, the rs7677751 single nucleotide polymorphism (SNP) at the platelet-derived growth factor receptor alpha (PDGFRA) locus was found to be associated with corneal astigmatism in people of Asian ancestry. In the present study, we sought to replicate this finding and identify other genetic markers of corneal astigmatism in an Australian population of Northern European ancestry. Data from two cohorts were included in this study. The first cohort consisted of 1,013 individuals who were part of the Western Australian Pregnancy Cohort (Raine) Study: 20-year follow-up Eye Study. The second cohort comprised 1,788 individuals of 857 twin families who were recruited through the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study. Corneal astigmatism was calculated as the absolute difference between the keratometry readings in two meridians, and genotype data were extracted from genome-wide arrays. Initially, each cohort was analyzed separately, before being combined for meta- and subsequent genome-wide pathway analysis. Following meta-analysis, SNP rs7677751 at the PDGFRA locus had a combined p=0.32. No variant was found to be statistically significantly associated with corneal astigmatism at the genome-wide level (p<5.0×10(-8)). The SNP with strongest association was rs1164064 (p=1.86×10(-6)) on chromosome 3q13. Gene-based pathway analysis identified a significant association between the Gene Ontology "segmentation" (GO:0035282) pathway, corrected p=0.009. Our data suggest that the PDGFRA locus does not transfer a major risk of corneal astigmatism in people of Northern European ancestry. Better-powered studies are required to validate the novel putative findings of our study.

Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children.

PubMed

Visscher, Henk; Ross, Colin J D; Rassekh, S Rod; Barhdadi, Amina; Dubé, Marie-Pierre; Al-Saloos, Hesham; Sandor, George S; Caron, Huib N; van Dalen, Elvira C; Kremer, Leontien C; van der Pal, Helena J; Brown, Andrew M K; Rogers, Paul C; Phillips, Michael S; Rieder, Michael J; Carleton, Bruce C; Hayden, Michael R

2012-05-01

Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease.

PubMed

Rachakonda, Sivaramakrishna P; Penack, Olaf; Dietrich, Sascha; Blau, Olga; Blau, Igor Wolfgang; Radujkovic, Aleksandar; Isermann, Berend; Ho, Anthony D; Uharek, Lutz; Dreger, Peter; Kumar, Rajiv; Luft, Thomas

2014-10-20

Steroid-refractory graft-versus-host disease (GVHD) is a major and often fatal complication after allogeneic stem-cell transplantation (alloSCT). Although the pathophysiology of steroid refractoriness is not fully understood, evidence is accumulating that endothelial cell stress is involved, and endothelial thrombomodulin (THBD) plays a role in this process. Here we assess whether single-nucleotide polymorphisms (SNPs) within the THBD gene predict outcome after alloSCT. Seven SNPs within the THBD gene were studied (rs1962, rs1042579, rs1042580, rs3176123, rs3176124, rs3176126, and rs3176134) in a training cohort of 306 patients. The relevant genotypes were then validated in an independent cohort (n = 321). In the training cohort, an increased risk of nonrelapse mortality (NRM) was associated with three of seven SNPs tested: rs1962, rs1042579 (in linkage disequilibrium with rs3176123), and rs1042580. When patients were divided into risk groups (one v no high-risk SNP), a strong correlation with NRM was observed (hazard ratio [HR], 2.31; 95% CI, 1.36 to 3.95; P = .002). More specifically, NRM was predicted by THBD SNPs in patients who later developed GVHD (HR, 3.03; 95% CI, 1.61 to 5.68; P < .001) but not in patients without GVHD. In contrast, THBD SNPs did not predict incidence of acute GVHD. Multivariable analyses adjusting for clinical variables confirmed the independent effect of THBD SNPs on NRM. All findings could be reproduced in the validation cohort. THBD SNPs predict mortality of manifest GVHD but not the risk of acquiring GVHD, supporting the hypothesis that endothelial vulnerability contributes to GVHD refractoriness. © 2014 by American Society of Clinical Oncology.

Development of a clinical algorithm for treating urethral strictures based on a large retrospective single-center cohort

PubMed Central

Tolkach, Yuri; Herrmann, Thomas; Merseburger, Axel; Burchardt, Martin; Wolters, Mathias; Huusmann, Stefan; Kramer, Mario; Kuczyk, Markus; Imkamp, Florian

2017-01-01

Aim: To analyze clinical data from male patients treated with urethrotomy and to develop a clinical decision algorithm. Materials and methods: Two large cohorts of male patients with urethral strictures were included in this retrospective study, historical (1985-1995, n=491) and modern cohorts (1996-2006, n=470). All patients were treated with repeated internal urethrotomies (up to 9 sessions). Clinical outcomes were analyzed and systemized as a clinical decision algorithm. Results: The overall recurrence rates after the first urethrotomy were 32.4% and 23% in the historical and modern cohorts, respectively. In many patients, the second procedure was also effective with the third procedure also feasible in selected patients. The strictures with a length ≤ 2 cm should be treated according to the initial length. In patients with strictures ≤ 1 cm, the second session could be recommended in all patients, but not with penile strictures, strictures related to transurethral operations or for patients who were 31-50 years of age. The third session could be effective in selected cases of idiopathic bulbar strictures. For strictures with a length of 1-2 cm, a second operation is possible for the solitary low-grade bulbar strictures, given that the age is > 50 years and the etiology is not post-transurethral resection of the prostate. For penile strictures that are 1-2 cm, urethrotomy could be attempted in solitary but not in high-grade strictures. Conclusions: We present data on the treatment of urethral strictures with urethrotomy from a single center. Based on the analysis, a clinical decision algorithm was suggested, which could be a reliable basis for everyday clinical practice. PMID:28529689

The influence of prophylactic proton pump inhibitor treatment on the development of symptomatic marginal ulceration in Roux-en-Y gastric bypass patients: a historic cohort study.

PubMed

Coblijn, Usha K; Lagarde, Sjoerd M; de Castro, Steve M M; Kuiken, Sjoerd D; van Tets, Willem F; van Wagensveld, Bart A

2016-02-01

Marginal ulceration at the gastrojejunostomy is a serious complication after laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) and occurs in 1%-16% of patients. Proton pump inhibitors (PPIs) might lower the occurrence of these ulcers. The aim of the present study was to evaluate the effect of 6 months prophylactic usage of PPIs on the development of marginal ulceration and compare this with a historic patient control group. A single institution cohort at a bariatric center of excellence, The Sint Lucas Andreas Zienkenhuis, Amsterdam A consecutive database of patients who underwent LRYGB from November 2007 to September 2012 in a single institution was retrospectively reviewed. From August 2011, patients received a standard dose of pantozol 40 mg once daily directly postoperatively for 6 months. No standard PPI prophylaxis was administered before August 2011, and the patients not using PPIs in this historic cohort served as the control group. A total of 610 patients underwent LRYGB, of which 128 patients (21.0%) underwent revisional surgery. Postoperative PPIs were administered in the intervention group of 337 patients, compared with the historic control group consisting of 273 patients. Six patients (1.2%) who received postoperative PPIs versus 20 patients (7.3 %) in the historic control group developed marginal ulceration (P = .001). Patients using proton pump inhibitors developed fewer gastrointestinal complaints postoperatively (P< .001). Routine usage of PPIs reduced the occurrence of marginal ulceration after LRYGB. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

CNVinspector: a web-based tool for the interactive evaluation of copy number variations in single patients and in cohorts.

PubMed

Knierim, Ellen; Schwarz, Jana Marie; Schuelke, Markus; Seelow, Dominik

2013-08-01

Many genetic disorders are caused by copy number variations (CNVs) in the human genome. However, the large number of benign CNV polymorphisms makes it difficult to delineate causative variants for a certain disease phenotype. Hence, we set out to create software that accumulates and visualises locus-specific knowledge and enables clinicians to study their own CNVs in the context of known polymorphisms and disease variants. CNV data from healthy cohorts (Database of Genomic Variants) and from disease-related databases (DECIPHER) were integrated into a joint resource. Data are presented in an interactive web-based application that allows inspection, evaluation and filtering of CNVs in single individuals or in entire cohorts. CNVinspector provides simple interfaces to upload CNV data, compare them with own or published control data and visualise the results in graphical interfaces. Beyond choosing control data from different public studies, platforms and methods, dedicated filter options allow the detection of CNVs that are either enriched in patients or depleted in controls. Alternatively, a search can be restricted to those CNVs that appear in individuals of similar clinical phenotype. For each gene of interest within a CNV, we provide a link to NCBI, ENSEMBL and the GeneDistiller search engine to browse for potential disease-associated genes. With its user-friendly handling, the integration of control data and the filtering options, CNVinspector will facilitate the daily work of clinical geneticists and accelerate the delineation of new syndromes and gene functions. CNVinspector is freely accessible under http://www.cnvinspector.org.

African American race but not genome-wide ancestry is negatively associated with atrial fibrillation among postmenopausal women in the Women's Health Initiative.

PubMed

Perez, Marco V; Hoffmann, Thomas J; Tang, Hua; Thornton, Timothy; Stefanick, Marcia L; Larson, Joseph C; Kooperberg, Charles; Reiner, Alex P; Caan, Bette; Iribarren, Carlos; Risch, Neil

2013-09-01

Atrial fibrillation (AF) is the most common arrhythmia in women and is associated with higher rates of stroke and death. Rates of AF are lower in African American subjects compared with European Americans, suggesting European ancestry could contribute to AF risk. The Women's Health Initiative (WHI) Observational Study (OS) followed up 93,676 women since the mid 1990s for various cardiovascular outcomes including AF. Multivariate Cox hazard regression analysis was used to measure the association between African American race and incident AF. A total of 8,119 African American women from the WHI randomized clinical trials and OS were genotyped on the Affymetrix Human SNP Array 6.0. Genome-wide ancestry and previously reported single nucleotide polymorphisms associated with AF in European cohorts were tested for association with AF using multivariate logistic regression analyses. Self-reported African American race was associated with lower rates of AF (hazard ratio 0.43, 95% CI 0.32-0.60) in the OS, independent of demographic and clinical risk factors. In the genotyped cohort, there were 558 women with AF. By contrast, genome-wide European ancestry was not associated with AF. None of the single nucleotide polymorphisms previously associated with AF in European populations, including rs2200733, were associated with AF in the WHI African American cohort. African American race is significantly and inversely correlated with AF in postmenopausal women. The etiology of this association remains unclear and may be related to unidentified environmental differences. Larger studies are necessary to identify genetic determinants of AF in African Americans. © 2013.

The effect of the introduction of a regional major trauma network on triage decisions made by a physician-staffed helicopter emergency medical service.

PubMed

Chesters, Adam; Fenton, Ronan

2015-12-01

A major trauma network (MTN) has been in place in the East of England, with a single hospital operating as the major trauma centre (MTC). The primary aim of this retrospective cohort study was to determine whether triage destination decisions with regard to trauma patients made by a helicopter-based doctor-paramedic team are affected by the introduction of a regional trauma network. In addition, we will describe and discuss the logistics of transfer of injured patients attended by the service. This is a retrospective database review that was carried out over two 12-month periods. The first period was before the introduction of an MTN, and the second was after its introduction. All patients who were conveyed to an MTC were identified. Nontrauma patients were excluded. The MTN trauma triage tool was retrospectively applied. A comparative analysis of the two cohorts was carried out. For the group of patients conveyed to the regional MTC, additional follow-up information was obtained. This included patient survival at 30 days and the final injury severity score for each patient. A total of 220 cases were identified in which a major trauma patient was conveyed to an MTC. There were 94 cases in the year before the introduction of the MTN (cohort 1) and 124 in the year during which the MTN was active (cohort 2). There was no significant difference in the number of patients conveyed to each MTC between cohort 1 and cohort 2. The trauma triage tool status was 'positive' in 52.1% of cases in cohort 1 and 55.6% of cases in cohort 2 (P=0.60). Advice of the consultant on call was more commonly used for patients in cohort 2 than for those in cohort 1 (66.9 vs. 40.6%; P<0. 01). The introduction of a regional MTN has not significantly affected the triage decisions made by our physician-paramedic teams.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

A hybrid Bayesian hierarchical model combining cohort and case-control studies for meta-analysis of diagnostic tests: Accounting for partial verification bias.

PubMed

Ma, Xiaoye; Chen, Yong; Cole, Stephen R; Chu, Haitao

2016-12-01

To account for between-study heterogeneity in meta-analysis of diagnostic accuracy studies, bivariate random effects models have been recommended to jointly model the sensitivities and specificities. As study design and population vary, the definition of disease status or severity could differ across studies. Consequently, sensitivity and specificity may be correlated with disease prevalence. To account for this dependence, a trivariate random effects model had been proposed. However, the proposed approach can only include cohort studies with information estimating study-specific disease prevalence. In addition, some diagnostic accuracy studies only select a subset of samples to be verified by the reference test. It is known that ignoring unverified subjects may lead to partial verification bias in the estimation of prevalence, sensitivities, and specificities in a single study. However, the impact of this bias on a meta-analysis has not been investigated. In this paper, we propose a novel hybrid Bayesian hierarchical model combining cohort and case-control studies and correcting partial verification bias at the same time. We investigate the performance of the proposed methods through a set of simulation studies. Two case studies on assessing the diagnostic accuracy of gadolinium-enhanced magnetic resonance imaging in detecting lymph node metastases and of adrenal fluorine-18 fluorodeoxyglucose positron emission tomography in characterizing adrenal masses are presented. © The Author(s) 2014.

A Hybrid Bayesian Hierarchical Model Combining Cohort and Case-control Studies for Meta-analysis of Diagnostic Tests: Accounting for Partial Verification Bias

PubMed Central

Ma, Xiaoye; Chen, Yong; Cole, Stephen R.; Chu, Haitao

2014-01-01

To account for between-study heterogeneity in meta-analysis of diagnostic accuracy studies, bivariate random effects models have been recommended to jointly model the sensitivities and specificities. As study design and population vary, the definition of disease status or severity could differ across studies. Consequently, sensitivity and specificity may be correlated with disease prevalence. To account for this dependence, a trivariate random effects model had been proposed. However, the proposed approach can only include cohort studies with information estimating study-specific disease prevalence. In addition, some diagnostic accuracy studies only select a subset of samples to be verified by the reference test. It is known that ignoring unverified subjects may lead to partial verification bias in the estimation of prevalence, sensitivities and specificities in a single study. However, the impact of this bias on a meta-analysis has not been investigated. In this paper, we propose a novel hybrid Bayesian hierarchical model combining cohort and case-control studies and correcting partial verification bias at the same time. We investigate the performance of the proposed methods through a set of simulation studies. Two case studies on assessing the diagnostic accuracy of gadolinium-enhanced magnetic resonance imaging in detecting lymph node metastases and of adrenal fluorine-18 fluorodeoxyglucose positron emission tomography in characterizing adrenal masses are presented. PMID:24862512

Childhood predictors of adult adiposity: findings from a longitudinal study.

PubMed

McLeod, Geraldine Fh; Fergusson, David M; Horwood, L John; Boden, Joseph M; Carter, Frances A

2018-03-23

The increasing prevalence of overweight and obesity has become a key challenge for New Zealand. The purpose of the present study was to examine childhood risk factors for adult adiposity in a longitudinal birth cohort. Data were gathered from the Christchurch Health and Development Study (CHDS), a birth cohort of 1,265 children born in Christchurch in 1977. Associations were examined between socio-demographic background, perinatal factors, infant and child characteristics, family functioning/child maltreatment and adiposity at ages 30 and 35 years. Adiposity was assessed using body mass index scores. At ages 30 and 35, approximately one-third of cohort members were overweight and one-fifth were obese. Generalised estimating equation models showed that statistically significant (p<.05) predictors of later adiposity and overweight/obesity were: male gender, being born into a single-parent family, having parents with larger body size, higher early infant growth, limited or no breastfeeding, lower levels of cognitive ability and exposure to severe sexual abuse. Overweight and obesity was associated with social and family background, biological endowment, cognitive ability and childhood adversity factors. These findings may assist in the development of structured adiposity intervention programmes in conjunction with established community organisations specialising in child and family health.

MMP12, lung function, and COPD in high-risk populations.

PubMed

Hunninghake, Gary M; Cho, Michael H; Tesfaigzi, Yohannes; Soto-Quiros, Manuel E; Avila, Lydiana; Lasky-Su, Jessica; Stidley, Chris; Melén, Erik; Söderhäll, Cilla; Hallberg, Jenny; Kull, Inger; Kere, Juha; Svartengren, Magnus; Pershagen, Göran; Wickman, Magnus; Lange, Christoph; Demeo, Dawn L; Hersh, Craig P; Klanderman, Barbara J; Raby, Benjamin A; Sparrow, David; Shapiro, Steven D; Silverman, Edwin K; Litonjua, Augusto A; Weiss, Scott T; Celedón, Juan C

2009-12-31

Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups. We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV(1)]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV(1) and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD. The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [-82A-->G]) was positively associated with FEV(1) in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2x10(-6)). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P=0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P=0.005) and among participants in a family-based study of early-onset COPD (P=0.006). The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers. 2009 Massachusetts Medical Society

Meta-GWAS and Meta-Analysis of Exome Array Studies Do Not Reveal Genetic Determinants of Serum Hepcidin

PubMed Central

Galesloot, Tessel E.; van Dijk, Freerk; Geurts-Moespot, Anneke J.; Girelli, Domenico; Kiemeney, Lambertus A. L. M.; Sweep, Fred C. G. J.; Swertz, Morris A.; van der Meer, Peter; Camaschella, Clara; Toniolo, Daniela; Vermeulen, Sita H.; van der Harst, Pim; Swinkels, Dorine W.

2016-01-01

Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants. PMID:27846281

[Mortality in the tire plant workers].

PubMed

Wilczyńska, U; Szadkowska-Stańczyk, I; Szeszenia-Dabrowska, N; Sobala, W; Strzelecka, A

2000-01-01

This paper describes a cohort study of the mortality among workers employed in one of Polish tyre plants. The scope of the study was limited to the analysis of mortality from main disease categories. Mortality from particular cancer sites will be discussed in a separate publication. The cohort comprised 17,747 workers (11,660 men and 6,087 women) employed during the years 1950-95 for at least three months in the tyre plant. As of 31 December 1995, the follow-up of the cohort was completed. A detailed analysis of mortality by causes was carried out using standardised mortality ratio (SMR) calculated by the person-years method. The general population of Poland was used as the reference. The results indicated general mortality significantly lower in the cohort (men: SMR = 72; women: SMR = 62), than in the reference population. The number of observed deaths from main disease categories was also lower than those expected. The analysis by specific causes revealed significant excess of deaths, due to hypertensive disease among men (36 deaths, SMR = 142; 95% CI: 99-197). SMRs were also calculated in sub-cohorts identified by activities performed (preparatory works: production of tyres and inner tubes; maintenance; storage; others). General mortality in sub-cohorts was similar to that in the total cohort. After analysis by causes of death, some non-significant excess mortality could be observed. It was very small or it applied only to single cases of death. Excess mortality from hypertensive disease in male maintenance workers (21 deaths, SMR = 262; 95% CI: 162-400) was the only exception. The absence of adverse health effects pronounced by significant excess mortality should be attributed to a relatively short period of exposure among the majority of the followed-up workers (over 58% of workers in the cohort employed in the plant for a period shorter than five years) and to their young age. Almost 56% of workers in the cohort were born in the 1950s or later which means that at the end of the follow-up they were not older than 45 years. In order to complete the final mortality assessment the follow-up should continue.

School Mobility, Dropout, and Graduation Rates across Student Disability Categories in Utah. REL 2015-055

ERIC Educational Resources Information Center

Barrat, Vanessa X.; Berliner, BethAnn; Voight, Adam; Tran, Loan; Huang, Chun-Wei; Yu, Airong; Chen-Gaddini, Min

2014-01-01

This report describes the characteristics of students with disabilities in Utah public schools, and presents the single-year mobility and dropout rates for students in grades 6-12, as well as the four-year cohort dropout and graduation rates, for students who started grade 9 for the first time in 2007/08 and constituted the 2011 cohort. Results…

ACE genotype, phenotype and all-cause mortality in different cohorts of patients with type 1 diabetes.

PubMed

Færch, Louise H; Sejling, Anne-Sophie; Lajer, Maria; Tarnow, Lise; Thorsteinsson, Birger; Pedersen-Bjergaard, Ulrik

2015-06-01

Carrying the D-allele of the angiotensin-converting enzyme (ACE) I/D polymorphism and high ACE activity are prognostic factors in diabetic nephropathy, which predicts mortality in type 1 diabetes. We studied the association between the ACE D-allele and ACE phenotype and long-term all-cause mortality in three single-institution outpatient cohorts. Genotype-based analyses were performed in 269 patients from Hillerød Hospital (HIH) (follow-up: 12 years) and in 439 patients with diabetic nephropathy and 437 patients with persistent normoalbuminuria from the Steno Diabetes Center (SDC) (follow-up: 9.5 years). Patients not on renin-angiotensin system (RAS)-blocking treatment were included in analyses of serum ACE activity (HIH: n = 208) and plasma ACE concentration (SDC: n=269). In the HIH cohort, carrying a D-allele was associated with excess mortality (hazard ratio (HR) = 4.0 (95% confidence interval (CI) 1.0-16)), but not in the SDC cohorts. At HIH, serum ACE activity was associated with excess mortality (HR=1.04 (95% CI 1.0-1.1 per unit increase)), but in the SDC cohort plasma ACE concentration was not. In unselected patients with type 1 diabetes, carrying the ACE D-allele and high spontaneous serum ACE activity were associated with 12-year excess mortality. These findings could not be reproduced in two other cohorts with persistent normoalbuminuria or diabetic nephropathy. © The Author(s) 2013.

The STK33-linked SNP rs4929949 is associated with obesity and BMI in two independent cohorts of Swedish and Greek children.

PubMed

Rask-Andersen, Mathias; Moschonis, George; Chrousos, George P; Marcus, Claude; Dedoussis, George V; Fredriksson, Robert; Schiöth, Helgi B

2013-01-01

Recent genome wide association studies (GWAS) have identified a locus on chromosome 11p15.5, closely associated with serine/threonine kinase 33 (STK33), to be associated with body mass. STK33, a relatively understudied protein, has been linked to KRAS mutation-driven cancers and explored as a potential antineoplastic drug target. The strongest association with body mass observed at this loci in GWAS was rs4929949, a single nucleotide polymorphism located within intron 1 of the gene encoding STK33. The functional implications of rs4929949 or related variants have not been explored as of yet. We have genotyped rs4929949 in two cohorts, an obesity case-control cohort of 991 Swedish children, and a cross-sectional cohort of 2308 Greek school children. We found that the minor allele of rs4929949 was associated with obesity in the cohort of Swedish children and adolescents (OR = 1.199 (95%CI: 1.002-1.434), p = 0.047), and with body mass in the cross-sectional cohort of Greek children (β = 0.08147 (95% CI: 0.1345-0.1618), p = 0.021). We observe the effects of rs4929949 on body mass to be detectable already at adolescence. Subsequent analysis did not detect any association of rs4929949 to phenotypic measurements describing body adiposity or to metabolic factors such as insulin levels, triglycerides and insulin resistance (HOMA).

The STK33-Linked SNP rs4929949 Is Associated with Obesity and BMI in Two Independent Cohorts of Swedish and Greek Children

PubMed Central

Rask-Andersen, Mathias; Moschonis, George; Chrousos, George P.; Marcus, Claude; Dedoussis, George V.; Fredriksson, Robert; Schiöth, Helgi B.

2013-01-01

Recent genome wide association studies (GWAS) have identified a locus on chromosome 11p15.5, closely associated with serine/threonine kinase 33 (STK33), to be associated with body mass. STK33, a relatively understudied protein, has been linked to KRAS mutation-driven cancers and explored as a potential antineoplastic drug target. The strongest association with body mass observed at this loci in GWAS was rs4929949, a single nucleotide polymorphism located within intron 1 of the gene encoding STK33. The functional implications of rs4929949 or related variants have not been explored as of yet. We have genotyped rs4929949 in two cohorts, an obesity case-control cohort of 991 Swedish children, and a cross-sectional cohort of 2308 Greek school children. We found that the minor allele of rs4929949 was associated with obesity in the cohort of Swedish children and adolescents (OR = 1.199 (95%CI: 1.002–1.434), p = 0.047), and with body mass in the cross-sectional cohort of Greek children (β = 0.08147 (95% CI: 0.1345–0.1618), p = 0.021). We observe the effects of rs4929949 on body mass to be detectable already at adolescence. Subsequent analysis did not detect any association of rs4929949 to phenotypic measurements describing body adiposity or to metabolic factors such as insulin levels, triglycerides and insulin resistance (HOMA). PMID:23967198

Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry.

PubMed

Mutharasan, Priscilla; Galdones, Eugene; Peñalver Bernabé, Beatriz; Garcia, Obed A; Jafari, Nadereh; Shea, Lonnie D; Woodruff, Teresa K; Legro, Richard S; Dunaif, Andrea; Urbanek, Margrit

2013-01-01

A previous genome-wide association study in Chinese women with polycystic ovary syndrome (PCOS) identified a region on chromosome 2p16.3 encoding the LH/choriogonadotropin receptor (LHCGR) and FSH receptor (FSHR) genes as a reproducible PCOS susceptibility locus. The objective of the study was to determine the role of the LHCGR and/or FSHR gene in the etiology of PCOS in women of European ancestry. This was a genetic association study in a European ancestry cohort of women with PCOS. The study was conducted at an academic medical center. Participants in the study included 905 women with PCOS diagnosed by National Institutes of Health criteria and 956 control women. We genotyped 94 haplotype-tagging single-nucleotide polymorphisms and two coding single-nucleotide polymorphisms mapping to the coding region of LHCGR and FSHR plus 20 kb upstream and downstream of the genes and test for association in the case control cohort and for association with nine quantitative traits in the women with PCOS. We found strong evidence for an association of PCOS with rs7562215 (P = 0.0037) and rs10495960 (P = 0.0046). Although the marker with the strongest association in the Chinese PCOS genome-wide association study (rs13405728) was not informative in the European populations, we identified and genotyped three markers (rs35960650, rs2956355, and rs7562879) within 5 kb of rs13405728. Of these, rs7562879 was nominally associated with PCOS (P = 0.020). The strongest evidence for association mapping to FSHR was observed with rs1922476 (P = 0.0053). Furthermore, markers with the FSHR gene region were associated with FSH levels in women with PCOS. Fine mapping of the chromosome 2p16.3 Chinese PCOS susceptibility locus in a European ancestry cohort provides evidence for association with two independent loci and PCOS. The gene products LHCGR and FSHR therefore are likely to be important in the etiology of PCOS, regardless of ethnicity.

Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort.

PubMed

Gambin, Tomasz; Akdemir, Zeynep C; Yuan, Bo; Gu, Shen; Chiang, Theodore; Carvalho, Claudia M B; Shaw, Chad; Jhangiani, Shalini; Boone, Philip M; Eldomery, Mohammad K; Karaca, Ender; Bayram, Yavuz; Stray-Pedersen, Asbjørg; Muzny, Donna; Charng, Wu-Lin; Bahrambeigi, Vahid; Belmont, John W; Boerwinkle, Eric; Beaudet, Arthur L; Gibbs, Richard A; Lupski, James R

2017-02-28

We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi-exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17-50% of pathogenic CNVs in different disease cohorts where 7.1-11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels.

PubMed

Uronen, Riikka-Liisa; Lundmark, Per; Orho-Melander, Marju; Jauhiainen, Matti; Larsson, Kristina; Siegbahn, Agneta; Wallentin, Lars; Zethelius, Björn; Melander, Olle; Syvänen, Ann-Christine; Ikonen, Elina

2010-08-01

To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels. In Npc1(-/-) mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1(-/-) mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1(-/-) mouse serum and hepatocytes. In Npc1(-/-) hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1(-/-) hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7 x 10(-4) for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals. This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.

Single Fasting Plasma Glucose Versus 75-g Oral Glucose-Tolerance Test in Prediction of Adverse Perinatal Outcomes: A Cohort Study.

PubMed

Shen, Songying; Lu, Jinhua; Zhang, Lifang; He, Jianrong; Li, Weidong; Chen, Niannian; Wen, Xingxuan; Xiao, Wanqing; Yuan, Mingyang; Qiu, Lan; Cheng, Kar Keung; Xia, Huimin; Mol, Ben Willem J; Qiu, Xiu

2017-02-01

There remains uncertainty regarding whether a single fasting glucose measurement is sufficient to predict risk of adverse perinatal outcomes. We included 12,594 pregnant women who underwent a 75-g oral glucose-tolerance test (OGTT) at 22-28weeks' gestation in the Born in Guangzhou Cohort Study, China. Outcomes were large for gestational age (LGA) baby, cesarean section, and spontaneous preterm birth. We calculated the area under the receiver operator characteristic curves (AUCs) to assess the capacity of OGTT glucose values to predict adverse outcomes, and compared the AUCs of different components of OGTT. 1325 women had a LGA baby (10.5%). Glucose measurements were linearly associated with LGA, with strongest associations for fasting glucose (odds ratio 1.37, 95% confidence interval 1.30-1.45). Weaker associations were observed for cesarean section and spontaneous preterm birth. Fasting glucose have a comparable discriminative power for prediction of LGA to the combination of fasting, 1h, and 2h glucose values during OGTT (AUCs, 0.611 vs. 0.614, P=0.166). The LGA risk was consistently increased in women with abnormal fasting glucose (≥5.1mmol/l), irrespective of 1h or 2h glucose levels. A single fasting glucose measurement performs comparably to 75-g OGTT in predicting risk of having a LGA baby. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Novel wound management system reduction of surgical site morbidity after ventral hernia repairs: a critical analysis.

PubMed

Soares, Kevin C; Baltodano, Pablo A; Hicks, Caitlin W; Cooney, Carisa M; Olorundare, Israel O; Cornell, Peter; Burce, Karen; Eckhauser, Frederic E

2015-02-01

Prophylactic incisional negative-pressure wound therapy use after ventral hernia repairs (VHRs) remains controversial. We assessed the impact of a modified negative-pressure wound therapy system (hybrid-VAC or HVAC) on outcomes of open VHR. A 5-year retrospective analysis of all VHRs performed by a single surgeon at a single institution compared outcomes after HVAC versus standard wound dressings. Multivariable logistic regression compared surgical site infections, surgical site occurrences, morbidity, and reoperation rates. We evaluated 199 patients (115 HVAC vs 84 standard wound dressing patients). Mean follow-up was 9 months. The HVAC cohort had lower surgical site infections (9% vs 32%, P < .001) and surgical site occurrences (17% vs 42%, P = .001) rates. Rates of major morbidity (19% vs 31%, P = .04) and 90-day reoperation (5% vs 14%, P = .02) were lower in the HVAC cohort. The HVAC system is associated with optimized outcomes following open VHR. Prospective studies should validate these findings and define the economic implications of this intervention. Copyright © 2015 Elsevier Inc. All rights reserved.

Predicting out-of-office blood pressure level using repeated measurements in the clinic: an observational cohort study

PubMed Central

Sheppard, James P.; Holder, Roger; Nichols, Linda; Bray, Emma; Hobbs, F.D. Richard; Mant, Jonathan; Little, Paul; Williams, Bryan; Greenfield, Sheila; McManus, Richard J.

2014-01-01

Objectives: Identification of people with lower (white-coat effect) or higher (masked effect) blood pressure at home compared to the clinic usually requires ambulatory or home monitoring. This study assessed whether changes in SBP with repeated measurement at a single clinic predict subsequent differences between clinic and home measurements. Methods: This study used an observational cohort design and included 220 individuals aged 35–84 years, receiving treatment for hypertension, but whose SBP was not controlled. The characteristics of change in SBP over six clinic readings were defined as the SBP drop, the slope and the quadratic coefficient using polynomial regression modelling. The predictive abilities of these characteristics for lower or higher home SBP readings were investigated with logistic regression and repeated operating characteristic analysis. Results: The single clinic SBP drop was predictive of the white-coat effect with a sensitivity of 90%, specificity of 50%, positive predictive value of 56% and negative predictive value of 88%. Predictive values for the masked effect and those of the slope and quadratic coefficient were slightly lower, but when the slope and quadratic variables were combined, the sensitivity, specificity, positive and negative predictive values for the masked effect were improved to 91, 48, 24 and 97%, respectively. Conclusion: Characteristics obtainable from multiple SBP measurements in a single clinic in patients with treated hypertension appear to reasonably predict those unlikely to have a large white-coat or masked effect, potentially allowing better targeting of out-of-office monitoring in routine clinical practice. PMID:25144295

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

PubMed

Ibrahim-Verbaas, Carla A; Fornage, Myriam; Bis, Joshua C; Choi, Seung Hoan; Psaty, Bruce M; Meigs, James B; Rao, Madhu; Nalls, Mike; Fontes, Joao D; O'Donnell, Christopher J; Kathiresan, Sekar; Ehret, Georg B; Fox, Caroline S; Malik, Rainer; Dichgans, Martin; Schmidt, Helena; Lahti, Jari; Heckbert, Susan R; Lumley, Thomas; Rice, Kenneth; Rotter, Jerome I; Taylor, Kent D; Folsom, Aaron R; Boerwinkle, Eric; Rosamond, Wayne D; Shahar, Eyal; Gottesman, Rebecca F; Koudstaal, Peter J; Amin, Najaf; Wieberdink, Renske G; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G; Destefano, Anita L; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A; Decarli, Charles; Ikram, M Arfan; Seshadri, Sudha; Mosley, Thomas H; Longstreth, W T; van Duijn, Cornelia M; Launer, Lenore J

2014-02-01

Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Epidemiology and Heritability of Major Depressive Disorder, Stratified by Age of Onset, Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS).

PubMed

Fernandez-Pujals, Ana Maria; Adams, Mark James; Thomson, Pippa; McKechanie, Andrew G; Blackwood, Douglas H R; Smith, Blair H; Dominiczak, Anna F; Morris, Andrew D; Matthews, Keith; Campbell, Archie; Linksted, Pamela; Haley, Chris S; Deary, Ian J; Porteous, David J; MacIntyre, Donald J; McIntosh, Andrew M

2015-01-01

The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.

Blastocyst development in single medium with or without renewal on day 3: a prospective cohort study on sibling donor oocytes in a time-lapse incubator.

PubMed

Costa-Borges, Nuno; Bellés, Marta; Meseguer, Marcos; Galliano, Daniela; Ballesteros, Agustin; Calderón, Gloria

2016-03-01

To evaluate the efficiency of using a continuous (one-step) protocol with a single medium for the culture of human embryos in a time-lapse incubator (TLI). Prospective cohort study on sibling donor oocytes. University-affiliated in vitro fertilization (IVF) center. Embryos from 59 patients. Culture in a TLI in a single medium with or without renewal of the medium on day-3. Embryo morphology and morphokinetic parameters, clinical pregnancy, take-home baby rate, and perinatal outcomes. The blastocyst rates (68.3 vs. 66.8%) and the proportion of good-quality blastocysts (transferred plus frozen) obtained with the two-step (80.0%) protocol were statistically significantly similar to those obtained in the one-step protocol (72.2%). Similarly, morphokinetic events from early cleavage until late blastocyst stages were statistically significantly equivalent between both groups. No differences were found either in clinical pregnancy rates when comparing pure transfers performed with embryos selected from the two-step (75.0%), one-step (70.0%, respectively), and mixed (57.1%) groups. A total of 55 out of 91 embryos transferred implanted successfully (60.4%), resulting in a total of 37 newborns with a comparable birth weight mean among groups. Our findings support the idea that in a TLI with a controlled air purification system, human embryos can be successfully cultured continuously from day 0 onward in single medium with no need to renew it on day-3. This strategy does not affect embryo morphokinetics or development to term and offers more stable culture conditions for embryos as well as practical advantages and reduced costs for the IVF laboratory. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

A Diagnostic Marker to Discriminate Childhood Apraxia of Speech From Speech Delay: II. Validity Studies of the Pause Marker.

PubMed

Shriberg, Lawrence D; Strand, Edythe A; Fourakis, Marios; Jakielski, Kathy J; Hall, Sheryl D; Karlsson, Heather B; Mabie, Heather L; McSweeny, Jane L; Tilkens, Christie M; Wilson, David L

2017-04-14

The purpose of this 2nd article in this supplement is to report validity support findings for the Pause Marker (PM), a proposed single-sign diagnostic marker of childhood apraxia of speech (CAS). PM scores and additional perceptual and acoustic measures were obtained from 296 participants in cohorts with idiopathic and neurogenetic CAS, adult-onset apraxia of speech and primary progressive apraxia of speech, and idiopathic speech delay. Adjusted for questionable specificity disagreements with a pediatric Mayo Clinic diagnostic standard, the estimated sensitivity and specificity, respectively, of the PM were 86.8% and 100% for the CAS cohort, yielding positive and negative likelihood ratios of 56.45 (95% confidence interval [CI]: [1.15, 2763.31]) and 0.13 (95% CI [0.06, 0.30]). Specificity of the PM for 4 cohorts totaling 205 participants with speech delay was 98.5%. These findings are interpreted as providing support for the PM as a near-conclusive diagnostic marker of CAS.

Whether the Autism Spectrum Quotient Consists of Two Different Subgroups? Cluster Analysis of the Autism Spectrum Quotient in General Population

ERIC Educational Resources Information Center

Kitazoe, Noriko; Fujita, Naofumi; Izumoto, Yuji; Terada, Shin-ichi; Hatakenaka, Yuhei

2017-01-01

The purpose of this study was to investigate whether the individuals in the general population with high scores on the Autism Spectrum Quotient constituted a single homogeneous group or not. A cohort of university students (n = 4901) was investigated by cluster analysis based on the original five subscales of the Autism Spectrum Quotient. Based on…

A Diagnostic Marker to Discriminate Childhood Apraxia of Speech from Speech Delay: II. Validity Studies of the Pause Marker

ERIC Educational Resources Information Center

Shriberg, Lawrence D.; Strand, Edythe A.; Fourakis, Marios; Jakielski, Kathy J.; Hall, Sheryl D.; Karlsson, Heather B.; Mabie, Heather L.; McSweeny, Jane L.; Tilkens, Christie M.; Wilson, David L.

2017-01-01

Purpose: The purpose of this 2nd article in this supplement is to report validity support findings for the Pause Marker (PM), a proposed single-sign diagnostic marker of childhood apraxia of speech (CAS). Method: PM scores and additional perceptual and acoustic measures were obtained from 296 participants in cohorts with idiopathic and…

Infinium HumanMethylation450 BeadChip

Cancer.gov

The HumanMethylation450 BeadChip offers a unique combination of comprehensive, expert-selected coverage and high throughput at a low price, making it ideal for screening large sample populations such as those used in genome-wide association study cohorts. By providing quantitative methylation measurement at the single-CpG–site level for normal and FFPE samples, this assay offers powerful resolution for understanding epigenetic changes.

Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort.

PubMed

Retterer, Kyle; Scuffins, Julie; Schmidt, Daniel; Lewis, Rachel; Pineda-Alvarez, Daniel; Stafford, Amanda; Schmidt, Lindsay; Warren, Stephanie; Gibellini, Federica; Kondakova, Anastasia; Blair, Amanda; Bale, Sherri; Matyakhina, Ludmila; Meck, Jeanne; Aradhya, Swaroop; Haverfield, Eden

2015-08-01

Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing. Exon-focused arrays and whole-genome chromosomal microarray analysis were used to test 14,228 and 14,000 individuals, respectively. Based on these results, we developed an algorithm to detect deletions/duplications in whole-exome sequencing data and a novel whole-exome array. In the exon array cohort, we observed a positive detection rate of 2.4% (25 duplications, 318 deletions), of which 39% involved one or two exons. Chromosomal microarray analysis identified 3,345 CNVs affecting single genes (18%). We demonstrate that our whole-exome sequencing algorithm resolves CNVs of three or more exons. These results demonstrate the clinical utility of single-exon resolution in CNV assays. Our whole-exome sequencing algorithm approaches this resolution but is complemented by a whole-exome array to unambiguously identify intragenic CNVs and single-exon changes. These data illustrate the next advancements in CNV analysis through whole-exome sequencing and whole-exome array.Genet Med 17 8, 623-629.

First-In-Human, Double-Blind, Placebo-Controlled, Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member, in Subjects with Unilateral Sciatica.

PubMed

Rolan, Paul E; O'Neill, Gilmore; Versage, Eve; Rana, Jitesh; Tang, Yongqiang; Galluppi, Gerald; Aycardi, Ernesto

2015-01-01

To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28. Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was rapidly distributed, with a prolonged terminal elimination phase. These data support the development of BG00010 for the treatment of neuropathic pain. ClinicalTrials.gov NCT00961766.

Mixed models, linear dependency, and identification in age-period-cohort models.

PubMed

O'Brien, Robert M

2017-07-20

This paper examines the identification problem in age-period-cohort models that use either linear or categorically coded ages, periods, and cohorts or combinations of these parameterizations. These models are not identified using the traditional fixed effect regression model approach because of a linear dependency between the ages, periods, and cohorts. However, these models can be identified if the researcher introduces a single just identifying constraint on the model coefficients. The problem with such constraints is that the results can differ substantially depending on the constraint chosen. Somewhat surprisingly, age-period-cohort models that specify one or more of ages and/or periods and/or cohorts as random effects are identified. This is the case without introducing an additional constraint. I label this identification as statistical model identification and show how statistical model identification comes about in mixed models and why which effects are treated as fixed and which are treated as random can substantially change the estimates of the age, period, and cohort effects. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Is it possible to prevent recurrent vulvovaginitis? The role of Lactobacillus plantarum I1001 (CECT7504).

PubMed

Palacios, S; Espadaler, J; Fernández-Moya, J M; Prieto, C; Salas, N

2016-10-01

The purpose of this study was to prospectively evaluate the impact of the use of L. plantarum I1001 applied vaginally on Vulvovaginal Candidiasis (VVC) time-until-recurrence after treatment with single-dose vaginal clotrimazole. This was a clinical open-label, prospective study of two non-randomized parallel cohorts with symptomatic acute VVC: (1) 33 sexually active women 18-50 years old, prescribed a standard single-dose 500 mg vaginal tablet of clotrimazole followed by vaginal tablets with L. plantarum I1001 as adjuvant therapy, and (2) 22 women of similar characteristics but prescribed single-dose clotrimazole only. Use of the probiotic and factors that might influence recurrence risk (age, recurrent VVC within previous year, antibiotic prior to study enrolment, diaphragm or IUD contraception, among others) were included in a multivariate Cox regression model to adjust for potential between-cohort differences. Probiotic use was associated with a three-fold reduction in the adjusted risk of recurrence (HR [95 %CI]: 0.30 [0.10-0.91]; P = 0.033). Adjusted free-survival recurrence was 72.83 % and 34.88 % for the probiotic and control groups, respectively. A higher cumulative recurrence was also observed in cases with use of antibiotics prior to enrolment (HR [95 %CI]: 10.46 [2.18-50.12]; P = 0.003). Similar findings were found at six months after azole treatment in women with RVVC. Overall, good compliance with the probiotic was reported for 91.3 % of women. The study suggests that follow-up therapy with vaginal tablets with L. plantarum I1001 could increase the effectiveness of single-dose 500 mg clotrimazole at preventing recurrence of VVC, an effect that was also observed in women with recurrent vulvovaginal candidiasis (RVVC) after six months of azole treatment.

A cross-sectional examination of the profile of chiropractors recruited to the Australian Chiropractic Research Network (ACORN): a sustainable resource for future chiropractic research.

PubMed

Adams, Jon; Peng, Wenbo; Steel, Amie; Lauche, Romy; Moore, Craig; Amorin-Woods, Lyndon; Sibbritt, David

2017-09-29

The Australian Chiropractic Research Network (ACORN) practice-based research network (PBRN) cohort was established to provide sustainable infrastructure necessary to address lack of rigorous investigation and to bridge the research-practice gap focused on chiropractic care for future years. This paper presents the profile of chiropractors recruited to the ACORN PBRN, a nationally representative sample of chiropractors working in Australia. Cross-sectional analysis of baseline data from a cohort study of chiropractors in Australia. All registered chiropractors in Australia were invited to participate in the ACORN study and those who completed a practitioner questionnaire and consent form were included in the PBRN cohort. A total of 1680 chiropractors (36%) were recruited to the cohort database. The average age of the PBRN participants is 41.9 years and 63% are male. The vast majority of the PBRN participants hold a university degree. General practitioners were identified as the most popular referral source for chiropractic care and low back pain and neck pain were the most common conditions 'often' treated by the PBRN chiropractors. The chiropractors in this PBRN cohort rated high velocity, low amplitude adjustment/manipulation/mobilisation as the most commonly used technique/method and soft tissue therapy as the most frequently employed musculoskeletal intervention in their patient management. The ACORN PBRN cohort constitutes the largest coverage of any single healthcare profession via a national voluntary PBRN providing a sustainable resource for future follow-up. The ACORN cohort provides opportunities for further nested substudies related to chiropractic care, chiropractors, their patients and a vast range of broader healthcare issues with a view to helping build a diverse but coordinated research programme and further research capacity building around Australian chiropractic. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Behçet's disease in the United States: A single center descriptive and comparative study.

