Prediction of remission of depression with clinical variables, neuropsychological performance, and serotonergic/dopaminergic gene polymorphisms.

PubMed

Gudayol-Ferré, Esteve; Herrera-Guzmán, Ixchel; Camarena, Beatriz; Cortés-Penagos, Carlos; Herrera-Abarca, Jorge E; Martínez-Medina, Patricia; Asbun-Bojalil, Juan; Lira-Islas, Yuridia; Reyes-Ponce, Celia; Guàrdia-Olmos, Joan

2012-11-01

The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms on the prediction of depression remission after 12 weeks' treatment with fluoxetine. These variables have been studied as potential predictors of depression remission, but they present poor prognostic sensitivity and specificity by themselves. Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluxetine treatment. Only the La allele of rs25531 polymorphism and the GG and AA forms of the val 108/158 Met polymorphism predict major depressive disorder remission after 12 weeks' treatment with fluoxetine. None of the clinical and neuropsychological variables studied predicted remission. Our results suggest that clinical and neuropsychological variables can initially predict early response to fluoxetine and mask the predictive role of genetic variables; but in remission, where clinical and neuropsychological symptoms associated with depression tend to disappear thanks to the treatment administered, the polymorphisms studied are the only variables in our model capable of predicting remission. However, placebo effects that are difficult to control require cautious interpretation of the results.

99mTc-sestamibi scintigraphy used to evaluate tumor response to neoadjuvant chemotherapy in locally advanced breast cancer: A quantitative analysis

PubMed Central

KOGA, KATIA HIROMOTO; MORIGUCHI, SONIA MARTA; NETO, JORGE NAHÁS; PERES, STELA VERZINHASSE; SILVA, EDUARDO TINÓIS DA; SARRI, ALMIR JOSÉ; MICHELIN, ODAIR CARLITO; MARQUES, MARIANGELA ESTHER ALENCAR; GRIVA, BEATRIZ LOTUFO

2010-01-01

To evaluate the tumor response to neoadjuvant chemotherapy, 99mTc-sestamibi breast scintigraphy was proposed as a quantitative method. Fifty-five patients with ductal carcinoma were studied. They underwent breast scintigraphy before and after neoadjuvant chemotherapy, along with clinical assessment and surgical specimen analysis. The regions of interest on the lesion and contralateral breast were identified, and the pixel counts were used to evaluate lesion uptake in relation to background radiation. The ratio of these counts before to after neoadjuvant chemotherapy was assessed. The decrease in uptake rate due to chemotherapy characterized the scintigraphy tumor response. The Kruskal-Wallis test was used to compare the mean scintigraphic tumor response and histological type. Dunn’s multiple comparison test was used to detect differences between histological types. The Mann-Whitney test was used to compare means between quantitative and qualitative variables: scintigraphic tumor response vs. clinical response and uptake before chemotherapy vs. scintigraphic tumor response. The Spearman’s test was used to correlate the quantitative variables of clinical reduction in tumor size and scintigraphic tumor response. All of the variables compared presented significant differences. The change in 99mTc-sestamibi uptake noted on breast scintigraphy, before to after neoadjuvant chemotherapy, may be used as an effective method for evaluating the response to neoadjuvant chemotherapy, since this quantification reflects the biological behavior of the tumor towards the chemotherapy regimen. Furthermore, additional analysis on the uptake rate before chemotherapy may accurately predict treatment response. PMID:22966312

Psychosocial predictors of immune response following bone marrow transplantation.

PubMed

Pulgar, Ángeles; Garrido, Sergio; Alcalá, Antonio; Reyes del Paso, Gustavo A

2012-01-01

This study analyzed the relationship between some psychosocial variables (depression, anxiety, stress, coping strategies, social support, optimism, rationality, and need for harmony) and clinical parameters indicative of immunological response after bone marrow transplantation (BMT; day of engraftment, number of infections and hemoglobin level) while controlling for demographic variables (age, educative level, civil state, and time from cancer diagnosis). Thirty-one post BMT hematological cancer patients were evaluated. Results show that higher educative levels are associated to lower number of infections, while age is associated with a delay in the time of engraftment; coping strategies, specially redefinition of the situation, relaxation, stoicism and passivity, are positively associated with the three clinical indices; depression is positively associated to number of infections during the hospitalization period; and rationality is associated with lower hemoglobin levels. These results suggest that psychosocial variables, especially coping strategies, play an important role in determining the immunological response after BMT.

Growth hormone responsiveness: peak stimulated growth hormone levels and other variables in idiopathic short stature (ISS): data from the National Cooperative Growth Study.

PubMed

Moore, Wayne V; Dana, Ken; Frane, James; Lippe, Barbara

2008-09-01

In children with idiopathic short stature (ISS), growth hormone (GH) response to a provocative test will be inversely related to the first year response to hGH and be a variable accounting for a degree of responsiveness. Because high levels of GH are a characteristic of GH insensitivity, such as in Laron syndrome, it is possible that a high stimulated GH is associated with a lower first year height velocity among children diagnosed as having ISS. We examined the relationship between the peak stimulated GH levels in 3 ISS groups; GH >10 -<25, 25-40, and >40 ng/mL and the first year growth response to rhGH therapy. We also looked at 8 other predictor variables (age, sex, height SDS, height age, body mass index (BMI), bone age, dose, and SDS deficit from target parental height. Multiple regression analysis with the first year height as the dependent variable and peak stimulated GH was the primary endpoint. The predictive value of adding each of the other variables was then assessed. Mean change in height velocity was similar among the three groups, with a maximum difference among the groups of 0.6 cm/yr. There was a small but statistically significant correlation (r=-0.12) between the stimulated GH and first year height velocity. The small correlation between first year growth response and peak GH is not clinically relevant in defining GH resistance. No cut off level by peak GH could be determined to enhance the usefulness of this measure to predict response. Baseline age was the only clinically significant predictor, R-squared, 6.4%. All other variables contributed less than an additional 2% to the R-squared.

Development of a Core Clinical Dataset to Characterize Serious Illness, Injuries, and Resource Requirements for Acute Medical Responses to Public Health Emergencies.

PubMed

Murphy, David J; Rubinson, Lewis; Blum, James; Isakov, Alexander; Bhagwanjee, Statish; Cairns, Charles B; Cobb, J Perren; Sevransky, Jonathan E

2015-11-01

In developed countries, public health systems have become adept at rapidly identifying the etiology and impact of public health emergencies. However, within the time course of clinical responses, shortfalls in readily analyzable patient-level data limit capabilities to understand clinical course, predict outcomes, ensure resource availability, and evaluate the effectiveness of diagnostic and therapeutic strategies for seriously ill and injured patients. To be useful in the timeline of a public health emergency, multi-institutional clinical investigation systems must be in place to rapidly collect, analyze, and disseminate detailed clinical information regarding patients across prehospital, emergency department, and acute care hospital settings, including ICUs. As an initial step to near real-time clinical learning during public health emergencies, we sought to develop an "all-hazards" core dataset to characterize serious illness and injuries and the resource requirements for acute medical response across the care continuum. A multidisciplinary panel of clinicians, public health professionals, and researchers with expertise in public health emergencies. Group consensus process. The consensus process included regularly scheduled conference calls, electronic communications, and an in-person meeting to generate candidate variables. Candidate variables were then reviewed by the group to meet the competing criteria of utility and feasibility resulting in the core dataset. The 40-member panel generated 215 candidate variables for potential dataset inclusion. The final dataset includes 140 patient-level variables in the domains of demographics and anthropometrics (7), prehospital (11), emergency department (13), diagnosis (8), severity of illness (54), medications and interventions (38), and outcomes (9). The resulting all-hazard core dataset for seriously ill and injured persons provides a foundation to facilitate rapid collection, analyses, and dissemination of information necessary for clinicians, public health officials, and policymakers to optimize public health emergency response. Further work is needed to validate the effectiveness of the dataset in a variety of emergency settings.

Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication of MTHFR rs1801133 and ATIC rs4673993 Polymorphisms

PubMed Central

Lima, Aurea; Monteiro, Joaquim; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Seabra, Vitor; Medeiros, Rui

2014-01-01

Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment. PMID:24967362

Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project

PubMed Central

Kim, Youn H.; Tavallaee, Mahkam; Sundram, Uma; Salva, Katrin A.; Wood, Gary S.; Li, Shufeng; Rozati, Sima; Nagpal, Seema; Krathen, Michael; Reddy, Sunil; Hoppe, Richard T.; Nguyen-Lin, Annie; Weng, Wen-Kai; Armstrong, Randall; Pulitzer, Melissa; Advani, Ranjana H.; Horwitz, Steven M.

2015-01-01

Purpose In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored. Patients and Methods In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety. Results Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event. Conclusion Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin. PMID:26195720

The value of item response theory in clinical assessment: a review.

PubMed

Thomas, Michael L

2011-09-01

Item response theory (IRT) and related latent variable models represent modern psychometric theory, the successor to classical test theory in psychological assessment. Although IRT has become prevalent in the measurement of ability and achievement, its contributions to clinical domains have been less extensive. Applications of IRT to clinical assessment are reviewed to appraise its current and potential value. Benefits of IRT include comprehensive analyses and reduction of measurement error, creation of computer adaptive tests, meaningful scaling of latent variables, objective calibration and equating, evaluation of test and item bias, greater accuracy in the assessment of change due to therapeutic intervention, and evaluation of model and person fit. The theory may soon reinvent the manner in which tests are selected, developed, and scored. Although challenges remain to the widespread implementation of IRT, its application to clinical assessment holds great promise. Recommendations for research, test development, and clinical practice are provided.

Night-to-Night Sleep Variability in Older Adults With Chronic Insomnia: Mediators and Moderators in a Randomized Controlled Trial of Brief Behavioral Therapy (BBT-I)

PubMed Central

Chan, Wai Sze; Williams, Jacob; Dautovich, Natalie D.; McNamara, Joseph P.H.; Stripling, Ashley; Dzierzewski, Joseph M.; Berry, Richard B.; McCoy, Karin J.M.; McCrae, Christina S.

2017-01-01

Study Objectives: Sleep variability is a clinically significant variable in understanding and treating insomnia in older adults. The current study examined changes in sleep variability in the course of brief behavioral therapy for insomnia (BBT-I) in older adults who had chronic insomnia. Additionally, the current study examined the mediating mechanisms underlying reductions of sleep variability and the moderating effects of baseline sleep variability on treatment responsiveness. Methods: Sixty-two elderly participants were randomly assigned to either BBT-I or self-monitoring and attention control (SMAC). Sleep was assessed by sleep diaries and actigraphy from baseline to posttreatment and at 3-month follow-up. Mixed models were used to examine changes in sleep variability (within-person standard deviations of weekly sleep parameters) and the hypothesized mediation and moderation effects. Results: Variabilities in sleep diary-assessed sleep onset latency (SOL) and actigraphy-assessed total sleep time (TST) significantly decreased in BBT-I compared to SMAC (Pseudo R2 = .12, .27; P = .018, .008). These effects were mediated by reductions in bedtime and wake time variability and time in bed. Significant time × group × baseline sleep variability interactions on sleep outcomes indicated that participants who had higher baseline sleep variability were more responsive to BBT-I; their actigraphy-assessed TST, SOL, and sleep efficiency improved to a greater degree (Pseudo R2 = .15 to .66; P < .001 to .044). Conclusions: BBT-I is effective in reducing sleep variability in older adults who have chronic insomnia. Increased consistency in bedtime and wake time and decreased time in bed mediate reductions of sleep variability. Baseline sleep variability may serve as a marker of high treatment responsiveness to BBT-I. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT02967185 Citation: Chan WS, Williams J, Dautovich ND, McNamara JP, Stripling A, Dzierzewski JM, Berry RB, McCoy KJ, McCrae CS. Night-to-night sleep variability in older adults with chronic insomnia: mediators and moderators in a randomized controlled trial of brief behavioral therapy (BBT-I). J Clin Sleep Med. 2017;13(11):1243–1254. PMID:28992829

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics.

PubMed

Abubakar, Murtala B; Gan, Siew Hua

2016-01-01

The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effects and inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed. © 2016 S. Karger AG, Basel.

Warfarin therapy: in need of improvement after all these years

PubMed Central

Kimmel, Stephen E

2010-01-01

Background Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal. Objective To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy. Results Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions. Conclusion Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes. PMID:18345947

Improved Endpoints for Cancer Immunotherapy Trials

PubMed Central

Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd

2010-01-01

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737

Preload assessment and optimization in critically ill patients.

PubMed

Voga, Gorazd

2010-01-01

Preload assessment and optimization is the basic hemodynamic intervention in critically ill. Beside clinical assessment, non-invasive or invasive assessment by measurement of various pressure or volume hemodynamic variables, are helpful for estimation of preload and fluid responsiveness. The use of dynamic variables is useful in particular subgroup of critically ill patients. In patients with inadequate preload, fluid responsiveness and inadequate flow, treatment with crystalloids or colloids is mandatory. When rapid hemodynamic response is necessary colloids are preferred.

Cross-talk between clinical and host-response parameters of periodontitis in smokers.