PubMed

Kilian, Nathan C; Sawalha, Amr H

2017-12-01

Behçet's disease is heterogeneous with clinical variability across ethnicities and geographic locations. The goal of this study was to analyze the clinical characteristics of our multi-ethnic Behçet's disease cohort at the University of Michigan. A detailed patient characterization was performed. Differences in disease characteristics between men and women, and between patients fulfilling the International Criteria for Behçet's Disease (ICBD) and the International Study Group criteria (ISG) were determined in our cohort. A total of 114 patients with a male to female ratio of ~ 1:4 were included. All patients met the ICBD criteria, including 76 who also met the ISG criteria. Over 95% of patients had recurrent genital ulcers, which is higher than generally reported. Retinitis was 5.3 times more likely in men than in women (p=0.009), and arthralgia was 3.3 times more likely in women than men (p=0.048). When comparing cohorts derived from the two different criteria, the ISG cohort had more skin manifestations (OR=3.3, p=0.0006). Acneiform lesions were associated with ~8 times higher odds of developing retinitis in our patients (p=0.0008), and superficial thrombophlebitis was associated with a trend for higher odds of developing uveitis (OR=4.1, p=0.057). Using the ICBD criteria, 38 additional patients were identified compared to only using the ISG criteria. Of these patients, 28 presented with only mucosal ulceration with or without joint involvement. We characterize Behçet's disease in a multi-ethnic cohort from North America. Using ICBD criteria in the United States significantly increases the likelihood of identifying Behçet's disease, particularly in patients with isolated mucosal involvement who constitute a substantial subset of patients in this region.

MACROD2 gene associated with autistic-like traits in a general population sample.

PubMed

Jones, Rachel M; Cadby, Gemma; Blangero, John; Abraham, Lawrence J; Whitehouse, Andrew J O; Moses, Eric K

2014-12-01

There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0×10. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.

Sociodemographic characteristics and attitudes towards motherhood among single women compared with cohabiting women treated with donor semen - a Danish multicenter study.

PubMed

Salomon, Maria; Sylvest, Randi; Hansson, Helena; Nyboe Andersen, Anders; Schmidt, Lone

2015-05-01

To examine sociodemographic characteristics, family backgrounds, reproductive histories, and attitudes towards motherhood in single vs. cohabiting women seeking treatment with donor semen. Baseline data collection in a multicenter cohort study. All nine public fertility clinics in Denmark. In total n = 311 childless women initiating assisted reproduction using donor semen. Self-reported questionnaire responses from n = 184 single women seeking treatment by using donor semen were compared with responses from n = 127 cohabiting women. Sociodemographic characteristics, family backgrounds, reproductive histories, attitudes towards motherhood. Single women were 3.5 years older on average when initiating treatment compared with cohabiting women. No significant differences were found regarding sociodemographic characteristics, previous long-term relationships, previous pregnancies, or attitudes towards motherhood between single women and cohabiting women. The vast majority of single women wanted to achieve parenthood with a partner, 85.8% wished to have a partner in the future, and approximately half of them preferred for a partner to take parental responsibilities. In this study single women seeking treatment with donor semen in the public health system did not differ from cohabiting women, except that they were older. To be a single mother by choice is not their preferred way of parenthood, but a solution they needed to accept. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

Genome-wide association study of the age of onset of childhood asthma.

PubMed

Forno, Erick; Lasky-Su, Jessica; Himes, Blanca; Howrylak, Judie; Ramsey, Clare; Brehm, John; Klanderman, Barbara; Ziniti, John; Melén, Erik; Pershagen, Goran; Wickman, Magnus; Martinez, Fernando; Mauger, Dave; Sorkness, Christine; Tantisira, Kelan; Raby, Benjamin A; Weiss, Scott T; Celedón, Juan C

2012-07-01

Childhood asthma is a complex disease with known heritability and phenotypic diversity. Although an earlier onset has been associated with more severe disease, there has been no genome-wide association study of the age of onset of asthma in children. We sought to identify genetic variants associated with earlier onset of childhood asthma. We conducted the first genome-wide association study of the age of onset of childhood asthma among participants in the Childhood Asthma Management Program (CAMP) and used 3 independent cohorts from North America, Costa Rica, and Sweden for replication. Two single nucleotide polymorphisms (SNPs) were associated with earlier onset of asthma in the combined analysis of CAMP and the replication cohorts: rs9815663 (Fisher P= 2.31 × 10(-8)) and rs7927044 (P= 6.54 × 10(-9)). Of these 2 SNPs, rs9815663 was also significantly associated with earlier asthma onset in an analysis including only the replication cohorts. Ten SNPs in linkage disequilibrium with rs9815663 were also associated with earlier asthma onset (2.24 × 10(-7)

Infliximab for Crohn's disease in the Swiss IBD Cohort Study: clinical management and appropriateness.

PubMed

Juillerat, Pascal; Pittet, Valérie; Vader, John-Paul; Burnand, Bernard; Gonvers, Jean-Jacques; de Saussure, Philippe; Mottet, Christian; Seibold, Frank; Rogler, Gerhard; Sagmeister, Markus; Felley, Christian; Michetti, Pierre; Froehlich, Florian

2010-11-01

Antitumor necrosis factor a agents have significantly improved the management of Crohn's disease (CD), but not all patients benefit from this therapy. We used data from the Swiss Inflammatory Bowel Disease Cohort Study and predefined appropriateness criteria to examine the appropriateness of use of infliximab (IFX) in CD patients. EPACT II (European Panel on the Appropriateness of CD Therapy, 2007; www.epact.ch) appropriateness criteria have been developed using a formal explicit panel process combining evidence from the published literature and expert opinion. Questionnaires relating to EPACT II criteria were used at enrollment and follow-up of all Swiss Inflammatory Bowel Disease Cohort Study patients. A step-by-step analysis of all possible indications for IFX therapy in a given patient allowed identification of the most appropriate indication and final classification in a single appropriateness category (appropriate, uncertain, inappropriate). Eight hundred and twenty-one CD patients were prospectively enrolled between November 2006 and March 2009. IFX was administered to 146 patients (18%) at enrollment and was most frequently used for complex fistulizing disease and for the maintenance of remission induced by biological therapy. IFX therapy was considered appropriate in 44%, uncertain in 44%, and inappropriate in 10% of patients. In this cohort, 9 out of 10 indications for IFX therapy were clinically generally acceptable (appropriate or uncertain) according to EPACT II criteria. Uncertain indications resulted mainly from the current more liberal use of IFX in clinical practice as compared with the EPACT II criteria.

Cosmesis, patient satisfaction, and quality of life after da Vinci Single-Site cholecystectomy and multiport laparoscopic cholecystectomy: short-term results from a prospective, multicenter, randomized, controlled trial.

PubMed

Kudsi, Omar Yusef; Castellanos, Andres; Kaza, Srinivas; McCarty, Justin; Dickens, Eugene; Martin, David; Tiesenga, Frederick M; Konstantinidis, Konstantinos; Hirides, Petros; Mehendale, Shilpa; Gonzalez, Anthony

2017-08-01

Single-incision laparoscopic cholecystectomy evolved from the traditional multiport laparoscopic technique. Prior trials have demonstrated improved cosmesis with the single-incision technique. Robotic single-site surgery minimizes the technical difficulties associated with laparoscopic single-incision approach. This is the first prospective, randomized, controlled study comparing robotic single-site cholecystectomy (RSSC) and multiport laparoscopic cholecystectomy (MPLC) in terms of cosmesis and patient satisfaction. Patients with symptomatic benign gallbladder disease were randomized to RSSC or MPLC. Data included perioperative variables such as operative time, conversion and complications and cosmesis satisfaction, body image perception, quality of life using validated questionnaires, at postoperative visits of 2, 6 weeks and 3 months. One hundred thirty-six patients were randomized to RSSC (N = 83) and MPLC (N = 53) at 8 institutions. Both cohorts were dominated by higher enrollment of females (RSSC = 78%, MPLC = 92%). The RSSC and MPLC cohorts were otherwise statistically matched. Operative time was longer for RSSC (61 min vs. 44 min, P < 0.0001). There were no differences in complication rates. RSSC demonstrated a significant superiority in cosmesis satisfaction and body image perception (P value < 0.05 at every follow-up). There was no statistically significant difference in patient-reported quality of life. Multivariate analysis of female patients demonstrated significantly higher preference for RSSC over MPLC in cosmesis satisfaction and body image perception with no difference seen in overall quality of life. Results from this trial show that RSSC is associated with improved cosmesis satisfaction and body image perception without a difference in observed complication rate. The uncompromised safety and the improved cosmesis satisfaction and body image perception provided by RSSC for female patients support consideration of the robotic single-site approach. ClinicalTrials.gov identifier NCT01932216.

Physical self-concept changes in a selective sport high school: a longitudinal cohort-sequence analysis of the big-fish-little-pond effect.

PubMed

Marsh, Herbert W; Morin, Alexandre J; Parker, Philip D

2015-04-01

Elite athletes and nonathletes (N = 1,268) attending the same selective sport high school (4 high school age cohorts, grades 7-10, mean ages varying from 10.9 to 14.1) completed the same physical self-concept instrument 4 times over a 2-year period (multiple waves). We introduce a latent cohort-sequence analysis that provides a stronger basis for assessing developmental stability/change than either cross-sectional (multicohort, single occasion) or longitudinal (single-cohort, multiple occasion) designs, allowing us to evaluate latent means across 10 waves spanning a 5-year period (grades 7-11), although each participant contributed data for only 4 waves, spanning 2 of the 5 years. Consistent with the frame-of-reference effects embodied in the big-fish-little-pond effect (BFLPE), physical self-concepts at the start of high school were much higher for elite athletes than for nonathlete classmates, but the differences declined over time so that by the end of high school there were no differences in the 2 groups. Gender differences in favor of males had a negative linear and quadratic trajectory over time, but the consistently smaller gender differences for athletes than for nonathletes did not vary with time.

Decision curve analysis and external validation of the postoperative Karakiewicz nomogram for renal cell carcinoma based on a large single-center study cohort.

PubMed

Zastrow, Stefan; Brookman-May, Sabine; Cong, Thi Anh Phuong; Jurk, Stanislaw; von Bar, Immanuel; Novotny, Vladimir; Wirth, Manfred

2015-03-01

To predict outcome of patients with renal cell carcinoma (RCC) who undergo surgical therapy, risk models and nomograms are valuable tools. External validation on independent datasets is crucial for evaluating accuracy and generalizability of these models. The objective of the present study was to externally validate the postoperative nomogram developed by Karakiewicz et al. for prediction of cancer-specific survival. A total of 1,480 consecutive patients with a median follow-up of 82 months (IQR 46-128) were included into this analysis with 268 RCC-specific deaths. Nomogram-estimated survival probabilities were compared with survival probabilities of the actual cohort, and concordance indices were calculated. Calibration plots and decision curve analyses were used for evaluating calibration and clinical net benefit of the nomogram. Concordance between predictions of the nomogram and survival rates of the cohort was 0.911 after 12, 0.909 after 24 months and 0.896 after 60 months. Comparison of predicted probabilities and actual survival estimates with calibration plots showed an overestimation of tumor-specific survival based on nomogram predictions of high-risk patients, although calibration plots showed a reasonable calibration for probability ranges of interest. Decision curve analysis showed a positive net benefit of nomogram predictions for our patient cohort. The postoperative Karakiewicz nomogram provides a good concordance in this external cohort and is reasonably calibrated. It may overestimate tumor-specific survival in high-risk patients, which should be kept in mind when counseling patients. A positive net benefit of nomogram predictions was proven.

Timing of cranioplasty after decompressive craniectomy for trauma.

PubMed

Piedra, Mark P; Nemecek, Andrew N; Ragel, Brian T

2014-01-01

The optimal timing of cranioplasty after decompressive craniectomy for trauma is unknown. The aim of this study was to determine if early cranioplasty after decompressive craniectomy for trauma reduces complications. Consecutive cases of patients who underwent autologous cranioplasty after decompressive craniectomy for trauma at a single Level I Trauma Center were studied in a retrospective 10 year data review. Associations of categorical variables were compared using Chi-square test or Fisher's exact test. A total of 157 patients were divided into early (<12 weeks; 78 patients) and late (≥12 weeks; 79 patients) cranioplasty cohorts. Baseline characteristics were similar between the two cohorts. Cranioplasty operative time was significantly shorter in the early (102 minutes) than the late (125 minutes) cranioplasty cohort (P = 0.0482). Overall complication rate in both cohorts was 35%. Infection rates were lower in the early (7.7%) than the late (14%) cranioplasty cohort as was bone graft resorption (15% early, 19% late), hydrocephalus rate (7.7% early, 1.3% late), and postoperative hematoma incidence (3.9% early, 1.3% late). However, these differences were not statistically significant. Patients <18 years of age were at higher risk of bone graft resorption than patients ≥18 years of age (OR 3.32, 95% CI 1.25-8.81; P = 0.0162). After decompressive craniectomy for trauma, early (<12 weeks) cranioplasty does not alter the incidence of complication rates. In patients <18 years of age, early (<12 weeks) cranioplasty increases the risk of bone resorption. Delaying cranioplasty (≥12 weeks) results in longer operative times and may increase costs.

DISTMIX: direct imputation of summary statistics for unmeasured SNPs from mixed ethnicity cohorts.

PubMed

Lee, Donghyung; Bigdeli, T Bernard; Williamson, Vernell S; Vladimirov, Vladimir I; Riley, Brien P; Fanous, Ayman H; Bacanu, Silviu-Alin

2015-10-01

To increase the signal resolution for large-scale meta-analyses of genome-wide association studies, genotypes at unmeasured single nucleotide polymorphisms (SNPs) are commonly imputed using large multi-ethnic reference panels. However, the ever increasing size and ethnic diversity of both reference panels and cohorts makes genotype imputation computationally challenging for moderately sized computer clusters. Moreover, genotype imputation requires subject-level genetic data, which unlike summary statistics provided by virtually all studies, is not publicly available. While there are much less demanding methods which avoid the genotype imputation step by directly imputing SNP statistics, e.g. Directly Imputing summary STatistics (DIST) proposed by our group, their implicit assumptions make them applicable only to ethnically homogeneous cohorts. To decrease computational and access requirements for the analysis of cosmopolitan cohorts, we propose DISTMIX, which extends DIST capabilities to the analysis of mixed ethnicity cohorts. The method uses a relevant reference panel to directly impute unmeasured SNP statistics based only on statistics at measured SNPs and estimated/user-specified ethnic proportions. Simulations show that the proposed method adequately controls the Type I error rates. The 1000 Genomes panel imputation of summary statistics from the ethnically diverse Psychiatric Genetic Consortium Schizophrenia Phase 2 suggests that, when compared to genotype imputation methods, DISTMIX offers comparable imputation accuracy for only a fraction of computational resources. DISTMIX software, its reference population data, and usage examples are publicly available at http://code.google.com/p/distmix. dlee4@vcu.edu Supplementary Data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder.

PubMed

de Moor, Marleen H M; van den Berg, Stéphanie M; Verweij, Karin J H; Krueger, Robert F; Luciano, Michelle; Arias Vasquez, Alejandro; Matteson, Lindsay K; Derringer, Jaime; Esko, Tõnu; Amin, Najaf; Gordon, Scott D; Hansell, Narelle K; Hart, Amy B; Seppälä, Ilkka; Huffman, Jennifer E; Konte, Bettina; Lahti, Jari; Lee, Minyoung; Miller, Mike; Nutile, Teresa; Tanaka, Toshiko; Teumer, Alexander; Viktorin, Alexander; Wedenoja, Juho; Abecasis, Goncalo R; Adkins, Daniel E; Agrawal, Arpana; Allik, Jüri; Appel, Katja; Bigdeli, Timothy B; Busonero, Fabio; Campbell, Harry; Costa, Paul T; Davey Smith, George; Davies, Gail; de Wit, Harriet; Ding, Jun; Engelhardt, Barbara E; Eriksson, Johan G; Fedko, Iryna O; Ferrucci, Luigi; Franke, Barbara; Giegling, Ina; Grucza, Richard; Hartmann, Annette M; Heath, Andrew C; Heinonen, Kati; Henders, Anjali K; Homuth, Georg; Hottenga, Jouke-Jan; Iacono, William G; Janzing, Joost; Jokela, Markus; Karlsson, Robert; Kemp, John P; Kirkpatrick, Matthew G; Latvala, Antti; Lehtimäki, Terho; Liewald, David C; Madden, Pamela A F; Magri, Chiara; Magnusson, Patrik K E; Marten, Jonathan; Maschio, Andrea; Medland, Sarah E; Mihailov, Evelin; Milaneschi, Yuri; Montgomery, Grant W; Nauck, Matthias; Ouwens, Klaasjan G; Palotie, Aarno; Pettersson, Erik; Polasek, Ozren; Qian, Yong; Pulkki-Råback, Laura; Raitakari, Olli T; Realo, Anu; Rose, Richard J; Ruggiero, Daniela; Schmidt, Carsten O; Slutske, Wendy S; Sorice, Rossella; Starr, John M; St Pourcain, Beate; Sutin, Angelina R; Timpson, Nicholas J; Trochet, Holly; Vermeulen, Sita; Vuoksimaa, Eero; Widen, Elisabeth; Wouda, Jasper; Wright, Margaret J; Zgaga, Lina; Porteous, David; Minelli, Alessandra; Palmer, Abraham A; Rujescu, Dan; Ciullo, Marina; Hayward, Caroline; Rudan, Igor; Metspalu, Andres; Kaprio, Jaakko; Deary, Ian J; Räikkönen, Katri; Wilson, James F; Keltikangas-Järvinen, Liisa; Bierut, Laura J; Hettema, John M; Grabe, Hans J; van Duijn, Cornelia M; Evans, David M; Schlessinger, David; Pedersen, Nancy L; Terracciano, Antonio; McGue, Matt; Penninx, Brenda W J H; Martin, Nicholas G; Boomsma, Dorret I

2015-07-01

Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases). To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P < .05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection

PubMed Central

Lemm, Julie; Eley, Timothy; Liu, Menping; Berglind, Anna; Sherman, Diane; Lawitz, Eric; Vutikullird, Apinya B.; Tebas, Pablo; Gao, Min; Pasquinelli, Claudio; Grasela, Dennis M.

2014-01-01

BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.) PMID:24733462

Incremental direct and indirect cost burden attributed to endometriosis surgeries in the United States.

PubMed

Soliman, Ahmed M; Taylor, Hugh S; Bonafede, Machaon; Nelson, James K; Castelli-Haley, Jane

2017-05-01

To compare direct and indirect costs between endometriosis patients who underwent endometriosis-related surgery (surgery cohort) and those who have not received surgery (no-surgery cohort). Retrospective cohort study. Not applicable. Endometriosis patients (aged 18-49 years) with (n = 124,530) or without (n = 37,106) a claim for endometriosis-related surgery were identified from the Truven Health MarketScan Commercial and Health and Productivity Management databases for 2006-2014. Not applicable. Primary outcomes were healthcare utilization during 12-month pre- and post-index periods, annual direct (healthcare) and indirect (absenteeism and short- and long-term disability) costs during the 12-month post-index period (in 2014 US dollars). Indirect costs were assessed for patients with available productivity data. Patients in the surgery cohort had significantly higher healthcare resource utilization during the post-index period and had mean annual total adjusted post-index direct costs approximately three times the costs among patients in the no-surgery cohort ($19,203 [SD $7,133] vs. $6,365 [SD $2,364]; average incremental annual direct cost = $12,838). The mean cost of surgery ($7,268 [SD $7,975]) was the single largest contributor to incremental annual direct cost. Mean estimated annual total indirect costs were $8,843 (surgery cohort) vs. $5,603 (no-surgery cohort); average incremental annual indirect cost = $3,240. Endometriosis patients who underwent surgery, compared with endometriosis patients who did not, incurred significantly higher direct costs due to healthcare utilization and indirect costs due to absenteeism or short-term disability. Regardless of the surgery type, the cost of index surgery contributed substantially to the total healthcare expenditure. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

PubMed

Suenaga, Mitsukuni; Schirripa, Marta; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Cremolini, Chiara; Antoniotti, Carlotta; Borelli, Beatrice; Mashima, Tetsuo; Okazaki, Satoshi; Berger, Martin D; Miyamoto, Yuji; Gopez, Roel; Barzi, Afsaneh; Lonardi, Sara; Yamaguchi, Toshiharu; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef

2018-06-01

The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Impact of Exercise Counseling on Physical Function in Chronic Kidney Disease: An Observational Study.

PubMed

Bohm, Clara J; Storsley, Leroy J; Hiebert, Brett M; Nelko, Serena; Tangri, Navdeep; Cheskin, Lawrence J; McAdams-DeMarco, Mara A; Rigatto, Claudio

2018-01-01

Individuals with chronic kidney disease (CKD) have low levels of physical activity and physical function. Although guidelines endorse exercise counseling for individuals with CKD, it is not yet part of routine care. We investigated the effect of attending a real-life exercise counseling clinic (ECC) on physical function in individuals with CKD. Retrospective analysis of prospectively collected observational data with quasi-experimental design. Patients with all stages of CKD registered in a large provincial renal program were eligible. The exposed cohort who attended the ECC between January 1, 2011, and March 15, 2014, included 214 individuals. The control cohort included 292 individuals enrolled in an observational study investigating longitudinal change in frailty during the same time period. Attendance at an ECC. Change in physical function as measured by Short Physical Performance Battery (SPPB) score, physical activity level (Human Activity Profile [HAP]/Physical Activity Scale for the Elderly [PASE]), and health-related quality of life (HRQOL; EQ5D/VAS) over 1 year. Eighty-seven individuals in the ECC cohort and 125 participants in the control cohort completed 1-year follow-up. Baseline median SPPB score was 10 (interquartile range [IQR]: 9-12) and 9 (IQR: 7-11) in the ECC and control cohorts, respectively ( P < .01). At 1 year, SPPB scores were 10 (IQR: 8-12) and 9 (IQR: 6-11) in the ECC and control cohorts, respectively ( P = .04). Mean change in SPPB over 1 year was not significantly different between groups: -0.33 (95% confidence interval [CI]: -0.81 to 0.15) in ECC and -0.22 (95% CI: -0.61 to 0.17) in control ( P = .72). There was no significant difference in the proportion of individuals in each cohort with an increase/decrease in SPPB score over time. There was no significant change in physical activity or HRQOL over time between groups. Quasi-experimental design, low rate of follow-up attendance. In this pragmatic study, exercise counseling had no significant effect on change in SPPB score, suggesting that a single exercise counseling session alone is inadequate to improve physical function in CKD.

Are changes in workplace bullying status related to changes in salivary cortisol? A longitudinal study among Danish employees.

PubMed

Gullander, Maria; Grynderup, Matias; Hansen, Åse Marie; Hogh, Annie; Persson, Roger; Kolstad, Henrik Albert; Mors, Ole; Kaerlev, Linda; Bonde, Jens Peter

2015-11-01

This study aims to investigate whether incident workplace bullying and its dicontinuance is related to subsequent change in morning and evening saliva cortisol concentrations. Participants came from two Danish cohort studies, the PRISME cohort (n=4489) and the Workplace Bullying and Harassment Cohort (n=3707). At baseline and follow-up exposure to bullying was measured by a single question on bullying (preceded by a definition). Two saliva samples to measure cortisol were collected during a work-day (30 min after awakening and at 8 p.m.). All participants responding to the item on workplace bullying, giving saliva samples and participated at both baseline and follow-up were included. The reference group consisted of non-bullied respondents at both baseline and follow-up. Multilevel mixed-effects linear regressions were used to test for changes in salivary cortisol after newly onset of and discontinuance of workplace bullying. All analyses were adjusted for the potentially confounding effect of differences from baseline to follow-up in education, smoking, alcohol consumption, body mass index, cohort, sampling waves, time of awakening, and time of sampling. We found no indication of statistically significant difference in saliva cortisol, neither when participants changed their self-labelling from not bullied at baseline to being bullied at follow-up, nor when they at follow-up two years later reported discontinuance of bullying. This longitudinal study on the impact of changes in bullying status on change in cortisol levels showed consistent lack of associations with onset and discontinuance of workplace bullying. Copyright © 2015 Elsevier Inc. All rights reserved.

Complications associated with distraction plate fixation of wrist fractures.

PubMed

Hanel, Douglas P; Ruhlman, Scott David; Katolik, Leo I; Allan, Christopher H

2010-05-01

This article discusses the major and minor complications of distal plating in the light of a cohort study carried out by the authors, who reviewed all patients undergoing bridge distraction plate fixation of distal radius fractures by three surgeons in a single level I trauma center. The article discusses the effectiveness and the complication rates associated with the technique. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Genome-wide association Scan of dental caries in the permanent dentition

PubMed Central

2012-01-01

Background Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults. Methods Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries phenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries. Results Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value ≤ 10E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens. Conclusions As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment. PMID:23259602

Cohort Study of Airway Mycobiome in Adult Cystic Fibrosis Patients: Differences in Community Structure between Fungi and Bacteria Reveal Predominance of Transient Fungal Elements

PubMed Central

Sauer-Heilborn, Annette; Welte, Tobias; Guzman, Carlos A.; Abraham, Wolf-Rainer; Höfle, Manfred G.

2015-01-01

The respiratory mycobiome is an important but understudied component of the human microbiota. Like bacteria, fungi can cause severe lung diseases, but their infection rates are much lower. This study compared the bacterial and fungal communities of sputum samples from a large cohort of 56 adult patients with cystic fibrosis (CF) during nonexacerbation periods and under continuous antibiotic treatment. Molecular fingerprinting based on single-strand conformation polymorphism (SSCP) analysis revealed fundamental differences between bacterial and fungal communities. Both groups of microorganisms were taxonomically classified by identification of gene sequences (16S rRNA and internal transcript spacer), and prevalences of single taxa were determined for the entire cohort. Major bacterial pathogens were frequently observed, whereas fungi of known pathogenicity in CF were detected only in low numbers. Fungal species richness increased without reaching a constant level (saturation), whereas bacterial richness showed saturation after 50 patients were analyzed. In contrast to bacteria, a large number of fungal species were observed together with high fluctuations over time and among patients. These findings demonstrated that the mycobiome was dominated by transient species, which strongly suggested that the main driving force was their presence in inhaled air rather than colonization. Considering the high exposure of human airways to fungal spores, we concluded that fungi have low colonization abilities in CF, and colonization by pathogenic fungal species may be considered a rare event. A comprehensive understanding of the conditions promoting fungal colonization may offer the opportunity to prevent colonization and substantially reduce or even eliminate fungus-related disease progression in CF. PMID:26135861

Predictors of Gleason Score (GS) upgrading on subsequent prostatectomy: a single Institution study in a cohort of patients with GS 6

PubMed Central

Mehta, Vikas; Rycyna, Kevin; Baesens, Bart MM; Barkan, Güliz A; Paner, Gladell P; Flanigan, Robert C; Wojcik, Eva M; Venkataraman, Girish

2012-01-01

Background Biopsy Gleason score (bGS) remains an important prognostic indicator for adverse outcomes in Prostate Cancer (PCA). In the light of recent studies purporting difference in prognostic outcomes for the subgroups of GS7 group (primary Gleason pattern 4 vs. 3), upgrading of a bGS of 6 to a GS≥7 has serious implications. We sought to identify pre-operative factors associated with upgrading in a cohort of GS6 patients who underwent prostatectomy. Design We identified 281 cases of GS6 PCA on biopsy with subsequent prostatectomies. Using data on pre-operative variables (age, PSA, biopsy pathology parameters), logistic regression models (LRM) were developed to identify factors that could be used to predict upgrading to GS≥7 on subsequent prostatectomy. A decision tree (DT) was constructed. Results 92 of 281 cases (32.7%) were upgraded on subsequent prostatectomy. LRM identified a model with two variables with statistically significant ability to predict upgrading, including pre-biopsy PSA (Odds Ratio 8.66; 2.03-37.49, 95% CI) and highest percentage of cancer at any single biopsy site (Odds Ratio 1.03, 1.01-1.05, 95% CI). This two-parameter model yielded an area under curve of 0.67. The decision tree was constructed using only 3 leave nodes; with a test set classification accuracy of 70%. Conclusions A simplistic model using clinical and biopsy data is able to predict the likelihood of upgrading of GS with an acceptable level of certainty. External validation of these findings along with development of a nomogram will aid in better stratifying the cohort of low risk patients as based on the GS. PMID:22949931

Integrating artificial intelligence with real-time intracranial EEG monitoring to automate interictal identification of seizure onset zones in focal epilepsy.

PubMed

Varatharajah, Yogatheesan; Berry, Brent; Cimbalnik, Jan; Kremen, Vaclav; Van Gompel, Jamie; Stead, Matt; Brinkmann, Benjamin; Iyer, Ravishankar; Worrell, Gregory

2018-08-01

An ability to map seizure-generating brain tissue, i.e. the seizure onset zone (SOZ), without recording actual seizures could reduce the duration of invasive EEG monitoring for patients with drug-resistant epilepsy. A widely-adopted practice in the literature is to compare the incidence (events/time) of putative pathological electrophysiological biomarkers associated with epileptic brain tissue with the SOZ determined from spontaneous seizures recorded with intracranial EEG, primarily using a single biomarker. Clinical translation of the previous efforts suffers from their inability to generalize across multiple patients because of (a) the inter-patient variability and (b) the temporal variability in the epileptogenic activity. Here, we report an artificial intelligence-based approach for combining multiple interictal electrophysiological biomarkers and their temporal characteristics as a way of accounting for the above barriers and show that it can reliably identify seizure onset zones in a study cohort of 82 patients who underwent evaluation for drug-resistant epilepsy. Our investigation provides evidence that utilizing the complementary information provided by multiple electrophysiological biomarkers and their temporal characteristics can significantly improve the localization potential compared to previously published single-biomarker incidence-based approaches, resulting in an average area under ROC curve (AUC) value of 0.73 in a cohort of 82 patients. Our results also suggest that recording durations between 90 min and 2 h are sufficient to localize SOZs with accuracies that may prove clinically relevant. The successful validation of our approach on a large cohort of 82 patients warrants future investigation on the feasibility of utilizing intra-operative EEG monitoring and artificial intelligence to localize epileptogenic brain tissue. Broadly, our study demonstrates the use of artificial intelligence coupled with careful feature engineering in augmenting clinical decision making.

No differences in subjective knee function between surgical techniques of anterior cruciate ligament reconstruction at 2-year follow-up: a cohort study from the Swedish National Knee Ligament Register.

PubMed

Hamrin Senorski, Eric; Sundemo, David; Murawski, Christopher D; Alentorn-Geli, Eduard; Musahl, Volker; Fu, Freddie; Desai, Neel; Stålman, Anders; Samuelsson, Kristian

2017-12-01

The purpose of this study was to investigate how different techniques of single-bundle anterior cruciate ligament (ACL) reconstruction affect subjective knee function via the Knee injury and Osteoarthritis Outcome Score (KOOS) evaluation 2 years after surgery. It was hypothesized that the surgical techniques of single-bundle ACL reconstruction would result in equivalent results with respect to subjective knee function 2 years after surgery. This cohort study was based on data from the Swedish National Knee Ligament Register during the 10-year period of 1 January 2005 through 31 December 2014. Patients who underwent primary single-bundle ACL reconstruction with hamstrings tendon autograft were included. Details on surgical technique were collected using a web-based questionnaire comprised of essential AARSC items, including utilization of accessory medial portal drilling, anatomic tunnel placement, and visualization of insertion sites and landmarks. A repeated measures ANOVA and an additional linear mixed model analysis were used to investigate the effect of surgical technique on the KOOS 4 from the pre-operative period to 2-year follow-up. A total of 13,636 patients who had undergone single-bundle ACL reconstruction comprised the study group for this analysis. A repeated measures ANOVA determined that mean subjective knee function differed between the pre-operative time period and at 2-year follow-up (p < 0.001). No differences were found with respect to the interaction between KOOS 4 and surgical technique or gender. Additionally, the linear mixed model adjusted for age at reconstruction, gender, and concomitant injuries showed no difference between surgical techniques in KOOS 4 improvement from baseline to 2-year follow-up. However, KOOS 4 improved significantly in patients for all surgical techniques of single-bundle ACL reconstruction (p < 0.001); the largest improvement was seen between the pre-operative time period and at 1-year follow-up. Surgical techniques of primary single-bundle ACL reconstruction did not demonstrate differences in the improvement in baseline subjective knee function as measured with the KOOS 4 during the first 2 years after surgery. However, subjective knee function improved from pre-operative baseline to 2-year follow-up independently of surgical technique.

Prospective, comparative cohort studies and their contribution to the benefit assessments of therapeutic options: heart failure treatment with and without Hawthorn special extract WS 1442.

PubMed

Habs, M

2004-08-01

In addition to testing a drug for its efficacy, pharmacological quality and safety, current policies are increasingly demanding evaluations of the therapeutic benefits provided by a drug in general practice with "non-selected" patients and increasingly restrictive economic considerations. One of the trials which addresses this task is the WISO cohort study (Efficacy and socio-economic relevance of treatment of chronic heart failure stage NYHA II with Crataegus extract WS 1442). It compares two different therapeutic strategies in the treatment of heart failure stage NYHA II, i.e. a conventional medication and a therapy which also includes hawthorn special extract WS 1442 (Crataegutt novo 450) in addition to chemical-synthetic drugs. In contrast to clinical trials, the patients in cohort studies are expressly not randomised and the physician in charge independently chooses the administered treatment. This comparative, non-interventional observation provides well-founded evidence of the "real-world effectiveness" of the tested preparation. 952 patients with heart failure (NYHA II) were enrolled in the study by 217 general practitioners. 588 patients received Crataegus special extract WS 1442 (Crataegutt novo 450) either as an add-on therapy or as a monotherapy (Crataegus cohort) and 364 patients received therapy without hawthorn (comparative cohort). These two groups had the same indication (heart failure NYHA II) but were significantly different regarding gender, age and concomitant cardiovascular disease. Basically, in view of the free choice of therapy made by the physician in charge, such differences are to be expected in comparative observational studies. A sufficient degree of patient comparability was provided by means of the matched-pairs technique, which replaced the randomisation procedure normally used in clinical studies. After 2 years, 130 patient pairs generated by this technique could be included in the interim assessment. The clinical symptoms with regard to all parameters investigated showed the same or a more pronounced improvement in the Crataegus cohort in the course of 2 years. After 2 years, the three cardinal symptoms of heart failure--fatigue (p = 0.036), stress dyspnoea (p = 0.020) and palpitations (p = 0.048)--were significantly less marked in the Crataegus cohort than in the comparative cohort. The particular design of the cohort study also provides valuable additional information: (1) Hawthorn special extract WS 1442 was prescribed in registered cardiological practices for the treatment of patients with heart failure stage NYHA II, partly as an alternative and partly as a supplement to the used chemical-synthetic drugs. (2) Favourable effects on the clinical symptoms were achieved although the patients in the Crataegus cohort received markedly fewer chemical-synthetic drugs than the patients in the comparative cohort (ACE-inhibitors: 36 vs. 54%, p = 0.004; cardiac glycosides: 18 vs. 37%, p = 0.001; diuretics: 49 vs. 61%, p = 0.061; beta-blockers: 22 vs. 33%, p = 0.052). The data show a clear benefit for patients with heart failure stage NYHA II treated with WS 1442. The single or add-on administration in addition to a chemical-synthetic medication resulted in objective improvements at comparable costs. Copyright 2004 S. Karger GmbH, Freiburg

Health care in adults with Down syndrome: a longitudinal cohort study.

PubMed

Jensen, K M; Davis, M M

2013-10-01

Individuals with Down syndrome increasingly survive into adulthood, yet little is known about their healthcare patterns as adults. Our study sought to characterise patterns of health care among adults with Down syndrome based on whether they had fully transitioned to adult-oriented providers by their inception in this cohort. In this retrospective observational cohort study, healthcare utilisation and annualised patient charges were evaluated in patients with Down syndrome aged 18-45 years who received care in a single academic health centre from 2000 to 2008. Comparisons were made based on patients' provider mix (only adult-focused or 'mixed' child- and adult-focused providers). The cohort included 205 patients with median index age = 28 years; 52% of these adult patients had incompletely transitioned to adult providers and received components of their care from child-focused providers. A higher proportion of these 'mixed' patients were seen exclusively by subspecialty providers (mixed = 81%, adult = 46%, P < 0.001), suggesting a need for higher intensity specialised services. Patients in the mixed provider group incurred higher annualised charges in analyses adjusted for age, mortality, total annualised encounters, and number of subspecialty disciplines accessed. These differences were most pronounced when stratified by whether patients were hospitalised during the study period (e.g., difference in adjusted means between mixed versus adult provider groups: $571 without hospitalisation, $19,061 with hospitalisation). In this unique longitudinal cohort of over 200 adults aged 18-45 years with Down syndrome, over half demonstrated incomplete transition to adult care. Persistent use of child-focused care, often with a subspecialty emphasis, has implications for healthcare charges. Future studies must identify reasons for distinct care patterns, examine their relationship with clinical outcomes, and evaluate which provider types deliver the highest quality care for adults with Down syndrome and a wide variety of comorbidities. © 2012 The Authors. Journal of Intellectual Disability Research © 2012 John Wiley & Sons Ltd, MENCAP & IASSID.

Health and Prevention Enhancement (H-PEACE): a retrospective, population-based cohort study conducted at the Seoul National University Hospital Gangnam Center, Korea.

PubMed

Lee, Changhyun; Choe, Eun Kyung; Choi, Ji Min; Hwang, Yunji; Lee, Young; Park, Boram; Chung, Su Jin; Kwak, Min-Sun; Lee, Jong-Eun; Kim, Joo Sung; Park, Sue Kyung; Cho, Sang-Heon

2018-04-19

The Health and Prevention Enhancement (H-PEACE) study was designed to investigate the association of diagnostic imaging results, biomarkers and the predisease stage of non-communicable diseases (NCDs), such as malignancies and metabolic diseases, in an average-risk population in Korea. This study enrolled a large-scale retrospective cohort at the Healthcare System Gangnam Center, Seoul National University Hospital, from October 2003 to December 2014. The baseline and follow-up information collected in the predisease stage of NCDs allows for evaluation of an individual's potential NCD risk, which is necessary for establishing personalised prevention strategies. A total of 91 336 health examinees were included in the cohort, and we repeatedly measured and collected information for 50.9% (n=46 484) of the cohort members. All participants completed structured questionnaires (lifestyle, medical history, mini-dietary assessment index, sex-specific variables and psychiatric assessment), doctors' physical examinations, laboratory blood and urine tests and digital chest X-ray imaging. For participants with available data, we also obtained information on specific diagnostic variables using advanced diagnostic tests, including coronary CT for coronary calcium scores, colonoscopy and brain MRI. Furthermore, 17 455 of the participants who provided informed consent and donated blood samples were enrolled into the Gene-environmental interaction and phenotype study, a subcohort of the H-PEACE, from October 2013, and we analysed genome-wide single-nucleotide polymorphism array data for 6579 of these blood samples. The data obtained from this cohort will be used to facilitate advanced and accurate diagnostic techniques related to NCDs while considering various phenotypes. Potential collaborators can access the dataset after receiving approval from our institutional review board. Applications can be submitted on the study homepage (http://en-healthcare.snuh.org/HPEACEstudy). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Phase II study of Gleevec® plus hydroxyurea in adults with progressive or recurrent low-grade glioma1

PubMed Central

Reardon, David A.; Desjardins, Annick; Vredenburgh, James J.; Herndon, James E.; Coan, April; Gururangan, Sridharan; Peters, Katherine B.; McLendon, Roger; Sathornsumetee, Sith; Rich, Jeremy N.; Lipp, Eric S.; Janney, Dorothea; Friedman, Henry S.

2013-01-01

Background We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. Methods A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival and radiographic response rate. Results Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had prior radiotherapy and 24 (38%) had received prior chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%) and diarrhea (3%). Conclusions Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible anti-tumor activity. PMID:22371319

Ten-year blood pressure trajectories, cardiovascular mortality, and life years lost in 2 extinction cohorts: the Minnesota Business and Professional Men Study and the Zutphen Study.

PubMed

Tielemans, Susanne M A J; Geleijnse, Johanna M; Menotti, Alessandro; Boshuizen, Hendriek C; Soedamah-Muthu, Sabita S; Jacobs, David R; Blackburn, Henry; Kromhout, Daan

2015-03-09

Blood pressure (BP) trajectories derived from measurements repeated over years have low measurement error and may improve cardiovascular disease prediction compared to single, average, and usual BP (single BP adjusted for regression dilution). We characterized 10-year BP trajectories and examined their association with cardiovascular mortality, all-cause mortality, and life years lost. Data from 2 prospective and nearly extinct cohorts of middle-aged men—the Minnesota Business and Professional Men Study (n=261) and the Zutphen Study (n=632)—were used. BP was measured annually during 1947-1957 in Minnesota and 1960-1970 in Zutphen. BP trajectories were identified by latent mixture modeling. Cox proportional hazards and linear regression models examined BP trajectories with cardiovascular mortality, all-cause mortality, and life years lost. Associations were adjusted for age, serum cholesterol, smoking, and diabetes mellitus. Mean initial age was about 50 years in both cohorts. After 10 years of BP measurements, men were followed until death on average 20 years later. All Minnesota men and 98% of Zutphen men died. Four BP trajectories were identified, in which mean systolic BP increased by 5 to 49 mm Hg in Minnesota and 5 to 20 mm Hg in Zutphen between age 50 and 60. The third systolic BP trajectories were associated with 2 to 4 times higher cardiovascular mortality risk, 2 times higher all-cause mortality risk, and 4 to 8 life years lost, compared to the first trajectory. Ten-year BP trajectories were the strongest predictors, among different BP measures, of cardiovascular mortality, all-cause mortality, and life years lost in Minnesota. However, average BP was the strongest predictor in Zutphen. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing's syndrome?

PubMed Central

Budyal, Sweta; Jadhav, Swati Sachin; Kasaliwal, Rajeev; Patt, Hiren; Khare, Shruti; Shivane, Vyankatesh; Lila, Anurag R; Bandgar, Tushar; Shah, Nalini S

2015-01-01

Variable prevalence of subclinical Cushing's syndrome (SCS) has been reported in patients with type 2 diabetes mellitus (T2DM), making the need for screening in this population uncertain. It is unknown if this variability is solely due to study-related methodological differences or a reflection of true differences in ethnic predisposition. The objective of this study is to explore the prevalence of SCS in Asian Indian patients with T2DM. In this prospective single center study conducted in a tertiary care referral center, 993 T2DM outpatients without any discriminatory clinical features (easy bruising, facial plethora, proximal muscle weakness, and/or striae) of hypercortisolism underwent an overnight 1 mg dexamethasone suppression test (ODST). ODST serum cortisol ≥1.8 μg/dl was considered positive, and those with positive results were subjected to 48 h, 2 mg/day low dose DST (LDDST). A stepwise evaluation for endogenous hypercortisolism was planned for patients with LDDST serum cortisol ≥1.8 μg/dl. Patients with positive ODST and negative LDDST were followed up clinically and re-evaluated a year later for the development of clinically evident Cushing's syndrome (CS). In this largest single center study reported to date, we found 37 out of 993 (3.72%) patients had ODST serum cortisol ≥1.8 μg/dl. None of them had LDDST cortisol ≥1.8 μg/dl, nor did they develop clinically evident CS over a follow-up period of 1 year. Specificity of ODST for screening of CS was 96.3% in our cohort. None of the T2DM outpatients in our cohort had SCS, hence cautioning against routine biochemical screening for SCS in this cohort. We suggest screening be based on clinical suspicion only. PMID:26420669

Measles, mumps and rubella (MMR) vaccination has no effect on cognitive development in children - the results of the Polish prospective cohort study.

PubMed

Mrozek-Budzyn, Dorota; Kiełtyka, Agnieszka; Majewska, Renata; Augustyniak, Małgorzata

2013-05-24

The aim of the study was to examine the hypothesis that MMR exposure has a negative influence on cognitive development in children. Furthermore, MMR was compared to single measles vaccine to determine the potential difference of these vaccines safety regarding children's cognitive development. The prospective birth cohort study with sample consisted of 369 infants born in Krakow. Vaccination history against measles (date and the type of the vaccine) was extracted from physicians' records. Child development was assessed using the Bayley Scales of Infant Development (BSID-II) up to 3rd year of life, Raven test in 5th and 8th year and Wechsler (WISC-R) in 6th and 7th year. Data on possible confounders came from mothers' interview, medical records and analyses of lead and mercury level at birth and at the end of 5th year of life. Linear and logistic regression models adjusted for potential confounders were used to assess the association. No significant differences in cognitive and intelligence tests results were observed between children vaccinated with MMR and those not vaccinated up to the end of the 2nd year of life. Children vaccinated with MMR had significantly higher Mental BSID-II Index (MDI) in the 36th month than those vaccinated with single measles vaccine (103.8±10.3 vs. 97.2±11.2, p=0.004). Neither results of Raven test nor WISC-R were significantly different between groups of children vaccinated with MMR and with single measles vaccine. After standardization to child's gender, maternal education, family economical status, maternal IQ, birth order and passive smoking all developmental tests were statistically insignificant. The results suggest that there is no relationship between MMR exposure and children's cognitive development. Furthermore, the safety of triple MMR is the same as the single measles vaccine with respect to cognitive development. Copyright © 2013 Elsevier Ltd. All rights reserved.

Severity of viral coinfection in hospitalized infants with respiratory syncytial virus infection.

PubMed

De Paulis, Milena; Gilio, Alfredo Elias; Ferraro, Alexandre Archanjo; Ferronato, Angela Esposito; do Sacramento, Patrícia Rossi; Botosso, Viviane Fongaro; Oliveira, Danielle Bruna Leal de; Marinheiro, Juliana Cristina; Hársi, Charlotte Marianna; Durigon, Edison Luiz; Vieira, Sandra Elisabete

2011-01-01

To compare the severity of single respiratory syncytial virus (RSV) infections with that of coinfections. A historical cohort was studied, including hospitalized infants with acute RSV infection. Nasopharyngeal aspirate samples were collected from all patients to detect eight respiratory viruses using molecular biology techniques. The following outcomes were analyzed: duration of hospitalization and of oxygen therapy, intensive care unit admission and need of mechanical ventilation. Results were adjusted for confounding factors (prematurity, age and breastfeeding). A hundred and seventy six infants with bronchiolitis and/or pneumonia were included in the study. Their median age was 4.5 months. A hundred and twenty one had single RSV infection and 55 had coinfections (24 RSV + adenovirus, 16 RSV + human metapneumovirus and 15 other less frequent viral associations). The four severity outcomes under study were similar in the group with single RSV infection and in the coinfection groups, independently of what virus was associated with RSV. Virus coinfections do not seem to affect the prognosis of hospitalized infants with acute RSV infection.

Quantifying sources of bias in longitudinal data linkage studies of child abuse and neglect: measuring impact of outcome specification, linkage error, and partial cohort follow-up.

PubMed

Parrish, Jared W; Shanahan, Meghan E; Schnitzer, Patricia G; Lanier, Paul; Daniels, Julie L; Marshall, Stephen W

2017-12-01

Health informatics projects combining statewide birth populations with child welfare records have emerged as a valuable approach to conducting longitudinal research of child maltreatment. The potential bias resulting from linkage misspecification, partial cohort follow-up, and outcome misclassification in these studies has been largely unexplored. This study integrated epidemiological survey and novel administrative data sources to establish the Alaska Longitudinal Child Abuse and Neglect Linkage (ALCANLink) project. Using these data we evaluated and quantified the impact of non-linkage misspecification and single source maltreatment ascertainment use on reported maltreatment risk and effect estimates. The ALCANLink project integrates the 2009-2011 Alaska Pregnancy Risk Assessment Monitoring System (PRAMS) sample with multiple administrative databases through 2014, including one novel administrative source to track out-of-state emigration. For this project we limited our analysis to the 2009 PRAMS sample. We report on the impact of linkage quality, cohort follow-up, and multisource outcome ascertainment on the incidence proportion of reported maltreatment before age 6 and hazard ratios of selected characteristics that are often available in birth cohort linkage studies of maltreatment. Failure to account for out-of-state emigration biased the incidence proportion by 12% (from 28.3% w to 25.2% w ), and the hazard ratio (HR) by as much as 33% for some risk factors. Overly restrictive linkage parameters biased the incidence proportion downwards by 43% and the HR by as much as 27% for some factors. Multi-source linkages, on the other hand, were of little benefit for improving reported maltreatment ascertainment. Using the ALCANLink data which included a novel administrative data source, we were able to observe and quantify bias to both the incidence proportion and HR in a birth cohort linkage study of reported child maltreatment. Failure to account for out-of-state emigration and low-quality linkage methods may induce bias in longitudinal data linkage studies of child maltreatment which other researchers should be aware of. In this study multi-agency linkage did not lead to substantial increased detection of reported maltreatment. The ALCANLink methodology may be a practical approach for other states interested in developing longitudinal birth cohort linkage studies of maltreatment that requires limited resources to implement, provides comprehensive data elements, and can facilitate comparability between studies.

Increasing mortality burden among adults with complex congenital heart disease.

PubMed

Greutmann, Matthias; Tobler, Daniel; Kovacs, Adrienne H; Greutmann-Yantiri, Mehtap; Haile, Sarah R; Held, Leonhard; Ivanov, Joan; Williams, William G; Oechslin, Erwin N; Silversides, Candice K; Colman, Jack M

2015-01-01

Progress in management of congenital heart disease has shifted mortality largely to adulthood. However, adult survivors with complex congenital heart disease are not cured and remain at risk of premature death as young adults. Thus, our aim was to describe the evolution and mortality risk of adult patient cohorts with complex congenital heart disease. Among 12,644 adults with congenital heart disease followed at a single center from 1980 to 2009, 176 had Eisenmenger syndrome, 76 had unrepaired cyanotic defects, 221 had atrial switch operations for transposition of the great arteries, 158 had congenitally corrected transposition of the great arteries, 227 had Fontan palliation, and 789 had repaired tetralogy of Fallot. We depict the 30-year evolution of these 6 patient cohorts, analyze survival probabilities in adulthood, and predict future number of deaths through 2029. Since 1980, there has been a steady increase in numbers of patients followed, except in cohorts with Eisenmenger syndrome and unrepaired cyanotic defects. Between 1980 and 2009, 308 patients in the study cohorts (19%) died. At the end of 2009, 85% of survivors were younger than 50 years. Survival estimates for all cohorts were markedly lower than for the general population, with important differences between cohorts. Over the upcoming two decades, we predict a substantial increase in numbers of deaths among young adults with subaortic right ventricles, Fontan palliation, and repaired tetralogy of Fallot. Anticipatory action is needed to prepare clinical services for increasing numbers of young adults at risk of dying from complex congenital heart disease. © 2014 The Authors. Congenital Heart Disease Published by Wiley Periodicals, Inc.

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

PubMed

Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

2015-02-01

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. © 2014, The American College of Clinical Pharmacology.

Association of Asian ethnicity with disease activity in SLE: an observational study from the Monash Lupus Clinic.

PubMed

Golder, V; Connelly, K; Staples, M; Morand, E; Hoi, A

2013-11-01

Systemic lupus erythematosus (SLE), an autoimmune condition with diverse clinical manifestations, is reported to have different expression in populations of different ancestry. Most previous studies compared patients of different ethnic groups from geographically distinct cohorts. In our study, we aimed to characterize disease manifestations in patients of different ethnic groups from a single centre, and studied patterns of disease activity over time. Demographics, baseline disease characteristics and autoantibody profiles, and disease activity (SLEDAI) measured at each visit, were captured from all consenting patients prospectively followed between 2007 and 2011 in an urban teaching hospital lupus clinic. Ethnicity was self-reported. Asian ethnicity was significantly associated with more clinically severe SLE. Time-adjusted mean SLEDAI (p = 0.01) and maximum SLEDAI (p = 0.0018) were significantly higher in Asian patients. Asians were more likely to have renal disease (OR 2.9, 95% CI 1.4-5.98; p = 0.004) and persistently active disease (PAD) (OR 2.14, 95% CI 1.05-4.38, p = 0.04). Asian lupus patients also had a significantly higher proportion of autoantibody positivity to anti-dsDNA, anti-RNP, anti-Sm, anti-Ro and anti-La, as well as increased likelihood of hypocomplementaemia and immunosuppressant use. In this single-cohort study, Asian ethnicity was found to be associated with increased SLE disease activity. This suggests significant inter-ethnic genetic contributions to the regulation of autoimmune responses and disease severity in SLE.

Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.

PubMed

Cortes, Jorge; Perl, Alexander E; Döhner, Hartmut; Kantarjian, Hagop; Martinelli, Giovanni; Kovacsovics, Tibor; Rousselot, Philippe; Steffen, Björn; Dombret, Hervé; Estey, Elihu; Strickland, Stephen; Altman, Jessica K; Baldus, Claudia D; Burnett, Alan; Krämer, Alwin; Russell, Nigel; Shah, Neil P; Smith, Catherine C; Wang, Eunice S; Ifrah, Norbert; Gammon, Guy; Trone, Denise; Lazzaretto, Deborah; Levis, Mark

2018-05-30

Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia. We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2. Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses. Ambit Biosciences/Daiichi Sankyo. Copyright © 2018 Elsevier Ltd. All rights reserved.

Adherence with single-pill amlodipine/atorvastatin vs a two-pill regimen

PubMed Central

Patel, Bimal V; Scott Leslie, R; Thiebaud, Patrick; Nichol, Michael B; Tang, Simon SK; Solomon, Henry; Honda, Dennis; Foody, JoAnne M

2008-01-01

While clinical trials demonstrate the benefits of blood pressure and cholesterol reduction, medication adherence in clinical practice is problematic. We hypothesized that a single-pill would be superior to a 2-pill regimen for achieving adherence. In this retrospective, cohort study based on pharmacy claims data, patients newly initiated on a calcium channel blocker (CCB) or statin simultaneously or within 30 days, regardless of sequence, were followed (N = 4703). Adherence was measured over 6 months as proportion of days covered (PDC). At baseline, mean age was 63.0 years, 51.6% were female, and mean number of other medications was 7.8. Overall, 16.9% of patients were on single-pill amlodipine/atorvastatin, 15.6% amlodipine + atorvastatin, 24.7% amlodipine + other statin, 13.9% other CCB + atorvastatin, 28.9% other CCB + other statin. Percentages of patients achieving adherence (PDC ≥ 80%) were: 67.7% amlodipine/atorvastatin; 49.9% amlodipine + atorvastatin; 40.4% amlodipine + other statin; 46.9% other CCB + atorvastatin; 37.4% other CCB +other statin. After adjusting for treatment selection and cohort differences, odds ratios for adherence with amlodipine/atorva-statin were 1.95 (95% confidence interval [CI], 1.80–2.13) vs amlodipine + atorvastatin, 3.10 (95% CI, 2.85–3.38) vs amlodipine + other statin, 2.06 (95% CI, 1.89–2.24) vs other CCB + atorvastatin, 2.85 (95% CI, 2.61–3.10) vs other CCB + other statin (all p <0.0001). Single-pill amlodipine/atorvastatin may provide clinical benefits through improving adherence, offering clinicians a practical solution for cardiovascular risk management. PMID:18827917

Developmental toxicity testing of monoclonal antibodies: an enhanced pre- and postnatal study design option.

PubMed

Stewart, Jane

2009-09-01

For many monoclonal antibodies (mAb), the preferred species for general and reproductive safety testing is often the cynomolgus monkey. This article describes the rationale for combining the traditional "segmented" embryofetal development study with the pre- and postnatal development (PPND) study into a single "enhanced" PPND study design in the cynomolgus monkey where a single cohort of animals is exposed throughout gestation and allowed to give birth naturally. The proposed "enhanced" PPND study design evaluates all the stages of the traditional two study design using fewer animals. It also assesses the functional consequences of mid to late gestational exposure. This is of particular relevance to the risk assessment of monoclonal antibodies where fetal exposure to maternal IgG increases as pregnancy progresses and where morphologic examination of a pre-term fetus may not be adequate to reveal the presence of adverse effects on functional development of key target organs.

Benefits gained, benefits lost: comparing baby boomers to other generations in a longitudinal cohort study of self-rated health.

PubMed

Badley, Elizabeth M; Canizares, Mayilee; Perruccio, Anthony V; Hogg-Johnson, Sheilah; Gignac, Monique A M

2015-03-01

POLICY POINTS: Despite beliefs that baby boomers are healthier than previous generations, we found no evidence that the health of baby boomers is substantially different from that of the previous or succeeding cohorts. The effects of increased education, higher income, and lower smoking rates on improving self-rated health were nearly counterbalanced by the adverse effect of increasing body mass index (BMI). Assumptions that baby boomers will require less health care as they age because of better education, more prosperity, and less propensity to smoke may not be realized because of increases in obesity. Baby boomers are commonly believed to be healthier than the previous generation. Using self-rated health (SRH) as an indicator of health status, this study examines the effects of age, period, and birth cohort on the trajectory of health across 4 generations: World War II (born between 1935 and 1944), older baby boomers (born between 1945 and 1954), younger baby boomers (born between 1955 and 1964), and Generation X (born between 1965 and 1974). We analyzed Canada's longitudinal National Population Health Survey 1994-2010 (n = 8,570 at baseline), using multilevel growth models to estimate the age trajectory of SRH by cohort, accounting for period and incorporating the influence of changes in education, household income, smoking status, and body mass index (BMI) on SRH over time. SRH worsened with increasing age in all cohorts. Cohort differences in SRH were modest (p = 0.034), but there was a significant period effect (p = 0.002). We found marked cohort effects for increasing education, income, and BMI, and decreasing smoking from the youngest to the oldest cohorts, which were much reduced (education and smoking) or removed (income and BMI) once period was taken into account. At the population level, multivariable analysis showed the benefits of increasing education and income and declines in smoking on the trajectory of improving SRH were almost counterbalanced by the effects of increasing BMI (obesity). We found no evidence to support the expectation that baby boomers will age more or less healthily than previous cohorts did. We also found that increasing BMI has likely undermined improvements in health that might have otherwise occurred, with possible implications for the need for health care. Period effects had a more profound effect than birth cohort effects. This suggests that interventions to improve health, such as reducing obesity, can be targeted to the entire, or a major portion of the, population and need not single out particular birth cohorts. © 2015 Milbank Memorial Fund.

Benefits Gained, Benefits Lost: Comparing Baby Boomers to Other Generations in a Longitudinal Cohort Study of Self-Rated Health

PubMed Central

BADLEY, ELIZABETH M; CANIZARES, MAYILEE; PERRUCCIO, ANTHONY V; HOGG-JOHNSON, SHEILAH; GIGNAC, MONIQUE AM

2015-01-01

Policy Points Despite beliefs that baby boomers are healthier than previous generations, we found no evidence that the health of baby boomers is substantially different from that of the previous or succeeding cohorts. The effects of increased education, higher income, and lower smoking rates on improving self-rated health were nearly counterbalanced by the adverse effect of increasing body mass index (BMI). Assumptions that baby boomers will require less health care as they age because of better education, more prosperity, and less propensity to smoke may not be realized because of increases in obesity. Context Baby boomers are commonly believed to be healthier than the previous generation. Using self-rated health (SRH) as an indicator of health status, this study examines the effects of age, period, and birth cohort on the trajectory of health across 4 generations: World War II (born between 1935 and 1944), older baby boomers (born between 1945 and 1954), younger baby boomers (born between 1955 and 1964), and Generation X (born between 1965 and 1974). Methods We analyzed Canada’s longitudinal National Population Health Survey 1994-2010 (n = 8,570 at baseline), using multilevel growth models to estimate the age trajectory of SRH by cohort, accounting for period and incorporating the influence of changes in education, household income, smoking status, and body mass index (BMI) on SRH over time. Findings SRH worsened with increasing age in all cohorts. Cohort differences in SRH were modest (p = 0.034), but there was a significant period effect (p = 0.002). We found marked cohort effects for increasing education, income, and BMI, and decreasing smoking from the youngest to the oldest cohorts, which were much reduced (education and smoking) or removed (income and BMI) once period was taken into account. At the population level, multivariable analysis showed the benefits of increasing education and income and declines in smoking on the trajectory of improving SRH were almost counterbalanced by the effects of increasing BMI (obesity). Conclusions We found no evidence to support the expectation that baby boomers will age more or less healthily than previous cohorts did. We also found that increasing BMI has likely undermined improvements in health that might have otherwise occurred, with possible implications for the need for health care. Period effects had a more profound effect than birth cohort effects. This suggests that interventions to improve health, such as reducing obesity, can be targeted to the entire, or a major portion of the, population and need not single out particular birth cohorts. PMID:25752350

Single-Sex Schooling and Labour Market Outcomes

ERIC Educational Resources Information Center

Sullivan, Alice; Joshi, Heather; Leonard, Diana

2011-01-01

One quarter of the 1958 British Birth cohort attended single-sex secondary schools. This paper asks whether sex-segregated schooling had any impact on the experience of gender differences in the labour market in mid-life. We examine outcomes at age 42, allowing for socio-economic origins and abilities measured in childhood. We find no net impact…

Prebreeding survival of Roseate Terns Sterna dougallii varies with sex, hatching order and hatching date

USGS Publications Warehouse

Nisbet, Ian C.T.; Monticelli, David; Spendelow, Jeffrey A.; Szczys, Patricia

2016-01-01

Unequal sex ratios can reduce the productivity of animal populations and are especially prevalent among endangered species. A cohort of 333 Roseate Tern Sterna dougallii chicks at a site where the adult sex ratio was skewed towards females was sexed at hatching and followed through fledging and return to the breeding area, and subsequently during adulthood. The entire regional metapopulation was sampled for returning birds. Prebreeding survival (from fledging to age 3 years) was lower in males than in females, but only among B-chicks (second in hatching order). Prebreeding survival also declined with hatching date. The proportion of females in this cohort increased from 54.6% at hatching to 56.2% at fledging and to an estimated 58.0% among survivors at age 3 years. This was more than sufficient to explain the degree of skew in the sex ratio of the adult population, but changes in this degree of skew during the study period make it difficult to identify the influence of a single cohort of recruits. Many studies of prebreeding survival in other bird species have identified effects of sex, hatching order or hatching date, but no previous study has tested for effects of all three factors simultaneously.

Association of β-defensin copy number and psoriasis in three cohorts of European origin

PubMed Central

Stuart, Philip E; Hüffmeier, Ulrike; Nair, Rajan P; Palla, Raquel; Tejasvi, Trilokraj; Schalkwijk, Joost; Elder, James T; Reis, Andre; Armour, John AL

2012-01-01

A single previous study has demonstrated significant association of psoriasis with copy number of beta-defensin genes, using DNA from psoriasis cases and controls from Nijmegen and Erlangen. In this study we attempted to replicate that finding in larger new cohorts from Erlangen (N = 2017) and Michigan (N = 5412), using improved methods for beta-defensin copy number determination based on the paralog ratio test (PRT), and enhanced methods of analysis and association testing implemented in the CNVtools resource. We demonstrate that the association with psoriasis found in the discovery sample is maintained after applying improved typing and analysis methods (p = 5.5 × 10−4, OR = 1.25). We also find that the association is replicated in 2616 cases and 2526 controls from Michigan, although at reduced significance (p = 0.014), but not in new samples from Erlangen (1396 cases and 621 controls, p = 0.38). Meta-analysis across all cohorts suggests a nominally significant association (p = 6.6 × 10−3/2 × 10−4) with an effect size (OR = 1.081) much lower than found in the discovery study (OR = 1.32). This reduced effect size and significance on replication is consistent with a genuine but weak association. PMID:22739795

A single pre-operative antibiotic dose is as effective as continued antibiotic prophylaxis in implant-based breast reconstruction: A matched cohort study.

PubMed

Townley, William A; Baluch, Narges; Bagher, Shaghayegh; Maass, Saskia W M C; O'Neill, Anne; Zhong, Toni; Hofer, Stefan O P

2015-05-01

Infections following implant-based breast reconstruction can lead to devastating consequences. There is currently no consensus on the need for post-operative antibiotics in preventing immediate infection. This study compared two different methods of infection prevention in this group of patients. A retrospective matched cohort study was performed on consecutive women undergoing implant-based breast reconstruction at University Health Network, Toronto (November 2008-December 2012). All patients received a single pre-operative intravenous antibiotic dose. Group A received minimal interventions and Group B underwent maximal prophylactic measures. Patient (age, smoking, diabetes, co-morbidities), oncologic and procedural variables (timing and laterality) were collected. Univariate and multivariate logistic regression were performed to compare outcomes between the two groups. Two hundred and eight patients underwent 647 implant procedures. After matching the two treatment groups by BMI, 94 patients in each treatment group yielding a total of 605 implant procedures were selected for analysis. The two groups were comparable in terms of patient and disease variables. Post-operative wound infection was similar in Group A (n = 11, 12%) compared with Group B (n = 9, 10%; p = 0.8). Univariate analysis revealed only pre-operative radiotherapy to be associated with the development of infection (0.004). Controlling for the effect of radiotherapy, multivariate analysis demonstrated that there was no statistically significant difference between the two methods for infection prevention. Our findings suggest that a single pre-operative dose of intravenous antibiotics is equally as effective as continued antibiotic prophylaxis in preventing immediate infection in patients undergoing implant-based breast reconstructions. Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gunn, G. Brandon; Blanchard, Pierre; Department of Radiation Oncology, Institut Gustave Roussy, Villejuif

Purpose: A single-institution prospective study was conducted to assess disease control and toxicity of proton therapy for patients with head and neck cancer. Methods and Materials: Disease control, toxicity, functional outcomes, and patterns of failure for the initial cohort of patients with oropharyngeal squamous carcinoma (OPC) treated with intensity modulated proton therapy (IMPT) were prospectively collected in 2 registry studies at a single institution. Locoregional failures were analyzed by using deformable image registration. Results: Fifty patients with OPC treated from March 3, 2011, to July 2014 formed the cohort. Eighty-four percent were male, 50% had never smoked, 98% had stagemore » III/IV disease, 64% received concurrent therapy, and 35% received induction chemotherapy. Forty-four of 45 tumors (98%) tested for p16 were positive. All patients received IMPT (multifield optimization to n=46; single-field optimization to n=4). No Common Terminology Criteria for Adverse Events grade 4 or 5 toxicities were observed. The most common grade 3 toxicities were acute mucositis in 58% of patients and late dysphagia in 12%. Eleven patients had a gastrostomy (feeding) tube placed during therapy, but none had a feeding tube at last follow-up. At a median follow-up time of 29 months, 5 patients had disease recurrence: local in 1, local and regional in 1, regional in 2, and distant in 1. The 2-year actuarial overall and progression-free survival rates were 94.5% and 88.6%. Conclusions: The oncologic, toxicity, and functional outcomes after IMPT for OPC are encouraging and provide the basis for ongoing and future clinical studies.« less

Determination of a cutoff value for pelvic floor distensibility using the Epi-no balloon to predict perineal integrity in vaginal delivery: ROC curve analysis. Prospective observational single cohort study.

PubMed

Zanetti, Miriam Raquel Diniz; Petricelli, Carla Dellabarba; Alexandre, Sandra Maria; Paschoal, Aline; Araujo Júnior, Edward; Nakamura, Mary Uchiyama

2016-04-01

Several risk factors are involved in perineal lacerations during vaginal delivery. However, little is known about the influence of perineal distensibility as a protective factor. The aim here was to determine a cutoff value for pelvic floor distensibility measured using the Epi-no balloon, which could be used as a predictive factor for perineal integrity in vaginal delivery. Prospective observational single cohort study conducted in a maternity hospital. A convenience sample of 227 consecutive at-term parturients was used. All women had a single fetus in the vertex presentation, with up to 9.0 cm of dilation. The maximum dilation of the Epi-no balloon was measured using a tape measure after it had been inflated inside the vagina up to the parturients' maximum tolerance. The receiver operating characteristic (ROC) curve was used to obtain the Epi-no circumference measurement with best sensitivity and specificity. Among the 161 patients who were included in the study, 50.9% underwent episiotomy, 21.8% presented lacerations and 27.3% retained an intact perineum. Age > 25.9 years; number of pregnancies > 3.4; number of deliveries > 2.2 and circumference measured by Epi-no > 21.4 cm were all directly correlated with an intact perineum. Circumference measurements using the Epi-no balloon that were greater than 20.8 cm showed sensitivity and specificity of 70.5% and 66.7% (area under curve = 0.713), respectively, as a predictive factor for an intact perineum in vaginal delivery. Circumferences greater than 20.8 cm achieved using the Epi-no balloon are a predictive factor for perineal integrity in parturients.

Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study.

PubMed

Hendriks, L E; Derks, J L; Postmus, P E; Damhuis, R A; Houben, R M A; Troost, E G C; Hochstenbag, M M; Smit, E F; Dingemans, A-M C

2015-11-01

To analyse the prognostic impact on overall survival (OS) of single versus multiple organ metastases, organ affected, and local disease status in a population based stage IV non-small cell lung cancer (NSCLC) cohort. In this observational study, data were analysed of all histologically confirmed stage IV NSCLC patients diagnosed between 1 January 2006 and 31 December 2012 registered in the Netherlands Cancer Registry. Location of metastases before treatment was registered. Multivariable survival analyses [age, gender, histology, M-status, local disease status, number of involved organs, actual organ affected] were performed for all patients and for an (18)fluorodeoxyglucose-positron emission tomography ((18)FDG-PET)-staged subgroup. 11,094 patients were selected: 60% male, mean age 65 years, 73% adenocarcinoma. Median OS for 1 (N = 5676), 2 (N = 3280), and ⩾ 3 (N = 2138) metastatically affected organs was 6.7, 4.3, 2.8 months, respectively (p < 0.001). Hazard ratio (HR) for 2 versus 1 organ(s) was 1.33 (p < 0.001), for ⩾ 3 versus 1 organ(s) 1.91 (p < 0.001). Results were confirmed in the (18)FDG-PET-staged cohort (N = 1517): patients with single organ versus 2 and ⩾ 3 organ metastases had higher OS (8.6, 5.7, 3.8 months, HR 1.40 and 2.17, respectively, p < 0.001). In single organ metastases, OS for low versus high TN-status was 8.5 versus 6.5 months [HR 1.40 (p < 0 .001)]. (18)FDG-PET-staged single organ metastases patients with low TN-status had a superior OS than those with high TN-status (11.6 versus 8.2 months, HR 1.62, p < 0.001). Patients with single organ metastases stage IV NSCLC have a favourable prognosis, especially in combination with low TN status. They have to be regarded as a separate subgroup of stage IV disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Using Y-Chromosomal Haplogroups in Genetic Association Studies and Suggested Implications.

PubMed

Erzurumluoglu, A Mesut; Baird, Denis; Richardson, Tom G; Timpson, Nicholas J; Rodriguez, Santiago

2018-01-22

Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing for associations between autosomal single nucleotide polymorphisms (SNPs) and phenotypes will yield difference in association. For proof of concept, we derived Y-DNA haplogroups from 6537 males from two epidemiological cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) ( n = 5080; 816 Y-DNA SNPs) and the 1958 Birth Cohort ( n = 1457; 1849 Y-DNA SNPs), and studied the robust associations between 32 SNPs and body mass index (BMI), including SNPs in or near Fat Mass and Obesity-associated protein ( FTO ) which yield the strongest effects. Overall, no association was replicated in both cohorts when Y-DNA haplogroups were considered and this suggests that, for BMI at least, there is little evidence of differences in phenotype or SNP association by Y-DNA structure. Further studies using other traits, phenome-wide association studies (PheWAS), other haplogroups and/or autosomal SNPs are required to test the generalisability and utility of this approach.

Long-Term Single and Joint Effects of Excessive Daytime Napping on the HOMA-IR Index and Glycosylated Hemoglobin: A Prospective Cohort Study.

PubMed

Li, Xue; Pang, Xiuyu; Zhang, Qiao; Qu, Qiannuo; Hou, Zhigang; Liu, Zhipeng; Lv, Lin; Na, Guanqiong; Zhang, Wei; Sun, Changhao; Li, Ying

2016-02-01

This prospective cohort study was conducted to assess the duration of daytime napping and its effect combined with night sleep deprivation on the risk of developing high HOMA-IR (homeostasis model assessment of insulin resistance) index and disadvantageous changes in glycosylated hemoglobin (HbA1c) levels.A total of 5845 diabetes-free subjects (2736 women and 3109 men), 30 to 65 years of age, were targeted for this cohort study since 2008. Multiple adjusted Cox regression models were performed to evaluate the single and joint effects of daytime napping on the risk of an elevated HbA1c level and high HOMA-IR index.After an average of 4.5 years of follow-up, >30 minutes of daytime napping was significantly associated with an increased risk of an elevated HbA1c level (>6.5%) in men and women (all P trend < 0.05). Hazard ratios (HRs) for an HbA1c level between 5.7% and 6.4% were also significant in the entire cohort and women, but nonsignificant in men. HRs (95% confidence interval, CIs) for the high HOMA-IR index in the entire cohort, men, and women were 1.33 (1.10-1.62), 1.46 (1.08-1.98), and 1.47 (1.12-1.91), respectively. The combination of sleep deprivation with no naps or >30 minutes napping and the combination of no sleep deprivation with >30 minutes daytime napping were all associated with an HbA1c level >6.5% (HR = 2.08, 95% CI = 1.24-3.51; HR = 4.00, 95% CI = 2.03-7.90; and HR = 2.05, 95% CI = 1.29-3.27, respectively). No sleep deprivation combined with >30 minutes daytime napping correlated with a high risk of an HbA1c level between 5.7% and 6.4% and high HOMA-IR index (HR = 2.12, 95% CI = 1.48-3.02; and HR = 1.35, 95% CI = 1.10-1.65, respectively).Daytime napping >30 minutes was associated with a high risk of an elevated HbA1c level and high HOMA-IR index. No sleep deprivation combined with napping >30 minutes carries a risk of abnormal glucose metabolism. Sleep deprivation combined with brief daytime napping <30 minutes was not associated with a risk for an elevated HbA1c level and high HOMA-IR index.

Transforaminal lumbar interbody graft placement using an articulating delivery arm facilitates increased segmental lordosis with superior anterior and midline graft placement.

PubMed

Shau, David N; Parker, Scott L; Mendenhall, Stephen K; Zuckerman, Scott L; Godil, Saniya S; Devin, Clinton J; McGirt, Matthew J

2015-05-01

Transforaminal lumbar interbody fusion (TLIF) is a frequently performed method of lumbar arthrodesis in patients failing medical management of back and leg pain. Accurate placement of the interbody graft and restoration of lordosis has been shown to be crucial when performing lumbar fusion procedures. We performed a single-surgeon, prospective, randomized study to determine whether a novel articulating versus traditional straight graft delivery arm system allows for superior graft placement and increased lordosis for single-level TLIF. Thirty consecutive patients undergoing single-level TLIF were included and prospectively randomized to one of the 2 groups (articulated vs. straight delivery arm system). Three radiographic characteristics were evaluated at 6-week follow-up: (1) degree of segmental lumbar lordosis at the fused level; (2) the percent anterior location of the interbody graft in disk space; and (3) the distance (mm) off midline of the interbody graft placement. Randomization yielded 16 patients in the articulated delivery arm cohort and 14 in the straight delivery arm cohort. The articulating delivery arm system yielded an average of 14.7-degree segmental lordosis at fused level, 35% anterior location, and 3.6 mm off midline. The straight delivery arm system yielded an average of 10.7-degree segmental lordosis at fused level, 46% anterior location, and 7.0 mm off midline. All 3 comparisons were statistically significant (P<0.05). The study suggests that an articulating delivery arm system facilitates superior anterior and midline TLIF graft placement allowing for increased segmental lordosis compared with a traditional straight delivery arm system.

Phase I trial of RV3-BB rotavirus vaccine: a human neonatal rotavirus vaccine.

PubMed

Danchin, M; Kirkwood, C D; Lee, K J; Bishop, R F; Watts, E; Justice, F A; Clifford, V; Cowley, D; Buttery, J P; Bines, J E

2013-05-28

RV3 is a human neonatal rotavirus strain (G3P[6]) that has been associated with asymptomatic neonatal infection and replicates well in the infant gut. RV3-BB rotavirus vaccine has been developed as a rotavirus vaccine candidate for administration at birth. A single-centre, double-blind, randomised placebo-controlled Phase I study evaluated the safety and tolerability of a single oral dose of the second generation RV3-BB rotavirus vaccine (8.3×10(6)FFU/mL) in 20 adults, 20 children and 20 infants (10 vaccine and 10 placebo per age cohort). Vaccine take was defined as seroconversion (a 3-fold increase in serum anti-rotavirus IgA or serum neutralising antibody (SNA) from baseline at day 28 post-dose) or evidence of RV3-BB viral replication in the faeces by RT-PCR analysis 3-6 days post-vaccination. RV3-BB presence was confirmed by sequence analysis. The RV3-BB vaccine was well tolerated in all participants, with no pattern of adverse events shown to be associated with the study vaccine. In the infant cohort, vaccine take was demonstrated in 8/9 infants following a single dose of vaccine compared with 2/7 placebo recipients. In the infant vaccine group, 5/9 infants exhibited either IgA or SNA seroconversion and 7/9 infants had evidence of RV3-BB replication on days 3-6, compared with 2/7 infants who seroconverted and 0/10 infants with evidence of replication in the placebo group. Two infants in the placebo group had serological evidence of a rotavirus infection within the 28-day study period: one demonstrated an IgA and the other an SNA response, with wild-type virus replication detected in another infant. A single dose of RV3-BB rotavirus vaccine was well tolerated in adults, children and infants. Most infants (8/9) who received RV3-BB demonstrated vaccine take following a single dose. These data support progression of RV3-BB to Phase II immunogenicity and efficacy trials. Copyright © 2013 Elsevier Ltd. All rights reserved.

Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis.

PubMed

Pickering, John W; Than, Martin P; Cullen, Louise; Aldous, Sally; Ter Avest, Ewoud; Body, Richard; Carlton, Edward W; Collinson, Paul; Dupuy, Anne Marie; Ekelund, Ulf; Eggers, Kai M; Florkowski, Christopher M; Freund, Yonathan; George, Peter; Goodacre, Steve; Greenslade, Jaimi H; Jaffe, Allan S; Lord, Sarah J; Mokhtari, Arash; Mueller, Christian; Munro, Andrew; Mustapha, Sebbane; Parsonage, William; Peacock, W Frank; Pemberton, Christopher; Richards, A Mark; Sanchis, Juan; Staub, Lukas P; Troughton, Richard; Twerenbold, Raphael; Wildi, Karin; Young, Joanna

2017-05-16

High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI). To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain. EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016). Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization. Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies. Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died. Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies. A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome. Emergency Care Foundation.

Thrombomodulin gene variants are associated with increased mortality after coronary artery bypass surgery in replicated analyses.

PubMed

Lobato, Robert L; White, William D; Mathew, Joseph P; Newman, Mark F; Smith, Peter K; McCants, Charles B; Alexander, John H; Podgoreanu, Mihai V

2011-09-13

We tested the hypothesis that genetic variation in thrombotic and inflammatory pathways is independently associated with long-term mortality after coronary artery bypass graft (CABG) surgery. Two separate cohorts of patients undergoing CABG surgery at a single institution were examined, and all-cause mortality between 30 days and 5 years after the index CABG was ascertained from the National Death Index. In a discovery cohort of 1018 patients, a panel of 90 single-nucleotide polymorphisms (SNPs) in 49 candidate genes was tested with Cox proportional hazard models to identify clinical and genomic multivariate predictors of incident death. After adjustment for multiple comparisons and clinical predictors of mortality, the homozygote minor allele of a common variant in the thrombomodulin (THBD) gene (rs1042579) was independently associated with significantly increased risk of all-cause mortality (hazard ratio, 2.26; 95% CI, 1.31 to 3.92; P=0.003). Six tag SNPs in the THBD gene, 1 of which (rs3176123) in complete linkage disequilibrium with rs1042579, were then assessed in an independent validation cohort of 930 patients. After multivariate adjustment for the clinical predictors identified in the discovery cohort and multiple testing, the homozygote minor allele of rs3176123 independently predicted all-cause mortality (hazard ratio, 3.6; 95% CI, 1.67 to 7.78; P=0.001). In 2 independent cardiac surgery cohorts, linked common allelic variants in the THBD gene are independently associated with increased long-term mortality risk after CABG and significantly improve the classification ability of traditional postoperative mortality prediction models.

A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease.

PubMed

Mente, Andrew; de Koning, Lawrence; Shannon, Harry S; Anand, Sonia S

2009-04-13

Although a wealth of literature links dietary factors and coronary heart disease (CHD), the strength of the evidence supporting valid associations has not been evaluated systematically in a single investigation. We conducted a systematic search of MEDLINE for prospective cohort studies or randomized trials investigating dietary exposures in relation to CHD. We used the Bradford Hill guidelines to derive a causation score based on 4 criteria (strength, consistency, temporality, and coherence) for each dietary exposure in cohort studies and examined for consistency with the findings of randomized trials. Strong evidence supports valid associations (4 criteria satisfied) of protective factors, including intake of vegetables, nuts, and "Mediterranean" and high-quality dietary patterns with CHD, and associations of harmful factors, including intake of trans-fatty acids and foods with a high glycemic index or load. Among studies of higher methodologic quality, there was also strong evidence for monounsaturated fatty acids and "prudent" and "western" dietary patterns. Moderate evidence (3 criteria) of associations exists for intake of fish, marine omega-3 fatty acids, folate, whole grains, dietary vitamins E and C, beta carotene, alcohol, fruit, and fiber. Insufficient evidence (< or =2 criteria) of association is present for intake of supplementary vitamin E and ascorbic acid (vitamin C); saturated and polyunsaturated fatty acids; total fat; alpha-linolenic acid; meat; eggs; and milk. Among the dietary exposures with strong evidence of causation from cohort studies, only a Mediterranean dietary pattern is related to CHD in randomized trials. The evidence supports a valid association of a limited number of dietary factors and dietary patterns with CHD. Future evaluation of dietary patterns, including their nutrient and food components, in cohort studies and randomized trials is recommended.

The Italian dementia with Lewy bodies study group (DLB-SINdem): toward a standardization of clinical procedures and multicenter cohort studies design.

PubMed

Bonanni, L; Cagnin, A; Agosta, F; Babiloni, C; Borroni, B; Bozzali, M; Bruni, A C; Filippi, M; Galimberti, D; Monastero, R; Muscio, C; Parnetti, L; Perani, D; Serra, L; Silani, V; Tiraboschi, P; Padovani, A

2017-01-01

Dementia with Lewy bodies (DLB) causes elevated outlays for the National Health Systems due to high institutionalization rate and patients' reduced quality of life and high mortality. Furthermore, DLB is often misdiagnosed as Alzheimer's disease. These data motivate harmonized multicenter longitudinal cohort studies to improve clinical management and therapy monitoring. The Italian DLB study group of the Italian Neurological Society for dementia (SINdem) developed and emailed a semi-structured questionnaire to 572 national dementia centers (from primary to tertiary) to prepare an Italian large longitudinal cohort. The questionnaire surveyed: (1) prevalence and incidence of DLB; (2) clinical assessment; (3) relevance and availability of diagnostic tools; (4) pharmacological management of cognitive, motor, and behavioural disturbances; (5) causes of hospitalization, with specific focus on delirium and its treatment. Overall, 135 centers (23.6 %) contributed to the survey. Overall, 5624 patients with DLB are currently followed by the 135 centers in a year (2042 of them are new patients). The percentage of DLB patients was lower (27 ± 8 %) than that of Alzheimer's disease and frontotemporal dementia (56 ± 27 %) patients. The majority of the centers (91 %) considered the clinical and neuropsychological assessments as the most relevant procedure for a DLB diagnosis. Nonetheless, most of the centers has availability of magnetic resonance imaging (MRI; 95 %), electroencephalography (EEG; 93 %), and FP-CIT single photon emission-computerized tomography (SPECT; 75 %) scan for clinical applications. It will be, therefore, possible to recruit a large harmonized Italian cohort of DLB patients for future cross-sectional and longitudinal multicenter studies.

Topical administration of regorafenib eye drops: phase I dose‐escalation study in healthy volunteers

PubMed Central

Höchel, Joachim; Becka, Michael; Boettger, Michael K.; Rohde, Beate; Schug, Barbara; Kunert, Kathleen S.; Donath, Frank

2018-01-01

Aim Regorafenib is a multikinase inhibitor under investigation for use in neovascular age‐related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. Methods This was a single‐centre, randomized, double‐masked, parallel‐group, dose‐escalation, placebo‐controlled study. Subjects received regorafenib eye drops (30 mg ml−1, 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. Results Thirty‐six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600–700‐fold lower than after multiple oral administration of 160 mg day−1, the dose approved in cancer indications. Conclusion These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml−1 tid for use in clinical studies. PMID:29315699

Single-nucleotide polymorphisms studied for associations with urinary toxicity from (125)I prostate brachytherapy implants.

PubMed

Usmani, Nawaid; Leong, Nelson; Martell, Kevin; Lan, Lanna; Ghosh, Sunita; Pervez, Nadeem; Pedersen, John; Yee, Don; Murtha, Albert; Amanie, John; Sloboda, Ron; Murray, David; Parliament, Matthew

2014-01-01

To identify clinical, dosimetric, and genetic factors that are associated with late urinary toxicity after a (125)I prostate brachytherapy implant. Genomic DNA from 296 men treated with (125)I prostate brachytherapy monotherapy was extracted from saliva samples for this study. A retrospective database was compiled including clinical, dosimetric, and toxicity data for this cohort of patients. Fourteen candidate single-nucleotide polymorphism (SNPs) from 13 genes (TP53, ERCC2, GSTP1, NOS, TGFβ1, MSH6, RAD51, ATM, LIG4, XRCC1, XRCC3, GSTA1, and SOD2) were tested in this cohort for correlations with toxicity. This study identified 217 men with at least 2 years of followup. Of these, 39 patients developed Grade ≥2 late urinary complications with a transurethral resection of prostate, urethral stricture, gross hematuria, or a sustained increase in their International Prostate Symptom Score. The only clinical or dosimetric factor that was associated with late urinary toxicity was age (p = 0.02). None of the 14 SNPs tested in this study were associated with late urinary toxicity in the univariate analysis. This study identified age as the only variable being associated with late urinary toxicity. However, the small sample size and the candidate gene approach used in this study mean that further investigations are essential. Genome-wide association studies are emerging as the preferred approach for future radiogenomic studies to overcome the limitations from a candidate gene approach. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Human Fetuin-A Rs4918 Polymorphism and its Association with Obesity in Healthy Persons and in Patients with Myocardial Infarction in Two Hungarian Cohorts.

PubMed

Temesszentandrási, György; Vörös, Krisztián; Márkus, Bernadett; Böröcz, Zoltán; Kaszás, Edit; Prohászka, Zoltán; Falus, András; Cseh, Károly; Kalabay, László

2016-08-04

BACKGROUND Human fetuin A (AHSG) has been associated with the development of obesity, insulin resistance, type 2 diabetes mellitus, and atherosclerosis. Observations on the role of AHSG rs4918 single-nucleotide polymorphism are contradictory. We investigated the association between variants of rs4918 and parameters of obesity, lipid status, tumor necrosis factor-α (TNFα), adipokines (adiponectin, resistin, leptin), and insulin resistance in healthy persons and in patients with previous myocardial infarction. MATERIAL AND METHODS This was a cross-sectional study comprising cohort 1 (81 healthy individuals) and cohort 2 (157 patients with previous myocardial infarction). We used the allele-specific KASP genotyping assay to detect rs4918 polymorphism. RESULTS In cohort 1, G-nucleotide carriers had significantly lower serum TNFα, adiponectin, and higher leptin concentrations than in non-G carriers. These differences, however, were not observed in cohort 2. In cohort 2, G-carriers had lower BMI and waist circumferences than in non-G carriers. The G allele was more frequent among lean than obese patients (RR=1.067, 95%CI=1.053-2.651, p=0.015). An association between BMI and rs4918 polymorphism was observed among patients without diabetes (CC/CG/GG genotypes: p=0.003, G vs. non-G allele: p=0.008) but not in diabetics. In addition, a strong linearity between BMI and the CC/CG/GG genotypes (association value: 4.416, p=0.036) and the frequency of the G allele (7.420, p=0.006) could be identified. In cohort 2, non-obese, non-diabetic G-carriers still had lower BMI and waist circumferences than in non-G carriers. CONCLUSIONS The rs4918 minor variant is associated with lower TNFα and adiponectin, higher leptin levels in healthy persons, and more favorable anthropomorphic parameters of obesity in cohort 2.

Human Fetuin-A Rs4918 Polymorphism and its Association with Obesity in Healthy Persons and in Patients with Myocardial Infarction in Two Hungarian Cohorts

PubMed Central

Temesszentandrási, György; Vörös, Krisztián; Márkus, Bernadett; Böröcz, Zoltán; Kaszás, Edit; Prohászka, Zoltán; Falus, András; Cseh, Károly; Kalabay, László

2016-01-01

Background Human fetuin A (AHSG) has been associated with the development of obesity, insulin resistance, type 2 diabetes mellitus, and atherosclerosis. Observations on the role of AHSG rs4918 single-nucleotide polymorphism are contradictory. We investigated the association between variants of rs4918 and parameters of obesity, lipid status, tumor necrosis factor-α (TNFα), adipokines (adiponectin, resistin, leptin), and insulin resistance in healthy persons and in patients with previous myocardial infarction. Material/Methods This was a cross-sectional study comprising cohort 1 (81 healthy individuals) and cohort 2 (157 patients with previous myocardial infarction). We used the allele-specific KASP genotyping assay to detect rs4918 polymorphism. Results In cohort 1, G-nucleotide carriers had significantly lower serum TNFα, adiponectin, and higher leptin concentrations than in non-G carriers. These differences, however, were not observed in cohort 2. In cohort 2, G-carriers had lower BMI and waist circumferences than in non-G carriers. The G allele was more frequent among lean than obese patients (RR=1.067, 95%CI=1.053–2.651, p=0.015). An association between BMI and rs4918 polymorphism was observed among patients without diabetes (CC/CG/GG genotypes: p=0.003, G vs. non-G allele: p=0.008) but not in diabetics. In addition, a strong linearity between BMI and the CC/CG/GG genotypes (association value: 4.416, p=0.036) and the frequency of the G allele (7.420, p=0.006) could be identified. In cohort 2, non-obese, non-diabetic G-carriers still had lower BMI and waist circumferences than in non-G carriers. Conclusions The rs4918 minor variant is associated with lower TNFα and adiponectin, higher leptin levels in healthy persons, and more favorable anthropomorphic parameters of obesity in cohort 2. PMID:27487851

Adjuvant trastuzumab with chemotherapy is effective in women with small, node-negative, HER2-positive breast cancer.