PubMed

Nagarajan, R; Miller, C S; Dawson, D; Al-Sabbagh, M; Ebersole, J L

2017-06-01

Periodontal diseases are a major public health concern leading to tooth loss and have also been shown to be associated with several chronic systemic diseases. Smoking is a major risk factor for the development of numerous systemic diseases, as well as periodontitis. While it is clear that smokers have a significantly enhanced risk for developing periodontitis leading to tooth loss, the population varies regarding susceptibility to disease associated with smoking. This investigation focused on identifying differences in four broad sets of variables, consisting of: (i) host-response molecules; (ii) periodontal clinical parameters; (iii) antibody responses to periodontal pathogens and oral commensal bacteria; and (iv) other variables of interest, in a population of smokers with (n = 171) and without (n = 117) periodontitis. Bayesian network structured learning (BNSL) techniques were used to investigate potential associations and cross-talk between the four broad sets of variables. BNSL revealed two broad communities with markedly different topology between the populations of smokers, with and without periodontitis. Confidence of the edges in the resulting network also showed marked variations within and between the periodontitis and nonperiodontitis groups. The results presented validated known associations and discovered new ones with minimal precedence that may warrant further investigation and novel hypothesis generation. Cross-talk between the clinical variables and antibody profiles of bacteria were especially pronounced in the case of periodontitis and were mediated by the antibody response profile to Porphyromonas gingivalis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Defining drug response for stratified medicine.

PubMed

Lonergan, Mike; Senn, Stephen J; McNamee, Christine; Daly, Ann K; Sutton, Robert; Hattersley, Andrew; Pearson, Ewan; Pirmohamed, Munir

2017-01-01

The premise for stratified medicine is that drug efficacy, drug safety, or both, vary between groups of patients, and biomarkers can be used to facilitate more targeted prescribing, with the aim of improving the benefit:risk ratio of treatment. However, many factors can contribute to the variability in response to drug treatment. Inadequate characterisation of the nature and degree of variability can lead to the identification of biomarkers that have limited utility in clinical settings. Here, we discuss the complexities associated with the investigation of variability in drug efficacy and drug safety, and how consideration of these issues a priori, together with standardisation of phenotypes, can increase both the efficiency of stratification procedures and identification of biomarkers with the potential for clinical impact. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Influence of Cytochrome P450 Pharmacogenetics on Disposition of Common Antidepressant and Antipsychotic Medications

PubMed Central

van der Weide, Jan; Hinrichs, John WJ

2006-01-01

Since the identification of all the major drug-metabolising cytochrome P450 (CYP) enzymes and their major gene variants, pharmacogenetics has had a major impact on psychotherapeutic drug therapy. CYP enzymes are responsible for the metabolism of most clinically used drugs. Individual variability in CYP activity is an important reason for drug therapy failure. Variability in CYP activity may be caused by various factors, including endogenous factors such as age, gender and morbidity as well as exogenous factors such as co-medication, food components and smoking habit. However, polymorphisms, present in most CYP genes, are responsible for a substantial part of this variability. Although CYP genotyping has been shown to predict the majority of aberrant phenotypes, it is currently rarely performed in clinical practice. PMID:16886044

Use of Social Desirability Scales in Clinical Psychology: A Systematic Review.

PubMed

Perinelli, Enrico; Gremigni, Paola

2016-06-01

There is still an open debate about the utility of social desirability indicators. This report systematically reviewed the use of social desirability scales in studies addressing social desirability in clinical psychology. A systematic review (January 2010-March 2015) was conducted, including 35 studies meeting the inclusion criteria of being published in peer-reviewed journals and describing quantitative findings about an association of social desirability with clinical psychology variables using a cross-sectional or longitudinal design. Social desirability was associated with self-reports of various clinical-psychological dimensions. Most of the included studies treated social desirability as a 1-dimensional variable and only 10 of 35 disentangled the impression management and self-deception components. Although theoretical literature does not consider social desirability a mere response bias, only 4 of the reviewed articles controlled for the possible suppressor effect of personality variables on social desirability, while the majority focused upon the stylistic (response bias) rather than the substantive (personality) nature of this construct. The present review highlighted some limitations in the use of social desirability scales in recent clinical psychology research and tried to offer a few suggestions for handling this issue. © 2016 Wiley Periodicals, Inc.

Exploring psychological mechanisms of clinical response to an internet-delivered psychological pain management program.

PubMed

Gandy, M; Karin, E; Jones, M P; McDonald, S; Sharpe, L; Titov, N; Dear, B F

2018-05-13

The evidence for Internet-delivered pain management programs for chronic pain is growing, but there is little empirical understanding of how they effect change. Understanding mechanisms of clinical response to these programs could inform their effective development and delivery. A large sample (n = 396) from a previous randomized controlled trial of a validated internet-delivered psychological pain management program, the Pain Course, was used to examine the influence of three potential psychological mechanisms (pain acceptance, pain self-efficacy, fear of movement/re-injury) on treatment-related change in disability, depression, anxiety and average pain. Analyses involved generalized estimating equation models for clinical outcomes that adjusted for co-occurring change in psychological variables. This was paired with cross-lagged analysis to assess for evidence of causality. Analyses involved two time points, pre-treatment and post-treatment. Changes in pain-acceptance were strongly associated with changes in three (depression, anxiety and average pain) of the four clinical outcomes. Changes in self-efficacy were also strongly associated with two (anxiety and average pain) clinical outcomes. These findings suggest that participants were unlikely to improve in these clinical outcomes without also experiencing increases in their pain self-efficacy and pain acceptance. However, there was no clear evidence from cross-lagged analyses to currently support these psychological variables as direct mechanisms of clinical improvements. There was only statistical evidence to suggest higher levels of self-efficacy moderated improvements in depression. The findings suggest that, while clinical improvements are closely associated with improvements in pain acceptance and self-efficacy, these psychological variables may not drive the treatment effects observed. This study employed robust statistical techniques to assess the psychological mechanisms of an established internet-delivered pain management program. While clinical improvements (e.g. depression, anxiety, pain) were closely associated with improvements in psychological variables (e.g. pain self-efficacy and pain acceptance), these variables do not appear to be treatment mechanisms. © 2018 European Pain Federation - EFIC®.

Discerning strain effects in microbial dose-response data.

PubMed

Coleman, Margaret E; Marks, Harry M; Golden, Neal J; Latimer, Heejeong K

In order to estimate the risk or probability of adverse events in risk assessment, it is necessary to identify the important variables that contribute to the risk and provide descriptions of distributions of these variables for well-defined populations. One component of modeling dose response that can create uncertainty is the inherent genetic variability among pathogenic bacteria. For many microbial risk assessments, the "default" assumption used for dose response does not account for strain or serotype variability in pathogenicity and virulence, other than perhaps, recognizing the existence of avirulent strains. However, an examination of data sets from human clinical trials in which Salmonella spp. and Campylobacter jejuni strains were administered reveals significant strain differences. This article discusses the evidence for strain variability and concludes that more biologically based alternatives are necessary to replace the default assumptions commonly used in microbial risk assessment, specifically regarding strain variability.

Hit parade for adoptive cell transfer therapy: the best T cells for superior clinical responses.

PubMed

Speiser, Daniel E

2013-04-01

Adoptive cell transfer (ACT) of T cells has great clinical potential, but the numerous variables of this therapy make choices difficult. A new study takes advantage of a novel technology for characterizing the T-cell responses of patients. If applied systematically, this approach may identify biomedical correlates of protection, thereby supporting treatment optimization. ©2013 AACR.

Clinical Geneticists’ Views of VACTERL/VATER Association

PubMed Central

Solomon, Benjamin D.; Bear, Kelly A.; Kimonis, Virginia; de Klein, Annelies; Scott, Daryl A.; Shaw-Smith, Charles; Tibboel, Dick; Reutter, Heiko; Giampietro, Philip F.

2012-01-01

VACTERL association (sometimes termed “VATER association” depending on which component features are included) is typically defined by the presence of at least three of the following congenital malformations, which tend to statistically co-occur in affected individuals: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. Although the clinical criteria for VACTERL association may appear to be straightforward, there is wide variability in the way clinical geneticists define the disorder and the genetic testing strategy they use when confronted with an affected patient. In order to describe this variability and determine the most commonly used definitions and testing modalities, we present the results of survey responses by 121 clinical geneticists. We discuss the results of the survey responses, provide a literature review and commentary from a group of physicians who are currently involved in clinical and laboratory-based research on VACTERL association, and offer an algorithm for genetic testing in patients with this association. PMID:23165726

Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis.

PubMed

Hu, Chuanpu; Zhou, Honghui

2016-02-01

Improving the quality of exposure-response modeling is important in clinical drug development. The general joint modeling of multiple endpoints is made possible in part by recent progress on the latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate, when modeling a continuous and a categorical clinical endpoint, the level of improvement achievable by joint modeling in the latent variable IDR modeling framework through the sharing of model parameters for the individual endpoints, guided by the appropriate representation of drug and placebo mechanism. This was illustrated with data from two phase III clinical trials of intravenously administered mAb X for the treatment of rheumatoid arthritis, with the 28-joint disease activity score (DAS28) and 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria were used as efficacy endpoints. The joint modeling framework led to a parsimonious final model with reasonable performance, evaluated by visual predictive check. The results showed that, compared with the more common approach of separately modeling the endpoints, it is possible for the joint model to be more parsimonious and yet better describe the individual endpoints. In particular, the joint model may better describe one endpoint through subject-specific random effects that would not have been estimable from data of this endpoint alone.

Chronic inflammatory demyelinating polyneuropathy in children: a report of four patients with variable relapsing courses

PubMed Central

Chang, Soo Jin; Lee, Ji Hyun; Kim, Shin Hye; Lee, Joon Soo; Kim, Heung Dong; Kang, Joon Won; Lee, Young Mock

2015-01-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing symmetric sensorimotor disorder presumed to occur because of immunologic antibody-mediated reactions. To understand the clinical courses of CIDP, we report variable CIDP courses in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. Four patients who were diagnosed with acute-onset and relapsing CIDP courses at Severance Children's Hospital, Seoul, Korea, were enrolled in this retrospective study. We diagnosed each patient on the basis of the CIDP diagnostic criteria developed in 2010 by the European Federation of Neurological Societies/Peripheral Nerve Society Guidelines. We present the cases of four pediatric patients diagnosed with CIDP to understand the variable clinical course of the disease in children. Our four patients were all between 8 and 12 years of age. Patients 1 and 2 were diagnosed with acute cerebellar ataxia or Guillain-Barré syndrome as initial symptoms. While patients 1 and 4 were given only intravenous dexamethasone (0.3 mg/kg/day) for 5 days at the first episode, Patients 2 and 3 were given a combination of intravenous immunoglobulin (2 g/kg) and dexamethasone (0.3 mg/kg/day). All patients were maintained with oral prednisolone at 30 mg/day, but their clinical courses were variable in both relapse intervals and severity. We experienced variable clinical courses of CIDP in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. PMID:26124851

Chronic inflammatory demyelinating polyneuropathy in children: a report of four patients with variable relapsing courses.

PubMed

Chang, Soo Jin; Lee, Ji Hyun; Kim, Shin Hye; Lee, Joon Soo; Kim, Heung Dong; Kang, Joon Won; Lee, Young Mock; Kang, Hoon-Chul

2015-05-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing symmetric sensorimotor disorder presumed to occur because of immunologic antibody-mediated reactions. To understand the clinical courses of CIDP, we report variable CIDP courses in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. Four patients who were diagnosed with acute-onset and relapsing CIDP courses at Severance Children's Hospital, Seoul, Korea, were enrolled in this retrospective study. We diagnosed each patient on the basis of the CIDP diagnostic criteria developed in 2010 by the European Federation of Neurological Societies/Peripheral Nerve Society Guidelines. We present the cases of four pediatric patients diagnosed with CIDP to understand the variable clinical course of the disease in children. Our four patients were all between 8 and 12 years of age. Patients 1 and 2 were diagnosed with acute cerebellar ataxia or Guillain-Barré syndrome as initial symptoms. While patients 1 and 4 were given only intravenous dexamethasone (0.3 mg/kg/day) for 5 days at the first episode, Patients 2 and 3 were given a combination of intravenous immunoglobulin (2 g/kg) and dexamethasone (0.3 mg/kg/day). All patients were maintained with oral prednisolone at 30 mg/day, but their clinical courses were variable in both relapse intervals and severity. We experienced variable clinical courses of CIDP in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval.

Recent developments in clopidogrel pharmacology and their relation to clinical outcomes.

PubMed

Gurbel, Paul A; Antonino, Mark J; Tantry, Udaya S

2009-08-01

Oral antiplatelet therapy with clopidogrel and aspirin is an important and widely prescribed strategy to prevent ischemic events in patients with cardiovascular diseases. However, the occurrence of thrombotic events including stent thrombosis is still high (> 10%). Current practice guidelines are mainly based on large-scale trials focusing on clinical endpoints and 'one size fits all' strategies of treating all patients with the same clopidogrel doses. Pharmacodynamic studies have demonstrated that the latter strategy is associated with wide response variability where a substantial percentage of patients show nonresponsivenes. Translational research studies have established the relation between clopidogrel nonresponsivenes or high on-treatment platelet reactivity to adverse clinical events, thereby establishing clopidogrel nonresponsivenes as an important emerging clinical entity. Clopidogrel response variability is primarily a pharmacokinetic phenomenon associated with insufficient active metabolite generation that is secondary to i) limited intestinal absorption affected by an ABCB1 gene polymorphism; ii) functional variability in P450 isoenzyme activity; and iii) a genetic polymorphism of CYP450 isoenzymes. Personalized antiplatelet treatment with higher clopidogrel doses in selected patients or with newer more potent P2Y(12) receptor blockers based on individual platelet function measurement can overcome some of the limitations of current clopidogrel treatment.

Changes in heart rate variability during TOVA testing in patients with major depressive disorder.