PubMed

McArthur, Heather L; Mahoney, Kathleen M; Morris, Patrick G; Patil, Sujata; Jacks, Lindsay M; Howard, Jane; Norton, Larry; Hudis, Clifford A

2011-12-15

Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node-negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted. Women with ≤ 2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥ 2) breast cancer were identified through an institutional database. A "no-trastuzumab" cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a "trastuzumab" cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods. The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the "no trastuzumab" and "trastuzumab" cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the "no trastuzumab" cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the "trastuzumab" cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the "no trastuzumab" and "trastuzumab" cohorts, respectively. Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. Copyright © 2011 American Cancer Society.

Single nucleotide polymorphisms associated with coronary heart disease predict incident ischemic stroke in the atherosclerosis risk in communities study.

PubMed

Morrison, Alanna C; Bare, Lance A; Luke, May M; Pankow, James S; Mosley, Thomas H; Devlin, James J; Willerson, James T; Boerwinkle, Eric

2008-01-01

Ischemic stroke and coronary heart disease (CHD) may share genetic factors contributing to a common etiology. This study investigates whether 51 single nucleotide polymorphisms (SNPs) associated with CHD in multiple antecedent studies are associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. From the multiethnic ARIC cohort of 14,215 individuals, 495 validated ischemic strokes were identified. Cox proportional hazards models, adjusted for age and gender, identified three SNPs in Whites and two SNPs in Blacks associated with incident stroke (p

Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.

PubMed

Garassino, Marina Chiara; Cho, Byoung-Chul; Kim, Joo-Hang; Mazières, Julien; Vansteenkiste, Johan; Lena, Hervé; Corral Jaime, Jesus; Gray, Jhanelle E; Powderly, John; Chouaid, Christos; Bidoli, Paolo; Wheatley-Price, Paul; Park, Keunchil; Soo, Ross A; Huang, Yifan; Wadsworth, Catherine; Dennis, Phillip A; Rizvi, Naiyer A

2018-04-01

Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7-21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8-23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2-43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines. In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted. AstraZeneca. Copyright © 2018 Elsevier Ltd. All rights reserved.

Risk Factors and Independent Predictors of 30-Day Readmission for Altered Mental Status After Elective Spine Surgery for Spine Deformity: A Single-Institutional Study of 1090 Patients.

PubMed

Elsamadicy, Aladine A; Adogwa, Owoicho; Reddy, Gireesh B; Sergesketter, Amanda; Warwick, Hunter; Jones, Terrell; Cheng, Joseph; Bagley, Carlos A; Karikari, Isaac O

2017-05-01

Altered mental status (AMS) has been associated with inferior surgical outcomes. The factors leading to AMS after spine surgery are unknown. The aim of this study is to determine the risk factors and independent predictors of 30-day readmission for AMS in patients with spine deformity after undergoing elective spine surgery. The medical records of 1090 adult (≥18 years old) patients with spine deformity undergoing elective spine surgery at a major academic institution from 2005 to 2015 were reviewed. We identified 18 patients (1.65%) who had AMS as the primary driver for 30-day readmission after surgery. Patient demographics, comorbidities, and intraoperative and postoperative complication rates were collected for each patient. The primary outcome investigated in this study was risk factors associated with 30-day readmission for AMS. Patient demographics and comorbidities were similar between both groups, with the AMS cohort being significantly older than the no-AMS cohort (70.11 vs. 61.93; P = 0.003). There were no significant differences in intraoperative variables and complication rates within the cohorts. The AMS cohort had a significantly higher proportion of patients transferred to the intensive care unit (AMS, 61.11% vs. no-AMS, 19.76%; P = 0.0002) and rate of pulmonary embolism (AMS, 11.11 vs. no-AMS, 0.93; P = 0.02) after surgery. Other postoperative complication rates were similar between the cohorts. In a multivariate stepwise regression analysis, age (P = 0.013) and ICU transfer (P = 0.0002) were independent predictors of 30-day readmission for AMS. Our study suggests that increasing age and intensice care unit transfer are independent predictors of 30-day readmission for AMS after spine surgery in patients with spine deformity. Copyright © 2017 Elsevier Inc. All rights reserved.

Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.

PubMed

Chen, Ming-Huei; Yanek, Lisa R; Backman, Joshua D; Eicher, John D; Huffman, Jennifer E; Ben-Shlomo, Yoav; Beswick, Andrew D; Yerges-Armstrong, Laura M; Shuldiner, Alan R; O'Connell, Jeffrey R; Mathias, Rasika A; Becker, Diane M; Becker, Lewis C; Lewis, Joshua P; Johnson, Andrew D; Faraday, Nauder

2017-11-29

Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10 -7 ) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.

[Prevalence of illicit drug use and associated factors during pregnancy in the BRISA cohort].

PubMed

Rocha, Priscila Coimbra; Britto e Alves, Maria Teresa Seabra Soares de; Chagas, Deysianne Costa das; Silva, Antônio Augusto Moura da; Batista, Rosangela Fernandes Lucena; Silva, Raimundo Antonio da

2016-01-01

This study analyzes the prevalence of illicit drug use and associated factors during pregnancy. This was a cross-sectional study of participants in the BRISA prenatal care cohort. Frequencies and hierarchical logistic regression were used. Estimated prevalence rates were 1.45% for illicit drug use, 22.32% for alcohol consumption, and 4.22% for smoking. The study population was mostly young (81% in the 20-34-year bracket), with 9 to 11 years of schooling (75.55%), with more than half of the women outside the workforce (52.18%), and in economic class "C" (67.61%). Pregnant women showed a high level of stress (24.46%), moderate to intense anxiety (40.84%), and severe depressive symptoms (28.8%). Approximately half (49.72%) of the pregnant women reported some type of violence, and they had wide networks (72.77%) and low social support (65.21%). Use of legal drugs, high stress levels, and single parenthood were independently associated with illicit drug use in pregnancy.

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

PubMed

Taylor, John C; Bongartz, Tim; Massey, Jonathan; Mifsud, Borbala; Spiliopoulou, Athina; Scott, Ian C; Wang, Jianmei; Morgan, Michael; Plant, Darren; Colombo, Marco; Orchard, Peter; Twigg, Sarah; McInnes, Iain B; Porter, Duncan; Freeston, Jane E; Nam, Jackie L; Cordell, Heather J; Isaacs, John D; Strathdee, Jenna L; Arnett, Donna; de Hair, Maria J H; Tak, Paul P; Aslibekyan, Stella; van Vollenhoven, Ronald F; Padyukov, Leonid; Bridges, S Louis; Pitzalis, Costantino; Cope, Andrew P; Verstappen, Suzanne M M; Emery, Paul; Barnes, Michael R; Agakov, Felix; McKeigue, Paul; Mushiroda, Taisei; Kubo, Michiaki; Weinshilboum, Richard; Barton, Anne; Morgan, Ann W; Barrett, Jennifer H

2018-05-25

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10 -7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Three-year incidence of Nd:YAG capsulotomy and posterior capsule opacification and its relationship to monofocal acrylic IOL biomaterial: a UK Real World Evidence study.

PubMed

Ursell, Paul G; Dhariwal, Mukesh; Majirska, Katarina; Ender, Frank; Kalson-Ray, Shoshannah; Venerus, Alessandra; Miglio, Cristiana; Bouchet, Christine

2018-06-11

To evaluate 3-year incidence of Nd:YAG capsulotomy and PCO and compare the effect of different IOL materials. Data were retrospectively collected from seven UK ophthalmology clinics using Medisoft electronic medical records. Eyes from patients ≥65 years undergoing cataract surgery with implantation of acrylic monofocal IOLs during 2010-2013 and 3-year follow-up were analysed. Nd:YAG capsulotomy and PCO incidence proportions were reported for 3 IOL cohorts: AcrySof, other hydrophobic and hydrophilic acrylic IOLs. Unadjusted/adjusted odds ratios (OR) of Nd:YAG capsulotomy were calculated through logistic regression for non-AcrySof cohorts versus AcrySof. A sub-group analysis in single-piece IOLs (>90% of sample eyes) was also performed. The AcrySof cohort included 13,329 eyes, non-AcrySof hydrophobic 19,025 and non-AcrySof hydrophilic 19,808. The 3-year Nd:YAG capsulotomy incidence (95% CI) for AcrySof (2.4%, 2.2-2.7%) was approximately two times lower than non-AcrySof hydrophobic IOLs (4.4%, 4.1-4.7%) and approximately fourfold lower than non-AcrySof hydrophilic IOLs (10.9%, 10.5-11.3%). Trends were similar in PCO incidence (AcrySof: 4.7%; non-AcrySof hydrophobic: 6.3%; non-AcrySof hydrophilic: 14.8%). Also in the analysis restricted to single-piece IOLs, the pattern remained (2.4% vs 5.1% vs. 10.9%, respectively). Adjusted regression analysis showed a approximately two and fivefold increased odds of Nd:YAG for non-AcrySof hydrophobic and hydrophilic acrylic IOLs respectively vs. AcrySof IOLs. Nd:YAG capsulotomy ORs were similar and remained statistically significant in the single-piece IOL sub-group. Real-world evidence shows that within 3 years following implantation, AcrySof IOLs are significantly superior in reducing Nd:YAG capsulotomy and PCO incidence compared to other hydrophilic and hydrophobic acrylic IOLs.

Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study.

PubMed

Hawcutt, Daniel B; Francis, Ben; Carr, Daniel F; Jorgensen, Andrea L; Yin, Peng; Wallin, Naomi; O'Hara, Natalie; Zhang, Eunice J; Bloch, Katarzyna M; Ganguli, Amitava; Thompson, Ben; McEvoy, Laurence; Peak, Matthew; Crawford, Andrew A; Walker, Brian R; Blair, Joanne C; Couriel, Jonathan; Smyth, Rosalind L; Pirmohamed, Munir

2018-06-01

A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. Between November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10 -6 ), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15-16·99; p=5·8 × 10 -8 ). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19-12·50; p=0·02) and adult COPD (2·41, 1·10-5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97-11·68; p=4·3 × 10 -9 ; and 4·05, 2·00-8·21; p=3·5 × 10 -10 ). Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively. Department of Health Chair in Pharmacogenetics. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

X-chromosome Forkhead Box P3 polymorphisms associate with atopy in girls in three Dutch birth cohorts.

PubMed

Bottema, R W B; Kerkhof, M; Reijmerink, N E; Koppelman, G H; Thijs, C; Stelma, F F; Smit, H A; Brunekreef, B; van Schayck, C P; Postma, D S

2010-07-01

The Forkhead Box P3 (FOXP3) gene, located on the X-chromosome, encodes a transcription factor that directs T cells toward a regulatory phenotype. Regulatory T cells may suppress development of atopy. We evaluated whether single-nucleotide polymorphisms (SNPs) of FOXP3 are associated with atopy development in childhood. Seven SNPs in FOXP3 were genotyped in 3062 children (51% boys) participating in the Allergenic study, which consists of three Dutch birth cohorts (PIAMA, PREVASC and KOALA). Association of FOXP3 SNPs with total serum IgE and sensitisation (presence of specific serum IgE to egg, milk, and indoor, i.e. house-dust mite, cat, and/or dog allergens) was investigated at ages 1, 2, 4, and 8. Analysis of variance and logistic regression were performed, stratified for gender. Our most consistent finding was observed for sensitisation to egg and indoor allergens. In girls, five FOXP3 SNPs (rs5906761, rs2294021, rs2294019, rs6609857 and rs3761548) were significantly associated with sensitisation to egg at ages 1 and 2 and with sensitisation to indoor allergens at age 2 (P < 0.05), but not at 4 and 8, a finding that was observed across the three cohorts. Rs5906761 and rs2294021 were associated with remission of sensitisation to food allergens in boys, as tested in the PIAMA cohort. This is the first study showing across three cohorts that X-chromosomal FOXP3 genotypes may contribute to development of sensitisation against egg and indoor allergens in girls in early childhood. In addition, an association with remission of sensitisation to food allergens existed in boys only.

A Defined Esophagectomy Perioperative Clinical Care Process Can Improve Outcomes and Costs.

PubMed

Cooke, David T; Calhoun, Royce F; Kuderer, Valerie; David, Elizabeth A

2017-01-01

Esophagectomy (EG) is a high-risk therapy for esophageal cancer and end-stage benign disease. This study compares the results of EG before and after implementation of a perioperative clinical care process including a health provider education program (EP) and institutional uncomplicated postoperative clinical pathway (POP) for purpose quality improvement. This is a single institution retrospective cohort study. The EP was provided to critical care and telemetry unit nurses and the POP was imbedded in the electronic health record. Patients undergoing elective EG with reconstruction with the stomach for benign disease or cancer were included from 2005 to 2011. Cohorts were pre- and postimplementation (PreI and PostI) of an EP and 8-day POP (August 2008). Patient, tumor and peri/postoperative-specific variables were compared between cohorts, as well as resource utilization and hospital costs. We identified 33 PreI and 41 PostI patients. Both cohorts had similar patient demographics, preoperative comorbidities, majority cancer diagnosis, and for cancer patients, majority adenocarcinoma and IIB/III pathologic stage. Both groups had one death and similar rate of discharge to home. The PostI cohort demonstrated reduced 30-day readmission rate (2.4% vs 24.2%); P < 0.05. In regard to clinical outcomes, the PostI group exhibited reduced deep venous thrombosis/pulmonary emboli (2.4% vs 18.2%); P < 0.05. The PostI group demonstrated significantly reduced radiographic test utilization and costs, as well as total overall 30-day readmission costs. A defined perioperative clinical process involving educating the patient care team and implementing a widely disseminated POP can reduce complications, 30-day readmission rates, and hospital costs after EG.

Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.

PubMed

Viney, Nicholas J; van Capelleveen, Julian C; Geary, Richard S; Xia, Shuting; Tami, Joseph A; Yu, Rosie Z; Marcovina, Santica M; Hughes, Steven G; Graham, Mark J; Crooke, Rosanne M; Crooke, Stanley T; Witztum, Joseph L; Stroes, Erik S; Tsimikas, Sotirios

2016-11-05

Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations. We did two randomised, double-blind, placebo-controlled trials. In a phase 2 trial (done in 13 study centres in Canada, the Netherlands, Germany, Denmark, and the UK), we assessed the effect of IONIS-APO(a) Rx , an oligonucleotide targeting apolipoprotein(a). Participants with elevated Lp(a) concentrations (125-437 nmol/L in cohort A; ≥438 nmol/L in cohort B) were randomly assigned (in a 1:1 ratio in cohort A and in a 4:1 ratio in cohort B) with an interactive response system to escalating-dose subcutaneous IONIS-APO(a) Rx (100 mg, 200 mg, and then 300 mg, once a week for 4 weeks each) or injections of saline placebo, once a week, for 12 weeks. Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration at day 85 or 99 in the per-protocol population (participants who received more than six doses of study drug) and safety and tolerability in the safety population. In a phase 1/2a first-in-man trial, we assessed the effect of IONIS-APO(a)-L Rx , a ligand-conjugated antisense oligonucleotide designed to be highly and selectively taken up by hepatocytes, at the BioPharma Services phase 1 unit (Toronto, ON, Canada). Healthy volunteers (Lp[a] ≥75 nmol/L) were randomly assigned to receive a single dose of 10-120 mg IONIS-APO(a)L Rx subcutaneously in an ascending-dose design or placebo (in a 3:1 ratio; single-ascending-dose phase), or multiple doses of 10 mg, 20 mg, or 40 mg IONIS-APO(a)L Rx subcutaneously in an ascending-dose design or placebo (in an 8:2 ratio) at day 1, 3, 5, 8, 15, and 22 (multiple-ascending-dose phase). Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration, safety, and tolerability at day 30 in the single-ascending-dose phase and day 36 in the multiple-ascending-dose phase in participants who were randomised and received at least one dose of study drug. In both trials, the randomised allocation sequence was generated by Ionis Biometrics or external vendor with a permuted-block randomisation method. Participants, investigators, sponsor personnel, and clinical research organisation staff who analysed the data were all masked to the treatment assignments. Both trials are registered with ClinicalTrials.gov, numbers NCT02160899 and NCT02414594. From June 25, 2014, to Nov 18, 2015, we enrolled 64 participants to the phase 2 trial (51 in cohort A and 13 in cohort B). 35 were randomly assigned to IONIS-APO(a) Rx and 29 to placebo. At day 85/99, participants assigned to IONIS-APO(a) Rx had mean Lp(a) reductions of 66·8% (SD 20·6) in cohort A and 71·6% (13·0) in cohort B (both p<0·0001 vs pooled placebo). From April 15, 2015, to Jan 11, 2016, we enrolled 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-L Rx . Of 28 participants in the single-ascending-dose phase, three were randomly assigned to 10 mg, three to 20 mg, three to 40 mg, six to 80 mg, six to 120 mg, and seven to placebo. Of 30 participants in the multiple-ascending-dose phase, eight were randomly assigned to 10 mg, eight to 20 mg, eight to 40 mg, and six to placebo. Significant dose-dependent reductions in mean Lp(a) concentrations were noted in all single-dose IONIS-APO(a)-L Rx groups at day 30. In the multidose groups, IONIS-APO(a)-L Rx resulted in mean reductions in Lp(a) of 66% (SD 21·8) in the 10 mg group, 80% (SD 13·7%) in the 20 mg group, and 92% (6·5) in the 40 mg group (p=0·0007 for all vs placebo) at day 36. Both antisense oligonucleotides were safe. There were two serious adverse events (myocardial infarctions) in the IONIS-APO(a) Rx phase 2 trial, one in the IONIS-APO(a) Rx and one in the placebo group, but neither were thought to be treatment related. 12% of injections with IONIS-APO(a) Rx were associated with injection-site reactions. IONIS-APO(a)-L Rx was associated with no injection-site reactions. IONIS-APO(a)-L Rx is a novel, tolerable, potent therapy to reduce Lp(a) concentrations. IONIS-APO(a)-L Rx might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a) concentrations with existing cardiovascular disease or calcific aortic valve stenosis. Ionis Pharmaceuticals. Copyright © 2016 Elsevier Ltd. All rights reserved.

What Is the Efficacy of Repeat Manipulations Under Anesthesia to Treat Stiffness Following Primary Total Knee Arthroplasty?

PubMed

Issa, Kimona; Pierce, Todd P; Brothers, Alexander; McInerney, Vincent K; Chughtai, Morad; Mistry, Jaydev B; Bryant, Wayne W; Delanois, Ronald E; Harwin, Steven F; Mont, Michael A

2016-04-01

Manipulation under anesthesia (MUA) can help post-total knee arthroplasty (TKA) patients who have knee stiffness regain range-of-motion. However, despite undergoing MUA, patients may have persistent knee stiffness. Often, this persistent knee stiffness is treated with a repeat MUA. Therefore, the purpose of this study was to evaluate repeat MUAs by assessing: (1) demographic characteristics, (2) range-of-motion, (3) clinical outcomes, and (4) rate of revision surgery in post-TKA patients with persistent knee stiffness who either underwent a single MUA or repeat MUAs. One-hundred-and-sixty-seven post-TKA who had undergone an MUA between 2005 and 2011 at two institutions were reviewed. Patients were stratified into those who had a single-MUA (138 knees) and those who had a repeat MUA (29 knees). The mean follow-up period was 63 months (range, 36 to 90 months). The incidence of repeat MUA within this cohort was determined. Demographics and ROM were compared using Student t-test and Chi-square as appropriate. Functional outcomes were assessed using Knee Society scores (KSS) and compared between the two cohorts. Among the 167 patients who underwent a MUA, 29 (17%) required repeat manipulations. The repeat MUA cohort was younger and more likely to have osteonecrosis as the underlying cause of knee disease. For the repeat MUA cohort, 17 patients (59%) had achieved satisfactory mean gains in ROM after their repeat MUAs. These patients had also achieved excellent mean Knee Society objective and functional scores. However, another seven knees (24%) had further persistent knee stiffness requiring arthrolysis of adhesions and five patients (17%) had undergone revision of the polyethylene spacer or patellar component to improve range-of-motion. In this study, the majority of patients who had undergone a repeat MUA were able to achieve improvements in flexion range-of-motion and functional outcomes. However, the remaining patients required more invasive procedure to treat persistent knee stiffness. In patients who have persistent knee stiffness after MUAs, a repeat MUA may be helpful to increase range-of-motion and function.

Congenital diaphragmatic hernia: Observed/expected lung-to-head ratio as a predictor of long-term morbidity.

PubMed

King, Sebastian K; Alfaraj, Malikah; Gaiteiro, Rose; O'Brien, Karel; Moraes, Theo; Humpl, Tilman; Marcon, Margaret; Chiang, Monping; Reyes, Janette; Haliburton, Beth; Ryan, Greg; Cox, Peter; Chiu, Priscilla P L

2016-05-01

The aim of this study was to investigate the association of observed/expected (O/E) lung-to-head ratio (LHR) with long-term morbidity for isolated fetal congenital diaphragmatic hernia (CDH) patients in a single institution. We performed a retrospective study of prenatally diagnosed CDH from 18 to 38weeks of gestation (01/2002-04/2010). Two cohorts of O/E LHR were defined (22.6-45%, 45.1-78.3%) based upon previous studies. Survivors with at least 1-year follow-up of prospectively collected long-term morbidity assessments were included. O/E LHR was available in 43 survivors (median 40%, range 22.8-78.3%). Follow-up data were available in 41 survivors (M:F=24:17, left CDH=39/41). Median follow-up was 6.5years (1-11years). Height/weight trajectories were similar between the two cohorts, with the majority below the 50th centile. There were no differences between the two cohorts by age 3years for Bayley scales (developmental domains) and/or REEL-3 (language development). In addition, V/Q scans in the two cohorts demonstrated similar degrees of mismatch (mean delta V/Q=35.4 versus 31.3). In fetuses with isolated CDH, a reduction in O/E LHR does not predict a worse outcome in long-term follow-up. There is no association between a lower O/E LHR and a reduction in REEL-3 or Bayley score nor V/Q mismatch. Copyright © 2016 Elsevier Inc. All rights reserved.

Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort.

PubMed

Chin, Yoon-Ming; Tan, Lu Ping; Abdul Aziz, Norazlin; Mushiroda, Taisei; Kubo, Michiaki; Mohd Kornain, Noor Kaslina; Tan, Geok Wee; Khoo, Alan Soo-Beng; Krishnan, Gopala; Pua, Kin-Choo; Yap, Yoke-Yeow; Teo, Soo-Hwang; Lim, Paul Vey-Hong; Nakamura, Yusuke; Lum, Chee Lun; Ng, Ching-Ching

2016-10-15

Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA  = 1.98 × 10(-2) ; pExpr-GSEA  = 1.27 × 10(-24) ; pBonf-Combined  = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA  = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort. © 2016 UICC.

The work ability index and single-item question: associations with sick leave, symptoms, and health--a prospective study of women on long-term sick leave.

PubMed

Ahlstrom, Linda; Grimby-Ekman, Anna; Hagberg, Mats; Dellve, Lotta

2010-09-01

This study investigated the association between the work ability index (WAI) and the single-item question on work ability among women working in human service organizations (HSO) currently on long-term sick leave. It also examined the association between the WAI and the single-item question in relation to sick leave, symptoms, and health. Predictive values of the WAI, the changed WAI, the single-item question and the changed single-item question were investigated for degree of sick leave, symptoms, and health. This cohort study comprised 324 HSO female workers on long-term (>60 days) sick leave, with follow-ups at 6 and 12 months. Participants responded to questionnaires. Data on work ability, sick leave, health, and symptoms were analyzed with regard to associations and predictability. Spearman correlation and mixed-model analysis were performed for repeated measurements over time. The study showed a very strong association between the WAI and the single-item question among all participants. Both the WAI and the single-item question showed similar patterns of associations with sick leave, health, and symptoms. The predictive value for the degree of sick leave and health-related quality of life (HRQoL) was strong for both the WAI and the single-item question, and slightly less strong for vitality, neck pain, both self-rated general and mental health, and behavioral and current stress. This study suggests that the single-item question on work ability could be used as a simple indicator for assessing the status and progress of work ability among women on long-term sick leave.

Age-Based Methods to Explore Time-Related Variables in Occupational Epidemiology Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janice P. Watkins, Edward L. Frome, Donna L. Cragle

2005-08-31

Although age is recognized as the strongest predictor of mortality in chronic disease epidemiology, a calendar-based approach is often employed when evaluating time-related variables. An age-based analysis file, created by determining the value of each time-dependent variable for each age that a cohort member is followed, provides a clear definition of age at exposure and allows development of diverse analytic models. To demonstrate methods, the relationship between cancer mortality and external radiation was analyzed with Poisson regression for 14,095 Oak Ridge National Laboratory workers. Based on previous analysis of this cohort, a model with ten-year lagged cumulative radiation doses partitionedmore » by receipt before (dose-young) or after (dose-old) age 45 was examined. Dose-response estimates were similar to calendar-year-based results with elevated risk for dose-old, but not when film badge readings were weekly before 1957. Complementary results showed increasing risk with older hire ages and earlier birth cohorts, since workers hired after age 45 were born before 1915, and dose-young and dose-old were distributed differently by birth cohorts. Risks were generally higher for smokingrelated than non-smoking-related cancers. It was difficult to single out specific variables associated with elevated cancer mortality because of: (1) birth cohort differences in hire age and mortality experience completeness, and (2) time-period differences in working conditions, dose potential, and exposure assessment. This research demonstrated the utility and versatility of the age-based approach.« less

Difference in causes and prognostic factors of early death between cohorts with de novo and relapsed acute promyelocytic leukemia.

PubMed

Zhao, Hongli; Zhao, Yanqiu; Zhang, Yingmei; Hou, Jinxiao; Yang, Huiyuan; Cao, Fenglin; Yang, Yiju; Hou, Wenyi; Sun, Jiayue; Jin, Bo; Fu, Jinyue; Li, Haitao; Wang, Ping; Ge, Fei; Zhou, Jin

2018-03-01

Early death (ED) remains the most critical issue in the current care of patients with acute promyelocytic leukemia (APL). Very limited data are available regarding ED in patients with relapsed APL. In this retrospective study, 285 de novo and 79 relapsed patients were included. All patients received single-agent arsenic trioxide as induction therapy. The differences in baseline clinical features, incidence, causes, and prognostic factors of ED were compared between the two patient cohorts. The relapse cohort exhibited a better overall condition than the de novo cohort upon hospital admission. The ED rate in the relapsed patients (24.1%) was somewhat higher than that in the de novo patients (17.9%), although the difference was not significant (P = 0.219). For both cohorts, hemorrhage was the main cause of ED, followed by differentiation syndrome, infection, and other causes. Increased serum creatinine level, older age, male sex, white blood cell (WBC) count > 10 × 10 9 /L, and fibrinogen < 1 g/L were independently risk factors for ED in the de novo patients, whereas WBC count > 10 × 10 9 /L, elevated serum uric acid level, and D-dimer > 4 mg/L were independent risk factors for ED in the relapsed patients. These data furnish clinically relevant information that might be useful for designing more appropriate risk-adapted treatment protocols aimed at reducing ED rate in patients with relapsed APL.

Decreased graft survival in liver transplant recipients of donors with positive blood cultures: a review of the United Network for Organ Sharing dataset.

PubMed

Huaman, Moises A; Vilchez, Valery; Mei, Xiaonan; Shah, Malay B; Daily, Michael F; Berger, Jonathan; Gedaly, Roberto

2017-06-01

Liver transplantation using blood culture positive donors (BCPD) has allowed a significant expansion of the donor pool. We aimed to characterize BCPD and assess the outcomes of BCPD liver transplant recipients. We retrieved data from the United Network for Organ Sharing (UNOS) registry on all adults who underwent primary, single-organ deceased-donor liver transplantation in the USA between 2008 and 2013. Patients were classified into two cohorts: the BCPD cohort and the non-BCPD cohort. One-year graft and patient survival were compared between cohorts using Kaplan-Meier estimates and Cox models. A total of 28 961 patients were included. There were 2316 (8.0%) recipients of BCPD. BCPD were more likely to be older, female, black, diabetic, hypertensive, and obese compared to non-BCPD. Graft survival was significantly lower in BCPD recipients compared to non-BCPD recipients (Kaplan-Meier, 0.85 vs. 0.87; P = 0.009). Results remained significant in propensity-matched analysis (P = 0.038). BCPD was independently associated with decreased graft survival (adjusted HR; 1.10, 95% CI 1.01-1.20; P = 0.04). There were no significant differences in patient survival between study groups. BCPD was associated with decreased graft survival in liver transplant recipients. Studies are needed to identify subgroups of BCPD with the highest risk of graft failure and characterize the underlying pathogenic mechanisms. © 2016 Steunstichting ESOT.

Low density lipoprotein subclasses in Asian and Caucasian adolescent boys.

PubMed

Raschke, Verena; Elmadfa, Ibrahim; Bermingham, Margaret A; Steinbeck, Kate

2006-01-01

South Asian adults are known to have very high rates of Coronary heart disease (CHD) and insulin resistance and, even as adolescents, may show higher risk factors for CHD. The aim of this study was to investigate the prevalence of small, dense low density lipoprotein (sdLDL) subclasses in a cohort of adolescent boys. The specific objective was to investigate the relationship between measures of fatness, ethnicity and LDL diameter in this cohort. Preformed native (non-denaturing) polyacrylamide 3-13% gradient gels and a multipurpose vertical electrophoresis system were used for the separation of LDL sub-fractions in a single school year cohort of boys aged 15-16 years (n=135). Latex beads and thyroglobulin standards were used to construct a calibration curve in order to calculate LDL particle diameters by regression (Total Lab Software v1.11). ANOVA was used to compare LDL size among different ethnic groups (SPSS and Stat View). The study sample was comprised of 45.2% Caucasians, 41.5% East Asians and 13.3% from the Indian subcontinent (South Asians). There was a non-significant trend for South Asians to have a lower LDL diameter than either Caucasians or East Asian boys which was independent of % total body fat (%TBF) and body mass index (BMI). This is the first adolescent cohort to examine sdLDL which included Caucasians, East and South Asians. It appears that the higher risk profile for CHD and diabetes noted in South Asian adults may be evident even during adolescence.

Utilisation and Safety of Deferasirox: Results from an Observational Cohort Study in England.

PubMed

Osborne, Vicki; Davies, Miranda; Layton, Deborah; Shakir, Saad A W

2018-03-01

Deferasirox (EXJADE ® , Novartis, UK) is an oral iron-chelating agent primarily used to reduce chronic iron overload in patients receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. The aim of this study was to examine the utilisation and safety of deferasirox used in general practice in England. A single exposure observational cohort study design was used. Patients were identified from dispensed prescriptions for deferasirox between September 2006 and September 2014. Outcome data were collected via postal questionnaires sent to prescribers ≥ 6 months after first dispensed prescription for an individual patient. Summary descriptive statistics were calculated. The evaluable cohort consisted of 122 patients, of which 41.8% were aged 2-17 years. Frequent reasons for prescribing were sickle cell anaemia (27/103 where specified, 26.2%) and beta thalassaemia (26, 25.2%). The majority of patients (43/51, 84.3%) were prescribed the licensed doses of 10 or 20 mg/kg/day at start. Prior measurements of serum creatinine were only reported for a small proportion this study (18/122, 14.8%). In total, 91 incident events were reported, including two of raised serum creatinine. These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile.

MMP12, Lung Function, and COPD in High-Risk Populations

PubMed Central

Hunninghake, Gary M.; Cho, Michael H.; Tesfaigzi, Yohannes; Soto-Quiros, Manuel E.; Avila, Lydiana; Lasky-Su, Jessica; Stidley, Chris; Melén, Erik; Söderhäll, Cilla; Hallberg, Jenny; Kull, Inger; Kere, Juha; Svartengren, Magnus; Pershagen, Göran; Wickman, Magnus; Lange, Christoph; Demeo, Dawn L.; Hersh, Craig P.; Klanderman, Barbara J.; Raby, Benjamin A.; Sparrow, David; Shapiro, Steven D.; Silverman, Edwin K.; Litonjua, Augusto A.; Weiss, Scott T.; Celedón, Juan C.

2010-01-01

BACKGROUND Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups. METHODS We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV1]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV1 and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD. RESULTS The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [−82A→G]) was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2×10−6). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P = 0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P = 0.005) and among participants in a family-based study of early-onset COPD (P = 0.006). CONCLUSIONS The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers. PMID:20018959

Cost savings associated with prevention of recurrent lumbar disc herniation with a novel annular closure device: a multicenter prospective cohort study.

PubMed

Parker, Scott L; Grahovac, Gordan; Vukas, Duje; Ledic, Darko; Vilendecic, Milorad; McGirt, Matthew J

2013-09-01

Same-level recurrent disc herniation is a well-defined complication following lumbar discectomy. Reherniation results in increased morbidity and health care costs. Techniques to reduce these consequences may improve outcomes and reduce cost after lumbar discectomy. In a prospective cohort study, we set out to evaluate the cost associated with surgical management of recurrent, same-level lumbar disc herniation following primary discectomy. Forty-six consecutive European patients undergoing lumbar discectomy for a single-level herniated disc at two institutions were prospectively followed with clinical and radiographic evaluations. A second consecutive cohort of 30 patients undergoing 31 lumbar discectomies with implantation of an annular closure device was followed at the same hospitals and same follow-up intervals. Cost estimates for reherniation were modeled on Medicare national allowable payment amounts (direct cost) and patient work-day losses (indirect cost). Annular closure and control cohorts were matched at baseline. By 2 years follow-up, symptomatic recurrent same-level disc herniation occurred in three (6.5%) patients in the control cohort versus zero (0%) patients in the annular closure cohort. For patients experiencing recurrent disc herniation, mean estimated direct and indirect cost of management of recurrent disc herniation was $34,242 and $3,778, respectively. Use of an annular closure device potentially results in a cost savings of $222,573 per 100 primary discectomy procedures performed (or $2,226 per discectomy), based solely on the reduction of reoperated reherniations when modeled on U.S. Medicare costs. Recurrent disc herniation did not occur in any patients after annular closure within the 12-month follow-up. The reduction in the incidence of reherniation was associated with potentially significant cost savings. Development of novel techniques to prevent recurrent lumbar disc herniation is warranted to decrease the associated morbidity and health care costs associated with this complication. Georg Thieme Verlag KG Stuttgart · New York.

Tropomyosin Receptor Antagonism in Cylindromatosis (TRAC), an early phase trial of a topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours: study protocol for a randomised controlled trial.

PubMed

Cranston, Amy; Stocken, Deborah D; Stamp, Elaine; Roblin, David; Hamlin, Julia; Langtry, James; Plummer, Ruth; Ashworth, Alan; Burn, John; Rajan, Neil

2017-03-07

Patients with germline mutations in a tumour suppressor gene called CYLD develop multiple, disfiguring, hair follicle tumours on the head and neck. The prognosis is poor, with up to one in four mutation carriers requiring complete surgical removal of the scalp. There are no effective medical alternatives to treat this condition. Whole genome molecular profiling experiments led to the discovery of an attractive molecular target in these skin tumour cells, named tropomyosin receptor kinase (TRK), upon which these cells demonstrate an oncogenic dependency in preclinical studies. Recently, the development of an ointment containing a TRK inhibitor (pegcantratinib - previously CT327 - from Creabilis SA) allowed for the assessment of TRK inhibition in tumours from patients with inherited CYLD mutations. Tropomysin Receptor Antagonism in Cylindromatosis (TRAC) is a two-part, exploratory, early phase, single-centre trial. Cohort 1 is a phase 1b open-labelled trial, and cohort 2 is a phase 2a randomised double-blinded exploratory placebo-controlled trial. Cohort 1 will determine the safety and acceptability of applying pegcantratinib for 4 weeks to a single tumour on a CYLD mutation carrier that is scheduled for a routine lesion excision (n = 8 patients). Cohort 2 will investigate if CYLD defective tumours respond following 12 weeks of treatment with pegcantratinib. As patients have multiple tumours, we intend to treat 10 tumours in each patient, 5 with active treatment and 5 with placebo. Patients will be allocated both active and placebo treatments to be applied randomly to tumours on the left or right side. The target is to treat 150 tumours in a maximum of 20 patients. Tumour volume will be measured at baseline and at 4 and 12 weeks. The primary outcome measure is the proportion of tumours responding to treatment by 12 weeks, based on change in tumour volume, with secondary measures based on adverse event profile, treatment compliance and acceptability, changes in tumour volume and surface area, patient quality of life and pain. Interventions for rare genetic skin diseases are often difficult to assess in an unbiased way due to small patient numbers and the challenges of incorporating adequate controls into trial design. Here we present a single-centre, randomised, placebo-controlled trial design that leverages the multiplicity of tumours seen in an inherited skin tumour syndrome that may inform the design of other studies in similar genetic diseases. International Standard Randomised Controlled Trial Number Registry, ISRCTN75715723 . Registered on 22 October 2014.

Complications and Short-Term Explantation Rate Following Artificial Urinary Sphincter Implantation: Results from a Large Middle European Multi-Institutional Case Series.

PubMed

Kretschmer, Alexander; Hüsch, Tanja; Thomsen, Frauke; Kronlachner, Dominik; Obaje, Alice; Anding, Ralf; Pottek, Tobias; Rose, Achim; Olianas, Roberto; Friedl, Alexander; Hübner, Wilhelm; Homberg, Roland; Pfitzenmaier, Jesco; Grein, Ulrich; Queissert, Fabian; Naumann, Carsten Maik; Schweiger, Josef; Wotzka, Carola; Nyarangi-Dix, Joanne N; Hofmann, Torben; Seiler, Roland; Haferkamp, Axel; Bauer, Ricarda M

2016-01-01

Background/Aims/Objectives: To analyze perioperative complication and short-term explantation rates after perineal or penoscrotal single-cuff and double-cuff artificial urinary sphincter (AUS) implantation in a large middle European multi-institutional patient cohort. 467 male patients with stress urinary incontinence underwent implantation of a perineal single-cuff (n = 152), penoscrotal single-cuff (n = 99), or perineal double-cuff (n = 216) AUS between 2010 and 2012. Postoperative complications and 6-month explantation rates were assessed. For statistical analysis, Fisher's exact test and Kruskal-Wallis rank sum test, and a multiple logistic regression model were used (p < 0.05). Compared to perineal single-cuff AUS, penoscrotal single-cuff implantation led to significantly increased short-term explantation rates (8.6% (perineal) vs. 19.2% (penoscrotal), p = 0.019). The postoperative infection rate was significantly higher after double-cuff compared to single-cuff implantation (6.0% (single-cuff) vs. 13.9% (double-cuff), p = 0.019). The short-term explantation rate after primary double-cuff placement was 6.5% (p = 0.543 vs. perineal single-cuff). In multivariate analysis, the penoscrotal approach (p = 0.004), intraoperative complications (p = 0.005), postoperative bleeding (p = 0.011), and perioperative infection (p < 0.001) were independent risk factors for short-term explantation. Providing data from a large contemporary multi-institutional patient cohort from high-volume and low-volume institutions, our results reflect the current standard of care in middle Europe. We indicate that the penoscrotal approach is an independent risk factor for increased short-term explantation rates. © 2016 S. Karger AG, Basel.

Prescription pattern of Chinese herbal products for heart failure in Taiwan: A population-based study.

PubMed

Tsai, Ming-Yen; Hu, Wen-Long; Lin, Che-Chen; Lee, Yi-Chiao; Chen, Shih-Yu; Hung, Yu-Chiang; Chen, Yung-Hsiang

2017-02-01

Certain Chinese herbal products (CHPs) may protect against the progression of heart failure (HF). However, there is a lack of research regarding the use of CHPs in patients with HF. The aims of this study were to analyze CHPs usage patterns in patients with HF and to identify the frequency and combination of CHPs most commonly used for HF. This retrospective, nationwide, population-based cohort study was conducted using a randomly sampled cohort of one million patients selected from the National Health Insurance Research Database (NHIRD) for the years 2000-2010 in Taiwan. CHP use and the top ten most frequently prescribed formulae and single herbs for treating HF were assessed, including total formulae number and average and frequency of prescriptions. Demographic characteristics, including sex and age at diagnosis of HF, were examined, together with existing comorbidities. The cohort included 19,988 newly diagnosed AD patients, who were given CHP treatment for HF between 2000 and 2010. Among them, female patients (53.3%) and those over 65years old (63.9%) were more likely to use CM. After adjusting for demographic factors, HF patients suffering from coronary artery disease (CAD) were more likely to seek traditional Chinese medicine (TCM) treatment than those with non-TCM users (57.6% vs. 52.6%). Zhi-Gan-Cao-Tang (4.07%) and Danshen (5.13%) were the most frequent formula CHP and single CHP prescribed by TCM practitioners for treating HF, respectively. Most people with HF who consumed CHPs used CHPs to supplement Yang-Qi, nourish the Ying-blood, and strengthen the heart spirit as complementary medicines to relieve HF-related symptoms, in addition to using standard anti-HF treatments. Further large-scale, randomized clinical trials are warranted in order to determine the effectiveness and safety of these herbal medicines. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cumulative impact of axial, structural, and repolarization ECG findings on long-term cardiovascular mortality among healthy individuals in Japan: National Integrated Project for Prospective Observation of Non-Communicable Disease and its Trends in the Aged, 1980 and 1990.

PubMed

Inohara, Taku; Kohsaka, Shun; Okamura, Tomonori; Watanabe, Makoto; Nakamura, Yasuyuki; Higashiyama, Aya; Kadota, Aya; Okuda, Nagako; Murakami, Yoshitaka; Ohkubo, Takayoshi; Miura, Katsuyuki; Okayama, Akira; Ueshima, Hirotsugu

2014-12-01

Various cohort studies have shown a close association between long-term cardiovascular disease (CVD) outcomes and individual electrocardiographic (ECG) abnormalities such as axial, structural, and repolarization changes. The combined effect of these ECG abnormalities, each assumed to be benign, has not been thoroughly investigated. Community-dwelling Japanese residents from the National Integrated Project for Perspective Observation of Non-Communicable Disease and its Trends in the Aged, 1980-2004 and 1990-2005 (NIPPON DATA80 and 90), were included in this study. Baseline ECG findings were classified using the Minnesota Code and categorized into axial (left axis deviation, clockwise rotation), structural (left ventricular hypertrophy, atrial enlargement), and repolarization (minor and major ST-T changes) abnormalities. The hazard ratios of the cumulative impacts of ECG findings on long-term CVD death were estimated by stratified Cox proportional hazard models, including adjustments for cohort strata. In all, 16,816 participants were evaluated. The average age was 51.2 ± 13.5 years; 42.7% participants were male. The duration of follow up was 300,924 person-years (mean 17.9 ± 5.8 years); there were 1218 CVD deaths during that time. Overall, 4203 participants (25.0%) had one or more categorical ECG abnormalities: 3648 (21.7%) had a single abnormality, and 555 (3.3%) had two or more. The risk of CVD mortality increased as the number of abnormalities accumulated (single abnormality HR 1.29, 95% CI 1.13-1.48; ≥2 abnormalities HR 2.10, 95% CI 1.73-2.53). Individual ECG abnormalities had an additive effect in predicting CVD outcome risk in our large-scale cohort study. © The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

A multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: The RADIANCE-HTN and REQUIRE clinical study designs.

PubMed

Mauri, Laura; Kario, Kazuomi; Basile, Jan; Daemen, Joost; Davies, Justin; Kirtane, Ajay J; Mahfoud, Felix; Schmieder, Roland E; Weber, Michael; Nanto, Shinsuke; Azizi, Michel

2018-01-01

Catheter-based renal denervation is a new approach to treat hypertension via modulation of the renal sympathetic nerves. Although nonrandomized and small, open-label randomized studies resulted in significant reductions in office blood pressure 6months after renal denervation with monopolar radiofrequency catheters, the first prospective, randomized, sham-controlled study (Symplicity HTN-3) failed to meet its blood pressure efficacy end point. New clinical trials with new catheters have since been designed to address the limitations of earlier studies. Accordingly, the RADIANCE-HTN and REQUIRE studies are multicenter, blinded, randomized, sham-controlled trials designed to assess the blood pressure-lowering efficacy of the ultrasound-based renal denervation system (Paradise) in patients with established hypertension either on or off antihypertensive medications, is designed to evaluate patients in 2 cohorts-SOLO and TRIO, in the United States and Europe. The SOLO cohort includes patients with essential hypertension, at low cardiovascular risk, and either controlled on 1 to 2 antihypertensive medications or uncontrolled on 0 to 2 antihypertensive medications. Patients undergo a 4-week medication washout period before randomization to renal denervation (treatment) or renal angiogram (sham). The TRIO cohort includes patients with hypertension resistant to at least 3 antihypertensive drugs including a diuretic. Patients will be stabilized on a single-pill, triple-antihypertensive-drug combination for 4weeks before randomization to treatment or sham. Reduction in daytime ambulatory systolic blood pressure (primary end point) will be assessed at 2months in both cohorts. A predefined medication escalation protocol, as needed for blood pressure control, is implemented between 2 and 6months in both cohorts by a study staff member blinded to the randomization process. At 6months, daytime ambulatory blood pressure and antihypertensive treatment score will be assessed. REQUIRE is designed to evaluate patients with resistant hypertension on standard of care medication in Japan and Korea. Reduction in 24-hour ambulatory systolic blood pressure will be assessed at 3months (primary end point). Both studies are enrolling patients, and their results are expected in 2018. Copyright © 2017 Elsevier Inc. All rights reserved.

A New Genomewide Association Meta-Analysis of Alcohol Dependence.

PubMed

Zuo, Lingjun; Tan, Yunlong; Zhang, Xiangyang; Wang, Xiaoping; Krystal, John; Tabakoff, Boris; Zhong, Chunlong; Luo, Xingguang

2015-08-01

Conventional meta-analysis based on genetic markers may be less powerful for heterogeneous samples. In this study, we introduced a new meta-analysis for 4 genomewide association studies on alcohol dependence that integrated the information of putative causal variants. A total of 12,481 subjects in 4 independent cohorts were analyzed, including 1 European American cohort (1,409 cases with alcohol dependence and 1,518 controls), 1 European Australian cohort (a total of 6,438 family subjects with 1,645 probands), 1 African American cohort from SAGE + COGA (681 cases and 508 controls), and 1 African American cohort from Yale (1,429 cases and 498 controls). The genomewide association analysis was conducted for each cohort, and then, a new meta-analysis was performed to derive the combined p-values. cis-Acting expression of quantitative locus (cis-eQTL) analysis of each risk variant in human tissues and RNA expression analysis of each risk gene in rat brain served as functional validation. In meta-analysis of European American and European Australian cohorts, we found 10 top-ranked single nucleotide polymorphisms (SNPs) (p < 10(-6) ) that were associated with alcohol dependence. They included 6 at SERINC2 (3.1 × 10(-8) ≤ p ≤ 9.6 × 10(-8) ), 1 at STK40 (p = 1.3 × 10(-7) ), 2 at KIAA0040 (3.3 × 10(-7) ≤ p ≤ 5.2 × 10(-7) ), and 1 at IPO11 (p = 6.9 × 10(-7) ). In meta-analysis of 2 African American cohorts, we found 2 top-ranked SNPs including 1 at SLC6A11 (p = 2.7 × 10(-7) ) and 1 at CBLN2 (p = 7.4 × 10(-7) ). In meta-analysis of all 4 cohorts, we found 2 top-ranked SNPs in PTP4A1-PHF3 locus (6.0 × 10(-7) ≤ p ≤ 7.2 × 10(-7) ). In an African American cohort only, we found 1 top-ranked SNP at PLD1 (p = 8.3 × 10(-7) ; OR = 1.56). Many risk SNPs had positive cis-eQTL signals, and all these risk genes except KIAA0040 were found to express in both rat and mouse brains. We found multiple genes that were significantly or suggestively associated with alcohol dependence. They are among the most appropriate for follow-up as contributors to risk for alcohol dependence. Copyright © 2015 by the Research Society on Alcoholism.

Associations between Common Variants in Iron-Related Genes with Haematological Traits in Populations of African Ancestry.

PubMed

Gichohi-Wainaina, Wanjiku N; Tanaka, Toshiko; Towers, G Wayne; Verhoef, Hans; Veenemans, Jacobien; Talsma, Elise F; Harryvan, Jan; Boekschoten, Mark V; Feskens, Edith J; Melse-Boonstra, Alida

2016-01-01

Large genome-wide association (GWA) studies of European ancestry individuals have identified multiple genetic variants influencing iron status. Studies on the generalizability of these associations to African ancestry populations have been limited. These studies are important given interethnic differences in iron status and the disproportionate burden of iron deficiency among African ancestry populations. We tested the associations of 20 previously identified iron status-associated single nucleotide polymorphisms (SNPs) in 628 Kenyans, 609 Tanzanians, 608 South Africans and 228 African Americans. In each study, we examined the associations present between 20 SNPs with ferritin and haemoglobin, adjusting for age, sex and CRP levels. In the meta analysis including all 4 African ancestry cohorts, we replicated previously reported associations with lowered haemoglobin concentrations for rs2413450 (β = -0.19, P = 0.02) and rs4820268 (β = -0.16, P = 0.04) in TMPRSS6. An association with increased ferritin concentrations was also confirmed for rs1867504 in TF (β = 1.04, P = <0.0001) in the meta analysis including the African cohorts only. In all meta analyses, we only replicated 4 of the 20 single nucleotide polymorphisms reported to be associated with iron status in large GWA studies of European ancestry individuals. While there is now evidence for the associations of a number of genetic variants with iron status in both European and African ancestry populations, the considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of iron status in ethnically diverse populations.

Associations between Common Variants in Iron-Related Genes with Haematological Traits in Populations of African Ancestry

PubMed Central

Tanaka, Toshiko; Towers, G. Wayne; Verhoef, Hans; Veenemans, Jacobien; Talsma, Elise F.; Harryvan, Jan; Boekschoten, Mark V.; Feskens, Edith J.; Melse-Boonstra, Alida

2016-01-01

Background Large genome-wide association (GWA) studies of European ancestry individuals have identified multiple genetic variants influencing iron status. Studies on the generalizability of these associations to African ancestry populations have been limited. These studies are important given interethnic differences in iron status and the disproportionate burden of iron deficiency among African ancestry populations. Methods We tested the associations of 20 previously identified iron status-associated single nucleotide polymorphisms (SNPs) in 628 Kenyans, 609 Tanzanians, 608 South Africans and 228 African Americans. In each study, we examined the associations present between 20 SNPs with ferritin and haemoglobin, adjusting for age, sex and CRP levels. Results In the meta analysis including all 4 African ancestry cohorts, we replicated previously reported associations with lowered haemoglobin concentrations for rs2413450 (β = -0.19, P = 0.02) and rs4820268 (β = -0.16, P = 0.04) in TMPRSS6. An association with increased ferritin concentrations was also confirmed for rs1867504 in TF (β = 1.04, P = <0.0001) in the meta analysis including the African cohorts only. Conclusions In all meta analyses, we only replicated 4 of the 20 single nucleotide polymorphisms reported to be associated with iron status in large GWA studies of European ancestry individuals. While there is now evidence for the associations of a number of genetic variants with iron status in both European and African ancestry populations, the considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of iron status in ethnically diverse populations. PMID:27332551

Assisted reproduction in a cohort of same-sex male couples and single men.

PubMed

Grover, Stephanie A; Shmorgun, Ziva; Moskovtsev, Sergey I; Baratz, Ari; Librach, Clifford L

2013-08-01

To date, there is limited published data on same-sex male couples and single men using assisted reproduction treatment to build their families. The objective of this retrospective study was to better understand treatment considerations and outcomes for this population when using assisted reproduction treatment. A total of 37 same-sex male couples and eight single men (seven homosexual and one heterosexual) who attended the CReATe Fertility Centre for assisted reproduction services were studied. There was a 21-fold increase in the number of same-sex male couples and single men undergoing assisted reproduction treatment since 2003. The mean age was 46years (24-58). Twenty-eight couples (76%) chose to use spermatozoa from both partners to fertilize their donated oocytes. Most men (32 same-sex male couples and seven single men; 87%) obtained oocytes from an anonymous donor, whereas five couples and one single man (13%) had a known donor. Anonymous donors who were open to be contacted by the child after the age of 18 were selected by 67% of patients. Of all 25 deliveries, eight (32%) were sets of twins. All of the twins were half genetic siblings. Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Association of Single vs. Dual Chamber ICDs with Mortality, Readmissions and Complications among Patients Receiving an ICD for Primary Prevention

PubMed Central

Peterson, Pamela N; Varosy, Paul D; Heidenreich, Paul A; Wang, Yongfei; Dewland, Thomas A; Curtis, Jeptha P; Go, Alan S; Greenlee, Robert T; Magid, David J; Normand, Sharon-Lise T; Masoudi, Frederick A

2013-01-01

Importance Randomized trials of implantable cardioverter defibrillators (ICDs) for primary prevention predominantly employed single chamber devices. In clinical practice, patients often receive dual chamber ICDs, even without clear indications for pacing. The outcomes of dual versus single chamber devices are uncertain. Objective Compare outcomes of single and dual chamber ICDs for primary prevention of sudden cardiac death. Design, Setting, and Participants Retrospective cohort study. Admissions in the National Cardiovascular Data Registry’s (NCDR®) ICD Registry™ from 2006–2009 that could be linked to CMS fee for service Medicare claims data were identified. Patients were included if they received an ICD for primary prevention and did not have a documented indication for pacing. Main Outcome Measures Adjusted risks of 1-year mortality, all-cause readmission, HF readmission and device-related complications within 90 days were estimated with propensity-score matching based on patient, clinician and hospital factors. Results Among 32,034 patients, 38% (n=12,246) received a single chamber device and 62% (n=19,788) received a dual chamber device. In a propensity-matched cohort, rates of complications were lower for single chamber devices (3.5% vs. 4.7%; p<0.001; risk difference −1.20; 95% CI −1.72, −0.69), but device type was not significantly associated with mortality or hospitalization outcomes (unadjusted rate 9.9% vs. 9.8%; HR 0.99, 95% CI 0.91–1.07; p=0.792 for 1-year mortality; unadjusted rate 43.9% vs. 44.8%; HR 1.00, 95% CI 0.97–1.04; p=0.821 for 1-year all-cause hospitalization; unadjusted rate 14.7% vs. 15.4%; HR 1.05, 95% CI 0.99–1.12; p=0.189 for 1-year HF hospitalization). Conclusions and Relevance Among patients receiving an ICD for primary prevention without indications for pacing, the use of a dual chamber device compared with a single chamber device was associated with a higher risk of device-related complications but not with different risks for mortality or hospitalization. Further studies should be performed to determine if other benefits of dual chamber devices exist, such as reduced device therapy or improved quality of life, to justify their use in this context. PMID:23677314

The Long-Term Effects of Organophosphates Poisoning as a Risk Factor of CVDs: A Nationwide Population-Based Cohort Study

PubMed Central

Lin, Cheng-Li; Chang, Shih-Yu; Sung, Fung-Chang; Tai, Sally C. W.

2015-01-01

Background Organophosphorus pesticides are widely used throughout the world. Because of their ease of availability, organophosphorus compounds are commonly used for self-poisoning in developing countries. The acute effects of exposure to organophosphorus pesticides are well known, but the chronic effects are unclear. Recent studies suggest that abnormalities of the central and peripheral nervous systems persisted for up to 5 years after acute poisoning due to a single large dose of organophosphates (OPs). However, the long-term effects on cardiovascular diseases are poorly understood. Methodology/Principal Findings An OPs-exposed cohort (N = 7,561) and an age- and gender-matched control cohort (N = 30,244), both identified from the National Health Insurance Research Database, were compared. We utilized the multivariable Cox proportional model to estimate the risks of developing arrhythmia, coronary artery disease (CAD) and congestive heart failure (CHF). The patients with acute poisoning from OPs had higher incidence rates of arrhythmia (5.89 vs. 3.61 per 1,000 person-years), CAD (9.10 vs. 6.88 per 1,000 person-years), and CHF (3.89 vs. 2.98 per 1,000 person-years) compared with that of the non-OPs poisoning cohort, with a crude subhazard ratio (SHR) of 1.40, 1.13, and 1.12, respectively. Additionally, a significantly higher risk of arrhythmia was observed in the OPs poisoning cohort (adjusted SHR = 1.25) compared with the non-OPs poisoning cohort, particularly in male patients (adjusted SHR = 1.33) and those under 49 years of age (adjusted SHR = 3.16). After accounting for the competing risks of death, there was a higher risk of arrhythmia and CAD during a three year follow-up period (adjusted SHR = 1.50 for arrhythmia; adjusted SHR = 1.10 for CAD). We also found an adjusted SHR of 1.36 associated with developing CHF after 6 years of follow-up for OPs poisoning cohort. Conclusions Acute OPs poisoning may continuously impact human health through mechanisms that are unclear. Any supportive measurements that could contribute to a reduction in the risk of heart disease may be beneficial in cases of OPs poisoning survivors. PMID:26339906

Global and regional annual brain volume loss rates in physiological aging.

PubMed

Schippling, Sven; Ostwaldt, Ann-Christin; Suppa, Per; Spies, Lothar; Manogaran, Praveena; Gocke, Carola; Huppertz, Hans-Jürgen; Opfer, Roland

2017-03-01

The objective is to estimate average global and regional percentage brain volume loss per year (BVL/year) of the physiologically ageing brain. Two independent, cross-sectional single scanner cohorts of healthy subjects were included. The first cohort (n = 248) was acquired at the Medical Prevention Center (MPCH) in Hamburg, Germany. The second cohort (n = 316) was taken from the Open Access Series of Imaging Studies (OASIS). Brain parenchyma (BP), grey matter (GM), white matter (WM), corpus callosum (CC), and thalamus volumes were calculated. A non-parametric technique was applied to fit the resulting age-volume data. For each age, the BVL/year was derived from the age-volume curves. The resulting BVL/year curves were compared between the two cohorts. For the MPCH cohort, the BVL/year curve of the BP was an increasing function starting from 0.20% at the age of 35 years increasing to 0.52% at 70 years (corresponding values for GM ranged from 0.32 to 0.55%, WM from 0.02 to 0.47%, CC from 0.07 to 0.48%, and thalamus from 0.25 to 0.54%). Mean absolute difference between BVL/year trajectories across the age range of 35-70 years was 0.02% for BP, 0.04% for GM, 0.04% for WM, 0.11% for CC, and 0.02% for the thalamus. Physiological BVL/year rates were remarkably consistent between the two cohorts and independent from the scanner applied. Average BVL/year was clearly age and compartment dependent. These results need to be taken into account when defining cut-off values for pathological annual brain volume loss in disease models, such as multiple sclerosis.

4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.

PubMed

Jirholt, Johan; Asling, Bengt; Hammond, Paul; Davidson, Geoffrey; Knutsson, Mikael; Walentinsson, Anna; Jensen, Jörgen M; Lehmann, Anders; Agreus, Lars; Lagerström-Fermer, Maria

2011-04-28

Gastro-esophageal reflux disease (GERD) is partly caused by genetic factors. The underlying susceptibility genes are currently unknown, with the exception of COL3A1. We used three independent GERD patient cohorts to identify GERD susceptibility genes. Thirty-six families, demonstrating dominant transmission of GERD were subjected to whole genome microsatellite genotyping and linkage analysis. Five linked regions were identified. Two families shared a linked region (LOD 3.9 and 2.0) on chromosome 16. We used two additional independent GERD patient cohorts, one consisting of 219 trios (affected child with parents) and the other an adult GERD case control cohort consisting of 256 cases and 485 controls, to validate individual genes in the linked region through association analysis. Sixty six single nucleotide polymorphism (SNP) markers distributed over the nine genes present in the linked region were genotyped in the independent GERD trio cohort. Transmission disequilibrium test analysis followed by multiple testing adjustments revealed a significant genetic association for one SNP located in an intron of the gene 4-aminobutyrate aminotransferase (ABAT) (P(adj) = 0.027). This association did not replicate in the adult case-control cohort, possibly due to the differences in ethnicity between the cohorts. Finally, using the selective ABAT inhibitor vigabatrin (γ-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3 ± 11.4 % (p = 0.007) and the reflux events from 3.1 ± 0.4 to 0.8 ± 0.4 (p = 0.007). Our results demonstrate the direct involvement of ABAT in pathways affecting lower esophageal sphincter (LES) control and identifies ABAT as a genetic risk factor for GERD.

A Randomized, Clinical Trial of Preadmission Chlorhexidine Skin Preparation for Lower Extremity Total Joint Arthroplasty.

PubMed

Kapadia, Bhaveen H; Elmallah, Randa K; Mont, Michael A

2016-12-01

Periprosthetic infections are devastating postoperative complications of total joint arthroplasty (TJA), with native skin flora commonly identified as causative organisms. We compared 2% chlorhexidine gluconate-impregnated cloths to standard-of-care antiseptic bathing in patients before TJA, to evaluate periprosthetic infection risk at 1-year follow-up. This was a prospective, randomized, controlled trial at a single institution of patients undergoing hip or knee arthroplasty. Chlorhexidine-treated patients (275 arthroplasties) applied 2% chlorhexidine gluconate-impregnated cloths the night before and morning of admission. The standard-of-care cohort (279 arthroplasties) bathed with soap and water preadmission. Patients were excluded according to the following: (1) unable to comply with study requirements, (2) pregnant, (3) <18 years, (4) medical history of immunosuppression or steroid use, (5) chronic hepatitis B/C infection, (6) had infection around joint requiring surgery, or (7) chose not to participate. A total of 539 patients (554 arthroplasties) were included in the final population. There were no significant differences in American Society of Anesthesiologists grade, cut time, risk scores, or diabetes and smoking prevalence between cohorts (P > .05). A lower periprosthetic infection rate was found in the chlorhexidine cohort (0.4%) when compared to standard-of-care cohorts (2.9%). The infection odds ratio was 8.15 (95% confidence interval = 1.01-65.6; P = .049) for the standard-of-care cohort compared to the chlorhexidine cohort. No differences in assessed risk factors were found between groups. No severe adverse events were observed. Preoperative chlorhexidine cloth use decreased the risk of periprosthetic infection. This may be an appropriate antiseptic protocol to implement for patients undergoing lower extremity TJA. Copyright © 2016 Elsevier Inc. All rights reserved.

Efficacy and safety of nab-paclitaxel in patients with previously treated metastatic colorectal cancer: a phase II COLO-001 trial.

PubMed

Ducreux, Michel; Bennouna, Jaafar; Adenis, Antoine; Conroy, Thierry; Lièvre, Astrid; Portales, Fabienne; Jeanes, Julie; Li, Li; Romano, Alfredo

2017-01-01

This single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with metastatic colorectal cancer (mCRC). Patients with mCRC (RAS wild-type and RAS mutant cohorts) received nab-paclitaxel 125 mg/m 2 days 1, 8, and 15 (28-day cycle). The primary endpoint was investigator-assessed progression-free survival (PFS) rate at week 8; secondary endpoints included overall survival, overall response rate, and safety. Stage 1 planned enrollment was 15 patients per cohort per Simon 2-stage design. Stage 2 enrollment was to continue unless ≤8 of the first 15 patients per cohort achieved PFS at 8 weeks. Stage 1 enrolled 41 patients (RAS wild type: n = 18; RAS mutant: n = 23). In both RAS cohorts, 3 of 15 patients initially enrolled were progression-free at week 8 (20%; 95% CI 4.0-48.0). Median PFS was 8.1 weeks (95% CI 7.7-8.6) and 7.9 weeks (95% CI 7.6-8.0) for RAS wild-type and RAS mutant cohorts, respectively. There were no complete or partial responses. The overall disease control rate was 16% (95% CI 6.0-32.0), and rates were similar in the RAS wild-type and RAS mutant cohorts (18 and 15%, respectively). No new safety signals were reported; the most common grade ≥3 adverse events included neutropenia, asthenia, and peripheral neuropathy. This study did not progress to stage 2 per the preplanned statistical stopping rule. In patients with heavily pretreated mCRC, nab-paclitaxel did not demonstrate promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is not supported. NCT02103062.

Do active surveillance and contact precautions reduce MRSA acquisition? A prospective interrupted time series.

PubMed

Marshall, Caroline; Richards, Michael; McBryde, Emma

2013-01-01

Consensus for methicillin-resistant Staphylococcus aureus (MRSA) control has still not been reached. We hypothesised that use of rapid MRSA detection followed by contact precautions and single room isolation would reduce MRSA acquisition. This study was a pre-planned prospective interrupted time series comparing rapid PCR detection and use of long sleeved gowns and gloves (contact precautions) plus single room isolation or cohorting of MRSA colonised patients with a control group. The study took place in a medical-surgical intensive care unit of a tertiary adult hospital between May 21(st) 2007 and September 21(st) 2009. The primary outcome was the rate of MRSA acquisition. A segmented regression analysis was performed to determine the trend in MRSA acquisition rates before and after the intervention. The rate of MRSA acquisition was 18.5 per 1000 at risk patient days in the control phase and 7.9 per 1000 at-risk patient days in the intervention phase, with an adjusted hazard ratio 0.39 (95% CI 0.24 to 0.62). Segmented regression analysis showed a decline in MRSA acquisition of 7% per month in the intervention phase, (95%CI 1.9% to 12.8% reduction) which was a significant change in slope compared with the control phase. Secondary analysis found prior exposure to anaerobically active antibiotics and colonization pressure were associated with increased acquisition risk. Contact precautions with single room isolation or cohorting were associated with a 60% reduction in MRSA acquisition. While this study was a quasi-experimental design, many measures were taken to strengthen the study, such as accounting for differences in colonisation pressure, hand hygiene compliance and individual risk factors across the groups, and confining the study to one centre to reduce variation in transmission. Use of two research nurses may limit its generalisability to units in which this level of support is available.

Vocal fold hypomobility secondary to elective endotracheal intubation: a general surgeon's perspective.

PubMed

Sariego, Jack

2010-01-01

This study was performed retrospectively to evaluate the incidence of documented vocal fold injury as a result of elective endotracheal intubation during general surgical procedures. Medical record review was performed at a single institution and all surgical cases reviewed which required endotracheal intubation in the nonemergent setting between April 1, 2003 and August, 31, 2007. Cases with unexpected and documented vocal fold immobility postoperatively formed the study cohort, and data were gathered regarding diagnosis and procedures performed. Of 23,010 general surgery cases performed during the study period, only seven documented cases of vocal fold paralysis were discovered (0.03%). There were five women and two men in the group; all were adults. Only one patient had a primary diagnosis related to the head and neck. Comorbidities were recorded as well, but there were no statistically significant patterns discerned. Furthermore, during the study period, a total of 31 patients overall (both surgical and nonsurgical) were admitted who carried a primary diagnosis of vocal fold paralysis. Therefore, the study cohort therefore constituted 22.6% of this total. Finally, cohort patients spent a total of 150 days in hospital during the study period; this length of stay (an average of 16.7 hospital days per patient) was significantly longer than the average of 5.1 days, presumably at least in part related to the vocal paralysis. Copyright 2010 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Surgical treatment of liver metastasis of gastric cancer: a retrospective multicenter cohort study (KSCC1302).

PubMed

Oki, Eiji; Tokunaga, Shoji; Emi, Yasunori; Kusumoto, Tetsuya; Yamamoto, Manabu; Fukuzawa, Kengo; Takahashi, Ikuo; Ishigami, Sumiya; Tsuji, Akihito; Higashi, Hidefumi; Nakamura, Toshihiko; Saeki, Hiroshi; Shirabe, Ken; Kakeji, Yoshihiro; Sakai, Kenji; Baba, Hideo; Nishimaki, Tadashi; Natsugoe, Shoji; Maehara, Yoshihiko

2016-07-01

The necessity of surgical treatment of liver metastases of gastric cancer is still controversial. We conducted a multicenter retrospective cohort study of liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria. Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3 %, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7 %, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival. To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.

Genotype-driven identification of a molecular network predictive of advanced coronary calcium in ClinSeq® and Framingham Heart Study cohorts.

PubMed

Oguz, Cihan; Sen, Shurjo K; Davis, Adam R; Fu, Yi-Ping; O'Donnell, Christopher J; Gibbons, Gary H

2017-10-26

One goal of personalized medicine is leveraging the emerging tools of data science to guide medical decision-making. Achieving this using disparate data sources is most daunting for polygenic traits. To this end, we employed random forests (RFs) and neural networks (NNs) for predictive modeling of coronary artery calcium (CAC), which is an intermediate endo-phenotype of coronary artery disease (CAD). Model inputs were derived from advanced cases in the ClinSeq®; discovery cohort (n=16) and the FHS replication cohort (n=36) from 89 th -99 th CAC score percentile range, and age-matched controls (ClinSeq®; n=16, FHS n=36) with no detectable CAC (all subjects were Caucasian males). These inputs included clinical variables and genotypes of 56 single nucleotide polymorphisms (SNPs) ranked highest in terms of their nominal correlation with the advanced CAC state in the discovery cohort. Predictive performance was assessed by computing the areas under receiver operating characteristic curves (ROC-AUC). RF models trained and tested with clinical variables generated ROC-AUC values of 0.69 and 0.61 in the discovery and replication cohorts, respectively. In contrast, in both cohorts, the set of SNPs derived from the discovery cohort were highly predictive (ROC-AUC ≥0.85) with no significant change in predictive performance upon integration of clinical and genotype variables. Using the 21 SNPs that produced optimal predictive performance in both cohorts, we developed NN models trained with ClinSeq®; data and tested with FHS data and obtained high predictive accuracy (ROC-AUC=0.80-0.85) with several topologies. Several CAD and "vascular aging" related biological processes were enriched in the network of genes constructed from the predictive SNPs. We identified a molecular network predictive of advanced coronary calcium using genotype data from ClinSeq®; and FHS cohorts. Our results illustrate that machine learning tools, which utilize complex interactions between disease predictors intrinsic to the pathogenesis of polygenic disorders, hold promise for deriving predictive disease models and networks.

No association of SORL1 SNPs with Alzheimer's disease.

PubMed

Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas

2008-08-01

SORL1 is an element of the amyloid precursor protein processing pathway and is therefore a good candidate for affecting Alzheimer's disease (AD) risk. Indeed, there have been reports of associations between variation in SORL1 and AD risk. We examined six statistically significant single-nucleotide polymorphisms from the initial observation in a large Caucasian American case-controls cohort (1000 late-onset AD [LOAD] cases and 1000 older controls). Analysis of allele, genotype and haplotype frequencies revealed no association with LOAD risk in our cohort.

Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals.

PubMed

Stram, Daniel O; Leigh Pearce, Celeste; Bretsky, Phillip; Freedman, Matthew; Hirschhorn, Joel N; Altshuler, David; Kolonel, Laurence N; Henderson, Brian E; Thomas, Duncan C

2003-01-01

The US National Cancer Institute has recently sponsored the formation of a Cohort Consortium (http://2002.cancer.gov/scpgenes.htm) to facilitate the pooling of data on very large numbers of people, concerning the effects of genes and environment on cancer incidence. One likely goal of these efforts will be generate a large population-based case-control series for which a number of candidate genes will be investigated using SNP haplotype as well as genotype analysis. The goal of this paper is to outline the issues involved in choosing a method of estimating haplotype-specific risk estimates for such data that is technically appropriate and yet attractive to epidemiologists who are already comfortable with odds ratios and logistic regression. Our interest is to develop and evaluate extensions of methods, based on haplotype imputation, that have been recently described (Schaid et al., Am J Hum Genet, 2002, and Zaykin et al., Hum Hered, 2002) as providing score tests of the null hypothesis of no effect of SNP haplotypes upon risk, which may be used for more complex tasks, such as providing confidence intervals, and tests of equivalence of haplotype-specific risks in two or more separate populations. In order to do so we (1) develop a cohort approach towards odds ratio analysis by expanding the E-M algorithm to provide maximum likelihood estimates of haplotype-specific odds ratios as well as genotype frequencies; (2) show how to correct the cohort approach, to give essentially unbiased estimates for population-based or nested case-control studies by incorporating the probability of selection as a case or control into the likelihood, based on a simplified model of case and control selection, and (3) finally, in an example data set (CYP17 and breast cancer, from the Multiethnic Cohort Study) we compare likelihood-based confidence interval estimates from the two methods with each other, and with the use of the single-imputation approach of Zaykin et al. applied under both null and alternative hypotheses. We conclude that so long as haplotypes are well predicted by SNP genotypes (we use the Rh2 criteria of Stram et al. [1]) the differences between the three methods are very small and in particular that the single imputation method may be expected to work extremely well. Copyright 2003 S. Karger AG, Basel

Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort.

PubMed

Dufouil, Carole; Dubois, Bruno; Vellas, Bruno; Pasquier, Florence; Blanc, Frédéric; Hugon, Jacques; Hanon, Olivier; Dartigues, Jean-François; Harston, Sandrine; Gabelle, Audrey; Ceccaldi, Mathieu; Beauchet, Olivier; Krolak-Salmon, Pierre; David, Renaud; Rouaud, Olivier; Godefroy, Olivier; Belin, Catherine; Rouch, Isabelle; Auguste, Nicolas; Wallon, David; Benetos, Athanase; Pariente, Jérémie; Paccalin, Marc; Moreaud, Olivier; Hommet, Caroline; Sellal, François; Boutoleau-Bretonniére, Claire; Jalenques, Isabelle; Gentric, Armelle; Vandel, Pierre; Azouani, Chabha; Fillon, Ludovic; Fischer, Clara; Savarieau, Helen; Operto, Gregory; Bertin, Hugo; Chupin, Marie; Bouteloup, Vincent; Habert, Marie-Odile; Mangin, Jean-François; Chêne, Geneviève

2017-08-29

The natural history and disease mechanisms of Alzheimer's disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements. In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR] <1). Baseline data collection included neurological and physical examinations as well as extensive neuropsychological testing. To be included in the MEMENTO cohort, participants had to agree to undergo both brain magnetic resonance imaging (MRI) and blood sampling. Cerebral 18 F-fluorodeoxyglucose positon emission tomography and lumbar puncture were optional. Automated analyses of cerebral MRI included assessments of volumes of whole-brain, hippocampal and white matter lesions. The 2323 participants, recruited from April 2011 to June 2014, were aged 71 years, on average (SD 8.7), and 62% were women. CDR was 0 in 40% of participants, and 30% carried at least one apolipoprotein E ε4 allele. We observed that more than half (52%) of participants had amnestic mild cognitive impairment (17% single-domain aMCI), 32% had non-amnestic mild cognitive impairment (16.9% single-domain naMCI) and 16% had isolated SCCs. Multivariable analyses of neuroimaging markers associations with cognitive categories showed that participants with aMCI had worse levels of imaging biomarkers than the others, whereas participants with naMCI had markers at intermediate levels between SCC and aMCI. The burden of white matter lesions tended to be larger in participants with aMCI. Independently of CDR, all neuroimaging and neuropsychological markers worsened with age, whereas differences were not consistent according to sex. MEMENTO is a large cohort with extensive clinical, neuropsychological and neuroimaging data and represents a platform for studying the natural history of ADRD in a large group of participants with different subtypes of MCI (amnestic or not amnestic) or isolated SCCs. Clinicaltrials.gov, NCT01926249 . Registered on 16 August 2013.

Utilisation of ART in single women and lesbian couples since the 2010 change in Victorian legislation.

PubMed

Fiske, Emily; Weston, Gareth

2014-10-01

Enactment of the Assisted Reproductive Treatment Act (Vic) 2008 in January 2010 allowed single persons and same sex couples in Victoria to access reproductive treatments. A retrospective cohort analysis of Monash IVF patients was conducted to identify trends in Assisted Reproductive Technology (ART) use amongst single women and lesbian couples after January 2010. A 102.8% increase in the utilisation of ART was observed amongst the single women group and a 248.8% increase in the lesbian couple population. © 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Dog ownership and the risk of cardiovascular disease and death - a nationwide cohort study.

PubMed

Mubanga, Mwenya; Byberg, Liisa; Nowak, Christoph; Egenvall, Agneta; Magnusson, Patrik K; Ingelsson, Erik; Fall, Tove

2017-11-17

Dogs may be beneficial in reducing cardiovascular risk in their owners by providing social support and motivation for physical activity. We aimed to investigate the association of dog ownership with incident cardiovascular disease (CVD) and death in a register-based prospective nation-wide cohort (n = 3,432,153) with up to 12 years of follow-up. Self-reported health and lifestyle habits were available for 34,202 participants in the Swedish Twin Register. Time-to-event analyses with time-updated covariates were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). In single- and multiple-person households, dog ownership (13.1%) was associated with lower risk of death, HR 0.67 (95% CI, 0.65-0.69) and 0.89 (0.87-0.91), respectively; and CVD death, HR 0.64 (0.59-0.70), and 0.85 (0.81-0.90), respectively. In single-person households, dog ownership was inversely associated with cardiovascular outcomes (HR composite CVD 0.92, 95% CI, 0.89-0.94). Ownership of hunting breed dogs was associated with lowest risk of CVD. Further analysis in the Twin Register could not replicate the reduced risk of CVD or death but also gave no indication of confounding by disability, comorbidities or lifestyle factors. In conclusion, dog ownership appears to be associated with lower risk of CVD in single-person households and lower mortality in the general population.

Social determinants of health and retention in HIV care in a clinical cohort in Ontario, Canada.

PubMed

Rachlis, Beth; Burchell, Ann N; Gardner, Sandra; Light, Lucia; Raboud, Janet; Antoniou, Tony; Bacon, Jean; Benoit, Anita; Cooper, Curtis; Kendall, Claire; Loutfy, Mona; Wobeser, Wendy; McGee, Frank; Rachlis, Anita; Rourke, Sean B

2017-07-01

Continuous HIV care supports antiretroviral therapy initiation and adherence, and prolongs survival. We investigated the association of social determinants of health (SDH) and subsequent retention in HIV care in a clinical cohort in Ontario, Canada. The Ontario HIV Treatment Network Cohort Study is a multi-site cohort of patients at 10 HIV clinics. Data were collected from medical charts, interviews, and via record linkage with the provincial public health laboratory for viral load tests. For participants interviewed in 2009, we used three-category multinomial logistic regression to identify predictors of retention in 2010-2012, defined as (1) continuous care (≥2 viral loads ≥90 days in all years; reference category); (2) discontinuous care (only 1 viral load/year in ≥1 year); and (3) a gap in care (≥1 year in 2010-2012 with no viral load). In total, 1838 participants were included. In 2010-2012, 71.7% had continuous care, 20.9% had discontinuous care, and 7.5% had a gap in care. Discontinuous care in 2009 was predictive (p < .0001) of future retention. SDH associated with discontinuous care were Indigenous ethnicity, being born in Canada, being employed, reporting hazardous drinking, and non-injection drug use. Being a heterosexual male was associated with having a gap in care, and being single and younger were associated with discontinuous care and a gap in care. Various SDH were associated with retention. Care discontinuity was highly predictive of future gaps. Targeted strategic interventions that better engage those at risk of suboptimal retention merit exploration. AOR: adjusted odds ratio; ART: antiretroviral therapy; AUDIT: Alcohol Use Disorders Identification Test; CES-D: Center for Epidemiologic Studies Depression Scale; CIs: confidence intervals; HIV: human immunodeficiency virus; IQR: interquartile range; MSM: men who have sex with men; NA-ACCORD: North American AIDS Cohort Collaboration on Research and Design; OCS: Ontario HIV Treatment Network Cohort Study; OHTN: Ontario HIV Treatment Network; OR: odds ratio; PHOL: Public Health Ontario Laboratories; REB: Research Ethics Board; SDH: social determinants of health; US: United States.

Accuracy of a Rapid Diagnostic Test (Cypress Chagas Quick Test®) for the Diagnosis of Chronic Chagas Disease in a Nonendemic Area: A Retrospective Longitudinal Study.

PubMed

Angheben, Andrea; Staffolani, Silvia; Anselmi, Mariella; Tais, Stefano; Degani, Monica; Gobbi, Federico; Buonfrate, Dora; Gobbo, Maria; Bisoffi, Zeno

2017-11-01

We analyzed the accuracy of Chagas Quick Test ® , a rapid diagnostic test, for the diagnosis of chronic Chagas disease through a retrospective study on a cohort of 669 patients consecutively examined at a single reference center in Italy, during a 7-year period. We observed high concordance with serological reference standard but low accuracy for screening purposes (sensitivity/specificity: 82.8%/98.7%) at least in our nonendemic context.

Genetic variants in loci 1p13 and 9p21 and fatal coronary heart disease in a Norwegian case-cohort study.

PubMed

Jansen, Mona Dverdal; Knudsen, Gun Peggy; Myhre, Ronny; Høiseth, Gudrun; Mørland, Jørg; Næss, Øyvind; Tambs, Kristian; Magnus, Per

2014-05-01

Single nucleotide polymorphisms (SNPs) in loci 1p13 and 9p21 have previously been found to be associated with incident coronary heart disease (CHD). This study aimed to investigate whether these SNPs show associations with fatal CHD in a population-based cohort study after adjustment for socioeconomic- and lifestyle-related CHD risk factors not commonly included in genetic association studies. Using the population-based Cohort of Norway (CONOR), a nested case-cohort study was set up and DNA from 2,953 subjects (829 cases and 2,124 non-cases) were genotyped. The association with fatal CHD was estimated for four SNPs, three from locus 1p13 and one from locus 9p21. Multivariable Cox regression was used to estimate unstratified and gender-stratified hazard ratios while adjusting for major CHD risk factors. The associations between three SNPs from locus 1p13 and non-HDL cholesterol levels were also estimated. Men homozygous for the risk alleles on rs1333049 (9p21) and rs14000 (1p13) were found to have significantly increased hazard ratios in crude and adjusted models, and the hazard ratios remained statistically significant when both genders were analyzed together. Adjustment for additional socioeconomic- and lifestyle-related CHD risk factors influenced the association estimates only slightly. No significant associations were observed between the other two SNPs in loci 1p13 (rs599839 and rs646776) and CHD mortality in either gender. Both rs599839 and rs646776 showed significant, gradual increases in non-HDL cholesterol levels with increasing number of risk alleles. This study confirms the association between 9p21 (rs1333049) and fatal CHD in a Norwegian population-based cohort. The effect was not influenced by several socioeconomic- and lifestyle-related risk factors. Our results show that 1p13 (rs14000) may also be associated with fatal CHD. SNPs at 1p13 (rs599839 and rs646776) were associated with non-HDL cholesterol levels.

Multiple Human Papilloma Virus Infections and Their Impact on the Development of High-Risk Cervical Lesions.

PubMed

Salazar, Katrina L; Zhou, Haijun Steve; Xu, Jiaqiong; Peterson, Leif E; Schwartz, Mary R; Mody, Dina R; Ge, Yimin

2015-01-01

Individuals are often infected with multiple genotypes of human papillomavirus (HPV) simultaneously, but the role these infections play in the development of cervical disease is not well established. This study aimed to determine the association of multiple HPV infections with high-risk cervical lesions (hrCLs). HPV genotyping was performed on 798 SurePath specimens collected between December 1, 2009, and April 30, 2011. The cases were classified as hrCL (n = 90) or non-hrCL (n = 708) based on cytology diagnoses. The association between hrCL and HPV infection patterns was analyzed. Multiple HPV infections were frequently encountered (38.2%) in the cohort. Increased frequency of hrCLs was associated with a single high-risk HPV (hrHPV) infection. An additive or synergistic effect was not observed for hrCL in multiple HPV infections. The hrCL rates appeared to decrease in various patterns of multiple HPV infections, but the reduction was not statistically significant. Multiple HPV infections are common with no additive or synergistic effect on the development of hrCL. Conversely, reduced hrCL rates were observed in various patterns of multiple HPV infections compared to their single-genotype infection counterparts, suggestive of possible intergenotypic competition or more effective immune response triggered by multiple infections. Further studies in larger cohorts are needed. © 2015 S. Karger AG, Basel.

Joint effect of unlinked genotypes: application to type 2 diabetes in the EPIC-Potsdam case-cohort study.

PubMed

Knüppel, Sven; Meidtner, Karina; Arregui, Maria; Holzhütter, Hermann-Georg; Boeing, Heiner

2015-07-01

Analyzing multiple single nucleotide polymorphisms (SNPs) is a promising approach to finding genetic effects beyond single-locus associations. We proposed the use of multilocus stepwise regression (MSR) to screen for allele combinations as a method to model joint effects, and compared the results with the often used genetic risk score (GRS), conventional stepwise selection, and the shrinkage method LASSO. In contrast to MSR, the GRS, conventional stepwise selection, and LASSO model each genotype by the risk allele doses. We reanalyzed 20 unlinked SNPs related to type 2 diabetes (T2D) in the EPIC-Potsdam case-cohort study (760 cases, 2193 noncases). No SNP-SNP interactions and no nonlinear effects were found. Two SNP combinations selected by MSR (Nagelkerke's R² = 0.050 and 0.048) included eight SNPs with mean allele combination frequency of 2%. GRS and stepwise selection selected nearly the same SNP combinations consisting of 12 and 13 SNPs (Nagelkerke's R² ranged from 0.020 to 0.029). LASSO showed similar results. The MSR method showed the best model fit measured by Nagelkerke's R² suggesting that further improvement may render this method a useful tool in genetic research. However, our comparison suggests that the GRS is a simple way to model genetic effects since it does not consider linkage, SNP-SNP interactions, and no non-linear effects. © 2015 John Wiley & Sons Ltd/University College London.

Multicohort Genomewide Association Study Reveals a New Signal of Protection Against HIV-1 Acquisition

PubMed Central

Limou, Sophie; Delaneau, Olivier; van Manen, Daniëlle; An, Ping; Sezgin, Efe; Le Clerc, Sigrid; Coulonges, Cédric; Troyer, Jennifer L.; Veldink, Jan H.; van den Berg, Leonard H.; Spadoni, Jean-Louis; Taing, Lieng; Labib, Taoufik; Montes, Matthieu; Delfraissy, Jean-François; Schachter, François; O’Brien, Stephen J.; Buchbinder, Susan; van Natta, Mark L.; Jabs, Douglas A.; Froguel, Philippe; Schuitemaker, Hanneke; Winkler, Cheryl A.

2012-01-01

Background. To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. Methods. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10−5 in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. Results. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: Pcombined = 7.76 × 10−8. Conclusions. We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation. PMID:22362864

Single site laparoscopy for fertility preservation: a cohort study.

PubMed

Núñez Valera, María José; Padilla Iserte, Pablo; Higueras García, Gema; Herraiz, Sonia; Rubio, José María; Romeu Villarroya, Mónica; Pellicer, Antonio; Díaz-García, César

2015-02-01

To compare operative and postoperative results of ovarian cortex retrieval by conventional laparoscopy (1cm umbilical site and 3 accessory 5-mm-reusable working ports) (HASS) versus single site laparoscopy (SSL). Prospective cohort study. Fertility Preservation Programme at La Fe University Hospital-University of Valencia, Valencia, Spain, 2011 to 2012. Fertility Preservation Programme at La Fe University Hospital of Valencia, Valencia, Spain. Twenty-one patients with cancer (breast cancer: n = 17; Hodgkin's lymphoma: n = 3; and non-Hodgkin's lymphoma: n = 1). Ovarian cortex retrieval either by conventional laparoscopy using an umbilical Hasson port and 3 accessory ports (HASS group: n = 11) or by SSL (SSL group: n = 10). Operative length, blood loss, postoperative pain (visual analog scale for pain at 6, 24, and 48 hours), need of additional analgesia, quality of life (European Quality of Life-5 Dimensions), cosmesis of the scar, and patient's self-perception were assessed at 24 and 48 hours and 3 months after surgery. Baseline characteristics were similar between groups. Estimated blood loss, operative length, and postoperative pain did not differ between groups. The start of chemotherapy was not delayed in either group, and cosmesis and image self-perception were also similar. The SSL approach can be considered a safe option compared with the classic multisite approach. Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.

Associations Among Quadriceps Strength and Rate of Torque Development 6 Weeks Post Anterior Cruciate Ligament Reconstruction and Future Hop and Vertical Jump Performance: A Prospective Cohort Study.

PubMed

Pua, Yong-Hao; Mentiplay, Benjamin F; Clark, Ross A; Ho, Jia-Ying

2017-11-01

Study Design Prospective cohort. Background Quadriceps strength is associated with hop distance and jump height in persons who have undergone anterior cruciate ligament (ACL) reconstruction. However, it is unknown whether the ability to rapidly generate quadriceps torque in the early phase of recovery is associated with future hopping and jumping performance in this population. Objective To evaluate the prospective associations among quadriceps strength and rate of torque development (RTD) and single-leg hop for distance, vertical jump height, vertical ground reaction force (vGRF), and vertical force loading rate during a landing task in persons who have undergone ACL reconstruction. Methods Seventy patients with unilateral ACL reconstruction participated. At 6 weeks post ACL reconstruction, isometric quadriceps strength and RTD were measured using a dynamometer. At 6 months following ACL reconstruction, patients performed the single-leg hop for distance test. Patients also performed the single-leg vertical jump test on a force plate that measured maximum jump height, vGRF, and average loading rate during landing. Results Both quadriceps strength and RTD at 6 weeks post ACL reconstruction were associated with all hopping and jumping measures at 6 months post ACL reconstruction (P≤.04). Single-leg hop distance was associated more closely with quadriceps strength than with quadriceps RTD (P = .05), and vertical jump height and vGRF measures were associated more closely with quadriceps RTD than with quadriceps strength (P = .05 and P<.01, respectively). Both quadriceps measures were associated with loading rate. Conclusion Quadriceps strength and RTD are complementary but distinct predictors of future hopping and jumping performance in persons who have undergone ACL reconstruction. These findings may contribute to improved rehabilitation of patients who are at risk for poor jumping/hopping performance and abnormal knee loading. J Orthop Sports Phys Ther 2017;47(11):845-852. Epub 13 Oct 2017. doi:10.2519/jospt.2017.7133.

Genome-wide interaction study of dust mite allergen on lung function in children with asthma.

PubMed

Forno, Erick; Sordillo, Joanne; Brehm, John; Chen, Wei; Benos, Takis; Yan, Qi; Avila, Lydiana; Soto-Quirós, Manuel; Cloutier, Michelle M; Colón-Semidey, Angel; Alvarez, Maria; Acosta-Pérez, Edna; Weiss, Scott T; Litonjua, Augusto A; Canino, Glorisa; Celedón, Juan C

2017-10-01

Childhood asthma is likely the result of gene-by-environment (G × E) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide G × E studies of dust mite allergen on asthma-related phenotypes. We sought to identify genetic variants whose effects on lung function in children with asthma are modified by the level of dust mite allergen exposure. A genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (Puerto Rico Genetics of Asthma and Lifestyle [PRGOAL]). Replication was attempted in 2 independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study. Single nucleotide polymorphism (SNP) rs117902240 showed a significant interaction effect on FEV 1 with dust mite allergen level in PRGOAL (interaction P = 3.1 × 10 -8 ), and replicated in the same direction in CAMP white children and CAMP Hispanic children (combined interaction P = .0065 for replication cohorts and 7.4 × 10 -9 for all cohorts). Rs117902240 was positively associated with FEV 1 in children exposed to low dust mite allergen levels, but negatively associated with FEV 1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CCAAT/enhancer-binding protein beta, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV 1 /forced vital capacity replicated in the independent cohorts. Dust mite allergen exposure modifies the estimated effect of rs117902240 on FEV 1 in children with asthma. Analysis of existing data suggests that this SNP may have transcription factor regulatory functions. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Long-term exposure to elemental constituents of particulate matter and cardiovascular mortality in 19 European cohorts: results from the ESCAPE and TRANSPHORM projects.