PubMed

Shen, Tsu-Wang; Liu, Fang-Chih; Chen, Shaw-Ji; Chen, Shao-Tsu

2013-01-01

The aim of this study was to identify major depressive disorder (MDD) based on heart rate variability (HRV) during tests of variables of attention (TOVA). Forty-five MDD patients without cardiovascular disease and 45 controls matched by age and gender participated in this study. Compared to the controls, the MDD group had lower resting HRV parameters, more omissions and variability and longer response times on TOVA, and failure of attention employment to decrease HRV. The resting HRV parameters may provide easily measured, clinically useful ways to identify patients with MDD and to monitor their progress in treatment. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

Cross-talk between Clinical and Host Response Parameters of Periodontitis in Smokers

PubMed Central

Nagarajan, R.; Miller, C.S.; Dawson, D.; Al-Sabbagh, M.; Ebersole, J.L.

2016-01-01

Periodontal diseases are a major public health concern leading to tooth loss and also shown to be associated with several chronic systemic diseases. Smoking is a major risk factor for developing numerous systemic diseases, as well as periodontitis. While it is clear that smokers have a significantly enhanced risk for developing periodontitis leading to tooth loss, the population varies with regards to susceptibility to disease associated with smoking. This investigation focuses on identifying differences in four broad sets of variables consisting of: (a) host response molecules, (b) periodontal clinical parameters, (c) antibody measures for periodontal pathogens and oral commensal bacteria challenge, and (d) other variables of interest in a smoking population with (n = 171) and without periodontitis (n = 117). Subsequently, Bayesian network structured learning techniques (BNSL) techniques were used to investigate potential associations and cross-talk between the four broad sets of variables. BNSL revealed two broad communities with markedly different topology between the non-periodontitis and periodontitis smoking population. Confidence of the edges in the resulting network also showed marked variations within and between the periodontitis and non-periodontitis groups. The results presented validated known associations, as well as discovered new ones with minimal precedence that may warrant further investigation and novel hypothesis generation. Cross-talk between the clinical variables and antibody profiles of bacteria were especially pronounced in the case of periodontitis and mediated by the antibody response profile to P. gingivalis. PMID:27431617

An assessment of antecedent events influencing noncompliance in an outpatient clinic.

PubMed Central

Call, Nathan A; Wacker, David P; Ringdahl, Joel E; Cooper-Brown, Linda J; Boeiter, Eric W

2004-01-01

Several studies have shown that various factors can influence noncompliance, including task novelty, rate of presentation, and task preference. This study examined the impact of selected antecedent variables on noncompliance in an outpatient clinic setting. In two experiments involving 6 typically developing children, the consequences for noncompliance remained constant. During Experiment 1, demands that included noncontingent access to adult attention were contrasted with the same demands that did not include attention within a multielement design. In Experiment 2, demands were altered by decreasing the difficulty or amount of work or providing access to attention. In both experiments, results indicated idiosyncratic responses to the manipulated variables, with decreases in noncompliance observed following introduction of one or more antecedent variables with 5 of the 6 participants. These results suggested that noncompliance can be reduced via changes in antecedent variables, including adding potential positive reinforcers to the task situation, and that it is possible to probe variables that alter noncompliance in an outpatient clinic setting. PMID:15293634

Influenza Vaccination in Patients with Common Variable Immunodeficiency (CVID).

PubMed

Mieves, Jan F; Wittke, Kirsten; Freitag, Helma; Volk, Hans-Dieter; Scheibenbogen, Carmen; Hanitsch, Leif G

2017-10-05

Vaccination against influenza in patients with primary antibody deficiency is recommended. Common variable immunodeficiency (CVID) is the most frequent and clinically relevant antibody deficiency disease and is by definition characterized by an impaired vaccination response. The purpose of this review is to present the current knowledge of humoral and cellular vaccine response to influenza in CVID patients. Studies conducted in CVID patients demonstrated an impaired humoral response upon influenza vaccination. Data on cellular immune response are in part conflicting, with two out of three studies showing responses similar to healthy controls. Available data suggest a benefit from influenza vaccination in CVID patients. Therefore, annual influenza vaccination in patients and their close household contacts is recommended.

Monoclonal protein reference change value as determined by gel-based serum protein electrophoresis.

PubMed

Salamatmanesh, Mina; McCudden, Christopher R; McCurdy, Arleigh; Booth, Ronald A

2018-01-01

The International Myeloma Working Group recommendations for monitoring disease progression or response include quantitation of the involved monoclonal immunoglobulin. They have defined the minimum change criteria of ≧25% with an absolute change of no <5g/L for either minimal response or progression. Limited evidence is available to accurately determine the magnitude of change in a monoclonal protein to reflect a true change in clinical status. Here we determined the analytical and biological variability of monoclonal proteins in stable monoclonal gammopathy of undetermined significance (MGUS) patients. Analytical variability (CVa) of normal protein fractions and monoclonal proteins were assessed agarose gel-based serum protein electrophoresis. Sixteen clinically stable MGUS patients were identified from our clinical hematology database. Individual biological variability (CVi) was determined and used to calculate a monoclonal protein reference change value (RCV). Analytical variability of the normal protein fractions (albumin, alpha-1, alpha-2, beta, total gamma) ranged from 1.3% for albumin to 5.8% for the alpha-1 globulins. CVa of low (5.6g/L) and high (32.2g/L) concentration monoclonal proteins were 3.1% and 22.2%, respectively. Individual CVi of stable patients ranged from 3.5% to 24.5% with a CVi of 12.9%. The reference change value (RCV) at a 95% probability was determined to be 36.7% (low) 39.6% (high) using our CVa and CVi. Serial monitoring of monoclonal protein concentration is important for MGUS and multiple myeloma patients. Accurate criteria for interpreting a change in monoclonal protein concentration are required for appropriate decision making. We used QC results and real-world conditions to assess imprecision of serum protein fractions including low and high monoclonal protein fractions and clinically stable MGUS patients to determine CVi and RCV. The calculated RCVs of 36.7% (low) and 39.6% (high) in this study were greater that reported previously and greater than the established criteria for relapse. Response criteria may be reassessed to increase sensitivity and specificity for detection of response. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Pro: 'The usefulness of biomarkers in glomerular diseases'. The problem: moving from syndrome to mechanism--individual patient variability in disease presentation, course and response to therapy.

PubMed

Mariani, Laura H; Kretzler, Matthias

2015-06-01

The diagnosis and treatment decisions in glomerular disease are principally based on renal pathology and nonspecific clinical laboratory measurements such as serum creatinine and urine protein. Using these classification approaches, patients have marked variability in rate of progression and response to therapy, exposing a significant number of patients to toxicity without benefit. Additionally, clinical trials are at risk of not being able to detect an efficacious therapy in relevant subgroups as patients with shared clinical-pathologic diagnoses have heterogeneous underlying pathobiology. To change this treatment paradigm, biomarkers that reflect the molecular mechanisms underlying the clinical-pathologic diagnoses are needed. Recent progress to identify such biomarkers has been aided by advances in molecular profiling, large-scale data generation and multi-scalar data integration, including prospectively collected clinical data. This article reviews the evolving success stories in glomerular disease biomarkers across the genotype-phenotype continuum and highlights opportunities to transition to precision medicine in glomerular disease. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Common variable immunodeficiency: experience in Puerto Rico.

PubMed

Santaella, María L; Font, Ivonne; Disdier, Orville

2005-03-01

Common variable immunodeficiency (CVI) is a primary immunodeficiency characterized by hypogammaglobulinemia and an increased susceptibility to infections. The degree and the type of deficiency of serum immunoglobulins, as well as, the clinical course vary from patient to patient, hence the term "variable". The aim of this report is to describe the clinical characteristics and the response to gammaglobulin therapy of a group of patients with CVI followed at the University Hospital of the Puerto Rico Medical Center. To our knowledge, no data on primary immunodeficiencies in Puerto Rico has been reported in the literature. The study group exhibits specific characteristics as compared to other reported series.

Pharmacogenetics of β-Blockers

PubMed Central

Shin, Jaekyu; Johnson, Julie A.

2009-01-01

β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice. PMID:17542770

Genetics of platelet inhibitor treatment

PubMed Central

Trenk, Dietmar; Hochholzer, Willibald

2014-01-01

Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is the standard of care in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) because this regimen has markedly decreased the rate of cardiovascular events. The substantial variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. Baseline demographic and clinical variables contributing to the observed variability have been identified. Besides this, research within the past decade has focused on the impact of genetic polymorphisms encoding transport systems or enzymes involved in the absorption and metabolism of these drugs. Loss-of-function polymorphisms in CYP2C19 are the strongest individual variables affecting pharmacokinetics and antiplatelet response to clopidogrel, but explain no more than 5 to 12% of the variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. No genetic variables contributing to clinical outcomes of patients treated with the newer P2Y12 receptor antagonists, prasugrel or ticagrelor, have been identified so far. This review aims to provide an update on the current status of genotype-based personalized therapy with clopidogrel. PMID:23981082

Proposal of a clinical response score and predictors of clinical response to 2 years of GH replacement therapy in adult GH deficiency.

PubMed

Schneider, Harald J; Buchfelder, Michael; Wallaschofski, Henri; Luger, Anton; Johannsson, Gudmundur; Kann, Peter H; Mattsson, Anders

2015-12-01

There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response. This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database). We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses. In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815). A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT. © 2015 European Society of Endocrinology.

Factors explaining children's responses to intravenous needle insertions.

PubMed

McCarthy, Ann Marie; Kleiber, Charmaine; Hanrahan, Kirsten; Zimmerman, M Bridget; Westhus, Nina; Allen, Susan

2010-01-01

Previous research shows that numerous child, parent, and procedural variables affect children's distress responses to procedures. Cognitive-behavioral interventions such as distraction are effective in reducing pain and distress for many children undergoing these procedures. The purpose of this report was to examine child, parent, and procedural variables that explain child distress during a scheduled intravenous insertion when parents are distraction coaches for their children. A total of 542 children, between 4 and 10 years of age, and their parents participated. Child age, gender, diagnosis, and ethnicity were measured by questions developed for this study. Standardized instruments were used to measure child experience with procedures, temperament, ability to attend, anxiety, coping style, and pain sensitivity. Questions were developed to measure parent variables, including ethnicity, gender, previous experiences, and expectations, and procedural variables, including use of topical anesthetics and difficulty of procedure. Standardized instruments were used to measure parenting style and parent anxiety, whereas a new instrument was developed to measure parent performance of distraction. Children's distress responses were measured with the Observation Scale of Behavioral Distress-Revised (behavioral), salivary cortisol (biological), Oucher Pain Scale (self-report), and parent report of child distress (parent report). Regression methods were used for data analyses. Variables explaining behavioral, child-report and parent-report measures include child age, typical coping response, and parent expectation of distress (p < .01). Level of parents' distraction coaching explained a significant portion of behavioral, biological, and parent-report distress measures (p < .05). Child impulsivity and special assistance at school also significantly explained child self-report of pain (p < .05). Additional variables explaining cortisol response were child's distress in the morning before clinic, diagnoses of attention deficit hyperactivity disorder or anxiety disorder, and timing of preparation for the clinic visit. The findings can be used to identify children at risk for high distress during procedures. This is the first study to find a relationship between child behavioral distress and level of parent distraction coaching.

Pharmacotherapy for primary delusional jealousy, a retrospective observational study of 32 cases with Othello syndrome.

PubMed

Liu, Chen-Chung; Wang, Yen-Chin; Hwang, Tzung-Jeng

2018-03-01

To determine whether primary delusional jealousy can be treated effectively with antipsychotics or antidepressants, and whether any clinical variables are associated with response to pharmacotherapy, we carried out a retrospective case series observational study by reviewing clinical records of patients with an International Classification of Disease, 9th ed., diagnostic code of 297 (delusional disorders) who were treated at the Department of Psychiatry of a university affiliated hospital from January 2010 to December 2015. Only those records showing obvious delusional jealousy not secondary to other medical conditions, dementia, or schizophrenia were scrutinized thoroughly with respect to types of pharmacotherapy, treatment response, and other demographic and clinical variables likely to be associated with clinical outcomes. All except one of 32 patients, 16 men and 16 women, between 37 and 79 (60.9±10.6) years of age, were treated with low-dose antipsychotics. The general response was favorable as 19 (59.4%) were rated as good and 13 as inadequate responders (seven partial and six limited). Compared with antipsychotic monotherapy, concomitant therapy with antidepressants had a higher rate of good response, although statistically insignificant (75 vs. 53%, P=0.21). Younger age (P=0.01) and presentation at the index visit with their suspected unfaithful spouse were associated with a good response (P=0.036); comorbidity with delusions other than the jealous type was associated with a poor response (P=0.006). The overall outcome for delusional jealousy looks promising if the patients can accept pharmacotherapy in an outpatient setting.

Improved modeling of clinical data with kernel methods.

PubMed

Daemen, Anneleen; Timmerman, Dirk; Van den Bosch, Thierry; Bottomley, Cecilia; Kirk, Emma; Van Holsbeke, Caroline; Valentin, Lil; Bourne, Tom; De Moor, Bart

2012-02-01

Despite the rise of high-throughput technologies, clinical data such as age, gender and medical history guide clinical management for most diseases and examinations. To improve clinical management, available patient information should be fully exploited. This requires appropriate modeling of relevant parameters. When kernel methods are used, traditional kernel functions such as the linear kernel are often applied to the set of clinical parameters. These kernel functions, however, have their disadvantages due to the specific characteristics of clinical data, being a mix of variable types with each variable its own range. We propose a new kernel function specifically adapted to the characteristics of clinical data. The clinical kernel function provides a better representation of patients' similarity by equalizing the influence of all variables and taking into account the range r of the variables. Moreover, it is robust with respect to changes in r. Incorporated in a least squares support vector machine, the new kernel function results in significantly improved diagnosis, prognosis and prediction of therapy response. This is illustrated on four clinical data sets within gynecology, with an average increase in test area under the ROC curve (AUC) of 0.023, 0.021, 0.122 and 0.019, respectively. Moreover, when combining clinical parameters and expression data in three case studies on breast cancer, results improved overall with use of the new kernel function and when considering both data types in a weighted fashion, with a larger weight assigned to the clinical parameters. The increase in AUC with respect to a standard kernel function and/or unweighted data combination was maximum 0.127, 0.042 and 0.118 for the three case studies. For clinical data consisting of variables of different types, the proposed kernel function--which takes into account the type and range of each variable--has shown to be a better alternative for linear and non-linear classification problems. Copyright © 2011 Elsevier B.V. All rights reserved.

Differences in clinical intrusive thoughts between obsessive-compulsive disorder, generalized anxiety disorder, and hypochondria.

PubMed

Romero-Sanchiz, Pablo; Nogueira-Arjona, Raquel; Godoy-Ávila, Antonio; Gavino-Lázaro, Aurora; Freeston, Mark H

2017-11-01

Differences and similarities between intrusive thoughts typical of obsessive-compulsive disorder, generalized anxiety disorder, and hypochondriasis are relevant for their differential diagnosis, formulation, and psychological treatment. Previous research in non-clinical samples pointed out the relevance of some process variables, such as responsibility, guilt, or neutralization strategies. This research is aimed to investigate the differences and similarities between clinical obsessions, worries, and illness intrusions in some of these process variables. A second aim is to identify models based on these variables that could reliably differentiate between them. Three groups of patients with obsessive-compulsive disorder (n = 35; 60% women, mean age 38.57), generalized anxiety disorder (n = 36; 61.1% women, mean age 41.50), and hypochondriasis (n = 34; 70.6% women, mean age 31.59) were evaluated using the Cognitive Intrusions Questionnaire-Transdiagnostic Version (Romero-Sanchiz, Nogueira-Arjona, Godoy-Ávila, Gavino-Lázaro, & Freeston, ). The results showed that some appraisals (e.g., responsibility or egodystonicity), emotions (e.g., guilt or insecurity), neutralization strategies, and other variables (e.g., verbal content or trigger from body sensation) are relevant for the discrimination between obsessions, worries, and illness intrusions. The results also showed 3 stable models based on these variables for the discrimination between these thoughts. The implication of these results in the diagnosis, formulation, and psychological treatment of obsessive-compulsive disorder, generalized anxiety disorder, and hypochondriasis is discussed. Copyright © 2017 John Wiley & Sons, Ltd.

Prediction of Response to Neoadjuvant Chemotherapy and Radiation Therapy with Baseline and Restaging 18F-FDG PET Imaging Biomarkers in Patients with Esophageal Cancer.

PubMed

Beukinga, Roelof J; Hulshoff, Jan Binne; Mul, Véronique E M; Noordzij, Walter; Kats-Ugurlu, Gursah; Slart, Riemer H J A; Plukker, John T M

2018-06-01

Purpose To assess the value of baseline and restaging fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) positron emission tomography (PET) radiomics in predicting pathologic complete response to neoadjuvant chemotherapy and radiation therapy (NCRT) in patients with locally advanced esophageal cancer. Materials and Methods In this retrospective study, 73 patients with histologic analysis-confirmed T1/N1-3/M0 or T2-4a/N0-3/M0 esophageal cancer were treated with NCRT followed by surgery (Chemoradiotherapy for Esophageal Cancer followed by Surgery Study regimen) between October 2014 and August 2017. Clinical variables and radiomic features from baseline and restaging 18 F-FDG PET were selected by univariable logistic regression and least absolute shrinkage and selection operator. The selected variables were used to fit a multivariable logistic regression model, which was internally validated by using bootstrap resampling with 20 000 replicates. The performance of this model was compared with reference prediction models composed of maximum standardized uptake value metrics, clinical variables, and maximum standardized uptake value at baseline NCRT radiomic features. Outcome was defined as complete versus incomplete pathologic response (tumor regression grade 1 vs 2-5 according to the Mandard classification). Results Pathologic response was complete in 16 patients (21.9%) and incomplete in 57 patients (78.1%). A prediction model combining clinical T-stage and restaging NCRT (post-NCRT) joint maximum (quantifying image orderliness) yielded an optimism-corrected area under the receiver operating characteristics curve of 0.81. Post-NCRT joint maximum was replaceable with five other redundant post-NCRT radiomic features that provided equal model performance. All reference prediction models exhibited substantially lower discriminatory accuracy. Conclusion The combination of clinical T-staging and quantitative assessment of post-NCRT 18 F-FDG PET orderliness (joint maximum) provided high discriminatory accuracy in predicting pathologic complete response in patients with esophageal cancer. © RSNA, 2018 Online supplemental material is available for this article.

A Prediction Algorithm for Drug Response in Patients with Mesial Temporal Lobe Epilepsy Based on Clinical and Genetic Information

PubMed Central

Carvalho, Benilton S.; Bilevicius, Elizabeth; Alvim, Marina K. M.; Lopes-Cendes, Iscia

2017-01-01

Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms (SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy. For this, we divided 237 patients into two groups: 75 responsive and 162 refractory to antiepileptic drug therapy. We genotyped 119 SNPs in ABCB1, ABCC2, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 genes. We used 98 additional SNPs to evaluate population stratification. We assessed a first scenario using only clinical variables and a second one including SNP information. The random forests algorithm combined with leave-one-out cross-validation was used to identify the best predictive model in each scenario and compared their accuracies using the area under the curve statistic. Additionally, we built a variable importance plot to present the set of most relevant predictors on the best model. The selected best model included the presence of hippocampal sclerosis and 56 SNPs. Furthermore, including SNPs in the model improved accuracy from 0.4568 to 0.8177. Our findings suggest that adding genetic information provided by SNPs, located on drug transport and metabolism genes, can improve the accuracy for predicting which patients with mesial temporal lobe epilepsy are likely to be refractory to drug treatment, making it possible to identify patients who may benefit from epilepsy surgery sooner. PMID:28052106

Best practices for veterinary toxicologic clinical pathology, with emphasis on the pharmaceutical and biotechnology industries.

PubMed

Tomlinson, Lindsay; Boone, Laura I; Ramaiah, Lila; Penraat, Kelley A; von Beust, Barbara R; Ameri, Mehrdad; Poitout-Belissent, Florence M; Weingand, Kurt; Workman, Heather C; Aulbach, Adam D; Meyer, Dennis J; Brown, Diane E; MacNeill, Amy L; Bolliger, Anne Provencher; Bounous, Denise I

2013-09-01

The purpose of this paper by the Regulatory Affairs Committee (RAC) of the American Society for Veterinary Clinical Pathology (ASVCP) is to review the current regulatory guidances (eg, guidelines) and published recommendations for best practices in veterinary toxicologic clinical pathology, particularly in the pharmaceutical and biotechnology industries, and to utilize the combined experience of ASVCP RAC to provide updated recommendations. Discussion points include (1) instrumentation, validation, and sample collection, (2) routine laboratory variables, (3) cytologic laboratory variables, (4) data interpretation and reporting (including peer review, reference intervals and statistics), and (5) roles and responsibilities of clinical pathologists and laboratory personnel. Revision and improvement of current practices should be in alignment with evolving regulatory guidance documents, new technology, and expanding understanding and utility of clinical pathology. These recommendations provide a contemporary guide for the refinement of veterinary toxicologic clinical pathology best practices. © 2013 American Society for Veterinary Clinical Pathology.

Continuous performance task in ADHD: Is reaction time variability a key measure?

PubMed

Levy, Florence; Pipingas, Andrew; Harris, Elizabeth V; Farrow, Maree; Silberstein, Richard B

2018-01-01

To compare the use of the Continuous Performance Task (CPT) reaction time variability (intraindividual variability or standard deviation of reaction time), as a measure of vigilance in attention-deficit hyperactivity disorder (ADHD), and stimulant medication response, utilizing a simple CPT X-task vs an A-X-task. Comparative analyses of two separate X-task vs A-X-task data sets, and subgroup analyses of performance on and off medication were conducted. The CPT X-task reaction time variability had a direct relationship to ADHD clinician severity ratings, unlike the CPT A-X-task. Variability in X-task performance was reduced by medication compared with the children's unmedicated performance, but this effect did not reach significance. When the coefficient of variation was applied, severity measures and medication response were significant for the X-task, but not for the A-X-task. The CPT-X-task is a useful clinical screening test for ADHD and medication response. In particular, reaction time variability is related to default mode interference. The A-X-task is less useful in this regard.

Characteristics of dental clinics in US children's hospitals.

PubMed

Ciesla, David; Kerins, Carolyn A; Seale, N Sue; Casamassimo, Paul S

2011-01-01

This study's purpose was to describe the workforce, patient, and service characteristics of dental clinics affiliated with US children's hospitals belonging to the National Association of Children's Hospital and Related Institutions (NACHRI). A 2-stage survey mechanism using ad hoc questionnaires sought responses from hospital administrators and dental clinic administrators. Questionnaires asked about: (1) clinic purpose; (2) workforce; (3) patient population; (4) dental services provided; (5) community professional relations; and (5) relationships with medical services. Of the 222 NACHRI-affiliated hospitals, 87 reported comprehensive dental clinics (CDCs) and 64 (74%) of CDCs provided data. Provision of tertiary medical services was significantly related to presence of a CDC. Most CDCs were clustered east of the Mississippi River. Size, workload, and patient characteristics were variable across CDCs. Most were not profitable. Medical diagnosis was the primary criterion for eligibility, with all but 1 clinic treating special needs children. Most clinics (74%) had dental residencies. Over 75% reported providing dental care prior to major medical care (cardiac, oncology, transplantation), but follow-up care was variable. Many children's hospitals reported comprehensive dental clinics, but the characteristics were highly variable, suggesting this element of the pediatric oral health care safety net may be fragile.

Dose requirements of alfentanil to eliminate autonomic responses during rapid-sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

PubMed

Abou-Arab, Mohammad H; Rostrup, Morten; Heier, Tom

2016-12-01

Opioids are integral part of anesthesia induction, but information on optimal dosing is limited. We aimed to determine doses of alfentanil needed to eliminate increases in 5 autonomic response variables (plasma concentrations of epinephrine, norepinephrine and vasopressin, arterial blood pressure [ABP], and heart rate) during rapid-sequence induction of anesthesia with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Prospective, randomized, observer-blinded, interventional clinical study. Large academic institution. Eighty-four healthy patients, aged 18 to 55 years, received 1 of 7 assessor-blinded doses of alfentanil (0, 10, 20, 30, 40, 50, and 60 μg/kg) together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg, administered in rapid succession (15 seconds). Laryngoscopy was initiated 40 seconds after rocuronium, and tracheal intubation was concluded within 15 seconds thereafter. An indwelling radial artery catheter was used for hemodynamic monitoring and blood sampling. Relationships between alfentanil dose and response variables were tested with linear regression, and the influence of covariates (sex, body weight, and age) was determined. Alfentanil dose needed to prevent increases in ABP >10% above baseline with 95% probability was estimated with logistic regression. Significant relationships were determined between alfentanil dose and response variables. Clinically interesting influence of covariates was not found. Alfentanil 55 μg/kg was needed to prevent increases in ABP postintubation >10% above baseline with 95% probability. One individual needed a bolus of vasopressor postintubation. Optimal control of autonomic responses during rapid-sequence induction was achieved with clinically relevant doses of alfentanil in healthy patients anesthetized with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

Inflammatory Cytokines and White Blood Cell Counts Response to Environmental Levels of Diesel Exhaust and Ozone Inhalation Exposures

EPA Science Inventory

Epidemiological observations of urban inhalation exposures to diesel exhaust (DE) and ozone (O3) have shown pre-clinical cardiopulmonary responses in humans. Identifying the key biological mechanisms that initiate these health bioindicators is difficult due to variability in envi...

[Placebo effect: a contribution of social psychology].

PubMed

Balez, R; Leroyer, C; Couturaud, F

2014-10-01

This article reviews the psychosocial variables, which are of interest in the relationship between the patient and the physician. According to a classical model of social psychology, such a relationship might contribute to the placebo/nocebo effects. We develop herein various relational and contextual variables, taking into account four dimensions (intra-individual, interpersonal, positional and ideological) and their potential effects on therapeutic responses. This applies both in the setting of daily clinical practice and of clinical trials. The placebo effect offers an opportunity for collaboration and dialogue between social scientists and physicians.

Emotional and Cognitive Variables Associated with Contamination-Related Obsessive-Compulsive Symptoms.