PubMed

Wang, Meng; Beelen, Rob; Stafoggia, Massimo; Raaschou-Nielsen, Ole; Andersen, Zorana Jovanovic; Hoffmann, Barbara; Fischer, Paul; Houthuijs, Danny; Nieuwenhuijsen, Mark; Weinmayr, Gudrun; Vineis, Paolo; Xun, Wei W; Dimakopoulou, Konstantina; Samoli, Evangelia; Laatikainen, Tiina; Lanki, Timo; Turunen, Anu W; Oftedal, Bente; Schwarze, Per; Aamodt, Geir; Penell, Johanna; De Faire, Ulf; Korek, Michal; Leander, Karin; Pershagen, Göran; Pedersen, Nancy L; Östenson, Claes-Göran; Fratiglioni, Laura; Eriksen, Kirsten Thorup; Sørensen, Mette; Tjønneland, Anne; Bueno-de-Mesquita, Bas; Eeftens, Marloes; Bots, Michiel L; Meliefste, Kees; Krämer, Ursula; Heinrich, Joachim; Sugiri, Dorothea; Key, Timothy; de Hoogh, Kees; Wolf, Kathrin; Peters, Annette; Cyrys, Josef; Jaensch, Andrea; Concin, Hans; Nagel, Gabriele; Tsai, Ming-Yi; Phuleria, Harish; Ineichen, Alex; Künzli, Nino; Probst-Hensch, Nicole; Schaffner, Emmanuel; Vilier, Alice; Clavel-Chapelon, Françoise; Declerq, Christophe; Ricceri, Fulvio; Sacerdote, Carlotta; Marcon, Alessandro; Galassi, Claudia; Migliore, Enrica; Ranzi, Andrea; Cesaroni, Giulia; Badaloni, Chiara; Forastiere, Francesco; Katsoulis, Michail; Trichopoulou, Antonia; Keuken, Menno; Jedynska, Aleksandra; Kooter, Ingeborg M; Kukkonen, Jaakko; Sokhi, Ranjeet S; Brunekreef, Bert; Katsouyanni, Klea; Hoek, Gerard

2014-05-01

Associations between long-term exposure to ambient particulate matter (PM) and cardiovascular (CVD) mortality have been widely recognized. However, health effects of long-term exposure to constituents of PM on total CVD mortality have been explored in a single study only. The aim of this study was to examine the association of PM composition with cardiovascular mortality. We used data from 19 European ongoing cohorts within the framework of the ESCAPE (European Study of Cohorts for Air Pollution Effects) and TRANSPHORM (Transport related Air Pollution and Health impacts--Integrated Methodologies for Assessing Particulate Matter) projects. Residential annual average exposure to elemental constituents within particle matter smaller than 2.5 and 10 μm (PM2.5 and PM10) was estimated using Land Use Regression models. Eight elements representing major sources were selected a priori (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc). Cohort-specific analyses were conducted using Cox proportional hazards models with a standardized protocol. Random-effects meta-analysis was used to calculate combined effect estimates. The total population consisted of 322,291 participants, with 9545 CVD deaths. We found no statistically significant associations between any of the elemental constituents in PM2.5 or PM10 and CVD mortality in the pooled analysis. Most of the hazard ratios (HRs) were close to unity, e.g. for PM10 Fe the combined HR was 0.96 (0.84-1.09). Elevated combined HRs were found for PM2.5 Si (1.17, 95% CI: 0.93-1.47), and S in PM2.5 (1.08, 95% CI: 0.95-1.22) and PM10 (1.09, 95% CI: 0.90-1.32). In a joint analysis of 19 European cohorts, we found no statistically significant association between long-term exposure to 8 elemental constituents of particles and total cardiovascular mortality. Copyright © 2014 Elsevier Ltd. All rights reserved.

Single dose filgastrim in cytotoxic-induced neutropaenia in children.

PubMed

Abdallah, F K

2008-01-01

To document the impact of fixed dose weight adjusted filgastrim (G-CSF) in cytotoxic-induced neutropaenia. A descriptive cross-sectional study. Paediatric Oncology Unit at Kenyatta National Hospital, Nairobi, Kenya. All paediatric oncology patients who had developed cytotoxic-induced neutropaenia. The following were documented for every tissue proven case of malignancy; age, sex, type of malignancy, treatment regimen and schedule, initial blood count at the time of neutropaenia; subsequent blood counts daily for five days from day one of single dose filgastrim, and the calculated neutrophil incremental count. Initially eight patients with solid tumours previously treated with filgastrim revealed that cytotoxic induced neutropaenia could be ameliorated by a single dose of filgastrim. Subsequently, the study listed thirty patients. This cohort consisted of; 37% rhabdomyosarcoma, 30% Burkitts, 27% acute lymphoblastic leukaemia and 6% Hodgkin's lymphoma. Increased neutrophil count after 48 hours was documented in 26 (87%) patients, with absolute neutrophil counts range of 0.5 to 31.5 x 10(9)/L. This response was significantly influenced by gender (p>0.0001), malignancy type and chemotherapy regimen (p>0.001). The study shows that chemotherapy induced neutropaenia can be alleviated by a single dose of filgastrim without adverse effects on lymphoblastic leukaemia. This study suggests that a single dose of filgastrim should be first tried in cytotoxic induced neutropaenia in the paediatric age group.

Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis.

PubMed

Chataway, Jeremy; Martin, Keith; Barrell, Kevin; Sharrack, Basil; Stolt, Pelle; Wraith, David C

2018-03-13

To assess safety, tolerability, and efficacy of the antigen-specific immunotherapy ATX-MS-1467 in participants with relapsing multiple sclerosis using different treatment protocols to induce tolerance. Two open-label trials in adult participants with relapsing multiple sclerosis were conducted. Study 1 was a multicenter, phase 1b safety evaluation comparing intradermal (i.d.) (cohort 1) with subcutaneous (cohort 2) administration in 43 participants. Both cohorts received ATX-MS-1467 dosed at 25, 50, 100, 400, and 800 μg at 14-day intervals over 8 weeks, followed by 8 weeks with 4 additional 800-μg doses at 14-day intervals and 32 weeks off study medication. Study 2 was a phase 2a, multicenter, single-arm trial enrolling 37 participants. ATX-MS-1467 was titrated from 50 μg i.d. on day 1 to 200 μg on day 15 and 800 μg on day 29 followed by biweekly administration of 800 μg for 16 weeks and 16 weeks off study medication. Efficacy was evaluated on MRI parameters and clinical variables. Safety endpoints included treatment-emergent adverse events and injection-site reactions. In study 1, there was a significant decrease in new/persisting T1 gadolinium-enhanced (GdE) lesions in cohort 1 from baseline to week 16, returning to baseline values at week 48. In study 2, the number of T1 GdE lesions were significantly reduced on treatment and remained reduced at study completion. Safety results were unremarkable in both studies. Relatively slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions and a sustained effect post treatment. Further trials of ATX-MS-1467 are warranted. This work provides Class IV evidence that for patients with relapsing multiple sclerosis, slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions. © 2018 American Academy of Neurology.

A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts

PubMed Central

McHugh, Leo; Seldon, Therese A.; Brandon, Roslyn A.; Kirk, James T.; Rapisarda, Antony; Sutherland, Allison J.; Presneill, Jeffrey J.; Venter, Deon J.; Lipman, Jeffrey; Thomas, Mervyn R.; Klein Klouwenberg, Peter M. C.; van Vught, Lonneke; Scicluna, Brendon; Bonten, Marc; Cremer, Olaf L.; Schultz, Marcus J.; van der Poll, Tom; Yager, Thomas D.; Brandon, Richard B.

2015-01-01

Background Systemic inflammation is a whole body reaction having an infection-positive (i.e., sepsis) or infection-negative origin. It is important to distinguish between these two etiologies early and accurately because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on peripheral blood RNAs could be discovered that would (1) determine which patients with systemic inflammation had sepsis, (2) be robust across independent patient cohorts, (3) be insensitive to disease severity, and (4) provide diagnostic utility. The goal of this study was to identify and validate such a molecular classifier. Methods and Findings We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICUs). Biomarker discovery utilized an Australian cohort (n = 105) consisting of 74 cases (sepsis patients) and 31 controls (post-surgical patients with infection-negative systemic inflammation) recruited at five tertiary care settings in Brisbane, Australia, from June 3, 2008, to December 22, 2011. A four-gene classifier combining CEACAM4, LAMP1, PLA2G7, and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte Lab, was validated using reverse transcription quantitative PCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Patients for validation were selected from the Molecular Diagnosis and Risk Stratification of Sepsis study (ClinicalTrials.gov, NCT01905033), which recruited ICU patients from the Academic Medical Center in Amsterdam and the University Medical Center Utrecht. Patients recruited from November 30, 2012, to August 5, 2013, were eligible for inclusion in the present study. Validation cohort 1 (n = 59) consisted entirely of unambiguous cases and controls; SeptiCyte Lab gave an area under curve (AUC) of 0.95 (95% CI 0.91–1.00) in this cohort. ROC curve analysis of an independent, more heterogeneous group of patients (validation cohorts 2–5; 249 patients after excluding 37 patients with an infection likelihood of “possible”) gave an AUC of 0.89 (95% CI 0.85–0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility of SeptiCyte Lab was evaluated by comparison to various clinical and laboratory parameters available to a clinician within 24 h of ICU admission. SeptiCyte Lab was significantly better at differentiating cases from controls than all tested parameters, both singly and in various logistic combinations, and more than halved the diagnostic error rate compared to procalcitonin in all tested cohorts and cohort combinations. Limitations of this study relate to (1) cohort compositions that do not perfectly reflect the composition of the intended use population, (2) potential biases that could be introduced as a result of the current lack of a gold standard for diagnosing sepsis, and (3) lack of a complete, unbiased comparison to C-reactive protein. Conclusions SeptiCyte Lab is a rapid molecular assay that may be clinically useful in managing ICU patients with systemic inflammation. Further study in population-based cohorts is needed to validate this assay for clinical use. PMID:26645559

RNA-Seq Meta-analysis identifies genes in skeletal muscle associated with gain and intake across a multi-season study of crossbred beef steers.

PubMed

Keel, Brittney N; Zarek, Christina M; Keele, John W; Kuehn, Larry A; Snelling, Warren M; Oliver, William T; Freetly, Harvey C; Lindholm-Perry, Amanda K

2018-06-04

Feed intake and body weight gain are economically important inputs and outputs of beef production systems. The purpose of this study was to discover differentially expressed genes that will be robust for feed intake and gain across a large segment of the cattle industry. Transcriptomic studies often suffer from issues with reproducibility and cross-validation. One way to improve reproducibility is by integrating multiple datasets via meta-analysis. RNA sequencing (RNA-Seq) was performed on longissimus dorsi muscle from 80 steers (5 cohorts, each with 16 animals) selected from the outside fringe of a bivariate gain and feed intake distribution to understand the genes and pathways involved in feed efficiency. In each cohort, 16 steers were selected from one of four gain and feed intake phenotypes (n = 4 per phenotype) in a 2 × 2 factorial arrangement with gain and feed intake as main effect variables. Each cohort was analyzed as a single experiment using a generalized linear model and results from the 5 cohort analyses were combined in a meta-analysis to identify differentially expressed genes (DEG) across the cohorts. A total of 51 genes were differentially expressed for the main effect of gain, 109 genes for the intake main effect, and 11 genes for the gain x intake interaction (P corrected  < 0.05). A jackknife sensitivity analysis showed that, in general, the meta-analysis produced robust DEGs for the two main effects and their interaction. Pathways identified from over-represented genes included mitochondrial energy production and oxidative stress pathways for the main effect of gain due to DEG including GPD1, NDUFA6, UQCRQ, ACTC1, and MGST3. For intake, metabolic pathways including amino acid biosynthesis and degradation were identified, and for the interaction analysis the pathways identified included GADD45, pyridoxal 5'phosphate salvage, and caveolar mediated endocytosis signaling. Variation among DEG identified by cohort suggests that environment and breed may play large roles in the expression of genes associated with feed efficiency in the muscle of beef cattle. Meta-analyses of transcriptome data from groups of animals over multiple cohorts may be necessary to elucidate the genetics contributing these types of biological phenotypes.

Impact of Exercise Counseling on Physical Function in Chronic Kidney Disease: An Observational Study

PubMed Central

Storsley, Leroy J.; Hiebert, Brett M.; Nelko, Serena; Cheskin, Lawrence J.; McAdams-DeMarco, Mara A.; Rigatto, Claudio

2018-01-01

Background: Individuals with chronic kidney disease (CKD) have low levels of physical activity and physical function. Although guidelines endorse exercise counseling for individuals with CKD, it is not yet part of routine care. Objective: We investigated the effect of attending a real-life exercise counseling clinic (ECC) on physical function in individuals with CKD. Design: Retrospective analysis of prospectively collected observational data with quasi-experimental design. Setting and Participants: Patients with all stages of CKD registered in a large provincial renal program were eligible. The exposed cohort who attended the ECC between January 1, 2011, and March 15, 2014, included 214 individuals. The control cohort included 292 individuals enrolled in an observational study investigating longitudinal change in frailty during the same time period. Predictor/Factor: Attendance at an ECC. Outcomes and Measurements: Change in physical function as measured by Short Physical Performance Battery (SPPB) score, physical activity level (Human Activity Profile [HAP]/Physical Activity Scale for the Elderly [PASE]), and health-related quality of life (HRQOL; EQ5D/VAS) over 1 year. Results: Eighty-seven individuals in the ECC cohort and 125 participants in the control cohort completed 1-year follow-up. Baseline median SPPB score was 10 (interquartile range [IQR]: 9-12) and 9 (IQR: 7-11) in the ECC and control cohorts, respectively (P < .01). At 1 year, SPPB scores were 10 (IQR: 8-12) and 9 (IQR: 6-11) in the ECC and control cohorts, respectively (P = .04). Mean change in SPPB over 1 year was not significantly different between groups: −0.33 (95% confidence interval [CI]: −0.81 to 0.15) in ECC and −0.22 (95% CI: −0.61 to 0.17) in control (P = .72). There was no significant difference in the proportion of individuals in each cohort with an increase/decrease in SPPB score over time. There was no significant change in physical activity or HRQOL over time between groups. Limitations: Quasi-experimental design, low rate of follow-up attendance. Conclusions: In this pragmatic study, exercise counseling had no significant effect on change in SPPB score, suggesting that a single exercise counseling session alone is inadequate to improve physical function in CKD. PMID:29487746

Effects of allergic diseases and age on the composition of serum IgG glycome in children

PubMed Central

Pezer, Marija; Stambuk, Jerko; Perica, Marija; Razdorov, Genadij; Banic, Ivana; Vuckovic, Frano; Gospic, Adrijana Miletic; Ugrina, Ivo; Vecenaj, Ana; Bakovic, Maja Pucic; Lokas, Sandra Bulat; Zivkovic, Jelena; Plavec, Davor; Devereux, Graham; Turkalj, Mirjana; Lauc, Gordan

2016-01-01

It is speculated that immunoglobulin G (IgG) plays a regulatory role in allergic reactions. The glycans on the Fc region are known to affect IgG effector functions, thereby possibly having a role in IgG modulation of allergic response. This is the first study investigating patients’ IgG glycosylation profile in allergic diseases. Subclass specific IgG glycosylation profile was analyzed in two cohorts of allergen sensitized and non-sensitized 3- to 11-year-old children (conducted at University of Aberdeen, UK and Children’s Hospital Srebrnjak, Zagreb, Croatia) with 893 subjects in total. IgG was isolated from serum/plasma by affinity chromatography on Protein G. IgG tryptic glycopeptides were analyzed by liquid chromatography electrospray ionization mass spectrometry. In the Zagreb cohort IgG glycome composition changed with age across all IgG subclasses. In both cohorts, IgG glycome composition did not differ in allergen sensitized subjects, nor children sensitized to individual allergens, single allergen mean wheal diameter or positive wheal sum values. In the Zagreb study the results were also replicated for high total serum IgE and in children with self-reported manifest allergic disease. In conclusion, our findings demonstrate no association between serum IgG glycome composition and allergic diseases in children. PMID:27616597

Hand Hygiene, Cohorting, or Antibiotic Restriction to Control Outbreaks of Multidrug-Resistant Enterobacteriaceae.

PubMed

Pelat, Camille; Kardaś-Słoma, Lidia; Birgand, Gabriel; Ruppé, Etienne; Schwarzinger, Michaël; Andremont, Antoine; Lucet, Jean-Christophe; Yazdanpanah, Yazdan

2016-03-01

The best strategy for controlling extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) transmission in intensive care units (ICUs) remains elusive. We developed a stochastic transmission model to quantify the effectiveness of interventions aimed at reducing the spread of ESBL-PE in an ICU. We modeled the evolution of an outbreak caused by the admission of a single carrier in a 10-bed ICU free of ESBL-PE. Using data obtained from recent muticenter studies, we studied 26 strategies combining different levels of the following 3 interventions: (1) increasing healthcare worker compliance with hand hygiene before and after contact with a patient; (2) cohorting; (3) reducing antibiotic prevalence at admission with or without reducing antibiotherapy duration. Improving hand hygiene compliance from 55% before patient contact and 60% after patient contact to 80% before and 80% after patient contact reduced the nosocomial incidence rate of ESBL-PE colonization by 91% at 90 days. Adding cohorting to hand hygiene improvement intervention decreased the proportion of ESBL-PE acquisitions by an additional 7%. Antibiotic restriction had the lowest impact on the epidemic. When combined with other interventions, it only marginally improved effectiveness, despite strong hypotheses regarding antibiotic impact on transmission. Our results suggest that hand hygiene is the most effective intervention to control ESBL-PE transmission in an ICU.

Stand dynamics following gap-scale exogenous disturbance in a single cohort mixed species stand in Morgan County, Tennessee

Treesearch

Brian S. Hughett; Wayne K. Clatterbuck

2014-01-01

Differences in composition, structure, and growth under canopy gaps created by the mortality of a single stem were analyzed using analysis of variance under two scenarios, with stem removed or with stem left as a standing snag. There were no significant differences in composition and structure of large diameter residual stems within upper canopy strata. Some...

A novel method to value real options in health care: the case of a multicohort human papillomavirus vaccination strategy.

PubMed

Favato, Giampiero; Baio, Gianluca; Capone, Alessandro; Marcellusi, Andrea; Saverio Mennini, Francesco

2013-07-01

A large number of economic evaluations have already confirmed the cost-effectiveness of different human papillomavirus (HPV) vaccination strategies. Standard analyses might not capture the full economic value of novel vaccination programs because the cost-effectiveness paradigm fails to take into account the value of active management. Management decisions can be seen as real options, a term used to refer to the application of option pricing theory to the valuation of investments in nonfinancial assets in which much of the value is attributable to flexibility and learning over time. The aim of this article was to discuss the potential advantages shown by using the payoff method in the valuation of the cost-effectiveness of competing HPV immunization programs. This was the first study, to the best of our knowledge, to use the payoff method to determine the real option values of 4 different HPV vaccination strategies targeting female subjects aged 12, 15, 18, and 25 years. The payoff method derives the real option value from the triangular payoff distribution of the project's net present value, which is treated as a triangular fuzzy number. To inform the real option model, cost-effectiveness data were derived from an empirically calibrated Bayesian model designed to assess the cost-effectiveness of a multicohort HPV vaccination strategy in the context of the current cervical cancer screening program in Italy. A net health benefit approach was used to calculate the expected fuzzy net present value for each of the 4 vaccination strategies evaluated. Costs per quality-adjusted life-year gained seemed to be related to the number of cohorts targeted: a single cohort of girls aged 12 years (€10,955 [95% CI, -1,021 to 28,212]) revealed the lowest cost among the 4 alternative strategies evaluated. The real option valuation challenged the cost-effectiveness dominance of a single cohort of 12-year-old girls. The simultaneous vaccination of 2 cohorts of girls aged 12 and 15 years yielded a real option value (€17,723) equivalent to that attributed to a single cohort of 12-year-old girls (€17,460). The payoff method showed distinctive advantages in the valuation of the cost-effectiveness of competing health care interventions, essentially determined by the replacement of the nonfuzzy numbers that are commonly used in cost-effectiveness analysis models, with fuzzy numbers as an input to inform the real option pricing method. The real option approach to value uncertainty makes policy making in health care an evolutionary process and creates a new "space" for decision-making choices. Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

Developing a one-stop tinnitus service: outcomes of a joined up management strategy: a retrospective observational cohort study.

PubMed

Farr, Matthew R B; Moraleda Deleito, Javier; Xu, Yanmin; Ray, Jaydip

2016-02-01

The pressure to deliver quality care with finite resources means that dealing with single-symptom conditions like tinnitus in an efficient and individualized manner has never been more important. Both primary and secondary care practitioners have an obligation to explore efficient delivery of simple management pathways. Commissioners of health care are in a unique position to affect evidence-based strategic change in the management of uncomplicated tinnitus. This study is an attempt to explore one such option. We present the outcomes of a tinnitus patient pathway designed for one-stop management, thereby minimizing unnecessary additional appointments. A retrospective observational cohort study of 452 patients referred to a NHS one-stop tinnitus clinic from 2008 to 2012. Clinical care guided was through the use of a structured approach to history taking, neurotological examination and management. 294 out of 452 (65%) of patients referred had unilateral tinnitus. The most common associated complaints were hearing loss (387/452, 86%) and hyperacusis (329/452, 73%). 210 (46%) of patients had their presenting complaint dealt with in a single clinic visit. A structured system for referral and management of tinnitus within the health system ensures patients have timely access to evidence-based investigation and treatment. A consistent approach to imaging aimed at identifying retrocochlear pathology can benefit patients through early diagnosis of central pathology and the reassurance provided by a negative scan. © 2015 John Wiley & Sons, Ltd.

Local bone graft harvesting and volumes in posterolateral lumbar fusion: a technical report.

PubMed

Carragee, Eugene J; Comer, Garet C; Smith, Micah W

2011-06-01

In lumbar surgery, local bone graft is often harvested and used in posterolateral fusion procedures. The volume of local bone graft available for posterolateral fusion has not been determined in North American patients. Some authors have described this as minimal, but others have suggested the volume was sufficient to be reliably used as a stand-alone bone graft substitute for single-level fusion. To describe the technique used and determine the volume of local bone graft available in a cohort of patients undergoing single-level primary posterolateral fusion by the authors harvesting technique. Technical description and cohort report. Consecutive patients undergoing lumbar posterolateral fusion with or without instrumentation for degenerative processes. Local bone graft volume. Consecutive patients undergoing lumbar posterolateral fusion with or without instrumentation for degenerative processes of were studied. Local bone graft was harvested by a standard method in each patient and the volume measured by a standard procedure. Twenty-five patients were studied, and of these 11 (44%) had a previous decompression. The mean volume of local bone graft harvested was measured to be 25 cc (range, 12-36 cc). Local bone graft was augmented by iliac crest bone in six of 25 patients (24%) if the posterolateral fusion bed was not well packed with local bone alone. There was a trend to greater local bone graft volumes in men and in patients without previous decompression. Large volumes of local bone can be harvested during posterolateral lumbar fusion surgery. Even in patients with previous decompression the volume harvested is similar to that reported harvested from the posterior iliac crest for single-level fusion. Copyright © 2011 Elsevier Inc. All rights reserved.

The low single nucleotide polymorphism heritability of plasma and saliva cortisol levels.

PubMed

Neumann, Alexander; Direk, Nese; Crawford, Andrew A; Mirza, Saira; Adams, Hieab; Bolton, Jennifer; Hayward, Caroline; Strachan, David P; Payne, Erin K; Smith, Jennifer A; Milaneschi, Yuri; Penninx, Brenda; Hottenga, Jouke J; de Geus, Eco; Oldehinkel, Albertine J; van der Most, Peter J; de Rijke, Yolanda; Walker, Brian R; Tiemeier, Henning

2017-11-01

Cortisol is an important stress hormone affected by a variety of biological and environmental factors, such as the circadian rhythm, exercise and psychological stress. Cortisol is mostly measured using blood or saliva samples. A number of genetic variants have been found to contribute to cortisol levels with these methods. While the effects of several specific single genetic variants is known, the joint genome-wide contribution to cortisol levels is unclear. Our aim was to estimate the amount of cortisol variance explained by common single nucleotide polymorphisms, i.e. the SNP heritability, using a variety of cortisol measures, cohorts and analysis approaches. We analyzed morning plasma (n=5705) and saliva levels (n=1717), as well as diurnal saliva levels (n=1541), in the Rotterdam Study using genomic restricted maximum likelihood estimation. Additionally, linkage disequilibrium score regression was fitted on the results of genome-wide association studies (GWAS) performed by the CORNET consortium on morning plasma cortisol (n=12,597) and saliva cortisol (n=7703). No significant SNP heritability was detected for any cortisol measure, sample or analysis approach. Point estimates ranged from 0% to 9%. Morning plasma cortisol in the CORNET cohorts, the sample with the most power, had a 6% [95%CI: 0-13%] SNP heritability. The results consistently suggest a low SNP heritability of these acute and short-term measures of cortisol. The low SNP heritability may reflect the substantial environmental and, in particular, situational component of these cortisol measures. Future GWAS will require very large sample sizes. Alternatively, more long-term cortisol measures such as hair cortisol samples are needed to discover further genetic pathways regulating cortisol concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cost comparison of transcatheter and operative closures of ostium secundum atrial septal defects

PubMed Central

O’Byrne, Michael L.; Gillespie, Matthew J.; Shinohara, Russell T.; Dori, Yoav; Rome, Jonathan J.; Glatz, Andrew C.

2015-01-01

Background Clinical outcomes for transcatheter and operative closures of atrial septal defects (ASDs) are similar. Economic cost for each method has not been well described. Methods A single-center retrospective cohort study of children and adults <30 years of age undergoing closure for single secundum ASD from January 1, 2007, to April 1, 2012, was performed to measure differences in inflation-adjusted cost of operative and transcatheter closures of ASD. A propensity score weight-adjusted multivariate regression model was used in an intention-to-treat analysis. Costs for reintervention and crossover admissions were included in primary analysis. Results A total of 244 subjects were included in the study (64% transcatheter and 36% operative), of which 2% (n = 5) were ≥18 years. Crossover rate from transcatheter to operative group was 3%. Risk of reintervention (P = .66) and 30-day mortality (P = .37) were not significantly different. In a multivariate model, adjusted cost of operative closure was 2012 US $60,992 versus 2012 US $55,841 for transcatheter closure (P < .001). Components of total cost favoring transcatheter closure were length of stay, medications, and follow-up radiologic and laboratory testing, overcoming higher costs of procedure and echocardiography. Professional costs did not differ. The rate of 30-day readmission was greater in the operative cohort, further increasing the cost advantage of transcatheter closure. Sensitivity analyses demonstrated that costs of follow-up visits influenced relative cost but that device closure remained favorable over a broad range of crossover and reintervention rates. Conclusion For single secundum ASD, cost comparison analysis favors transcatheter closure over the short term. The cost of follow-up regimens influences the cost advantage of transcatheter closure. PMID:25965721

The characteristics of post-neurosurgical bacterial meningitis in elective neurosurgery in 2012: A single institute study.

PubMed

Tian, Runfa; Hao, Shuyu; Hou, Zonggang; Gao, Zhixian; Liu, Baiyun

2015-12-01

Most post-neurosurgical meningitis research has been focused on large cohorts with numerous cases followed over several years. However, the characteristics of post-neurosurgical meningitis in an entire single year are still unclear, and knowledge of these characteristics might influence the selection of appropriate antibiotics and therapeutic strategies for the successful management of this disease. Our aim is to obtain a better understanding of post-neurosurgical meningitis over a single entire year. Patients with positive meningitis cultures after neurosurgical operations in our hospital during the entire year of 2012 were included in the analysis. We report demographic characteristics, morbidity during different seasons, clinical and bacteriological profiles, sensitivity to antibiotics and causes of the post-neurosurgical meningitis infections in our cohort. Of the 6407 patients who underwent neurosurgical procedures during the study period, 146 developed post-neurosurgical meningitis and the overall incidence of meningitis was 2.28%. The incidence of meningitis was significantly higher in patients who underwent surgery in the autumn and winter than spring or summer (p=0.000). The most common organisms causing meningitis were Gram-positive bacteria, followed by the Klebsiella and Baumannii species. Compound sulfamethoxazole (52.6%) and vancomycin (10.5%) were the most active antibiotics against Gram-positive bacteria strains, whereas meropenem (43.8%) and polymyxin (18.8%) were active against Gram-negative bacillus strains. Post-neurosurgical meningitis usually occurs in the autumn and winter of the year in our hospital. Gram-positive organisms, which are sensitive to compound sulfamethoxazole and vancomycin, are the most common causative pathogens of post-neurosurgical meningitis in the northern mainland of China. Copyright © 2015 Elsevier B.V. All rights reserved.

Exploring genetic variants predisposing to diabetes mellitus and their association with indicators of socioeconomic status.

PubMed

Schmidt, Börge; Dragano, Nico; Scherag, André; Pechlivanis, Sonali; Hoffmann, Per; Nöthen, Markus M; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne

2014-06-16

The relevance of disease-related genetic variants for the explanation of social inequalities in complex diseases is unclear and empirical analyses are largely missing. The aim of our study was to examine whether genetic variants predisposing to diabetes mellitus are associated with socioeconomic status in a population-based cohort. We genotyped 11 selected diabetes-related single nucleotide polymorphisms in 4655 participants (age 45-75 years) of the Heinz Nixdorf Recall study. Diabetes status was self-reported or defined by blood glucose levels. Education, income and paternal occupation were assessed as indicators of socioeconomic status. Multiple regression analyses were used to examine the association of socioeconomic status and diabetes by estimating sex-specific and age-adjusted prevalence ratios and their corresponding 95%-confidence intervals. To explore the relationship between individual single nucleotide polymorphisms and socioeconomic status sex- and age-adjusted odds ratios were computed. We adjusted the alpha-level for multiple testing of 11 single nucleotide polymorphisms using Bonferroni's method (α(BF) ~ 0.005). In addition, we explored the association of a genetic risk score with socioeconomic status. Social inequalities in diabetes were observed for all indicators of socioeconomic status. However, there were no significant associations between individual diabetes-related risk alleles and socioeconomic status with odds ratios ranging from 0.87 to 1.23. Similarly, the genetic risk score analysis revealed no evidence for an association. Our data provide no evidence for an association between 11 diabetes-related risk alleles and different indicators of socioeconomic status in a population-based cohort, suggesting that the explored genetic variants do not contribute to health inequalities in diabetes.

Strategies for Managing a Multigenerational Workforce

NASA Astrophysics Data System (ADS)

Iden, Ronald

The multigenerational workforce presents a critical challenge for business managers, and each generation has different expectations. A human resource management study of organizations with more than 500 employees reported 58% of the managers experiencing conflict between younger and older workers. The purpose of this single case study was to explore the multigenerational strategies used by 3 managers from a Franklin County, Ohio manufacturing facility with a population size of 6 participants. The conceptual framework for this study was built upon generational theory and cohort group theory. The data were collected through face-to-face semistructured interviews, company documents, and a reflexive journal. Member checking was completed to strengthen the credibility and trustworthiness of the interpretation of participants' responses. A modified van Kaam method enabled separation of themes following the coding of data. Four themes emerged from the data: (a) required multigenerational managerial skills, (b) generational cohort differences, (c) most effective multigenerational management strategies, and (d) least effective multigenerational management strategies. Findings from this study may contribute to social change through better understanding, acceptance, and appreciation of the primary generations in the workforce, and, in turn, improve community relationships.

Clonal evolution in breast cancer revealed by single nucleus genome sequencing.

PubMed

Wang, Yong; Waters, Jill; Leung, Marco L; Unruh, Anna; Roh, Whijae; Shi, Xiuqing; Chen, Ken; Scheet, Paul; Vattathil, Selina; Liang, Han; Multani, Asha; Zhang, Hong; Zhao, Rui; Michor, Franziska; Meric-Bernstam, Funda; Navin, Nicholas E

2014-08-14

Sequencing studies of breast tumour cohorts have identified many prevalent mutations, but provide limited insight into the genomic diversity within tumours. Here we developed a whole-genome and exome single cell sequencing approach called nuc-seq that uses G2/M nuclei to achieve 91% mean coverage breadth. We applied this method to sequence single normal and tumour nuclei from an oestrogen-receptor-positive (ER(+)) breast cancer and a triple-negative ductal carcinoma. In parallel, we performed single nuclei copy number profiling. Our data show that aneuploid rearrangements occurred early in tumour evolution and remained highly stable as the tumour masses clonally expanded. In contrast, point mutations evolved gradually, generating extensive clonal diversity. Using targeted single-molecule sequencing, many of the diverse mutations were shown to occur at low frequencies (<10%) in the tumour mass. Using mathematical modelling we found that the triple-negative tumour cells had an increased mutation rate (13.3×), whereas the ER(+) tumour cells did not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.

Single living predicts a higher mortality in both women and men with chronic heart failure.

PubMed

Mard, Shan; Nielsen, Finn Erland

2016-09-01

We examined the impact of single living on all-cause mortality in patients with chronic heart failure and determined if this association was modified by gender. This historical cohort study included 637 patients who were admitted to the Department of Cardiology, Herlev Hospital, Denmark, between 1 July 2005 and 30 June 2007. Baseline clinical data were obtained from patient records. Data on survival rates were obtained from the Danish Civil Registration System. Cox proportional hazard analysis was used to compute the hazard ratio (HR) of all-cause mortality, controlling for confounding factors. The median follow-up time was 2.8 years. A total of 323 (50.7%) patients died during the follow-up period. After adjustment for confounding factors, risk of death was associated with being single (HR = 1.53 (95% confidence interval: 1.19-1.96)). In a gender-stratified analysis, the risk of death did not differ among single-living women and men. Single living is a prognostic determinant of all-cause mortality in men and women with chronic heart failure. none. not relevant.

Novel Signs and Their Clinical Utility in Diagnosing Complex Regional Pain Syndrome (CRPS): A Prospective Observational Cohort Study.

PubMed

Kuttikat, Anoop; Shaikh, Maliha; Oomatia, Amin; Parker, Richard; Shenker, Nicholas

2017-06-01

Delays in diagnosis occur with complex regional pain syndrome (CRPS). We define and prospectively demonstrate that novel bedside tests measuring body perception disruption can identify patients with CRPS postfracture. The objectives of our study were to define and validate 4 bedside tests, to identify the prevalence of positive tests in patients with CRPS and other chronic pain conditions, and to assess the clinical utility (sensitivity, specificity, positive predictive value, negative predictive value) for identifying CRPS within a Fracture cohort. This was a single UK teaching hospital prospective cohort study with 313 recruits from pain-free volunteers and patients with chronic pain conditions.Four novel tests were Finger Perception (FP), Hand Laterality identification (HL), Astereognosis (AS), and Body Scheme (BS) report. Five questionnaires (Brief Pain Inventory, Upper Extremity Functional Index, Lower Extremity Functional Index, Neglect-like Symptom Questionnaire, Hospital Anxiety and Depression Score) assessed the multidimensional pain experience. FP and BS were the best performing tests. Prospective monitoring of fracture patients showed that out of 7 fracture patients (total n=47) who had both finger misperception and abnormal BS report at initial testing, 3 developed persistent pain with 1 having a formal diagnosis of CRPS. Novel signs are reliable, easy to perform, and present in chronic pain patients. FP and BS have significant clinical utility in predicting persistent pain in a fracture group thereby allowing targeted early intervention.

Screening LGI1 in a cohort of 26 lateral temporal lobe epilepsy patients with auditory aura from Turkey detects a novel de novo mutation.

PubMed

Kesim, Yesim F; Uzun, Gunes Altiokka; Yucesan, Emrah; Tuncer, Feyza N; Ozdemir, Ozkan; Bebek, Nerses; Ozbek, Ugur; Iseri, Sibel A Ugur; Baykan, Betul

2016-02-01

Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is an autosomal dominant epileptic syndrome characterized by focal seizures with auditory or aphasic symptoms. The same phenotype is also observed in a sporadic form of lateral temporal lobe epilepsy (LTLE), namely idiopathic partial epilepsy with auditory features (IPEAF). Heterozygous mutations in LGI1 account for up to 50% of ADLTE families and only rarely observed in IPEAF cases. In this study, we analysed a cohort of 26 individuals with LTLE diagnosed according to the following criteria: focal epilepsy with auditory aura and absence of cerebral lesions on brain MRI. All patients underwent clinical, neuroradiological and electroencephalography examinations and afterwards they were screened for mutations in LGI1 gene. The single LGI1 mutation identified in this study is a novel missense variant (NM_005097.2: c.1013T>C; p.Phe338Ser) observed de novo in a sporadic patient. This is the first study involving clinical analysis of a LTLE cohort from Turkey and genetic contribution of LGI1 to ADLTE phenotype. Identification of rare LGI1 gene mutations in sporadic cases supports diagnosis as ADTLE and draws attention to potential familial clustering of ADTLE in suggestive generations, which is especially important for genetic counselling. Copyright © 2015 Elsevier B.V. All rights reserved.

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.

PubMed

van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

2016-07-14

Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)). Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Ibrutinib (PCI-32765) in Chronic Lymphocytic Leukemia

PubMed Central

Jain, Nitin; O’Brien, Susan

2015-01-01

SYNOPSIS B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are currently being studied as potential therapeutic targets. These include Lyn, Syk, PI3 and Bruton tyrosine (BTK). Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of BTK. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation. In addition, it also affects CLL cell migration and homing. Early clinical data in CLL and non-Hodgkin’s lymphoma patients is very encouraging. In relapsed-refractory patients with CLL, a 67% response rate was observed (420mg dose cohort) with single-agent ibrutinib. Long-term follow-up of these studies and other ongoing/planned studies of ibrutinib either as single-agent or in combination with monoclonal antibodies and chemoimmunotherapy is eagerly awaited. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy. PMID:23915749

Long-term effective population size dynamics of an intensively monitored vertebrate population

PubMed Central

Mueller, A-K; Chakarov, N; Krüger, O; Hoffman, J I

2016-01-01

Long-term genetic data from intensively monitored natural populations are important for understanding how effective population sizes (Ne) can vary over time. We therefore genotyped 1622 common buzzard (Buteo buteo) chicks sampled over 12 consecutive years (2002–2013 inclusive) at 15 microsatellite loci. This data set allowed us to both compare single-sample with temporal approaches and explore temporal patterns in the effective number of parents that produced each cohort in relation to the observed population dynamics. We found reasonable consistency between linkage disequilibrium-based single-sample and temporal estimators, particularly during the latter half of the study, but no clear relationship between annual Ne estimates () and census sizes. We also documented a 14-fold increase in between 2008 and 2011, a period during which the census size doubled, probably reflecting a combination of higher adult survival and immigration from further afield. Our study thus reveals appreciable temporal heterogeneity in the effective population size of a natural vertebrate population, confirms the need for long-term studies and cautions against drawing conclusions from a single sample. PMID:27553455

Homeopathy in the Age of Antimicrobial Resistance: Is It a Viable Treatment for Upper Respiratory Tract Infections?

PubMed

Fixsen, Alison

2018-05-01

 Acute upper respiratory tract infections (URTIs) and their complications are the most frequent cause of antibiotic prescribing in primary care. With multi-resistant organisms proliferating, appropriate alternative treatments to these conditions are urgently required. Homeopathy presents one solution; however, there are many methods of homeopathic prescribing. This review of the literature considers firstly whether homeopathy offers a viable alternative therapeutic solution for acute URTIs and their complications, and secondly how such homeopathic intervention might take place.  Critical review of post 1994 clinical studies featuring homeopathic treatment of acute URTIs and their complications. Study design, treatment intervention, cohort group, measurement and outcome were considered. Discussion focused on the extent to which homeopathy is used to treat URTIs, rate of improvement and tolerability of the treatment, complications of URTIs, prophylactic and long-term effects, and the use of combination versus single homeopathic remedies.  Multiple peer-reviewed studies were found in which homeopathy had been used to treat URTIs and associated symptoms (cough, pharyngitis, tonsillitis, otitis media, acute sinusitis, etc.). Nine randomised controlled trials (RCTs) and 8 observational/cohort studies were analysed, 7 of which were paediatric studies. Seven RCTs used combination remedies with multiple constituents. Results for homeopathy treatment were positive overall, with faster resolution, reduced use of antibiotics and possible prophylactic and longer-term benefits.  Variations in size, location, cohort and outcome measures make comparisons and generalisations concerning homeopathic clinical trials for URTIs problematic. Nevertheless, study findings suggest at least equivalence between homeopathy and conventional treatment for uncomplicated URTI cases, with fewer adverse events and potentially broader therapeutic outcomes. The use of non-individualised homeopathic compounds tailored for the paediatric population merits further investigation, including through cohort studies. In the light of antimicrobial resistance, homeopathy offers alternative strategies for minor infections and possible prevention of recurring URTIs. The Faculty of Homeopathy.

The Effects of Playing Multiple High School Sports on National Basketball Association Players' Propensity for Injury and Athletic Performance.

PubMed

Rugg, Caitlin; Kadoor, Adarsh; Feeley, Brian T; Pandya, Nirav K

2018-02-01

Athletes who specialize in their sport at an early age may be at risk for burnout, overuse injury, and reduced attainment of elite status. Timing of sport specialization has not been studied in elite basketball athletes. National Basketball Association (NBA) players who played multiple sports during adolescence would be less likely to experience injury and would have higher participation rates in terms of games played and career length compared with single-sport athletes. Descriptive epidemiology study. First-round draft picks from 2008 to 2015 in the NBA were included in the study. From publically available records from the internet, the following data were collected for each athlete: participation in high school sports, major injuries sustained in the NBA, percentage of games played in the NBA, and whether the athlete was still active in the NBA. Athletes who participated in sports in addition to basketball during high school were defined as multisport athletes and were compared with athletes who participated only in basketball in high school. Two hundred thirty-seven athletes were included in the study, of which 36 (15%) were multisport athletes and 201 (85%) were single-sport athletes in high school. The multisport cohort played in a statistically significantly greater percentage of total games (78.4% vs 72.8%; P < .001). Participants in the multisport cohort were less likely to sustain a major injury during their career (25% vs 43%, P = .03). Finally, a greater percentage of the multisport athletes were active in the league at time of data acquisition, indicating increased longevity in the NBA (94% vs 81.1%; P = .03). While a minority of professional basketball athletes participated in multiple sports in high school, those who were multisport athletes participated in more games, experienced fewer major injuries, and had longer careers than those who participated in a single sport. Further research is needed to determine the reasons behind these differences.

Correlates of circulating 25-hydroxyvitamin D: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.

PubMed

McCullough, Marjorie L; Weinstein, Stephanie J; Freedman, D Michal; Helzlsouer, Kathy; Flanders, W Dana; Koenig, Karen; Kolonel, Laurence; Laden, Francine; Le Marchand, Loic; Purdue, Mark; Snyder, Kirk; Stevens, Victoria L; Stolzenberg-Solomon, Rachael; Virtamo, Jarmo; Yang, Gong; Yu, Kai; Zheng, Wei; Albanes, Demetrius; Ashby, Jason; Bertrand, Kimberly; Cai, Hui; Chen, Yu; Gallicchio, Lisa; Giovannucci, Edward; Jacobs, Eric J; Hankinson, Susan E; Hartge, Patricia; Hartmuller, Virginia; Harvey, Chinonye; Hayes, Richard B; Horst, Ronald L; Shu, Xiao-Ou

2010-07-01

Low vitamin D status is common globally and is associated with multiple disease outcomes. Understanding the correlates of vitamin D status will help guide clinical practice, research, and interpretation of studies. Correlates of circulating 25-hydroxyvitamin D (25(OH)D) concentrations measured in a single laboratory were examined in 4,723 cancer-free men and women from 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, which covers a worldwide geographic area. Demographic and lifestyle characteristics were examined in relation to 25(OH)D using stepwise linear regression and polytomous logistic regression. The prevalence of 25(OH)D concentrations less than 25 nmol/L ranged from 3% to 36% across cohorts, and the prevalence of 25(OH)D concentrations less than 50 nmol/L ranged from 29% to 82%. Seasonal differences in circulating 25(OH)D were most marked among whites from northern latitudes. Statistically significant positive correlates of 25(OH)D included male sex, summer blood draw, vigorous physical activity, vitamin D intake, fish intake, multivitamin use, and calcium supplement use. Significant inverse correlates were body mass index, winter and spring blood draw, history of diabetes, sedentary behavior, smoking, and black race/ethnicity. Correlates varied somewhat within season, race/ethnicity, and sex. These findings help identify persons at risk for low vitamin D status for both clinical and research purposes.

GWA meta-analysis of personality in Korean cohorts.