PubMed

García-Soriano, Gemma; Rosell-Clari, Vicent; Serrano, Miguel Ángel

2016-05-23

Different variables have been associated with the development/ maintenance of contamination-related obsessive-compulsive disorder (OCD), although the relevance of these factors has not been clearly established. The present study aimed to analyze the relevance and specificity of these variables. Forty-five women with high scores on obsessive-compulsive contamination symptoms (n = 16) or checking symptoms (n = 15), or non-clinical scores (n = 14) participated in a behavioral approach/avoidance task (BAT) with a contamination-OCD stimulus. Vulnerability variables and participants' emotional, cognitive, physiological and behavioral responses to the BAT were appraised. Results show that fear of illness was a relevant vulnerability variable specific to contamination participants (p = .001; η2 p = .291). Contamination participants responded with significantly higher subjective disgust (p =.001; η2 p = .269), anxiety (p = .001; η2 p = .297), urge to wash (p < .001; η2 p = 370), threat from emotion (p < .001; η2 p = .338) and contamination severity (p = .002; η2 p = .260) appraisals, and with lower behavioral approach (p = .008; η2 p = .208) than the other two groups. Moreover, contamination participants showed lower heart rate acceleration (p = .046; η2 p = .170) and higher contamination likelihood appraisals (p < .001; η2 p = .342) than the non-clinical group. Urge to wash was predicted by state disgust (R 2 change = .346) and threat from emotion (R 2 change = .088). These responses were predicted by general anxiety sensitivity (R 2 change = .161), disgust propensity (R 2 change = .255) and fear of illness (R 2 change = .116), but not by other vulnerability variables such as dysfunctional beliefs about thoughts (Responsibility and Overestimation of threat) or disgust sensitivity. State disgust, threat from disgust, anxiety sensitivity and fear of illness were found to be the most relevant variables in contamination symptoms.

Emerging biomarkers in anaplastic oligodendroglioma: implications for clinical investigation and patient management.

PubMed

Sahebjam, Solmaz; McNamara, Mairéad G; Mason, Warren P

2013-07-01

Oligodendrogliomas are heterogeneous tumors with a variable response to treatment. This clinical variability underlines the urgent need for markers that can reliably aid diagnosis and guide clinical decision-making. Long-term follow-up data from the EORTC 26951 and RTOG 9402 clinical trials in newly diagnosed anaplastic oligodendroglioma have established chromosome 1p19q codeletion as a predictive marker of response to procarbazine, lomustine and vincristine chemotherapy in anaplastic oligodendrogliomas. In addition, MGMT promoter hypermethylation has been strongly associated with glioma CpG island hypermethylation phenotype (G-CIMP+) status, this has been suggested as an epiphenomenon of genome-wide methylation, conferring a more favorable prognosis. Molecular profiling of these tumors has identified several other markers with potential clinical significance: mutations of IDH, CIC, FUBP1 and CDKN2A require further validation before they can be implemented as clinical decision-making tools. Additionally, recent data on the clinical significance of intrinsic glioma subtyping appears promising. Indeed, existing evidence suggests that comprehensive analyses such as intrinsic glioma subtyping or G-CIMP status are superior to single molecular markers. Clearly, with evolving treatment strategies and in the era of individualized therapy, broader omics-based molecular evaluations are required to improve outcome prediction and to identify patients who will benefit from specific treatment strategies.

Use of reflectance spectrophotometry to predict the response of port wine stains to pulsed dye laser.

PubMed

Halachmi, Shlomit; Azaria, Ron; Inbar, Roy; Ad-El, Dean; Lapidoth, Moshe

2014-01-01

Reflectance spectroscopy can be used to quantitate subtle differences in color. We applied a portable reflectance spectrometer to determine its utility in the evaluation of pulsed dye laser treatment of port wine stains (PWS) and in prediction of clinical outcome, in a prospective study. Forty-eight patients with PWS underwent one to nine pulsed dye laser treatments. Patient age and skin color as well as PWS surface area, anatomic location, and color were recorded. Pretreatment spectrophotometric measurements were performed. The subjective clinical results of treatment and the quantitative spectrophotometry results were evaluated by two independent teams, and the findings were correlated. The impact of the clinical characteristics on the response to treatment was assessed as well. Patients with excellent to good clinical results of laser treatments had pretreatment spectrophotometric measurements which differed by more than 10%, whereas patients with fair to poor results had spectrophotometric measurements with a difference of of less than 10%. The correlation between the spectrophotometric results and the clinical outcome was 73% (p < 0.01). The impact of the other clinical variables on outcome agreed with the findings in the literature. Spectrophotometry has a higher correlation with clinical outcome and a better predictive value than other nonmeasurable, nonquantitative, dependent variables.

Responses to clinical uncertainty in Australian general practice trainees: a cross-sectional analysis.

PubMed

Cooke, Georga; Tapley, Amanda; Holliday, Elizabeth; Morgan, Simon; Henderson, Kim; Ball, Jean; van Driel, Mieke; Spike, Neil; Kerr, Rohan; Magin, Parker

2017-12-01

Tolerance for ambiguity is essential for optimal learning and professional competence. General practice trainees must be, or must learn to be, adept at managing clinical uncertainty. However, few studies have examined associations of intolerance of uncertainty in this group. The aim of this study was to establish levels of tolerance of uncertainty in Australian general practice trainees and associations of uncertainty with demographic, educational and training practice factors. A cross-sectional analysis was performed on the Registrar Clinical Encounters in Training (ReCEnT) project, an ongoing multi-site cohort study. Scores on three of the four independent subscales of the Physicians' Reaction to Uncertainty (PRU) instrument were analysed as outcome variables in linear regression models with trainee and practice factors as independent variables. A total of 594 trainees contributed data on a total of 1209 occasions. Trainees in earlier training terms had higher scores for 'Anxiety due to uncertainty', 'Concern about bad outcomes' and 'Reluctance to disclose diagnosis/treatment uncertainty to patients'. Beyond this, findings suggest two distinct sets of associations regarding reaction to uncertainty. Firstly, affective aspects of uncertainty (the 'Anxiety' and 'Concern' subscales) were associated with female gender, less experience in hospital prior to commencing general practice training, and graduation overseas. Secondly, a maladaptive response to uncertainty (the 'Reluctance to disclose' subscale) was associated with urban practice, health qualifications prior to studying medicine, practice in an area of higher socio-economic status, and being Australian-trained. This study has established levels of three measures of trainees' responses to uncertainty and associations with these responses. The current findings suggest differing 'phenotypes' of trainees with high 'affective' responses to uncertainty and those reluctant to disclose uncertainty to patients. More research is needed to examine the relationship between clinical uncertainty and clinical outcomes, temporal changes in tolerance for uncertainty, and strategies that might assist physicians in developing adaptive responses to clinical uncertainty. © 2017 John Wiley & Sons Ltd and The Association for the Study of Medical Education.

Reduced Short Interval Cortical Inhibition Correlates with Atomoxetine Response in Children with ADHD

PubMed Central

Chen, Tina H.; Wu, Steve W.; Welge, Jeffrey A.; Dixon, Stephan; Shahana, Nasrin; Huddleston, David A.; Sarvis, Adam R.; Sallee, Floyd R.; Gilbert, Donald L.

2014-01-01

Clinical trials in children with Attention Deficit Hyperactivity Disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX). The objective of this study was to determine whether Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (SICI) might be a biomarker predicting, or correlating with, clinical ATX response. At baseline and after 4 weeks of ATX treatment in 7–12 year old children with ADHD, TMS-SICI was measured, blinded to clinical improvement. Primary analysis was by multivariate ANCOVA. Baseline SICI did not predict clinical responses. However, paradoxically, after 4 weeks of ATX, mean SICI was reduced 31.9% in responders and increased 6.1% in non-responders (ANCOVA t41=2.88; p = .0063). Percent reductions in SICI correlated with reductions in ADHD-Rating Scale (ADHDRS) (r = .50; p = .0005). In children ages 7–12 years with ADHD treated with ATX, improvements in clinical symptoms are correlated with reductions in motor cortex SICI. PMID:24413361

Increased temporal variability of striatum region facilitating the early antidepressant response in patients with major depressive disorder.

PubMed

Hou, Zhenghua; Kong, Youyong; He, Xiaofu; Yin, Yingying; Zhang, Yuqun; Yuan, Yonggui

2018-07-13

The aim of this study is to identify the difference of temporal variability among major depressive disorder (MDD) patients (with different early antidepressant responses) and healthy controls (HC), and further explore the relationship between pre-treatment temporal variability and early antidepressant response. At baseline, 77 treatment-naïve inpatients with MDD and 42 matched HC received clinical assessments and 3.0 Tesla resting-state functional magnetic resonance imaging scans. After 2 weeks' antidepressant treatment, the patients were subgrouped into responsive depression (RD, n = 40) and non-responding depression (NRD, n = 37) based on the reduction of Hamilton depression rating scale (HAMD). The temporal variability of 90 brain nodes was calculated for further analysis. Compared with the HC group, both the RD and NRD subjects showed greater baseline temporal variability (i.e., greater dynamic) in the left inferior occipital gyrus. Significantly greater temporal variability in the left pallidum was found in the RD group than the NRD and the HC groups, and the higher variability of left pallidum correlated positively with the HAMD reduction. Moreover, the pooled MDD (i.e., RD and NRD) group showed greater baseline temporal variability in the right inferior frontal gyrus, the left inferior occipital gyrus, the bilateral fusiform gyri and the left Heschl gyrus than the HC group. The distinctive pattern of dynamically reorganized networks may provide a crucial scaffold to facilitate early antidepressant response, and the temporal variability may serve as a promising indicator for the personalized therapy of MDD. Copyright © 2018 Elsevier Inc. All rights reserved.

Maximizing the clinical utility of antimüllerian hormone testing in women's health

PubMed Central

Leader, Benjamin; Baker, Valerie L.

2014-01-01

Purpose of review To provide an update on the latest clinical applications of serum antimüllerian hormone (AMH) testing with practical approaches to mitigate the impact of significant variability in AMH results. Recent findings Recent studies continue to demonstrate that AMH is the best single serum test for ovarian response management with, at most, a weak-to-moderate age-independent association with live-birth rate and time to conception. Data confirm serum AMH levels improve menopause prediction, monitoring of ovarian damage, and identification of women at risk for several ovary-related disorders such as polycystic ovary syndrome and premature or primary ovarian insufficiency. However, it is now recognized that serum AMH results can have dramatic variability due to common, biologic fluctuations within some individuals, use of hormonal contraceptives or other medications, certain surgical procedures, specimen treatment, assay changes, and laboratory calibration differences. Practical guidelines are provided to minimize the impact of variability in AMH results and maximize the accuracy of clinical decision-making. Summary AMH is an ovarian biomarker of central importance which improves the clinical management of women's health. However, with the simultaneous rapid expansion of AMH clinical applications and recognition of variability in AMH results, consensus regarding the clinical cutpoints is increasingly difficult. Therefore, a careful approach to AMH measurement and interpretation in clinical care is essential. PMID:24978853

Differences in activation of MAP kinases and variability in the polyglutamine tract of Slt2 in clinical and non-clinical isolates of Saccharomyces cerevisiae.

PubMed

de Llanos, Rosa; Hernández-Haro, Carolina; Barrio, Eladio; Querol, Amparo; Fernández-Espinar, María Teresa; Molina, María

2010-08-01

The concept of Saccharomyces cerevisiae as an emerging opportunistic pathogen is relatively new and it is due to an increasing number of human infections during the past 20 years. There are still few studies addressing the mechanisms of infection of this yeast species. Moreover, little is known about how S. cerevisiae cells sense and respond to the harsh conditions imposed by the host, and whether this response is different between clinical isolates and non-pathogenic strains. In this regard, mitogen-activated protein kinase (MAPK) pathways constitute one of the major mechanisms for controlling transcriptional responses and, in some cases, virulence in fungi. Here we show differences among clinical and non-clinical isolates of S. cerevisiae in the level of activation of the MAPKs Kss1, which controls pseudohyphal and invasive growth, and Slt2, which is required for maintaining the integrity of the cell wall under stress conditions and in the absence of stimulating conditions. Moreover, we report for the first time the existence of length variability in SLT2 alleles of strains with a clinical origin. This is due to the expansion in the number of glutamine-encoding triplets in the microsatellite region coding for the polyglutamine (poly-Q) tract of this gene, which range from 12 to more than 38 repetitions. We suggest that this variability may influence biological features of the Slt2 protein, allowing it to adapt swiftly in order to survive in unusual environments. Copyright (c) 2010 John Wiley & Sons, Ltd.

Sci-Sat AM: Radiation Dosimetry and Practical Therapy Solutions - 12: Suitability of plan class specific reference fields for estimating dosimeter correction factors for small clinical CyberKnife fields

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

Vandervoort, Eric; Christiansen, Eric; Belec, Jaso

Purpose: The purpose of this work is to investigate the utility of plan class specific reference (PCSR) fields for predicting dosimeter response within isocentric and non-isocentric composite clinical fields using the smallest fields employed by the CyberKnife radiosurgery system. Methods: Monte Carlo dosimeter response correction factors (CFs) were calculated for a plastic scintillator and microchamber dosimeter in 21 clinical fields and 9 candidate plan-class PCSR fields which employ the 5, 7.5 and 10 mm diameter collimators. Measurements were performed in 5 PCSR fields to confirm the predicted relative response of detectors in the same field. Results: Ratios of corrected measuredmore » dose in the PCSR fields agree to within 1% of unity. Calculated CFs for isocentric fields agree within 1.5% of those for PCSR fields. Large and variable microchamber CFs are required for non-isocentric fields, with differences as high as 5% between different clinical fields in the same plan class and 4% within the same field depending on the point of measurement. Non-isocentric PCSR fields constructed to have relatively homogenous dose over a region larger than the detector have very different ion chamber CFs from clinical fields. The plastic scintillator detector has much more consistent response within each plan class but still require 3–4% corrections in some fields. Conclusions: While the PCSR field concept is useful for small isocentric fields, this approach may not be appropriate for non-isocentric clinical fields which exhibit large and variable ion chamber CFs which differ significantly from CFs for homogenous field PCSRs.« less

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

PubMed Central

Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

2011-01-01

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119

Impact of advanced monitoring variables on intraoperative clinical decision-making: an international survey.

PubMed

Joosten, Alexandre; Desebbe, Olivier; Suehiro, Koichi; Essiet, Mfonobong; Alexander, Brenton; Ricks, Cameron; Rinehart, Joseph; Faraoni, David; Cecconi, Maurizio; Van der Linden, Philippe; Cannesson, Maxime

2017-02-01

To assess the relationship between the addition of advanced monitoring variables and changes in clinical decision-making. A 15-questions survey was anonymously emailed to international experts and physician members of five anesthesia societies which focused on assessing treatment decisions of clinicians during three realistic clinical scenarios measured at two distinct time points. The first is when typical case information and basic monitoring (T1) were provided, and then once again after the addition of advanced monitoring variables (T2). We hypothesized that the addition of advanced variables would increase the incidence of an optimal therapeutic decision (a priori defined as the answer with the highest percentage of expert agreement) and decrease the variability among the physician's suggested treatments. The survey was completed by 18 experts and 839 physicians. Overall, adding advanced monitoring did not significantly increase physician response accuracy, with the least substantial changes noted on questions related to volume expansion or vasopressor administration. Moreover, advanced monitoring data did not significantly decrease the high level of initial practice variability in physician suggested treatments (P = 0.13), in contrast to the low variability observed within the expert group (P = 0.039). Additionally, 5-10 years of practice (P < 0.0001) and a cardiovascular subspecialty (P = 0.048) were both physician characteristics associated with a higher rate of optimal therapeutic decisions. The addition of advanced variables was of limited benefit for most physicians, further indicating the need for more in depth education on the clinical value and technical understanding of such variables.

Logic Learning Machine and standard supervised methods for Hodgkin's lymphoma prognosis using gene expression data and clinical variables.

PubMed

Parodi, Stefano; Manneschi, Chiara; Verda, Damiano; Ferrari, Enrico; Muselli, Marco

2018-03-01

This study evaluates the performance of a set of machine learning techniques in predicting the prognosis of Hodgkin's lymphoma using clinical factors and gene expression data. Analysed samples from 130 Hodgkin's lymphoma patients included a small set of clinical variables and more than 54,000 gene features. Machine learning classifiers included three black-box algorithms ( k-nearest neighbour, Artificial Neural Network, and Support Vector Machine) and two methods based on intelligible rules (Decision Tree and the innovative Logic Learning Machine method). Support Vector Machine clearly outperformed any of the other methods. Among the two rule-based algorithms, Logic Learning Machine performed better and identified a set of simple intelligible rules based on a combination of clinical variables and gene expressions. Decision Tree identified a non-coding gene ( XIST) involved in the early phases of X chromosome inactivation that was overexpressed in females and in non-relapsed patients. XIST expression might be responsible for the better prognosis of female Hodgkin's lymphoma patients.

Response to Infant Cry in Clinically Depressed and Non-Depressed Mothers

PubMed Central

Manian, Nanmathi; Truzzi, Anna; Bornstein, Marc H.

2017-01-01

Background Bowlby and Ainsworth hypothesized that maternal responsiveness is displayed in the context of infant distress. Depressed mothers are less responsive to infant distress vocalizations (cry) than non-depressed mothers. The present study focuses on acoustical components of infant cry that give rise to responsive caregiving in clinically depressed (n = 30) compared with non-depressed mothers (n = 30) in the natural setting of the home. Methods Analyses of infant and mother behaviors followed three paths: (1) tests of group differences in acoustic characteristics of infant cry, (2) tests of group differences of mothers’ behaviors during their infant’s crying, and (3) tree-based modeling to ascertain which variable(s) best predict maternal behaviors during infant cry. Results (1) Infants of depressed mothers cried as frequently and for equal durations as infants of non-depressed mothers; however, infants of depressed mothers cried with a higher fundamental frequency (f0) and in a more restricted range of f0. (2) Depressed mothers fed, rocked, and touched their crying infants less than non-depressed mothers, and depressed mothers were less responsive to their infants overall. (3) Novel tree-based analyses confirmed that depressed mothers engaged in less caregiving during their infants’ cry and indicated that depressed mothers responded only to cries at higher f0s and shorter durations. Older non-depressed mothers were the most interactive with infants. Conclusions Clinical depression affects maternal responsiveness during infant cry, leading to patterns of action that appear poorly attuned to infant needs. PMID:28046020

Intra-individual variability in information processing speed reflects white matter microstructure in multiple sclerosis.

PubMed

Mazerolle, Erin L; Wojtowicz, Magdalena A; Omisade, Antonina; Fisk, John D

2013-01-01

Slowed information processing speed is commonly reported in persons with multiple sclerosis (MS), and is typically investigated using clinical neuropsychological tests, which provide sensitive indices of mean-level information processing speed. However, recent studies have demonstrated that within-person variability or intra-individual variability (IIV) in information processing speed may be a more sensitive indicator of neurologic status than mean-level performance on clinical tests. We evaluated the neural basis of increased IIV in mildly affected relapsing-remitting MS patients by characterizing the relation between IIV (controlling for mean-level performance) and white matter integrity using diffusion tensor imaging (DTI). Twenty women with relapsing-remitting MS and 20 matched control participants completed the Computerized Test of Information Processing (CTIP), from which both mean response time and IIV were calculated. Other clinical measures of information processing speed were also collected. Relations between IIV on the CTIP and DTI metrics of white matter microstructure were evaluated using tract-based spatial statistics. We observed slower and more variable responses on the CTIP in MS patients relative to controls. Significant relations between white matter microstructure and IIV were observed for MS patients. Increased IIV was associated with reduced integrity in more white matter tracts than was slowed information processing speed as measured by either mean CTIP response time or other neuropsychological test scores. Thus, despite the common use of mean-level performance as an index of cognitive dysfunction in MS, IIV may be more sensitive to the overall burden of white matter disease at the microstructural level. Furthermore, our study highlights the potential value of considering within-person fluctuations, in addition to mean-level performance, for uncovering brain-behavior relationships in neurologic disorders with widespread white matter pathology.

The Paediatric Rheumatology International Trials Organisation provisional criteria for the evaluation of response to therapy in juvenile dermatomyositis.

PubMed

Ruperto, Nicolino; Pistorio, Angela; Ravelli, Angelo; Rider, Lisa G; Pilkington, Clarissa; Oliveira, Sheila; Wulffraat, Nico; Espada, Graciela; Garay, Stella; Cuttica, Ruben; Hofer, Michael; Quartier, Pierre; Melo-Gomes, Jose; Reed, Ann M; Wierzbowska, Malgorzata; Feldman, Brian M; Harjacek, Miroslav; Huppertz, Hans-Iko; Nielsen, Susan; Flato, Berit; Lahdenne, Pekka; Michels, Harmut; Murray, Kevin J; Punaro, Lynn; Rennebohm, Robert; Russo, Ricardo; Balogh, Zsolt; Rooney, Madeleine; Pachman, Lauren M; Wallace, Carol; Hashkes, Philip; Lovell, Daniel J; Giannini, Edward H; Gare, Boel Andersson; Martini, Alberto

2010-11-01

To develop a provisional definition for the evaluation of response to therapy in juvenile dermatomyositis (DM) based on the Paediatric Rheumatology International Trials Organisation juvenile DM core set of variables. Thirty-seven experienced pediatric rheumatologists from 27 countries achieved consensus on 128 difficult patient profiles as clinically improved or not improved using a stepwise approach (patient's rating, statistical analysis, definition selection). Using the physicians' consensus ratings as the "gold standard measure," chi-square, sensitivity, specificity, false-positive and-negative rates, area under the receiver operating characteristic curve, and kappa agreement for candidate definitions of improvement were calculated. Definitions with kappa values >0.8 were multiplied by the face validity score to select the top definitions. The top definition of improvement was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 1 of the remaining worsening by more than 30%, which cannot be muscle strength. The second-highest scoring definition was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 2 of the remaining worsening by more than 25%, which cannot be muscle strength (definition P1 selected by the International Myositis Assessment and Clinical Studies group). The third is similar to the second with the maximum amount of worsening set to 30%. This indicates convergent validity of the process. We propose a provisional data-driven definition of improvement that reflects well the consensus rating of experienced clinicians, which incorporates clinically meaningful change in core set variables in a composite end point for the evaluation of global response to therapy in juvenile DM. Copyright © 2010 by the American College of Rheumatology.

Blood pressure response to patterns of weather fluctuations and effect on mortality.

PubMed

Aubinière-Robb, Louise; Jeemon, Panniyammakal; Hastie, Claire E; Patel, Rajan K; McCallum, Linsay; Morrison, David; Walters, Matthew; Dawson, Jesse; Sloan, William; Muir, Scott; Dominiczak, Anna F; McInnes, Gordon T; Padmanabhan, Sandosh

2013-07-01

Very few studies have looked at longitudinal intraindividual blood pressure responses to weather conditions. There are no data to suggest that specific response to changes in weather will have an impact on survival. We analyzed >169 000 clinic visits of 16 010 Glasgow Blood Pressure Clinic patients with hypertension. Each clinic visit was mapped to the mean West of Scotland monthly weather (temperature, sunshine, rainfall) data. Percentage change in blood pressure was calculated between pairs of consecutive clinic visits, where the weather alternated between 2 extreme quartiles (Q(1)-Q(4) or Q(4)-Q(1)) or remained in the same quartile (Q(n)-Q(n)) of each weather parameter. Subjects were also categorized into 2 groups depending on whether their blood pressure response in Q(1)-Q(4) or Q(4)-Q(1) were concordant or discordant to Q(n)-Q(n). Generalized estimating equations and Cox proportional hazards model were used to model the effect on longitudinal blood pressure and mortality, respectively. Q(n)-Q(n) showed a mean 2% drop in blood pressure consistently, whereas Q(4)-Q(1) showed a mean 2.1% and 1.6% rise in systolic and diastolic blood pressure, respectively. However, Q(1)-Q(4) did not show significant changes in blood pressure. Temperature-sensitive subjects had significantly higher mortality (1.35 [95% confidence interval, 1.06-1.71]; P=0.01) and higher follow-up systolic blood pressure (1.85 [95% confidence interval, 0.24-3.46]; P=0.02) compared with temperature-nonsensitive subjects. Blood pressure response to temperature may be one of the underlying mechanisms that determine long-term blood pressure variability. Knowing a patient's blood pressure response to weather can help reduce unnecessary antihypertensive treatment modification, which may in turn increase blood pressure variability and, thus, risk.

Post-marketing survey on clinical response to interferon beta in relapsing multiple sclerosis: the Roman experience.

PubMed

Pozzilli, C; Prosperini, L; Sbardella, E; De Giglio, L; Onesti, E; Tomassini, V

2005-12-01

Safety, tolerability and efficacy profiles of interferon beta (IFNbeta) therapy in relapsing multiple sclerosis (MS) has been widely verified both in trial settings and in daily clinical practice. However, for a variable percentage of treated patients, it remains only partially effective. In this study, we reported the post-marketing experience of the efficacy of IFNbeta therapy for a large cohort of MS patients regularly attending the MS Outpatient Clinic of "La Sapienza University" in Rome. In this cohort we also sought clinical and paraclinical variables responsible for the clinical course of MS during IFNbeta therapy. Patients that received treatment with one of the IFNbeta formulations for at least 1 year were included. Clinical outcomes (i. e., relapses and disability score) were monitored throughout the entire study period. Magnetic resonance imaging (MRI) scans were performed twice for each subject: at baseline and after 1 year of therapy. The occurrence of more than one relapse during the study period or a sustained disability progression in the Expanded Disability Status Scale (EDSS) score were considered as criteria for the definition of suboptimal clinical response to IFNbeta therapy. During IFNbeta therapy (number of patients 242, mean length of treatment 4.3+/-2.3 years) a reduction in the annualised relapse rate of 59% (p<0.001) was observed. Eighty-six patients (35%) fulfilled the criterion for defining "suboptimal responder" on the basis of relapses, and 69 (28.5%) did the same on the basis of EDSS sustained progression. Twenty-seven (11.1%) patients showed both an EDSS progression and two or more relapses. The presence of T1-enhancing lesions and new T2 hyperintense lesions on the scan performed after the first year of therapy were the best MRI features associated with both the occurrence of relapses during the treatment period (OR for enhancing lesions and relapses 3.6; OR for new T2 lesion and relapses 2.8). The present post-marketing experience confirms the efficacy of IFNbeta in modifying the natural course of MS and encourages the use of paraclinical variables measuring subclinical disease activity as surrogate markers to monitor the clinical course of MS during IFNbeta therapy.

Creatine Kinase Clinical Considerations: Ethnicity, Gender and Genetics

DTIC Science & Technology

2009-10-01

reported that the CC genotype was associated with exaggerated CK responses to exercise (37), inspection of their data and a letter to the editor (19...variation, response to eccentric exercise , and association of inflammatory mediators with muscle damage variables. J Appl Physiol. 104:451-458, 2008...174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise . Eur J Appl Physiol. 104

Variable selection for distribution-free models for longitudinal zero-inflated count responses.