PubMed

Kim, Bo-Hye; Kim, Han-Na; Roh, Seung-Ju; Lee, Mi Kyeong; Yang, Sarah; Lee, Seung Ku; Sung, Yeon-Ah; Chung, Hye Won; Cho, Nam H; Shin, Chol; Sung, Joohon; Kim, Hyung-Lae

2015-08-01

Personality is a determinant of behavior and lifestyle that is associated with health and human diseases. Despite the heritability of personality traits is well established, the understanding of the genetic contribution to personality trait variation is extremely limited. To identify genetic variants associated with each of the five dimensions of personality, we performed a genome-wide association (GWA) meta-analysis of three cohorts, followed by comparison of a family cohort. Personality traits were measured with the Revised NEO Personality Inventory for the five-factor model (FFM) of personality. We investigated the top five single-nucleotide polymorphisms (SNPs) for each trait, and revealed the most highly association with neuroticism and TACC2 (rs1010657, P=8.79 × 10(-7)), extraversion and PTPN12 (rs12537271, P=1.47 × 10(-7)), openness and IMPAD1 (rs16921695, P=5 × 10(-8)), agreeableness and RPS29 (rs8015351, P=1.27 × 10(-6)) and conscientiousness and LMO4 (rs912765, P=2.91 × 10(-6)). It had no SNP reached the GWA study threshold (P<5 × 10(-8)). When expanded the SNPs up to top 100, the correlation of PTPRD (rs1029089) and agreeableness was confirmed in Healthy Twin cohort with other 13 SNPs. This GWA meta-analysis on FFM personality traits is meaningful as it was the first on a non-Caucasian population targeted to FFM of personality traits.

Effect of maternal intravenous fluid therapy on external cephalic version at term: a prospective cohort study.

PubMed

Burgos, Jorge; Quintana, Eider; Cobos, Patricia; Osuna, Carmen; Centeno, María del Mar; Melchor, Juan Carlos

2014-12-01

We sought to analyze whether maternal intravenous fluid therapy prior to external cephalic version (ECV) increases the amount of amniotic fluid and the success rate of the procedure. This was a prospective single-center cohort study of 200 women with a consecutive cohort of 100 pregnant women with a breech presentation at term who were administered intravenous fluid therapy with 2 L of hypotonic saline before the version attempt, compared to a control cohort of 100 pregnant women not given hydration treatment. The mean increase in the amniotic fluid index (AFI) after intravenous maternal hydration was 3.75 ± 2.71 cm. The amount of fluid before hydration was the only variable found to be associated with increases in amniotic fluid levels, both in absolute and relative terms (odds ratio, -0.21; 95% confidence interval, -0.37 to -0.05 and odds ratio, -4.62; 95% confidence interval, -6.17 to -3.06; P < .01, respectively). We did not observe any severe complications secondary to the intravenous fluid therapy. The ECV success rate was 43% in the study group compared to 47% in the control group (P = .67). The success rate was significantly lower the larger the relative increase in the AFI, although no correlation was found in absolute terms (χ(2) for linear trend = 0.03 and 0.34, respectively). Maternal intravenous fluid therapy with 2 L of hypotonic saline prior to ECV is an effective and safe technique for increasing the AFI. However, its use in ECV does not increase the success rate of the procedure. Copyright © 2014 Elsevier Inc. All rights reserved.

Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study.

PubMed

Katsanos, Konstantinos H; Tatsioni, Athina; Pedersen, Natalia; Shuhaibar, Mary; Ramirez, Vicent Hernandez; Politi, Patrizia; Rombrechts, Evelien; Pierik, Marieke; Clofent, Juan; Beltrami, Marina; Bodini, Paolo; Freitas, Joao; Mouzas, Ioannis; Fornaciari, Giovanni; Moum, Bjorn; Lakatos, Peter Laszlo; Vermeire, Severine; Langholz, Ebbe; Odes, Selwyn; Morain, Colm O'; Stockbrügger, Reinhold; Munkholm, Pia; Tsianos, Epameinondas V

2011-10-01

To determine the occurrence of intestinal and extraintestinal cancers in the 1993-2009 prospective European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. A physician per patient form was completed for 681 inflammatory bowel disease patients (445UC/236CD) from 9 centers (7 countries) derived from the original EC-IBD cohort. For the 15-year follow up period, rates of detection of intestinal and extraintestinal cancers were computed. Patient follow-up time was fifteen years. In total 62/681 patients (9.1%) [41 with ulcerative colitis/21 with Crohn's disease, 36 males/26 females] were diagnosed with sixty-six cancers (four patients with double cancers). Colorectal cancer was diagnosed in 9/681 patients [1.3%] (1 Crohn's disease and 8 ulcerative colitis). The remaining 53 cancers were extraintestinal. There was a higher prevalence of intestinal cancer in the Northern centers compared to Southern centers [p=NS]. Southern centers had more cases of extraintestinal cancer compared to Northern centers [p=NS]. The frequency of all observed types of cancers in Northern and in Southern centers did not differ compared to the expected one in the background population. In the fifteen-year follow up of the EC-IBD Study Group cohort the prevalence of cancer was 9.1% with most patients having a single neoplasm and an extraintestinal neoplasm. In Northern centers there were more intestinal cancers while in Southern centers there were more extraintestinal cancers compared to Northern centers. In this IBD cohort the frequency of observed cancers was not different from that expected in the background population. Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Biologic treatment eligibility for real-world patients with severe asthma: The IDEAL study.

PubMed

Albers, Frank C; Müllerová, Hana; Gunsoy, Necdet B; Shin, Ji-Yeon; Nelsen, Linda M; Bradford, Eric S; Cockle, Sarah M; Suruki, Robert Y

2018-02-01

Severe asthma comprises several distinct phenotypes. Consequently, patients with severe asthma can be eligible for more than one biologic treatment targeting Th2 inflammation, such as anti-interleukin (IL)-5 and anti-immunoglobulin (Ig) E. The objective of this study was to describe treatment eligibility and overlap in treatment eligibility for mepolizumab (anti-IL-5), omalizumab (anti-IgE) and reslizumab (anti-IL-5) in patients with severe asthma, who were recruited from clinical practice. This cross-sectional, single-visit, observational study in six countries enrolled patients with severe asthma (defined by American Thoracic Society/European Respiratory Society guidelines). Assessable patients were analysed as a total cohort and a sub-cohort, who were not currently receiving omalizumab. Treatment eligibility was defined according to the local prescribing information or protocol-defined inclusion/exclusion criteria. Patients currently receiving omalizumab were automatically categorised as omalizumab-eligible. The total cohort comprised 670 patients who met the analysis criteria, of whom 20% were eligible for mepolizumab, 31-41% were eligible for omalizumab (depending on eligibility criteria used), and 5% were eligible for reslizumab. In patients not currently receiving omalizumab (n = 502), proportions eligible for each biologic were similar (mepolizumab: 20%, reslizumab 6%) or lower (omalizumab 7-21%) than those for the total cohort. Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab (n = 101), 27-37% were omalizumab-eligible and 18% were reslizumab-eligible. Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab. Although there was some overlap in treatment eligibility, the patient groups eligible for treatment with anti-IL-5 or anti-IgE therapies were often distinct, emphasising the different phenotypes and endotypes in severe asthma.

Social disparities in BMI trajectories across adulthood by gender, race/ethnicity and lifetime socio-economic position: 1986-2004.

PubMed

Clarke, Philippa; O'Malley, Patrick M; Johnston, Lloyd D; Schulenberg, John E

2009-04-01

The prevalence of obesity and overweight is rapidly increasing in industrialized countries, with long-term health and social consequences. There is also a strong social patterning of obesity and overweight, with a higher prevalence among women, racial/ethnic minorities and those from a lower socio-economic position (SEP). Most of the existing work in this area, however, is based on cross-sectional data or single cohort studies. No national studies to date have examined how social disparities in obesity and overweight differ by age and historical period using longitudinal data with repeated measures. We used panel data from the nationally representative Monitoring the Future Study (1986-2004) to examine social disparities in trajectories of body mass index (BMI) over adulthood (age 18-45). Self-reported height and weight were collected in this annual US survey of high-school seniors, followed biennially since 1976. Using growth curve models, we analysed BMI trajectories over adulthood by gender, race/ethnicity and lifetime SEP (measured by parents' education and respondent's education). BMI trajectories exhibit a curvilinear rate of change from age 18 to 45, but there was a strong period effect, such that weight gain was more rapid for more recent cohorts. As a result, successive cohorts become overweight (BMI>25) at increasingly earlier points in the life course. BMI scores were also consistently higher for women, racial/ethnic minority groups and those from a lower SEP. However, BMI scores for socially advantaged groups in recent cohorts were actually higher than those for their socially disadvantaged counterparts who were born 10 years earlier. Results highlight the importance of social status and socio-economic resources for maintaining optimal weight. Yet, even those in advantaged social positions have experienced an increase in BMI in recent years.

Clinical and economic impact of herpes zoster vaccination in elderly in Italy.

PubMed

Boccalini, Sara; Alicino, Cristiano; Martinelli, Domenico; Bechini, Angela; Tiscione, Emilia; Pellizzari, Barbara; Prato, Rosa; Icardi, Giancarlo; Iannazzo, Stefania; Bonanni, Paolo

2017-02-01

Herpes zoster (HZ) is a very relevant pathology among elderly people (≥ 60 years of age), with a considerable disease burden and loss of quality of life. In the last years a new vaccine against HZ became available in Italy. Therefore, the Italian decision makers are now confronted with the decision whether that vaccination should be implemented. Pharmaco-economic analyses represent useful tools to value the feasibility of new immunization programs and their sustainability. To this aim, an ad hoc population model was developed in order to value the clinical and economic impact of HZ vaccination program for the elderly in Italy. Particularly, different immunization scenarios were modeled: vaccination of 60 years-old subjects (single cohort strategy), simultaneous vaccination of people aged 60 and 65 years (double cohort strategy) and, lastly, immunization of people aged 60, 65 and 70 years (triple cohort strategy), thus leading to the vaccination of 5, 10 and 15 cohorts during the first 5 years of the program. The mathematical model valued the clinical impact of vaccination on the number of HZ, post-herpetic neuralgia (PHN) and ophthalmic HZ. The results of the analysis show that, in Italy, a cohort-based HZ vaccination program in elderly could have a relevant impact on the reduction of clinical cases and a favorable economic profile for the National Health Service (NHS), as already foreseen in other countries. In addition, further benefits could be obtained when extending the study period beyond the 5-year horizon of our analysis.

Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent

PubMed Central

Winham, Stacey J.; Preuss, Ulrich W.; Geske, Jennifer R.; Zill, Peter; Heit, John A.; Bakalkin, Georgy; Biernacka, Joanna M.; Karpyak, Victor M.

2015-01-01

We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p  =  0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific. PMID:26502829

Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent.

PubMed

Winham, Stacey J; Preuss, Ulrich W; Geske, Jennifer R; Zill, Peter; Heit, John A; Bakalkin, Georgy; Biernacka, Joanna M; Karpyak, Victor M

2015-10-27

We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p  =  0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific.

Hip Fractures and the Bundle: A Cost Analysis of Patients Undergoing Hip Arthroplasty for Femoral Neck Fracture vs Degenerative Joint Disease.

PubMed

Grace, Trevor R; Patterson, Joseph T; Tangtiphaiboontana, Jennifer; Krogue, Justin D; Vail, Thomas P; Ward, Derek T

2018-06-01

The purpose of this study is to determine whether episode Target Prices in the Bundled Payment for Care Improvement (BPCI) initiative sufficiently match the complexities and expenses expected for patients undergoing hip arthroplasty for femoral neck fracture (FNF) as compared to hip degenerative joint disease (DJD). Claims data under BPCI Model 2 were collected for patients undergoing hip arthroplasty at a single institution over a 2-year period. Payments from the index hospitalization to 90 days postoperatively were aggregated by Medicare Severity Diagnosis-Related Group (469 or 470), indication (DJD vs FNF), and categorized as index procedure, postacute services, and related hospital readmissions. Actual episode costs and Target Prices were compared in both the FNF and DJD cohorts undergoing hip arthroplasty to gauge the cost discrepancy in each group. A total of 183 patients were analyzed (31 with FNFs, 152 with DJD). In total, the FNF cohort incurred a $415,950 loss under the current episode Target Prices, whereas the DJD cohort incurred a $172,448 gain. Episode Target Prices were significantly higher than actual episode prices for the DJD cohort ($32,573 vs $24,776, P < .001). However, Target Prices were significantly lower than actual episode prices for the FNF cohort ($32,672 vs $49,755, P = .021). Episode Target Prices in the current BPCI model fall dramatically short of the actual expenses incurred by FNF patients undergoing hip arthroplasty. Better risk-adjusting Target Prices for this fragile population should be considered to avoid disincentives and delays in care. Copyright © 2018 Elsevier Inc. All rights reserved.

Phase I study of pazopanib plus TH-302 in advanced solid tumors.

PubMed

Riedel, Richard F; Meadows, Kellen L; Lee, Paula H; Morse, Michael A; Uronis, Hope E; Blobe, Gerard C; George, Daniel J; Crawford, Jeffrey; Niedzwiecki, Donna; Rushing, Christel N; Arrowood, Christy C; Hurwitz, Herbert I

2017-03-01

To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors. This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard "3 + 3" dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1-28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m 2 (cohort 1) or 480 mg/m 2 (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles. Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m 2 TH-302 cohort and 6 patients in the 480 mg/m 2 TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m 2 TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m 2 TH-302 cohort. The 340 mg/m 2 TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11). The RPTD for this novel combination is pazopanib 800 mg daily on days 1-28 plus TH-302 340 mg/m 2 on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

A new era of prospective real-world safety evaluation primary report of XIENCE V USA (XIENCE V Everolimus Eluting Coronary Stent System condition-of-approval post-market study).

PubMed

Krucoff, Mitchell W; Rutledge, David R; Gruberg, Luis; Jonnavithula, Lalitha; Katopodis, John N; Lombardi, William; Mao, Vivian W; Sharma, Samin K; Simonton, Charles A; Tamboli, Hoshedar P; Wang, Jin; Wilburn, Olivia; Zhao, Weiying; Sudhir, Krishnankutty; Hermiller, James B

2011-12-01

The XIENCE V USA (XIENCE V Everolimus Eluting Coronary Stent System Condition-of-Approval Post-Market study) sought to: 1) evaluate the safety of everolimus-eluting coronary stent systems (EECSS) in a contemporary cohort of real-world subjects; and 2) prospectively test the quality of event reporting with analysis of matched patients from the randomized SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions) trial. Randomized trials have demonstrated the safety and efficacy of EECSS in selected "standard-risk" patients. The XIENCE V USA trial was a prospective, multicenter, single-arm study in unselected patients. The primary endpoint was Academic Research Consortium (ARC)-defined definite and probable stent thrombosis (ST); the co-primary endpoint was the composite of cardiac death and myocardial infarction at 1 year. Secondary analyses included: 1) stratification by standard-risk and extended-risk cohorts; and 2) late ST after dual antiplatelet therapy interruption. Of 5,054 participants (1,875 standard-risk; 3,179 extended-risk), 4,958 (98.1%) reached 1-year follow-up. The rate of ARC-defined definite and probable ST was 0.84% (95% confidence interval [CI]: 0.60% to 1.14%) in the overall population and 0.33% (95% CI: 0.12% to 10.72%) and 1.14% (95% CI: 0.80% to 11.58%) in the standard-risk and extended-risk cohorts, respectively. No late ST was observed after dual antiplatelet therapy interruption in either cohort after 6 months. The composite rate of cardiac death and ARC-defined myocardial infarction was 6.5% (95% CI: 5.79% to 17.17%) in the overall population, 3.8% (95% CI: 2.98% to 14.78%) in the standard-risk cohort, and 8.0% (95% CI: 7.09% to 19.02%) in the extended-risk cohort. This study comprehensively reports ST rates for EECSS in a contemporary real-world population. The absence of ST after dual antiplatelet therapy interruption beyond 6 months in standard-risk and high-risk patients is notable. Consistent safety outcomes between matched standard-risk cohorts from the XIENCE V USA study and the SPIRIT IV randomized trial suggest that this study affords a reliable benchmark for understanding the safety of EECSS in the context of real-world clinical practice. (XIENCE V Everolimus Eluting Coronary Stent System [EECSS] USA Post-Approval Study; NCT00676520). Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

GH replacement therapy and second neoplasms in adult survivors of childhood cancer: a retrospective study from a single institution.

PubMed

Brignardello, E; Felicetti, F; Castiglione, A; Fortunati, N; Matarazzo, P; Biasin, E; Sacerdote, C; Ricardi, U; Fagioli, F; Corrias, A; Arvat, E

2015-02-01

Growth hormone deficiency (GHD) is the most common endocrine late effect observed in childhood cancer survivors (CCS) previously submitted to cranial irradiation. Radiation therapy can also increase the risk of second neoplasms (SNs). Since in previous studies GH replacement therapy was associated with increased incidence of neoplasia, we explored the association between SNs and GH replacement therapy in a cohort of CCS with GHD. Within the clinical cohort of CCS referred to the Transition Unit for Childhood Cancer Survivors of Turin between November 2001 and December 2012, we considered all patients who developed GHD as a consequence of cancer therapies. GHD was always diagnosed in childhood. To evaluate the quality of data, our cohort was linked to the Childhood Cancer Registry of Piedmont. GHD was diagnosed in 49 out of 310 CCS included in our clinical cohort. At least one SN was diagnosed in 14 patients, meningioma and basal cell carcinoma being the most common SNs. The cumulative incidence of SNs was similar in GH-treated and -untreated patients (8 SNs out of 26 GH-treated and 6 out of 23 GH-untreated patients; p = 0.331). Age, sex and paediatric cancer type had no impact on SNs development. In our CCS, GH replacement therapy does not seem to increase the risk of SNs. Anyway, independently from replacement therapy, in these patients we observed an elevated risk of SNs, possibly related to previous radiation therapy, which suggests the need of a close long-term follow-up.

Validity of the Medical College Admission Test for predicting MD-PhD student outcomes.

PubMed

Bills, James L; VanHouten, Jacob; Grundy, Michelle M; Chalkley, Roger; Dermody, Terence S

2016-03-01

The Medical College Admission Test (MCAT) is a quantitative metric used by MD and MD-PhD programs to evaluate applicants for admission. This study assessed the validity of the MCAT in predicting training performance measures and career outcomes for MD-PhD students at a single institution. The study population consisted of 153 graduates of the Vanderbilt Medical Scientist Training Program (combined MD-PhD program) who matriculated between 1963 and 2003 and completed dual-degree training. This population was divided into three cohorts corresponding to the version of the MCAT taken at the time of application. Multivariable regression (logistic for binary outcomes and linear for continuous outcomes) was used to analyze factors associated with outcome measures. The MCAT score and undergraduate GPA (uGPA) were treated as independent variables; medical and graduate school grades, time-to-PhD defense, USMLE scores, publication number, and career outcome were dependent variables. For cohort 1 (1963-1977), MCAT score was not associated with any assessed outcome, although uGPA was associated with medical school preclinical GPA and graduate school GPA (gsGPA). For cohort 2 (1978-1991), MCAT score was associated with USMLE Step II score and inversely correlated with publication number, and uGPA was associated with preclinical GPA (mspGPA) and clinical GPA (mscGPA). For cohort 3 (1992-2003), the MCAT score was associated with mscGPA, and uGPA was associated with gsGPA. Overall, MCAT score and uGPA were inconsistent or weak predictors of training metrics and career outcomes for this population of MD-PhD students.

Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts

PubMed Central

COUSTET, BAPTISTE; AGARWAL, SANDEEP K.; GOURH, PRAVITT; GUEDJ, MICKAEL; MAYES, MAUREEN D.; DIEUDE, PHILIPPE; WIPFF, JULIEN; AVOUAC, JEROME; HACHULLA, ERIC; DIOT, ELISABETH; CRACOWSKI, JEAN LUC; TIEV, KIET; SIBILIA, JEAN; MOUTHON, LUC; FRANCES, CAMILLE; AMOURA, ZAHIR; CARPENTIER, PATRICK; MEYER, OLIVIER; KAHAN, ANDRE; BOILEAU, CATHERINE; ARNETT, FRANK C.; ALLANORE, YANNICK

2012-01-01

Objective Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations. Methods SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort. Results The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls. Conclusion These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes. PMID:21362770

External validation of the CAPRA-S score to predict biochemical recurrence, metastasis and mortality after radical prostatectomy in a European cohort.

PubMed

Tilki, Derya; Mandel, Philipp; Schlomm, Thorsten; Chun, Felix K-H; Tennstedt, Pierre; Pehrke, Dirk; Haese, Alexander; Huland, Hartwig; Graefen, Markus; Salomon, Georg

2015-06-01

The CAPRA-S score predicts prostate cancer recurrence based on pathological information from radical prostatectomy. To our knowledge CAPRA-S has never been externally validated in a European cohort. We independently validated CAPRA-S in a single institution European database. The study cohort comprised 14,532 patients treated with radical prostatectomy between January 1992 and August 2012. Prediction of biochemical recurrence, metastasis and cancer specific mortality by CAPRA-S was assessed by Kaplan-Meier analysis and the c-index. CAPRA-S performance to predict biochemical recurrence was evaluated by calibration plot and decision curve analysis. Median followup was 50.8 months (IQR 25.0-96.0). Biochemical recurrence developed in 20.3% of men at a median of 21.2 months (IQR 7.7-44.9). When stratifying patients by CAPRA-S risk group, estimated 5-year biochemical recurrence-free survival was 91.4%, 70.4% and 29.3% in the low, intermediate and high risk groups, respectively. The CAPRA-S c-index to predict biochemical recurrence, metastasis and cancer specific mortality was 0.80, 0.85 and 0.88, respectively. Metastasis developed in 417 men and 196 men died of prostate cancer. The CAPRA-S score was accurate when applied in a European study cohort. It predicted biochemical recurrence, metastasis and cancer specific mortality after radical prostatectomy with a c-index of greater than 0.80. The score can be valuable in regard to decision making for adjuvant therapy. Copyright © 2015. Published by Elsevier Inc.

IL4R alpha mutations are associated with asthma exacerbations and mast cell/IgE expression.

PubMed

Wenzel, Sally E; Balzar, Silvana; Ampleford, Elizabeth; Hawkins, Gregory A; Busse, William W; Calhoun, William J; Castro, Mario; Chung, K Fan; Erzurum, Serpil; Gaston, Benjamin; Israel, Elliot; Teague, W Gerald; Curran-Everett, Douglas; Meyers, Deborah A; Bleecker, Eugene R

2007-03-15

Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor alpha (IL4Ralpha) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. Allelic substitutions in IL4Ralpha are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Ralpha. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. SNPs in IL4Ralpha, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database

PubMed Central

Koeks, Zaïda; Bladen, Catherine L.; Salgado, David; van Zwet, Erik; Pogoryelova, Oksana; McMacken, Grace; Monges, Soledad; Foncuberta, Maria E.; Kekou, Kyriaki; Kosma, Konstantina; Dawkins, Hugh; Lamont, Leanne; Bellgard, Matthew I.; Roy, Anna J.; Chamova, Teodora; Guergueltcheva, Velina; Chan, Sophelia; Korngut, Lawrence; Campbell, Craig; Dai, Yi; Wang, Jen; Barišić, Nina; Brabec, Petr; Lähdetie, Jaana; Walter, Maggie C.; Schreiber-Katz, Olivia; Karcagi, Veronika; Garami, Marta; Herczegfalvi, Agnes; Viswanathan, Venkatarman; Bayat, Farhad; Buccella, Filippo; Ferlini, Alessandra; Kimura, En; van den Bergen, Janneke C.; Rodrigues, Miriam; Roxburgh, Richard; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Santos, Rosário; Neagu, Elena; Artemieva, Svetlana; Rasic, Vedrana Milic; Vojinovic, Dina; Posada, Manuel; Bloetzer, Clemens; Klein, Andrea; Díaz-Manera, Jordi; Gallardo, Eduard; Karaduman, A. Ayşe; Oznur, Tunca; Topaloğlu, Haluk; El Sherif, Rasha; Stringer, Angela; Shatillo, Andriy V.; Martin, Ann S.; Peay, Holly L.; Kirschner, Jan; Flanigan, Kevin M.; Straub, Volker; Bushby, Kate; Béroud, Christophe; Verschuuren, Jan J.; Lochmüller, Hanns

2017-01-01

Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. Objective: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. Methods: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Results: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. Conclusions: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field. PMID:29125504

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

PubMed

Koeks, Zaïda; Bladen, Catherine L; Salgado, David; van Zwet, Erik; Pogoryelova, Oksana; McMacken, Grace; Monges, Soledad; Foncuberta, Maria E; Kekou, Kyriaki; Kosma, Konstantina; Dawkins, Hugh; Lamont, Leanne; Bellgard, Matthew I; Roy, Anna J; Chamova, Teodora; Guergueltcheva, Velina; Chan, Sophelia; Korngut, Lawrence; Campbell, Craig; Dai, Yi; Wang, Jen; Barišić, Nina; Brabec, Petr; Lähdetie, Jaana; Walter, Maggie C; Schreiber-Katz, Olivia; Karcagi, Veronika; Garami, Marta; Herczegfalvi, Agnes; Viswanathan, Venkatarman; Bayat, Farhad; Buccella, Filippo; Ferlini, Alessandra; Kimura, En; van den Bergen, Janneke C; Rodrigues, Miriam; Roxburgh, Richard; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Santos, Rosário; Neagu, Elena; Artemieva, Svetlana; Rasic, Vedrana Milic; Vojinovic, Dina; Posada, Manuel; Bloetzer, Clemens; Klein, Andrea; Díaz-Manera, Jordi; Gallardo, Eduard; Karaduman, A Ayşe; Oznur, Tunca; Topaloğlu, Haluk; El Sherif, Rasha; Stringer, Angela; Shatillo, Andriy V; Martin, Ann S; Peay, Holly L; Kirschner, Jan; Flanigan, Kevin M; Straub, Volker; Bushby, Kate; Béroud, Christophe; Verschuuren, Jan J; Lochmüller, Hanns

2017-01-01

Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.

An Ai Chi-based aquatic group improves balance and reduces falls in community-dwelling adults: A pilot observational cohort study.

PubMed

Skinner, Elizabeth H; Dinh, Tammy; Hewitt, Melissa; Piper, Ross; Thwaites, Claire

2016-11-01

Falls are associated with morbidity, loss of independence, and mortality. While land-based group exercise and Tai Chi programs reduce the risk of falls, aquatic therapy may allow patients to complete balance exercises with less pain and fear of falling; however, limited data exist. The objective of the study was to pilot the implementation of an aquatic group based on Ai Chi principles (Aquabalance) and to evaluate the safety, intervention acceptability, and intervention effect sizes. Pilot observational cohort study. Forty-two outpatients underwent a single 45-minute weekly group aquatic Ai Chi-based session for eight weeks (Aquabalance). Safety was monitored using organizational reporting systems. Patient attendance, satisfaction, and self-reported falls were also recorded. Balance measures included the Timed Up and Go (TUG) test, the Four Square Step Test (FSST), and the unilateral Step Tests. Forty-two patients completed the program. It was feasible to deliver Aquabalance, as evidenced by the median (IQR) attendance rate of 8.0 (7.8, 8.0) out of 8. No adverse events occurred and participants reported high satisfaction levels. Improvements were noted on the TUG, 10-meter walk test, the Functional Reach Test, the FSST, and the unilateral step tests (p < 0.05). The proportion of patients defined as high falls risk reduced from 38% to 21%. The study was limited by its small sample size, single-center nature, and the absence of a control group. Aquabalance was safe, well-attended, and acceptable to participants. A randomized controlled assessor-blinded trial is required.

A risk score for predicting near-term incidence of hypertension: the Framingham Heart Study.

PubMed

Parikh, Nisha I; Pencina, Michael J; Wang, Thomas J; Benjamin, Emelia J; Lanier, Katherine J; Levy, Daniel; D'Agostino, Ralph B; Kannel, William B; Vasan, Ramachandran S

2008-01-15

Studies suggest that targeting high-risk, nonhypertensive individuals for treatment may delay hypertension onset, thereby possibly mitigating vascular complications. Risk stratification may facilitate cost-effective approaches to management. To develop a simple risk score for predicting hypertension incidence by using measures readily obtained in the physician's office. Longitudinal cohort study. Framingham Heart Study, Framingham, Massachusetts. 1717 nonhypertensive white individuals 20 to 69 years of age (mean age, 42 years; 54% women), without diabetes and with both parents in the original cohort of the Framingham Heart Study, contributed 5814 person-examinations. Scores were developed for predicting the 1-, 2-, and 4-year risk for new-onset hypertension, and performance characteristics of the prediction algorithm were assessed by using calibration and discrimination measures. Parental hypertension was ascertained from examinations of the original cohort of the Framingham Heart Study. During follow-up (median time over all person-examinations, 3.8 years), 796 persons (52% women) developed new-onset hypertension. In multivariable analyses, age, sex, systolic and diastolic blood pressure, body mass index, parental hypertension, and cigarette smoking were significant predictors of hypertension. According to the risk score based on these factors, the 4-year risk for incident hypertension was classified as low (<5%) in 34% of participants, medium (5% to 10%) in 19%, and high (>10%) in 47%. The c-statistic for the prediction model was 0.788, and calibration was very good. The risk score findings may not be generalizable to persons of nonwhite race or ethnicity or to persons with diabetes. The risk score algorithm has not been validated in an independent cohort and is based on single measurements of risk factors and blood pressure. The hypertension risk prediction score can be used to estimate an individual's absolute risk for hypertension on short-term follow-up, and it represents a simple, office-based tool that may facilitate management of high-risk individuals with prehypertension.

Systems Biology Methods for Alzheimer's Disease Research Toward Molecular Signatures, Subtypes, and Stages and Precision Medicine: Application in Cohort Studies and Trials.

PubMed

Castrillo, Juan I; Lista, Simone; Hampel, Harald; Ritchie, Craig W

2018-01-01

Alzheimer's disease (AD) is a complex multifactorial disease, involving a combination of genomic, interactome, and environmental factors, with essential participation of (a) intrinsic genomic susceptibility and (b) a constant dynamic interplay between impaired pathways and central homeostatic networks of nerve cells. The proper investigation of the complexity of AD requires new holistic systems-level approaches, at both the experimental and computational level. Systems biology methods offer the potential to unveil new fundamental insights, basic mechanisms, and networks and their interplay. These may lead to the characterization of mechanism-based molecular signatures, and AD hallmarks at the earliest molecular and cellular levels (and beyond), for characterization of AD subtypes and stages, toward targeted interventions according to the evolving precision medicine paradigm. In this work, an update on advanced systems biology methods and strategies for holistic studies of multifactorial diseases-particularly AD-is presented. This includes next-generation genomics, neuroimaging and multi-omics methods, experimental and computational approaches, relevant disease models, and latest genome editing and single-cell technologies. Their progressive incorporation into basic research, cohort studies, and trials is beginning to provide novel insights into AD essential mechanisms, molecular signatures, and markers toward mechanism-based classification and staging, and tailored interventions. Selected methods which can be applied in cohort studies and trials, with the European Prevention of Alzheimer's Dementia (EPAD) project as a reference example, are presented and discussed.

Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics.

PubMed

Nieuweboer, A J M; Smid, M; de Graan, A-J M; Elbouazzaoui, S; de Bruijn, P; Eskens, F A L M; Hamberg, P; Martens, J W M; Sparreboom, A; de Wit, R; van Schaik, R H N; Mathijssen, R H J

2016-11-01

Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.

PTGER4 Expression-Modulating Polymorphisms in the 5p13.1 Region Predispose to Crohn's Disease and Affect NF-κB and XBP1 Binding Sites

PubMed Central

Czamara, Darina; Pasciuto, Giulia; Diegelmann, Julia; Wetzke, Martin; Olszak, Torsten; Wolf, Christiane; Müller-Myhsok, Bertram; Balschun, Tobias; Achkar, Jean-Paul; Kamboh, M. Ilyas; Franke, Andre; Duerr, Richard H.; Brand, Stephan

2012-01-01

Background Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. Methodology/Principal Findings A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10−5; 0.76 [0.67–0.87]) and of rs7720838 (p = 6.91×10−4; 0.81 [0.71–0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10−7 for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. Conclusions/Significance We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility. PMID:23300802

PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites.

PubMed

Glas, Jürgen; Seiderer, Julia; Czamara, Darina; Pasciuto, Giulia; Diegelmann, Julia; Wetzke, Martin; Olszak, Torsten; Wolf, Christiane; Müller-Myhsok, Bertram; Balschun, Tobias; Achkar, Jean-Paul; Kamboh, M Ilyas; Franke, Andre; Duerr, Richard H; Brand, Stephan

2012-01-01

Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.

Attrition during graduate medical education: medical school perspective.

PubMed

Andriole, Dorothy A; Jeffe, Donna B; Hageman, Heather L; Klingensmith, Mary E; McAlister, Rebecca P; Whelan, Alison J

2008-12-01

To identify predictors of attrition during graduate medical education (GME) in a single medical school cohort of contemporary US medical school graduates. Retrospective cohort study. Single medical institution. Recent US allopathic medical school graduates. Attrition from initial GME program. Forty-seven of 795 graduates (6%) did not complete the GME in their initial specialty of choice. At bivariate analysis, attrition was associated with election to the Alpha Omega Alpha Honor Medical Society, being an MD-PhD degree holder, and specialty choice (all P < .05). Attrition was not associated with graduation year (P = .91), sex (P = .67), or age (P = .12). In a multivariate logistic regression model, MD-PhD degree holder (odds ratio, 3.43; 95% confidence interval, 1.27-9.26; P = .02), election to Alpha Omega Alpha (2.19; 1.04-4.66; P = .04), choice of general surgery for GME (5.32; 1.98-14.27; P < .001), and choice of 5-year surgical specialty including those surgical specialties with a GME training requirement of 5 years or longer (2.74; 1.16-6.44; P = .02) each independently predicted greater likelihood of attrition. Academically highly qualified graduates and graduates who chose training in general surgery or in a 5-year surgical specialty were at increased risk of attrition during GME.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma

PubMed Central

Yates, Katherine P.; Zhou, Xiaobo; Guo, Feng; Sternberg, Alice L.; Van Natta, Mark L.; Wise, Robert A.; Szefler, Stanley J.; Sharma, Sunita; Kho, Alvin T.; Cho, Michael H.; Croteau-Chonka, Damien C.; Castaldi, Peter J.; Jain, Gaurav; Sanyal, Amartya; Zhan, Ye; Lajoie, Bryan R.; Dekker, Job; Stamatoyannopoulos, John; Covar, Ronina A.; Zeiger, Robert S.; Adkinson, N. Franklin; Williams, Paul V.; Kelly, H. William; Grasemann, Hartmut; Vonk, Judith M.; Koppelman, Gerard H.; Postma, Dirkje S.; Raby, Benjamin A.; Houston, Isaac; Lu, Quan; Fuhlbrigge, Anne L.; Tantisira, Kelan G.; Silverman, Edwin K.; Tonascia, James; Strunk, Robert C.; Weiss, Scott T.

2016-01-01

Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays. Measurements and Main Results: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10−9; odds ratio, 2.8; 95% confidence interval, 2.0–4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575). PMID:27367781

Mapping Quantitative Trait Loci (QTL) in sheep. III. QTL for carcass composition traits derived from CT scans and aligned with a meta-assembly for sheep and cattle carcass QTL.

PubMed

Cavanagh, Colin R; Jonas, Elisabeth; Hobbs, Matthew; Thomson, Peter C; Tammen, Imke; Raadsma, Herman W

2010-09-16

An (Awassi × Merino) × Merino single-sire backcross family with 165 male offspring was used to map quantitative trait loci (QTL) for body composition traits on a framework map of 189 microsatellite loci across all autosomes. Two cohorts were created from the experimental progeny to represent alternative maturity classes for body composition assessment. Animals were raised under paddock conditions prior to entering the feedlot for a 90-day fattening phase. Body composition traits were derived in vivo at the end of the experiment prior to slaughter at 2 (cohort 1) and 3.5 (cohort 2) years of age, using computed tomography. Image analysis was used to gain accurate predictions for 13 traits describing major fat depots, lean muscle, bone, body proportions and body weight which were used for single- and two-QTL mapping analysis. Using a maximum-likelihood approach, three highly significant (LOD ≥ 3), 15 significant (LOD ≥ 2), and 11 suggestive QTL (1.7 ≤ LOD < 2) were detected on eleven chromosomes. Regression analysis confirmed 28 of these QTL and an additional 17 suggestive (P < 0.1) and two significant (P < 0.05) QTL were identified using this method. QTL with pleiotropic effects for two or more tissues were identified on chromosomes 1, 6, 10, 14, 16 and 23. No tissue-specific QTL were identified.A meta-assembly of ovine QTL for carcass traits from this study and public domain sources was performed and compared with a corresponding bovine meta-assembly. The assembly demonstrated QTL with effects on carcass composition in homologous regions on OAR1, 2, 6 and 21.

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

PubMed Central

Parker, Margaret M.; Chen, Han; Lao, Taotao; Hardin, Megan; Qiao, Dandi; Hawrylkiewicz, Iwona; Sliwinski, Pawel; Yim, Jae-Joon; Kim, Woo Jin; Kim, Deog Kyeom; Castaldi, Peter J.; Hersh, Craig P.; Morrow, Jarrett; Celli, Bartolome R.; Pinto-Plata, Victor M.; Criner, Gerald J.; Marchetti, Nathaniel; Bueno, Raphael; Agustí, Alvar; Make, Barry J.; Crapo, James D.; Calverley, Peter M.; Donner, Claudio F.; Lomas, David A.; Wouters, Emiel F. M.; Vestbo, Jorgen; Paré, Peter D.; Levy, Robert D.; Rennard, Stephen I.; Zhou, Xiaobo; Laird, Nan M.; Lin, Xihong; Beaty, Terri H.; Silverman, Edwin K.

2016-01-01

Rationale: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. Objectives: To identify coding variants associated with COPD. Methods: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. Measurements and Main Results: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10−14) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10−6) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10−8) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. Conclusions: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis. PMID:26771213

Limited sampling strategy for determining metformin area under the plasma concentration–time curve

PubMed Central

Santoro, Ana Beatriz; Stage, Tore Bjerregaard; Struchiner, Claudio José; Christensen, Mette Marie Hougaard; Brosen, Kim

2016-01-01

Aim The aim was to develop and validate limited sampling strategy (LSS) models to predict the area under the plasma concentration–time curve (AUC) for metformin. Methods Metformin plasma concentrations (n = 627) at 0–24 h after a single 500 mg dose were used for LSS development, based on all subsets linear regression analysis. The LSS‐derived AUC(0,24 h) was compared with the parameter ‘best estimate’ obtained by non‐compartmental analysis using all plasma concentration data points. Correlation between the LSS‐derived and the best estimated AUC(0,24 h) (r 2), bias and precision of the LSS estimates were quantified. The LSS models were validated in independent cohorts. Results A two‐point (3 h and 10 h) regression equation with no intercept estimated accurately the individual AUC(0,24 h) in the development cohort: r 2 = 0.927, bias (mean, 95% CI) –0.5, −2.7–1.8% and precision 6.3, 4.9–7.7%. The accuracy of the two point LSS model was verified in study cohorts of individuals receiving single 500 or 1000 mg (r 2 = –0.933–0.934) or seven 1000 mg daily doses (r 2 = 0.918), as well as using data from 16 published studies covering a wide range of metformin doses, demographics, clinical and experimental conditions (r 2 = 0.976). The LSS model reproduced previously reported results for effects of polymorphisms in OCT2 and MATE1 genes on AUC(0,24 h) and renal clearance of metformin. Conclusions The two point LSS algorithm may be used to assess the systemic exposure to metformin under diverse conditions, with reduced costs of sampling and analysis, and saving time for both subjects and investigators. PMID:27324407

Safety Study: Intraventricular Injection of a Modified Oncolytic Measles Virus into Measles-Immune, hCD46-Transgenic, IFNαRko Mice.

PubMed

Lal, Sangeet; Peng, Kah-Whye; Steele, Michael B; Jenks, Nathan; Ma, Hong; Kohanbash, Gary; Phillips, Joanna J; Raffel, Corey

2016-12-01

The modified Edmonston vaccine strain of measles virus (MV) has shown potent oncolytic efficacy against various tumor types and is being investigated in clinical trials. Our laboratory showed that MV effectively kills medulloblastoma tumor cells in both localized disease and when tumor cells are disseminated through cerebrospinal fluid (CSF). Although the safety of repeated intracerebral injection of modified MV in rhesus macaques has been established, the safety of administering MV into CSF has not been adequately investigated. In this study, we assessed the safety of MV-NIS (MV modified to express the human sodium iodide symporter protein) injected into the CSF of measles-immunized and measles virus-susceptible transgenic (CD46, IFNαRko) mice. Treated animals were administered a single intraventricular injection of 1 × 10 5 or 1 × 10 6 TCID 50 (50% tissue culture infective dose) of MV-NIS. Detailed clinical observation was performed over a 90-day period. Clinically, we did not observe any measles-related toxic effects or behavioral abnormality in animals of any treated cohort. The complete blood count and blood chemistry analysis results were found to be within normal range for all the cohorts. Histologic examination of brains and spinal cords revealed inflammatory changes, mostly related to the needle track; these resolved by day 21 postinjection. To assess viral biodistribution, quantitative RT-PCR to detect the measles virus N-protein was performed on blood and brain samples. Viral RNA was not detectable in the blood as soon as 2 days after injection, and virus cleared from the brain by 45 days postadministration in all treatment cohorts. In conclusion, our data suggest that a single injection of modified MV into the CSF is safe and can be used in future therapeutic applications.

No association of SORL1 SNPs with Alzheimer’s disease

PubMed Central

Minster, Ryan L.; DeKosky, Steven T.; Kamboh, M. Ilyas

2008-01-01

SORL1 is an element of the amyloid precursor protein processing pathway and is therefore a good candidate for affecting Alzheimer’s disease (AD) risk. Indeed, there have been reports of associations between variation in SORL1 and AD risk. We examined six statistically significant single-nucleotide polymorphisms from the initial observation in a large Caucasian American case–controls cohort (1000 late-onset AD [LOAD] cases and 1000 older controls). Analysis of allele, genotype and haplotype frequencies revealed no association with LOAD risk in our cohort. PMID:18562096

Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

PubMed Central

Shrine, Nick R. G.; Loehr, Laura R.; Zhao, Jing Hua; Manichaikul, Ani; Lopez, Lorna M.; Smith, Albert Vernon; Heckbert, Susan R.; Smolonska, Joanna; Tang, Wenbo; Loth, Daan W.; Curjuric, Ivan; Hui, Jennie; Latourelle, Jeanne C.; Henry, Amanda P.; Aldrich, Melinda; Bakke, Per; Beaty, Terri H.; Bentley, Amy R.; Borecki, Ingrid B.; Brusselle, Guy G.; Burkart, Kristin M.; Chen, Ting-hsu; Couper, David; Crapo, James D.; Davies, Gail; Dupuis, Josée; Franceschini, Nora; Gulsvik, Amund; Hancock, Dana B.; Harris, Tamara B.; Hofman, Albert; Imboden, Medea; James, Alan L.; Khaw, Kay-Tee; Lahousse, Lies; Launer, Lenore J.; Litonjua, Augusto; Liu, Yongmei; Lohman, Kurt K.; Lomas, David A.; Lumley, Thomas; Marciante, Kristin D.; McArdle, Wendy L.; Meibohm, Bernd; Morrison, Alanna C.; Musk, Arthur W.; Myers, Richard H.; North, Kari E.; Postma, Dirkje S.; Psaty, Bruce M.; Rich, Stephen S.; Rivadeneira, Fernando; Rochat, Thierry; Rotter, Jerome I.; Artigas, María Soler; Starr, John M.; Uitterlinden, André G.; Wareham, Nicholas J.; Wijmenga, Cisca; Zanen, Pieter; Province, Michael A.; Silverman, Edwin K.; Deary, Ian J.; Palmer, Lyle J.; Cassano, Patricia A.; Gudnason, Vilmundur; Barr, R. Graham; Loos, Ruth J. F.; Strachan, David P.; London, Stephanie J.; Boezen, H. Marike; Probst-Hensch, Nicole; Gharib, Sina A.; Hall, Ian P.; O’Connor, George T.; Tobin, Martin D.; Stricker, Bruno H.

2012-01-01

Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction. PMID:22837378

Asymmetry in gait pattern following bicondylar tibial plateau fractures-A prospective one-year cohort study.

PubMed

Elsoe, Rasmus; Larsen, Peter

2017-07-01

Despite the high number of studies evaluating outcomes following tibial plateau fractures, the literature lacks studies including the objective assessment of gait pattern. The purpose of the present study was to evaluate asymmetry in gait patterns at 12 months after frame removal following ring fixation of a tibial plateau fracture. The study design was a prospective cohort study. The primary outcome measurement was the gait patterns 12 months after frame removal measured with a pressure-sensitive mat. The mat registers footprints and present gait speed, cadence, as well as temporal and spatial parameters of the gait cycle. Gait patterns were compared to a healthy reference population. Twenty-three patients were included with a mean age of 54.4 years (32-78 years). Patients presented with a shorter step-length of the injured leg compared to the non-injured leg (asymmetry of 11.3%). Analysis of single-support showed shorter support time of the injured leg compared to the non-injured leg (asymmetry of 8.7%). Moreover, analysis of swing-time showed increased swing-time of the injured leg (asymmetry of 8.9%). Compared to a healthy reference population, increased asymmetry in all gait patterns was observed. The association between asymmetry and health-related quality of life (HRQOL) showed moderate associations (single-support: R=0.50, P=0.03; step-length: R=0.43, P=0.07; swing-time: R=0.46, P=0.05). Compared to a healthy reference population, gait asymmetry is common 12 months after frame removal in patients treated with external ring fixation following a tibial plateau fracture of the tibia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of a single-item screening question to detect limited health literacy in peritoneal dialysis patients.