PubMed

Chen, Tian; Wu, Pan; Tang, Wan; Zhang, Hui; Feng, Changyong; Kowalski, Jeanne; Tu, Xin M

2016-07-20

Zero-inflated count outcomes arise quite often in research and practice. Parametric models such as the zero-inflated Poisson and zero-inflated negative binomial are widely used to model such responses. Like most parametric models, they are quite sensitive to departures from assumed distributions. Recently, new approaches have been proposed to provide distribution-free, or semi-parametric, alternatives. These methods extend the generalized estimating equations to provide robust inference for population mixtures defined by zero-inflated count outcomes. In this paper, we propose methods to extend smoothly clipped absolute deviation (SCAD)-based variable selection methods to these new models. Variable selection has been gaining popularity in modern clinical research studies, as determining differential treatment effects of interventions for different subgroups has become the norm, rather the exception, in the era of patent-centered outcome research. Such moderation analysis in general creates many explanatory variables in regression analysis, and the advantages of SCAD-based methods over their traditional counterparts render them a great choice for addressing this important and timely issues in clinical research. We illustrate the proposed approach with both simulated and real study data. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Combining clinical variables to optimize prediction of antidepressant treatment outcomes.

PubMed

Iniesta, Raquel; Malki, Karim; Maier, Wolfgang; Rietschel, Marcella; Mors, Ole; Hauser, Joanna; Henigsberg, Neven; Dernovsek, Mojca Zvezdana; Souery, Daniel; Stahl, Daniel; Dobson, Richard; Aitchison, Katherine J; Farmer, Anne; Lewis, Cathryn M; McGuffin, Peter; Uher, Rudolf

2016-07-01

The outcome of treatment with antidepressants varies markedly across people with the same diagnosis. A clinically significant prediction of outcomes could spare the frustration of trial and error approach and improve the outcomes of major depressive disorder through individualized treatment selection. It is likely that a combination of multiple predictors is needed to achieve such prediction. We used elastic net regularized regression to optimize prediction of symptom improvement and remission during treatment with escitalopram or nortriptyline and to identify contributing predictors from a range of demographic and clinical variables in 793 adults with major depressive disorder. A combination of demographic and clinical variables, with strong contributions from symptoms of depressed mood, reduced interest, decreased activity, indecisiveness, pessimism and anxiety significantly predicted treatment outcomes, explaining 5-10% of variance in symptom improvement with escitalopram. Similar combinations of variables predicted remission with area under the curve 0.72, explaining approximately 15% of variance (pseudo R(2)) in who achieves remission, with strong contributions from body mass index, appetite, interest-activity symptom dimension and anxious-somatizing depression subtype. Escitalopram-specific outcome prediction was more accurate than generic outcome prediction, and reached effect sizes that were near or above a previously established benchmark for clinical significance. Outcome prediction on the nortriptyline arm did not significantly differ from chance. These results suggest that easily obtained demographic and clinical variables can predict therapeutic response to escitalopram with clinically meaningful accuracy, suggesting a potential for individualized prescription of this antidepressant drug. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A Randomized Clinical Trial Comparison Between Pivotal Response Treatment (PRT) and Structured Applied Behavior Analysis (ABA) Intervention for Children with Autism

PubMed Central

Mohammadzaheri, Fereshteh; Koegel, Lynn Kern; Rezaee, Mohammad; Rafiee, Seyed Majid

2014-01-01

Accumulating studies are documenting specific motivational variables that, when combined into a naturalistic teaching paradigm, can positively influence the effectiveness of interventions for children with autism spectrum disorder (ASD). The purpose of this study was to compare two ABA intervention procedures, a naturalistic approach, Pivotal Response Treatment (PRT) with a structured ABA approach in a school setting. A Randomized Clinical Trial design using two groups of children, matched according to age, sex and mean length of utterance was used to compare the interventions. The data showed that the PRT approach was significantly more effective in improving targeted and untargeted areas after three months of intervention. The results are discussed in terms of variables that produce more rapid improvements in communication for children with ASD. PMID:24840596

Bioinformatics and variability in drug response: a protein structural perspective

PubMed Central

Lahti, Jennifer L.; Tang, Grace W.; Capriotti, Emidio; Liu, Tianyun; Altman, Russ B.

2012-01-01

Marketed drugs frequently perform worse in clinical practice than in the clinical trials on which their approval is based. Many therapeutic compounds are ineffective for a large subpopulation of patients to whom they are prescribed; worse, a significant fraction of patients experience adverse effects more severe than anticipated. The unacceptable risk–benefit profile for many drugs mandates a paradigm shift towards personalized medicine. However, prior to adoption of patient-specific approaches, it is useful to understand the molecular details underlying variable drug response among diverse patient populations. Over the past decade, progress in structural genomics led to an explosion of available three-dimensional structures of drug target proteins while efforts in pharmacogenetics offered insights into polymorphisms correlated with differential therapeutic outcomes. Together these advances provide the opportunity to examine how altered protein structures arising from genetic differences affect protein–drug interactions and, ultimately, drug response. In this review, we first summarize structural characteristics of protein targets and common mechanisms of drug interactions. Next, we describe the impact of coding mutations on protein structures and drug response. Finally, we highlight tools for analysing protein structures and protein–drug interactions and discuss their application for understanding altered drug responses associated with protein structural variants. PMID:22552919

Weak ventral striatal responses to monetary outcomes predict an unwillingness to resist cigarette smoking.

PubMed

Wilson, Stephen J; Delgado, Mauricio R; McKee, Sherry A; Grigson, Patricia S; MacLean, R Ross; Nichols, Travis T; Henry, Shannon L

2014-12-01

As a group, cigarette smokers exhibit blunted subjective, behavioral, and neurobiological responses to nondrug incentives and rewards, relative to nonsmokers. Findings from recent studies suggest, however, that there are large individual differences in the devaluation of nondrug rewards among smokers. Moreover, this variability appears to have significant clinical implications, since reduced sensitivity to nondrug rewards is associated with poorer smoking cessation outcomes. Currently, little is known about the neurobiological mechanisms that underlie these individual differences in the responsiveness to nondrug rewards. Here, we tested the hypothesis that individual variability in reward devaluation among smokers is linked to the functioning of the striatum. Specifically, functional magnetic resonance imaging was used to examine variability in the neural response to monetary outcomes in nicotine-deprived smokers anticipating an opportunity to smoke-circumstances found to heighten the devaluation of nondrug rewards by smokers in prior work. We also investigated whether individual differences in reward-related brain activity in those expecting to have access to cigarettes were associated with the degree to which the same individuals subsequently were willing to resist smoking in order to earn additional money. Our key finding was that deprived smokers who exhibited the weakest response to rewards (i.e., monetary gains) in the ventral striatum were least willing to refrain from smoking for monetary reinforcement. These results provide evidence that outcome-related signals in the ventral striatum serve as a marker for clinically meaningful individual differences in reward-motivated behavior among nicotine-deprived smokers.

Rheumatoid and psoriatic knee synovitis: clinical, grey scale, and power Doppler ultrasound assessment of the response to etanercept

PubMed Central

Fiocco, U; Ferro, F; Vezzu, M; Cozzi, L; Checchetto, C; Sfriso, P; Botsios, C; Ciprian, L; Armellin, G; Nardacchione, R; Piccoli, A; Todesco, S; Rubaltelli, L

2005-01-01

Objective: To determine the effect of tumour necrosis factor α (TNFα) blockade with etanercept in refractory knee joint synovitis (KJS) in rheumatoid and psoriatic arthritis, by local and systemic disease activity assessment and combined grey scale and power Doppler ultrasonographic monitoring. Methods: 27 knees affected by rheumatoid KJS (n = 12) and psoriatic KJS (n = 8) were assessed before receiving treatment and at 3 and 12 months' follow up. Time dependent clinical changes in disease activity were monitored by C reactive protein, erythrocyte sedimentation rate (ESR), global health status (GHS), and Ritchie (RAI) and knee joint articular (KJAI) indices; synovial changes were monitored by ultrasonographic and power Doppler indices for grey scale synovial thickening and for distinct intrasynovial vessel power Doppler flow configurations (fluid/synovium interface (F/SI-PD) and pannus/cartilage interface (P/CI-PD)). Interobserver and intraobserver variability of grey scale and power Doppler ultrasonographic was evaluated. Response to treatment was assessed by analysis of variance for repeated measures on clinical and ultrasonographic variables. Results: Rapid (3 months) reduction in F/SI-PD flow (p<0.001), parallel to reductions of C reactive protein (p<0.05), ESR (p<0.001), KJAI (p<0.002), RAI, and GHS (p<0.001), was sustained at 12 months when it was accompanied by reduction in both synovial thickening and P/CI-PD flow (p<0.001). No differences (ANOVA) were noted at baseline or at 12 months in clinical and ultrasonographic variables between either the rheumatoid or the psoriatic KJS groups. Conclusion: Grey scale and power Doppler ultrasonography are reliable measures of long term change in rheumatoid and psoriatic KJS disease activity in response to anti-TNFα treatment with etanercept. PMID:15567814

Childhood Depression: Relation to Adaptive, Clinical and Predictor Variables

PubMed Central

Garaigordobil, Maite; Bernarás, Elena; Jaureguizar, Joana; Machimbarrena, Juan M.

2017-01-01

The study had two goals: (1) to explore the relations between self-assessed childhood depression and other adaptive and clinical variables (2) to identify predictor variables of childhood depression. Participants were 420 students aged 7–10 years old (53.3% boys, 46.7% girls). Results revealed: (1) positive correlations between depression and clinical maladjustment, school maladjustment, emotional symptoms, internalizing and externalizing problems, problem behaviors, emotional reactivity, and childhood stress; and (2) negative correlations between depression and personal adaptation, global self-concept, social skills, and resilience (sense of competence and affiliation). Linear regression analysis including the global dimensions revealed 4 predictors of childhood depression that explained 50.6% of the variance: high clinical maladjustment, low global self-concept, high level of stress, and poor social skills. However, upon introducing the sub-dimensions, 9 predictor variables emerged that explained 56.4% of the variance: many internalizing problems, low family self-concept, high anxiety, low responsibility, low personal self-assessment, high social stress, few aggressive behaviors toward peers, many health/psychosomatic problems, and external locus of control. The discussion addresses the importance of implementing prevention programs for childhood depression at early ages. PMID:28572787

Improving B-cell depletion in systemic lupus erythematosus and rheumatoid arthritis.

PubMed

Mota, Pedro; Reddy, Venkat; Isenberg, David

2017-07-01

Rituximab-based B-cell depletion (BCD) therapy is effective in refractory rheumatoid arthritis (RA) and although used to treat patients with refractory systemic lupus erythematosus (SLE) in routine clinical practice, rituximab failed to meet the primary endpoints in two large randomised controlled trials (RCTs) of non-renal (EXPLORER) and renal (LUNAR) SLE. Areas covered: We review how BCD could be improved to achieve better clinical responses in RA and SLE. Insights into the variability in clinical response to BCD in RA and SLE may help develop new therapeutic strategies. To this end, a literature search was performed using the following terms: rheumatoid arthritis, systemic erythematosus lupus, rituximab and B-cell depletion. Expert commentary: Poor trial design may have, at least partly, contributed to the apparent lack of response to BCD in the two RCTs of patients with SLE. Enhanced B-cell depletion and/or sequential therapy with belimumab may improve clinical response at least in some patients with SLE.

The Computer Book of the Internal Medicine Resident: competence acquisition and achievement of learning objectives.

PubMed

Oristrell, J; Oliva, J C; Casanovas, A; Comet, R; Jordana, R; Navarro, M

2014-01-01

The Computer Book of the Internal Medicine resident (CBIMR) is a computer program that was validated to analyze the acquisition of competences in teams of Internal Medicine residents. To analyze the characteristics of the rotations during the Internal Medicine residency and to identify the variables associated with the acquisition of clinical and communication skills, the achievement of learning objectives and resident satisfaction. All residents of our service (n=20) participated in the study during a period of 40 months. The CBIMR consisted of 22 self-assessment questionnaires specific for each rotation, with items on services (clinical workload, disease protocolization, resident responsibilities, learning environment, service organization and teamwork) and items on educational outcomes (acquisition of clinical and communication skills, achievement of learning objectives, overall satisfaction). Associations between services features and learning outcomes were analyzed using bivariate and multivariate analysis. An intense clinical workload, high resident responsibilities and disease protocolization were associated with the acquisition of clinical skills. High clinical competence and teamwork were both associated with better communication skills. Finally, an adequate learning environment was associated with increased clinical competence, the achievement of educational goals and resident satisfaction. Potentially modifiable variables related with the operation of clinical services had a significant impact on the acquisition of clinical and communication skills, the achievement of educational goals, and resident satisfaction during the specialized training in Internal Medicine. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Using a handbook to improve nurses' continence care.

PubMed

Williams, K; Roe, B; Sindhu, F

Nursing care should be based on sound research evidence with demonstrated clinical effectiveness. Dissemination of this research evidence is, therefore, of paramount importance. A study using focus groups was undertaken during 1993-1994 to evaluate the dissemination of a clinical handbook for continence care to qualified nurses, in relation to reported nursing practice in care of the elderly wards/units in one health authority. A total of 124 nurses participated in the study and 98 variables were included. Improvements were recorded in nurses' responses between the pre-test and post-test for 84 (86 per cent) variables in the experimental group and 58 (59 per cent) in the control group. This demonstrates the positive value of the clinical handbook as a method of disseminating research evidence.

Review article: closed-loop systems in anesthesia: is there a potential for closed-loop fluid management and hemodynamic optimization?