PubMed

Jain, Deepika; Sheth, Heena; Bender, Filitsa H; Weisbord, Steven D; Green, Jamie A

2014-01-01

Studies have shown that a single-item question might be useful in identifying patients with limited health literacy. However, the utility of the approach has not been studied in patients receiving maintenance peritoneal dialysis (PD). We assessed health literacy in a cohort of 31 PD patients by administering the Rapid Estimate of Adult Literacy in Medicine (REALM) and a single-item health literacy (SHL) screening question "How confident are you filling out medical forms by yourself?" (Extremely, Quite a bit, Somewhat, A little bit, or Not at all). To determine the accuracy of the single-item question for detecting limited health literacy, we performed sensitivity and specificity analyses of the SHL and plotted the area under the receiver operating characteristic (AUROC) curve using the REALM as a reference standard. Using a cut-off of "Somewhat" or less confident, the sensitivity of the SHL for detecting limited health literacy was 80%, and the specificity was 88%. The positive likelihood ratio was 6.9. The SHL had an AUROC of 0.79 (95% confidence interval: 0.52 to 1.00). Our results show that the SHL could be effective in detecting limited health literacy in PD patients.

Genome-wide association study (GWAS) for molar-incisor hypomineralization (MIH).

PubMed

Kühnisch, Jan; Thiering, Elisabeth; Heitmüller, Daniela; Tiesler, Carla M T; Grallert, Harald; Heinrich-Weltzien, Roswitha; Hickel, Reinhard; Heinrich, Joachim

2014-01-01

This genome-wide association study (GWAS) investigated the relationship between molar-incisor hypomineralization (MIH) and possible genetic loci. Clinical and genetic data from the 10-year follow-up of 668 children from the Munich GINI-plus and LISA-plus birth cohort studies were analyzed. The dental examinations included the diagnosis of MIH according to the criteria of the European Academy of Paediatric Dentistry (EAPD). Children with MIH were categorized as those with a minimum of one hypomineralized first permanent molar. A GWAS was implemented following a quality-control step and an additive genetic effect was assumed. A total of 2,013,491 single-nucleotide polymorphisms (SNPs) were available for analysis. Rs13058467, which is located near the SCUBE1 gene on chromosome 22 (p < 3.72E-7), was identified as a possible locus linked to MIH when using a threshold of p value <1E-6. After considering the limitations of the present study (e.g., limited sample size and lack of an independent replication sample), it can be concluded that (1) replication analyses in an independent cohort study are strongly recommended and (2) large-scale and well-powered studies are needed to investigate a possible genetic link to MIH.

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

PubMed

Vogl, Dan T; Martin, Thomas G; Vij, Ravi; Hari, Parameswaran; Mikhael, Joseph R; Siegel, David; Wu, Ka Lung; Delforge, Michel; Gasparetto, Cristina

2017-08-01

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m 2 . Dose-limiting toxicities (DLTs) at 2.4 mg/m 2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

The Association Between Clusterin and APOE Polymorphisms and Late-Onset Alzheimer Disease in a Turkish Cohort.

PubMed

Alaylıoğlu, Merve; Gezen-Ak, Duygu; Dursun, Erdinç; Bilgiç, Başar; Hanağası, Haşmet; Ertan, Turan; Gürvit, Hakan; Emre, Murat; Eker, Engin; Uysal, Ömer; Yılmazer, Selma

2016-07-01

Previous studies have demonstrated that clusterin (CLU), which is also known as apolipoprotein J, is involved in the pathogenesis of Alzheimer disease (AD). In this study, we investigated the association between rs2279590, rs11136000, and rs9331888 single-nucleotide polymorphisms (SNPs) in CLU and apolipoprotein E (APOE) genotypes in a cohort of Turkish patients with late-onset AD (LOAD). There were 183 patients with LOAD and 154 healthy controls included in the study. The CLU and APOE polymorphisms were genotyped using the LightSNiP assay. The "GG" genotype of rs9331888 was significantly more frequent in patients with LOAD. The "CC" genotype of the SNP was significantly more frequent in controls. The rs9331888 "GG" genotype in patients and the "CC" genotype in controls were significantly higher in non-∊4 allele carriers of APOE The haplotype analysis showed the CLU "GCG" haplotype was a risk haplotype. Our findings indicate the rs9331888 SNP of CLU is associated with LOAD independent of APOE. © The Author(s) 2016.

A clinical prognostic model compared to the newly adopted UICC staging in an independent validation cohort of P16 negative/positive head and neck cancer patients.

PubMed

Rasmussen, Jacob H; Håkansson, Katrin; Rasmussen, Gregers B; Vogelius, Ivan R; Friborg, Jeppe; Fischer, Barbara M; Bentzen, Søren M; Specht, Lena

2018-06-01

A previously published prognostic model in patients with head and neck squamous cell carcinoma (HNSCC) was validated in both a p16-negative and a p16-positive independent patient cohort and the performance was compared with the newly adopted 8th edition of the UICC staging system. Consecutive patients with HNSCC treated at a single institution from 2005 to 2012 were included. The cohort was divided in three. 1.) Training cohort, patients treated from 2005 to 2009 excluding patients with p16-positive oropharyngeal squamous cell carcinomas (OPSCC); 2.) A p16-negative validation cohort and 3.) A p16-positive validation cohort. A previously published prognostic model (clinical model) with the significant covariates (smoking status, FDG uptake, and tumor volume) was refitted in the training cohort and validated in the two validation cohorts. The clinical model was used to generate four risk groups based on the predicted risk of disease recurrence after 2 years and the performance was compared with UICC staging 8th edition using concordance index. Overall 568 patients were included. Compared to UICC the clinical model had a significantly better concordance index in the p16-negative validation cohort (AUC = 0.63 for UICC and AUC = 0.73 for the clinical model; p = 0.003) and a borderline significantly better concordance index in the p16-positive cohort (AUC = 0.63 for UICC and 0.72 for the clinical model; p = 0.088). The validated clinical model provided a better prognostication of risk of disease recurrence than UICC stage in the p16-negative validation cohort, and similar prognostication as the newly adopted 8th edition of the UICC staging in the p16-positive patient cohort. Copyright © 2018 Elsevier Ltd. All rights reserved.

Methodology Series Module 1: Cohort Studies

PubMed Central

Setia, Maninder Singh

2016-01-01

Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1) Framingham Cohort study, (2) Swiss HIV Cohort study, and (3) The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models) are useful in analysis of these studies. PMID:26955090

Methodology Series Module 1: Cohort Studies.

PubMed

Setia, Maninder Singh

2016-01-01

Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1) Framingham Cohort study, (2) Swiss HIV Cohort study, and (3) The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models) are useful in analysis of these studies.

Effects of physical activity calorie expenditure (PACE) labeling: study design and baseline sample characteristics.

PubMed

Viera, Anthony J; Tuttle, Laura; Olsson, Emily; Gras-Najjar, Julie; Gizlice, Ziya; Hales, Derek; Linnan, Laura; Lin, Feng-Chang; Noar, Seth M; Ammerman, Alice

2017-09-12

Obesity and physical inactivity are responsible for more than 365,000 deaths per year and contribute substantially to rising healthcare costs in the US, making clear the need for effective public health interventions. Calorie labeling on menus has been implemented to guide consumer ordering behaviors, but effects on calories purchased has been minimal. In this project, we tested the effect of physical activity calorie expenditure (PACE) food labels on actual point-of-decision food purchasing behavior as well as physical activity. Using a two-group interrupted time series cohort study design in three worksite cafeterias, one cafeteria was assigned to the intervention condition, and the other two served as controls. Calories from food purchased in the cafeteria were assessed by photographs of meals (accompanied by notes made on-site) using a standardized calorie database and portion size-estimation protocol. Primary outcomes will be average calories purchased and minutes of moderate to vigorous physical activity (MVPA) by individuals in the cohorts. We will compare pre-post changes in study outcomes between study groups using piecewise generalized linear mixed model regressions (segmented regressions) with a single change point in our interrupted time-series study. The results of this project will provide evidence of the effectiveness of worksite cafeteria menu labeling, which could potentially inform policy intervention approaches. Labels that convey information in a more readily understandable manner may be more effective at motivating behavior change. Strengths of this study include its cohort design and its robust data capture methods using food photographs and accelerometry.

Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.

PubMed

Chiriboga, Claudia A; Swoboda, Kathryn J; Darras, Basil T; Iannaccone, Susan T; Montes, Jacqueline; De Vivo, Darryl C; Norris, Daniel A; Bennett, C Frank; Bishop, Kathie M

2016-03-08

To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. Results from this study support continued development of nusinersen for treatment of SMA. This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. © 2016 American Academy of Neurology.

The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants.

PubMed

Meah, Farah A; DiMeglio, Linda A; Greenbaum, Carla J; Blum, Janice S; Sosenko, Jay M; Pugliese, Alberto; Geyer, Susan; Xu, Ping; Evans-Molina, Carmella

2016-06-01

The incidence of type 1 diabetes is increasing at a rate of 3-5% per year. Genetics cannot fully account for this trend, suggesting an influence of environmental factors. The accelerator hypothesis proposes an effect of metabolic factors on type 1 diabetes risk. To test this in the TrialNet Pathway to Prevention (PTP) cohort, we analysed the influence of BMI, weight status and insulin resistance on progression from single to multiple islet autoantibodies (Aab) and progression from normoglycaemia to diabetes. HOMA1-IR was used to estimate insulin resistance in Aab-positive PTP participants. Cox proportional hazards models were used to evaluate the effects of BMI, BMI percentile (BMI%), weight status and HOMA1-IR on the progression of autoimmunity or the development of diabetes. Data from 1,310 single and 1,897 multiple Aab-positive PTP participants were included. We found no significant relationships between BMI, BMI%, weight status or HOMA1-IR and the progression from one to multiple Aabs. Similarly, among all Aab-positive participants, no significant relationships were found between BMI, weight status or HOMA1-IR and progression to diabetes. Diabetes risk was modestly increased with increasing BMI% among the entire cohort, in obese participants 13-20 years of age and with increasing HOMA1-IR in adult Aab-positive participants. Analysis of the accelerator hypothesis in the TrialNet PTP cohort does not suggest a broad influence of metabolic variables on diabetes risk. Efforts to identify other potentially modifiable environmental factors should continue.

Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.

PubMed

Tönjes, Anke; Scholz, Markus; Krüger, Jacqueline; Krause, Kerstin; Schleinitz, Dorit; Kirsten, Holger; Gebhardt, Claudia; Marzi, Carola; Grallert, Harald; Ladenvall, Claes; Heyne, Henrike; Laurila, Esa; Kriebel, Jennifer; Meisinger, Christa; Rathmann, Wolfgang; Gieger, Christian; Groop, Leif; Prokopenko, Inga; Isomaa, Bo; Beutner, Frank; Kratzsch, Jürgen; Fischer-Rosinsky, Antje; Pfeiffer, Andreas; Krohn, Knut; Spranger, Joachim; Thiery, Joachim; Blüher, Matthias; Stumvoll, Michael; Kovacs, Peter

2018-02-01

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 × 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 × 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Issues in Design and Implementation in an Urban Birth Cohort Study: The Syracuse AUDIT Project

PubMed Central

Crawford, Judith A.; Hargrave, Teresa M.; Hunt, Andrew; Liu, Chien-Chih; Anbar, Ran D.; Hall, Geralyn E.; Naishadham, Deepa; Czerwinski, Maria H.; Webster, Noah; Lane, Sandra D.

2006-01-01

The Syracuse AUDIT (Assessment of Urban Dwellings for Indoor Toxics) project is a birth cohort study of wheezing in the first year of life in a low-income urban setting. Such studies are important because of the documented serious risks to children's health and the lack of attention and published work on asthma development and intervention in communities of this size. We studied 103 infants of mothers with asthma, living predominantly in inner-city households. Our study combines measurements of a large panel of indoor environmental agents, in-home infant assessments, and review of all prenatal and postnatal medical records through the first year of life. We found multiple environmental pollution sources and potential health risks in study homes including high infant exposure to tobacco smoke. The prevalence of maternal smoking during pregnancy was 54%; postnatal environmental tobacco smoke (ETS) exposure was nearly 90%. The majority (73%) of homes showed signs of dampness. Participants' lives were complicated by poverty, unemployment and single-parenthood. Thirty-three percent of fathers were not involved with their children, and 62% of subjects moved at least once during the study period. These socioeconomic issues had an impact on project implementation and led to modification of study eligibility criteria. Extensive outreach, follow up, and relationship-building were required in order to recruit and retain families and resulted in considerable work overload for study staff. Our experiences implementing the project will inform further studies on this and other similar populations. Future reports on this cohort will address the role of multiple environmental variables and their effects on wheezing outcome during the first year of life. PMID:16845500

Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index

PubMed Central

Minster, Ryan L.; Sanders, Jason L.; Singh, Jatinder; Kammerer, Candace M.; Barmada, M. Michael; Matteini, Amy M.; Zhang, Qunyuan; Wojczynski, Mary K.; Daw, E. Warwick; Brody, Jennifer A.; Arnold, Alice M.; Lunetta, Kathryn L.; Murabito, Joanne M.; Christensen, Kaare; Perls, Thomas T.; Province, Michael A.

2015-01-01

Background. The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. Methods. We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts. Results. There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10− 6) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24–p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest. Conclusions. ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity. PMID:25758594

A new approach for deciphering between single and multiple accumulation events using intra-tooth isotopic variations: Application to the Middle Pleistocene bone bed of Schöningen 13 II-4.

PubMed

Julien, Marie-Anne; Rivals, Florent; Serangeli, Jordi; Bocherens, Hervé; Conard, Nicholas J

2015-12-01

It is often difficult to differentiate between archaeological bonebeds formed by one event such as a mass kill of a single herd, and those formed by multiple events that occurred over a longer period of time. The application of high temporal resolution studies such as intra-tooth isotopic profiles on archaeological mammal cohorts offers new possibilities for exploring this issue, allowing investigators to decipher between single and multiple accumulation events. We examined (18)O and (13)C isotopic variations from the enamel carbonate of 23 horse third molars from the Middle Pleistocene archaeological site of Schöningen. We employed a new approach to investigate processes of fossil accumulation that uses both bulk and intra-tooth isotopic variations and takes into account animal behavior, age at death and dental development to test the degree of isotopic affinity of animals from the same fossil assemblage. Oxygen and carbon isotope bulk values indicate that the horses from Schöningen 13 II-4 experienced relatively similar climatic and dietary regimes. Inter-individual differences of the bulk values of the horses sampled in the current study present nevertheless inter-individual variability similar to individuals from multi-layered localities. In addition, the intra-tooth isotopic variation of specimens of the same age at death seems to indicate that the studied cohort corresponds to a mix of individuals that recorded both similar and different isotopic histories. Finally, the conditions recorded in the isotopic signal shortly before death (i.e., for teeth not fully mineralized) varied between sampled individuals, suggesting possible differences in the seasonality of death. Considering those results, we discuss the possibility that the horses from Schöningen 13 II-4 correspond to an accumulation of different death events. Copyright © 2015 Elsevier Ltd. All rights reserved.

The role of renin-angiotensin-aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

PubMed

Kelly, Tanika N; Raj, Dominic; Rahman, Mahboob; Kretzler, Matthias; Kallem, Radhakrishna R; Ricardo, Ana C; Rosas, Sylvia E; Tao, Kaixiang; Xie, Dawei; Hamm, Lotuce Lee; He, Jiang

2015-10-01

We conducted single-marker, gene- and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene- and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m(2)/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P < 1.00 × 10(-6)). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10(-6)). No single-marker associations with CKD progression were observed. The current study provides strong evidence for a role of the RAAS in CKD progression. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

The role of renin–angiotensin–aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study

PubMed Central

Kelly, Tanika N.; Raj, Dominic; Rahman, Mahboob; Kretzler, Matthias; Kallem, Radhakrishna R.; Ricardo, Ana C.; Rosas, Sylvia E.; Tao, Kaixiang; Xie, Dawei; Hamm, Lotuce Lee; He, Jiang; Appel, J.; Feldman, Harold I.; Go, Alan S.; Kusek, John W.; Lash, James P.; Ojo, Akinlolu; Townsend, Raymond R.

2015-01-01

Background We conducted single-marker, gene- and pathway-based analyses to examine the association between renin–angiotensin–aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. Methods A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene- and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Results Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m2/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P < 1.00 × 10−6). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10−6). No single-marker associations with CKD progression were observed. Conclusions The current study provides strong evidence for a role of the RAAS in CKD progression. PMID:25906781

The effect of leg dominance and landing height on ACL loading among female athletes.

PubMed

Mokhtarzadeh, Hossein; Ewing, Katie; Janssen, Ina; Yeow, Chen-Hua; Brown, Nicholas; Lee, Peter Vee Sin

2017-07-26

Female athletes are more prone to anterior cruciate ligament (ACL) injury. A neuromuscular imbalance called leg dominance may provide a biomechanical explanation. Therefore, the purpose of this study was to compare the side-to-side lower limb differences in movement patterns, muscle forces and ACL forces during a single-leg drop-landing task from two different heights. We hypothesized that there will be significant differences in lower limb movement patterns (kinematics), muscle forces and ACL loading between the dominant and non-dominant limbs. Further, we hypothesized that significant differences between limbs will be present when participants land from a greater drop-landing height. Eight recreational female participants performed dominant and non-dominant single-leg drop landings from 30 to 60cm. OpenSim software was used to develop participant-specific musculoskeletal models and to calculate muscle forces. We also predicted ACL loading using our previously established method. There were no significant differences between dominant and non-dominant leg landing except in ankle dorsiflexion and GMED muscle forces at peak GRF. Landing from a greater height resulted in significant differences among most kinetics and kinematics variables and ACL forces. Minimal differences in lower-limb muscle forces and ACL loading between the dominant and non-dominant legs during single-leg landing may suggest similar risk of injury across limbs in this cohort. Further research is required to confirm whether limb dominance may play an important role in the higher incidence of ACL injury in female athletes with larger and sport-specific cohorts. Copyright © 2017 Elsevier Ltd. All rights reserved.

Risk Factors for Mycobacterium abscessus subsp. bolletii infection after laparoscopic surgery during an outbreak in Brazil.

PubMed

Baruque Villar, Gabriela; de Mello Freitas, Felipe Teixeira; Pais Ramos, Jesus; Dias Campos, Carlos Eduardo; de Souza Caldas, Paulo Cesar; Santos Bordalo, Fernanda; Amorim Ramos, Tatyana Costa; do Nascimento Pereira, Vívian; Cordeiro-Santos, Marcelo; Abdalla Santos, Joao Hugo; Coelho Motta, Glauco; Gomes, Suzie Marie; Mendes de Souza, Verena Maria; de Araujo, Wildo Navegantes

2015-01-01

OBJECTIVE To identify risk factors related to Mycobacterium abscessus subsp. bolletii infection during an outbreak, associated with laparoscopic surgery and to propose recommendations for preventing new cases. DESIGN A retrospective cohort study. SETTING A private hospital in Manaus, Brazil. PATIENTS A cohort of 222 patients who underwent laparoscopic surgery between July 2009 and August 2010 by a single surgical team. METHODS We collected information about the patients and the surgical procedure using a standard form. We included sex, age, and variables with P≤0.2 in the bivariate analysis in a logistic regression model. Additionally, we reviewed the procedures for reprocessing the laparoscopic surgery equipment, and the strains obtained with culture were identified by molecular methods. RESULTS We recorded 60 (27%) cases of infection. After multivariate analysis, the duration of surgery beyond 1 hour (odds ratio [OR] 2.4; 95% confidence interval [CI] 1.2-4.5), not to have been the first operated patient on a given day (OR, 2.7; 95% CI, 1.4-5.2), and the use of permanent trocar (OR, 2.2; 95% CI, 1.1-4.2) were associated with infection. We observed that the surgical team attempted to sterilize the equipment in glutaraldehyde solution when sanitary authorities had already prohibited it. Eleven strains presented 100% DNA identity with a single strain, known as BRA100 clone. CONCLUSIONS Because contaminated material can act as vehicle for infection, ensuring adequate sterilization processing of video-assisted surgery equipment was crucial to stopping this single clonal outbreak of nonturbeculous mycobacteria in Brazil.

Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection.

PubMed

Fischer, Janett; Weber, Alexander N R; Böhm, Stephan; Dickhöfer, Sabine; El Maadidi, Souhayla; Deichsel, Danilo; Knop, Viola; Klinker, Hartwig; Möller, Bernd; Rasenack, Jens; Wang, Lisa; Sharma, Manu; Hinrichsen, Holger; Spengler, Ulrich; Buggisch, Peter; Sarrazin, Christoph; Pawlita, Michael; Waterboer, Tim; Wiese, Manfred; Probst-Müller, Elsbeth; Malinverni, Raffaele; Bochud, Pierre-Yves; Gardiner, Clair; O'Farrelly, Cliona; Berg, Thomas

2017-10-01

As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, TLR9 promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression. Therefore, the TLR9 SNPs and the interferon lambda 4 ( IFNL4 ) rs12979860 were genotyped in chronically HCV type 1 infected (n=333), in patients who spontaneously cleared the infection (n=161), in the Swiss HCV cohort (n=1057) and the well-characterised German (n=305) and Irish (n=198) 'anti-D' cohorts. Functional analyses were done with promoter reporter constructs of human TLR9 in B cells and assessing TLR9 mRNA levels in whole blood of healthy volunteers. The TLR9 rs187084 C allele was associated with spontaneous virus clearance in women of the study cohort (OR=2.15 (95% CI 1.18 to 3.90) p=0.012), of the Swiss HCV cohort (OR=2.06 (95% CI 1.02 to 4.18) p=0.044) and in both 'anti-D' cohorts (German: OR=2.01 (95% CI 1.14 to 3.55) p=0.016; Irish: OR=1.93 (95% CI 1.10 to 3.68) p=0.047). Multivariate analysis in the combined study and Swiss HCV cohorts supported the results (OR=1.99 (95% CI 1.30 to 3.05) p=0.002). Functional analyses revealed higher transcriptional activities for both TLR9 variants and an association of the C allele of rs5743836 with allele-specific TLR9 mRNA regulation by oestrogens in women. TLR9 promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Overall survival and the response to radiotherapy among molecular subtypes of breast cancer brain metastases treated with targeted therapies.

PubMed

Miller, Jacob A; Kotecha, Rupesh; Ahluwalia, Manmeet S; Mohammadi, Alireza M; Chao, Samuel T; Barnett, Gene H; Murphy, Erin S; Vogelbaum, Michael A; Angelov, Lilyana; Peereboom, David M; Suh, John H

2017-06-15

The current study was conducted to investigate survival and the response to radiotherapy among patients with molecular subtypes of breast cancer brain metastases treated with or without targeted therapies. Patients diagnosed with breast cancer brain metastases at a single tertiary care institution were included. The primary outcome was overall survival, whereas secondary outcomes included the cumulative incidences of distant intracranial failure, local failure, and radiation necrosis. Competing risks regression was used to model secondary outcomes. Within the study period, 547 patients presented with 3224 brain metastases and met inclusion criteria. Among patients with human epidermal growth factor receptor 2 (HER2)-amplified disease, 80% received HER2 antibodies and 38% received HER2/epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The median survival was significantly shorter in the basal cohort (8.4 months), and progressively increased in the luminal A (12.3 months), HER2-positive (15.4 months), and luminal B (18.8 months) cohorts (P<.001). Among patients with HER2-amplified disease, the median survival was extended with the use of both HER2 antibodies (17.9 months vs 15.1 months; P = .04) and TKIs (21.1 months vs 15.4 months; P = .03). The 12-month cumulative incidences of local failure among molecular subtypes were 6.0% in the luminal A cohort, 10.3% in the luminal B cohort, 15.4% in the HER2-positive cohort, and 9.9% in the basal cohort (P = .01). Concurrent HER2/epidermal growth factor receptor TKIs with stereotactic radiosurgery significantly decreased the 12-month cumulative incidence of local failure from 15.1% to 5.7% (P<.001). Molecular subtypes appear to be prognostic for survival and predictive of the response to radiotherapy. TKIs were found to improve survival and local control, and may decrease the rate of distant failure. To preserve neurocognition, these results support a paradigm of upfront radiosurgery and HER2-directed therapy in the HER2-amplified population, reserving whole-brain radiotherapy for salvage. Cancer 2017;123:2283-2293. © 2017 American Cancer Society. © 2017 American Cancer Society.

Multimodal neural correlates of cognitive control in the Human Connectome Project.

PubMed

Lerman-Sinkoff, Dov B; Sui, Jing; Rachakonda, Srinivas; Kandala, Sridhar; Calhoun, Vince D; Barch, Deanna M

2017-12-01

Cognitive control is a construct that refers to the set of functions that enable decision-making and task performance through the representation of task states, goals, and rules. The neural correlates of cognitive control have been studied in humans using a wide variety of neuroimaging modalities, including structural MRI, resting-state fMRI, and task-based fMRI. The results from each of these modalities independently have implicated the involvement of a number of brain regions in cognitive control, including dorsal prefrontal cortex, and frontal parietal and cingulo-opercular brain networks. However, it is not clear how the results from a single modality relate to results in other modalities. Recent developments in multimodal image analysis methods provide an avenue for answering such questions and could yield more integrated models of the neural correlates of cognitive control. In this study, we used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) to identify multimodal patterns of variation related to cognitive control. We used two independent cohorts of participants from the Human Connectome Project, each of which had data from four imaging modalities. We replicated the findings from the first cohort in the second cohort using both independent and predictive analyses. The independent analyses identified a component in each cohort that was highly similar to the other and significantly correlated with cognitive control performance. The replication by prediction analyses identified two independent components that were significantly correlated with cognitive control performance in the first cohort and significantly predictive of performance in the second cohort. These components identified positive relationships across the modalities in neural regions related to both dynamic and stable aspects of task control, including regions in both the frontal-parietal and cingulo-opercular networks, as well as regions hypothesized to be modulated by cognitive control signaling, such as visual cortex. Taken together, these results illustrate the potential utility of multi-modal analyses in identifying the neural correlates of cognitive control across different indicators of brain structure and function. Copyright © 2017 Elsevier Inc. All rights reserved.

Development and validation of visceral fat quantification as a surrogate marker for differentiation of Crohn's disease and intestinal tuberculosis.

PubMed

Yadav, Dawesh Prakash; Madhusudhan, Kumble Seetharama; Kedia, Saurabh; Sharma, Raju; Pratap Mouli, Venigalla; Bopanna, Sawan; Dhingra, Rajan; Pradhan, Rajesh; Goyal, Sandeep; Sreenivas, Vishnubhatla; Vikram, Naval K; Makharia, Govind; Ahuja, Vineet

2017-02-01

Crohn's disease (CD) and intestinal tuberculosis (ITB) have close phenotypic resemblance. Mesenteric fat (a component of visceral fat [VF]) hypertrophy and fat wrapping, which is visible radiologically as fibrofatty proliferation, is seen more commonly in CD than in ITB. The present study was conducted to study the role of VF in differentiating CD and ITB. Visceral fat area and subcutaneous (SC) fat area were measured on computed tomography in two cohorts (development and validation). VF/SC ratio was also calculated for all patients. In the development cohort, retrospective data collection was carried out for 75 patients with CD and ITB who were on follow-up from January 2012 to November 2014. In the validation cohort, 82 patients were recruited prospectively from December 2014 to December 2015 and were diagnosed as CD or ITB according to standard diagnostic criteria. Visceral fat area and VF/SC ratio were significantly higher in CD patients (n = 42: development, n = 46: validation) than in ITB patients (n = 33: development, n = 36: validation) in both the development (106.2 ± 63.5 vs 37.3 ± 22, P = <0.001; 1.1 ± 0.57 vs 0.43 ± 0.24, P = <0.001) and validation cohorts (102.2 ± 69.8 vs 55.8 ± 44.9, P = 0.01; 1.2 ± 0.68 vs 0.56 ± 0.33, P = <0.001). A cut-off of 0.63 for VF/SC ratio in the development cohort had a high sensitivity (82%) and specificity (81%) in differentiating CD and ITB. Similar sensitivity (81%) and specificity (78%) were seen when this cut-off was applied in the validation cohort. The VF/SC ratio is a simple, cost-effective, non-invasive and single objective parameter with a good sensitivity and specificity to differentiate CD and ITB. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Can teaching research methodology influence students' attitude toward science? Cohort study and nonrandomized trial in a single medical school.

PubMed

Vujaklija, Ana; Hren, Darko; Sambunjak, Dario; Vodopivec, Ivana; Ivanis, Ana; Marusić, Ana; Marusić, Matko

2010-02-01

Medical teaching aims to develop attitudes and behaviors underlying professional competence of future physicians. We investigated whether a mandatory course on scientific methodology in the second study year could affect students' attitudes toward science in medicine. In a longitudinal study, students (n = 241) enrolling in 2001-2002 academic year at a single medical school were followed up until graduation in 2006-2007. Each year, they filled out a Likert-type questionnaire of 18 statements evaluating attitude toward science. Direct influence of the course on students' attitudes was tested in a nonrandomized controlled trial with the 2006-2007 second year student cohort. Positive students' attitudes toward science increased during study years (mean [SD] score of the maximum score of 90): from 57.6 (6.0) in the first to 69.8 (10.4) in the sixth year. There was a significant trend of increase in attitudes with the years of study (cubic trend by polynomial contrasts analysis, P = 0.011). Attendance of a course on research methodology significantly increased positive attitudes (score, 67.0 [7.0] before and 70.8 [7.5] after course, P = 0.032 vs control group), regardless of grade point average. The intervention had an effect even when the influence of the initial attitude was accounted for (F1,140 = 9.25, P = 0.003; analysis of covariance). The attitude changes after the course was greatest in students with low initial attitude scores (Spearman rinitial score, score difference, -0.44). Medical students have positive attitudes toward science and scientific method in medicine. Attendance of a course on research methodology had positive short-term effect on students' attitudes toward science. This positive effect should be maintained by vertical integration of the course in the medical curriculum.

Curative Treatment of Stage I Non-Small-Cell Lung Cancer in Patients With Severe COPD: Stereotactic Radiotherapy Outcomes and Systematic Review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palma, David, E-mail: david.palma@uwo.ca; Division of Radiation Oncology, London Regional Cancer Program, London, Ontario; Lagerwaard, Frank

2012-03-01

Objectives: Patients with severe chronic obstructive pulmonary disease (COPD) have a high risk of lung cancer and of postsurgical complications. We studied outcomes after stereotactic body radiotherapy (SBRT) in patients with severe COPD, as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, and performed a systematic review of the literature on outcomes after SBRT or surgery in these patients. Methods: A single-institution cohort of 176 patients with COPD GOLD III-IV and Stage I non-small-cell lung cancer (NSCLC) treated with SBRT was evaluated. A systematic review identified studies reporting outcomes after SBRT or surgery for Stage I NSCLCmore » in patients with GOLD III-IV or a predicted postoperative forced expiratory volume in 1 second (FEV1) of {<=}40%. Results: In the single-institution cohort, median follow-up was 21 months and median overall survival (OS) was 32 months. Actuarial 3-year local control was 89%, and 1- and 3-year OS were 79% and 47%, respectively. COPD severity correlated with OS (p = 0.01). The systematic review identified four other studies (two surgical, two SBRT, n = 196 patients). SBRT studies were published more recently and included older patients than surgical studies. Mean 30-day mortality was 0% post-SBRT and 10% after surgery. Local or locoregional control was high ({>=}89%) after both treatments. Post-SBRT, actuarial OS was 79-95% at 1 year and 43-70% at 3 years. Postsurgical actuarial OS was 45-86% at 1 year and 31-66% at 3 years. Conclusions: SBRT and surgery differ in risk of 30-day mortality in patients with severe COPD. Despite the negative selection of SBRT patients, survival at 1 and 3 years is comparable between the two treatments.« less

Risk of Human Papillomavirus (HPV) Infection and Cervical Neoplasia after Pregnancy.

PubMed

Trottier, Helen; Mayrand, Marie-Hélène; Baggio, Maria Luiza; Galan, Lenice; Ferenczy, Alex; Villa, Luisa L; Franco, Eduardo L

2015-10-07

Parity is well established as a risk factor for cervical cancer. It is not clear, however, how pregnancy influences the natural history of HPV infection and cervical neoplasia. Our objective was to study the risk of HPV infection and cervical squamous intraepithelial lesions (SIL) after pregnancy. We used the Ludwig-McGill cohort study which includes 2462 women recruited in Sao Paulo, Brazil in 1993-97 and followed for up to 10 years. Cellular specimens were collected every 4-6 months for Pap cytology and HPV detection and genotyping by a polymerase chain reaction protocol. Study nurses recorded pregnancy occurrence during follow-up. HPV and Pap results from pregnant women were available before and after, but not during pregnancy. The associations between pregnancy and post-partum HPV infection/SIL were studied using generalized estimating equation models with logistic link. Adjusted odds ratios (OR) were estimated with empirical adjustment for confounding. We recorded 122 women with a history of pregnancy during follow-up. Of these, 29 reintegrated the cohort study after delivery. No association between HPV and pregnancy was found. A single SIL case (high grade SIL) occurred post-partum. Likewise, there was no association between pregnancy and risk of low grade SIL or any-grade SIL at the next visit (adjusted OR = 0.84, 95 % CI: 0.46-15.33) after controlling for confounders. No associations were found between pregnancy and HPV or LSIL. The single observed case of HSIL post-partum was more than would be expected based on the rate of these abnormalities among non-pregnant women. As this association was found with only one case, caution is required in the interpretation of these results.

Whole-brain background-suppressed pCASL MRI with 1D-accelerated 3D RARE Stack-Of-Spirals readout

PubMed Central

Vidorreta, Marta; Wang, Ze; Chang, Yulin V.; Wolk, David A.; Fernández-Seara, María A.; Detre, John A.

2017-01-01

Arterial Spin Labeled (ASL) perfusion MRI enables non-invasive, quantitative measurements of tissue perfusion, and has a broad range of applications including brain functional imaging. However, ASL suffers from low signal-to-noise ratio (SNR), limiting image resolution. Acquisitions using 3D readouts are optimal for background-suppression of static signals, but can be SAR intensive and typically suffer from through-plane blurring. In this study, we investigated the use of accelerated 3D readouts to obtain whole-brain, high-SNR ASL perfusion maps and reduce SAR deposition. Parallel imaging was implemented along the partition-encoding direction in a pseudo-continuous ASL sequence with background-suppression and 3D RARE Stack-Of-Spirals readout, and its performance was evaluated in three small cohorts. First, both non-accelerated and two-fold accelerated single-shot versions of the sequence were evaluated in healthy volunteers during a motor-photic task, and the performance was compared in terms of temporal SNR, GM-WM contrast, and statistical significance of the detected activation. Secondly, single-shot 1D-accelerated imaging was compared to a two-shot accelerated version to assess benefits of SNR and spatial resolution for applications in which temporal resolution is not paramount. Third, the efficacy of this approach in clinical populations was assessed by applying the single-shot 1D-accelerated version to a larger cohort of elderly volunteers. Accelerated data demonstrated the ability to detect functional activation at the subject level, including cerebellar activity, without loss in the perfusion signal temporal stability and the statistical power of the activations. The use of acceleration also resulted in increased GM-WM contrast, likely due to reduced through-plane partial volume effects, that were further attenuated with the use of two-shot readouts. In a clinical cohort, image quality remained excellent, and expected effects of age and sex on cerebral blood flow could be detected. The sequence is freely available upon request for academic use and could benefit a broad range of cognitive and clinical neuroscience research. PMID:28837640

Genetic association between Interleukin-17A gene polymorphisms and the pathogenesis of Graves' disease in the Han Chinese population.

PubMed

Qi, Yicheng; Zheng, Huan; Liu, Nan; Guo, Ting; Zhu, Wei; Wang, Shu; Cui, Bin; Ning, Guang

2015-01-19

Graves' disease, one of the commonest autoimmune disorders, has a complex genetic basis. Interleukin-17A (IL-17A) is an important cytokine involved in innate and adaptive immune responses. This case-control study sought to investigate genetic association between the IL-17A gene and the process of Graves' disease (GD). Our pilot study was performed on a cohort from Shanghai, which included 713 patients with GD and 756 healthy controls. A replicate cohort was from Xiamen, recruiting 444 patients with GD and 427 healthy subjects. Six single nucleotide polymorphisms (SNPs) (rs4711998, rs3819024, rs2275913, rs8193037, rs3819025 and rs3748067) within the IL-17A gene were genotyped by the SNPstream Genotyping Systems and Taqman PCR method. In Shanghai cohorts, the frequencies of rs8193037 alleles were strongly different between patients with Graves' disease (G, 87·6% and A, 12·4%) and healthy controls (G, 91·4% and A, 8·6%) (P = 0·00067). The A carriers were associated with increased Graves' disease risks when compared with the G carriers (OR = 1·51, 95%CI = 1·19-1·92). In replicate cohorts, the proportion of individuals carrying the A allele of rs8193037 was significantly higher in patients with Graves' disease than in controls [Graves' disease vs control, 14·3% vs 9·1%, OR = 1·66 (95% CI: 1·23-2·24), P allele  = 0·0082]. In addition, rs8193037 and rs3748067 were found to be different in both genotype and allele distributions in Graves' disease-associated ophthalmopathy patients and controls in Shanghai cohorts. Haplotype association analysis also identified five main haplotypes of those six SNPs. These results suggested that the polymorphism of IL-17A rs8193037 was strongly associated with Graves' disease susceptibility in the Chinese Han population.z. © 2015 John Wiley & Sons Ltd.

INCREASE IN SINGLE-TABLET REGIMEN USE AND ASSOCIATED IMPROVEMENTS IN ADHERENCE-RELATED OUTCOMES IN HIV-INFECTED WOMEN

PubMed Central

HANNA, DAVID B.; HESSOL, NANCY A.; GOLUB, ELIZABETH T.; COCOHOBA, JENNIFER M.; COHEN, MARDGE H.; LEVINE, ALEXANDRA M.; WILSON, TRACEY E.; YOUNG, MARY; ANASTOS, KATHRYN; KAPLAN, ROBERT C.

2014-01-01

Introduction The use of single-tablet ART regimens and its implications on adherence among HIV-infected women have not been well-described. Methods Participants were enrolled in the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women. We examined semiannual trends in single-tablet regimen use and ART adherence, defined as self-reported 95% adherence in the past 6 months, during 2006–2013. In a nested cohort study, we assessed the comparative effectiveness of a single-tablet versus a multiple-tablet regimen with respect to adherence, virologic suppression, quality of life, and AIDS-defining events, using propensity score matching to account for demographic, behavioral, and clinical confounders. We also examined these outcomes in a subset of women switching from a multiple- to single-tablet regimen, using a case-crossover design. Results 15,523 person-visits, representing 1,727 women (53% black, 29% Hispanic, 25% IDU, median age 47), were included. Use of single-tablet regimens among ART users increased from 7% in 2006 to 27% in 2013; adherence increased from 78% to 85% during the same period (both p<0.001). Single-tablet regimen use was significantly associated with increased adherence (adjusted RR 1.05, 95% CI 1.03–1.08) and virologic suppression (RR 1.06, 95% CI 1.01–1.11), while associations with improved quality of life and fewer AIDS-defining events did not achieve statistical significance. Similar findings were observed among the subset of switchers. Conclusion Single-tablet regimen use was associated with increased adherence and virologic suppression. Despite this, 15% of women prescribed ART were still not optimally adherent; additional interventions are needed to maximize therapeutic benefits. PMID:24326606

Increase in single-tablet regimen use and associated improvements in adherence-related outcomes in HIV-infected women.

PubMed

Hanna, David B; Hessol, Nancy A; Golub, Elizabeth T; Cocohoba, Jennifer M; Cohen, Mardge H; Levine, Alexandra M; Wilson, Tracey E; Young, Mary; Anastos, Kathryn; Kaplan, Robert C

2014-04-15

The use of single-tablet antiretroviral therapy (ART) regimens and its implications on adherence among HIV-infected women have not been well described. Participants were enrolled in the Women's Interagency HIV Study, a longitudinal study of HIV infection in US women. We examined semiannual trends in single-tablet regimen use and ART adherence, defined as self-reported 95% adherence in the past 6 months, during 2006-2013. In a nested cohort study, we assessed the comparative effectiveness of a single-tablet versus a multiple-tablet regimen with respect to adherence, virologic suppression, quality of life, and AIDS-defining events, using propensity score matching to account for demographic, behavioral, and clinical confounders. We also examined these outcomes in a subset of women switching from a multiple- to single-tablet regimen using a case-crossover design. We included 15,523 person-visits, representing 1727 women (53% black, 29% Hispanic, 25% IDU, median age 47). Use of single-tablet regimens among ART users increased from 7% in 2006% to 27% in 2013; adherence increased from 78% to 85% during the same period (both P < 0.001). Single-tablet regimen use was significantly associated with increased adherence (adjusted risk ratio: 1.05; 95% confidence interval: 1.03 to 1.08) and virologic suppression (risk ratio: 1.06; 95% confidence interval: 1.01 to 1.11), while associations with improved quality of life and fewer AIDS-defining events did not achieve statistical significance. Similar findings were observed among the subset of switchers. Single-tablet regimen use was associated with increased adherence and virologic suppression. Despite this, 15% of women prescribed ART were still not optimally adherent; additional interventions are needed to maximize therapeutic benefits.

Study designs for determining and comparing sensitivities of disease screening tests.

PubMed

Prorok, Philip C; Kramer, Barnett S; Miller, Anthony B

2015-12-01

To investigate the capability of various study designs to determine the sensitivity of a disease screening test. Quantities that can be calculated from these designs were derived and examined for their relationship to true sensitivity (the ability to detect unrecognized disease that would surface clinically in the absence of screening) and overdiagnosis. To examine the sensitivity of one test, the single cohort design, in which all participants receive the test, is particularly weak, providing only an upper bound on the true sensitivity, and yields no information about overdiagnosis. A randomized design, with one control arm and participants tested in the other, that includes sufficient post-screening follow-up, allows calculation of bounds on, and an approximation to, true sensitivity and also determination of overdiagnosis. Without follow-up, bounds on the true sensitivity can be calculated. To compare two tests, the single cohort paired design in which all participants receive both tests is precarious. The three arm randomized design with post screening follow-up is preferred, yielding an approximation to the true sensitivity, bounds on the true sensitivity, and the extent of overdiagnosis of each test. Without post screening follow-up, bounds on the true sensitivities can be calculated. When an unscreened control arm is not possible, the two-arm randomized design is recommended. Individual test sensitivities cannot be determined, but with sufficient post-screening follow-up, an order relationship can be established, as can the difference in overdiagnosis between the two tests. © The Author(s) 2015.

Monitoring of fetal radiation exposure during pregnancy.

PubMed

Chandra, Venita; Dorsey, Chelsea; Reed, Amy B; Shaw, Palma; Banghart, Dawn; Zhou, Wei

2013-09-01

One unique concern of vascular surgeons and trainees is radiation exposure associated with increased endovascular practice. The safety of childbearing is a particular worry for current and future women in vascular surgery. Little is known regarding actual fetal radiation exposure. This multi-institutional study aimed to evaluate the radiation dosages recorded on fetal dosimeter badges and compare them to external badges worn by the same cohort of women. All women who declared pregnancy with potential radiation exposure were required to wear two radiation monitors at each institution, one outside and the other inside the lead apron. Maternal (external) and fetal monitor dosimeter readings were analyzed. Maternal radiation exposures prior to, during, and postpregnancy were also assessed to determine any associated behavior modification. Eighty-one women declared pregnancy from 2008 to 2011 and 32 had regular radiation exposure during pregnancy. Maternal whole-body exposures ranged from 21-731 mrem. The average fetal dosimeter recordings for the cohort rounded to zero. Only two women had positive fetal dosimeter recordings; one had a single recording of 3 mrem and the other had a single recording of 7 mrem. There was no significant difference between maternal exposures prior to, during, and postpregnancy. Lack of knowledge of fetal radiation exposure has concerned many vascular surgeons, prompting them to wear double lead aprons during pregnancy, and perhaps prevented numerous other women from entering the field. Our study showed negligible radiation exposure on fetal monitoring suggesting that with the appropriate safety precautions, these concerns may be unwarranted. Published by Mosby, Inc.

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.

PubMed

Perez-Andreu, Virginia; Roberts, Kathryn G; Xu, Heng; Smith, Colton; Zhang, Hui; Yang, Wenjian; Harvey, Richard C; Payne-Turner, Debbie; Devidas, Meenakshi; Cheng, I-Ming; Carroll, William L; Heerema, Nyla A; Carroll, Andrew J; Raetz, Elizabeth A; Gastier-Foster, Julie M; Marcucci, Guido; Bloomfield, Clara D; Mrózek, Krzysztof; Kohlschmidt, Jessica; Stock, Wendy; Kornblau, Steven M; Konopleva, Marina; Paietta, Elisabeth; Rowe, Jacob M; Luger, Selina M; Tallman, Martin S; Dean, Michael; Burchard, Esteban G; Torgerson, Dara G; Yue, Feng; Wang, Yanli; Pui, Ching-Hon; Jeha, Sima; Relling, Mary V; Evans, William E; Gerhard, Daniela S; Loh, Mignon L; Willman, Cheryl L; Hunger, Stephen P; Mullighan, Charles G; Yang, Jun J

2015-01-22

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10(-8) in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 × 10(-9)). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10(-11)). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.