PubMed

Rinehart, Joseph; Liu, Ngai; Alexander, Brenton; Cannesson, Maxime

2012-01-01

Closed-loop (automated) controllers are encountered in all aspects of modern life in applications ranging from air-conditioning to spaceflight. Although these systems are virtually ubiquitous, they are infrequently used in anesthesiology because of the complexity of physiologic systems and the difficulty in obtaining reliable and valid feedback data from the patient. Despite these challenges, closed-loop systems are being increasingly studied and improved for medical use. Two recent developments have made fluid administration a candidate for closed-loop control. First, the further description and development of dynamic predictors of fluid responsiveness provides a strong parameter for use as a control variable to guide fluid administration. Second, rapid advances in noninvasive monitoring of cardiac output and other hemodynamic variables make goal-directed therapy applicable for a wide range of patients in a variety of clinical care settings. In this article, we review the history of closed-loop controllers in clinical care, discuss the current understanding and limitations of the dynamic predictors of fluid responsiveness, and examine how these variables might be incorporated into a closed-loop fluid administration system.

Patient, physician and presentational influences on clinical decision making for breast cancer: results from a factorial experiment.

PubMed

McKinlay, J B; Burns, R B; Durante, R; Feldman, H A; Freund, K M; Harrow, B S; Irish, J T; Kasten, L E; Moskowitz, M A

1997-02-01

This study examines the influence of six patient characteristics (age, race, socioeconomic status, comorbidities, mobility and presentational style) and two physician characteristics (medical specialty and years of clinical experience) on physicians' clinical decision making behaviour in the evaluation treatment of an unknown and known breast cancer. Physicians' variability and certainty associated with diagnostic and treatment behaviour were also examined. Separate analyses explored the influence of these non-medical factors on physicians' cognitive processes. Using a fractional factorial design, 128 practising physicians were shown two videotaped scenarios and asked about possible diagnoses and medical recommendations. Results showed that physicians displayed considerable variability in response to several patient-based factors. Physician characteristics also emerged as important predictors of clinical behaviour, thus confirming the complexity of the medical decision-making process.

[Final clinical indications and etiology in 1,023 enucleations. Descriptive databank evaluation with SPSS software in variable response mode with dummy variables].

PubMed

Becker, H; Bialasiewicz, A A; Schaudig, U; Schäfer, H; von Domarus, D

2002-05-01

A new data bank developed for ophthalmopathology using a computer-generated, multidigital data code is expected to be able to accomplish complex clinicopathologic correlations of diagnoses and signs, as provided by (multiple) clinical events and histopathologically proven etiologies, and to facilitate the documentation of new data. In the ophthalmopathology laboratory 2890 eyes were examined between January 20, 1975 and December 12, 1996. The main diagnoses and patient data from this 22-year period were recorded. To facilitate the presentation of data, a 10-year period with eyes of 976 patients enucleated from December, 1986 to December, 1996 was chosen. Principal and secondary diagnoses served for establishing the data bank. The frequencies of successive histologic and clinical diagnoses were evaluated by a descriptive computing program using an SPSS-multi-response mode with dummy variables and a categorical variable listing of the software (SPSS version 10.0) classified as (a) non-filtered random, (b) filtered by multiple etiologies, and (c) filtered by multiple events. The principal groups (e.g., histologic diagnoses concerning etiology) and subgroups (e.g., trauma, neoplasia, surgery, systemic diseases, and inflammations) were defined and correlated with 798 separate diagnoses. From 11 diagnoses/events ascribed to the clinical cases, 11,198 namings resulted. Thus, a comparative study of complex etiologies and events leading to enucleation in different hospitals of a specific area may be performed using this electronic ophthalmopathologic data bank system. The complexity of rare disease and integration into a superimposed structure can be managed with this custom-made data bank. A chronologically and demographically oriented consideration of reasons for enucleation is thus feasible.

Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy.

PubMed

Xiong, Zhengming; Ampudia-Mesias, Elisabet; Shaver, Rob; Horbinski, Craig M; Moertel, Christopher L; Olin, Michael R

2016-09-01

There are over 400 ongoing clinical trials using tumor-derived vaccines. This approach is especially attractive for many types of brain tumors, including glioblastoma, yet so far the clinical response is highly variable. One contributor to poor response is CD200, which acts as a checkpoint blockade, inducing immune tolerance. We demonstrate that, in response to vaccination, glioma-derived CD200 suppresses the anti-tumor immune response. In contrast, a CD200 peptide inhibitor that activates antigen-presenting cells overcomes immune tolerance. The addition of the CD200 inhibitor significantly increased leukocyte infiltration into the vaccine site, cytokine and chemokine production, and cytolytic activity. Our data therefore suggest that CD200 suppresses the immune system's response to vaccines, and that blocking CD200 could improve the efficacy of cancer immunotherapy.

Improving clinical outcomes for naltrexone as a management of problem alcohol use

PubMed Central

Hulse, Gary K

2013-01-01

Despite being a relatively effective and safe treatment, the clinical management of alcohol abuse/dependence by oral naltrexone can be compromised due to the patient's non-compliance with daily use of this medication. Over the past decade an increasing body of research has suggested that the use of sustained release depot naltrexone preparations can overcome this issue and deliver improved clinical outcomes. However, at the same time, research findings from diverse areas of pharmacogenetics, neurobiology and behavioural psychology have also been converging to identify variables including genetic markers, patient psychosocial characteristics and drug use history differences, or clusters of these variables that play a major role in mediating the response of alcohol abuse/dependent persons to treatment by naltrexone. While this article does not attempt to review all available data pertaining to an individual alcohol dependent patient's response to treatment by naltrexone, it does identify relevant research areas and highlights the importance of data arising from them. The characterization of clinical markers, to identify those patients who are most likely to benefit from naltrexone and to tailor a more individual naltrexone treatment, will ultimately provide significant benefit to both patients and clinicians by optimizing treatment outcome. PMID:22946873

Combining censored and uncensored data in a U-statistic: design and sample size implications for cell therapy research.

PubMed

Moyé, Lemuel A; Lai, Dejian; Jing, Kaiyan; Baraniuk, Mary Sarah; Kwak, Minjung; Penn, Marc S; Wu, Colon O

2011-01-01

The assumptions that anchor large clinical trials are rooted in smaller, Phase II studies. In addition to specifying the target population, intervention delivery, and patient follow-up duration, physician-scientists who design these Phase II studies must select the appropriate response variables (endpoints). However, endpoint measures can be problematic. If the endpoint assesses the change in a continuous measure over time, then the occurrence of an intervening significant clinical event (SCE), such as death, can preclude the follow-up measurement. Finally, the ideal continuous endpoint measurement may be contraindicated in a fraction of the study patients, a change that requires a less precise substitution in this subset of participants.A score function that is based on the U-statistic can address these issues of 1) intercurrent SCE's and 2) response variable ascertainments that use different measurements of different precision. The scoring statistic is easy to apply, clinically relevant, and provides flexibility for the investigators' prospective design decisions. Sample size and power formulations for this statistic are provided as functions of clinical event rates and effect size estimates that are easy for investigators to identify and discuss. Examples are provided from current cardiovascular cell therapy research.

Rostral anterior cingulate cortex morphology predicts treatment response to internet-based CBT for depression

PubMed Central

Webb, Christian A.; Olson, Elizabeth A.; Killgore, William D.S.; Pizzagalli, Diego A.; Rauch, Scott L.; Rosso, Isabelle M.

2018-01-01

Background Rostral and subgenual anterior cingulate cortex (rACC and sgACC) activity and, to a lesser extent, volume have been shown to predict depressive symptom improvement across different antidepressant treatments. This study extends prior work by examining whether rACC and/or sgACC morphology predicts treatment response to internet-based cognitive behavioral therapy (iCBT) for major depressive disorder (MDD). This is the first study to examine neural predictors of response to iCBT. Methods Hierarchical linear modeling tested whether pre-treatment rACC and sgACC volumes predicted depressive symptom improvement during a 6-session (10-week) randomized clinical trial of iCBT (n = 35) vs. a monitored attention control (MAC; n = 38). Analyses also tested whether pre-treatment rACC and sgACC volumes differed between patients who achieved depression remission versus those who did not remit. Results Larger pre-treatment right rACC volume was a significant predictor of greater depressive symptom improvement in iCBT, even when controlling for demographic (age, gender, race) and clinical (baseline depression, anhedonia and anxiety) variables previously linked to treatment response. In addition, pre-treatment right rACC volume was larger among iCBT patients whose depression eventually remitted relative to those who did not remit. Corresponding analyses in the MAC group and for the sgACC were not significant. Conclusions rACC volume prior to iCBT demonstrated incremental predictive validity beyond clinical and demographic variables previously found to predict symptom improvement. Such findings may help inform our understanding of the mediating anatomy of iCBT and, if replicated, may suggest neural targets to augment treatment response (e.g., via modulation of rACC function). ClinicalTrials.gov Identifier NCT01598922 PMID:29486867

Metabolomic responses to lumacaftor/ivacaftor in cystic fibrosis.

PubMed

Kopp, Benjamin T; McCulloch, Scott; Shrestha, Chandra L; Zhang, Shuzhong; Sarzynski, Lisa; Woodley, Frederick W; Hayes, Don

2018-05-01

Cystic fibrosis (CF) is a life-limiting disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lumacaftor/Ivacaftor is a novel CFTR modulator approved for patients that are homozygous for Phe508del CFTR, but its clinical effectiveness varies amongst patients, making it difficult to determine clinical responders. Therefore, identifying biochemical biomarkers associated with drug response are clinically important for follow-up studies. Serum metabolomics was performed on twenty patients with CF pre- and 6-month post-Lumacaftor/Ivacaftor response via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Correlation with clinical variables was performed. Metabolomics analysis demonstrated 188 differentially regulated metabolites between patients pre- and post-Lumacaftor/Ivacaftor initiation, with a predominance of lipid and amino acid alterations. The top 30 metabolites were able to differentiate pre- and post-Lumacaftor/Ivacaftor status in greater than 90% of patients via a random-forest confusion matrix. Alterations in bile acids, phospholipids, and bacteria-associated metabolites were the predominant changes associated with drug response. Importantly, changes in metabolic patterns were associated with clinical responders. Selected key lipid and amino acid metabolic pathways were significantly affected by Lumacaftor/Ivacaftor initiation and similar pathways were affected in clinical responders. Targeted metabolomics may provide useful and relevant biomarkers of CFTR modulator responses. © 2018 Wiley Periodicals, Inc.

Attitudes towards informed consent, confidentiality, and substitute treatment decisions in southern African medical students: a case study from Zimbabwe.

PubMed

Hipshman, L

1999-08-01

This study explored the attitudes of biomedical science students (medical students) in a non-Western setting towards three medical ethics concepts that are based on fundamental Western culture ethical principles. A dichotomous (agree/disagree) response questionnaire was constructed using Western ethnocentric culture (WEC) based perspectives of informed consent, confidentiality, and substitute decision-making. Hypothesized WEC-Biased responses were assigned to the questionnaire's questions or propositions. A number of useful responses (169) were obtained from a large, cross-sectional, convenience sample of the MBChB students at the University of Zimbabwe Medical School. Statistical analysis described the differences in response patterns between the student's responses compared to the hypothesized WEC-Biased response. The effect of the nine independent variables on selected dependent variables (responses to certain questionnaire questions) was analyzed by stepwise logistic regression. Students concurred with the hypothesized WEC-Biased responses for two-thirds of the questionnaire items. This agreement included support for the role of legal advocacy in the substitute decision-making process. The students disagreed with the hypothesized WEC-Biased responses in several important medical ethics aspects. Most notably, the students indicated that persons with mental dysfunctions, as a class, were properly considered incompetent to make treatment decisions. None of the studied independent variables was often associated with students' responses, but training year was more frequently implicated than either ethnicity or gender. In order to develop internationally and culturally relevant medical ethics standards, non-Western perspectives ought to be acknowledged and incorporated. Two main areas for further efforts include: curriculum development in ethics reasoning and related clinical (medico-legal) decision-making processes that would be relevant to medical students from various cultures, and; the testing of models that could increase legal system input in the clinical process in societies with limited jurisprudence resources.

Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation

PubMed Central

Frey, N; Laveille, C; Paraire, M; Francillard, M; Holford, N H G; Jochemsen, Roeline

2003-01-01

Aims To study the relationship between the pharmacokinetics (PK) of gliclazide and its long-term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability. Methods A PKPD database of 634 Type 2 diabetic patients with a total of 5258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease-progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR. Results Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half-life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l−1 year−1 (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1-year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control. Conclusions This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long-term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control. PMID:12580986

The complex association between the antioxidant defense system and clinical status in early psychosis

PubMed Central

García, Saínza; Alberich, Susana; Martínez-Cengotitabengoa, Mónica; Arango, Celso; Castro-Fornieles, Josefina; Parellada, Mara; Baeza, Inmaculada; Moreno, Carmen; Micó, Juan Antonio; Berrocoso, Esther; Graell, Montserrat; Otero, Soraya; Simal, Tatiana

2018-01-01

Oxidative stress is a pathophysiological mechanism potentially involved in psychiatric disorders. The objective of this study was to assess the relationship between total antioxidant status (TAS) and the functional status of patients with a first episode of psychosis at the onset of the disease. For this purpose, a sample of 70 patients aged between 9 and 17 years with a first episode of psychosis were followed up for a period of two years. Blood samples were drawn to measure TAS levels at three time points: at baseline, at one year, and at two years. Clinical symptoms and functioning were also assessed at the same time points using various scales. Linear regression analysis was performed to investigate the relationship between TAS and clinical status at each assessment, adjusting for potential confounding factors. The distribution of clinical variables was grouped in different percentiles to assess the dose-response in the relation between clinical variables and TAS. At baseline, patient's score on Children's Global Assessment Scale (CGAS) was directly and significantly associated with TAS with a monotonic increase in percentiles, and surprising this association was reversed after one and two years of follow-up with a monotonic decrease. In summary at the onset of the illness, TAS is positively related to clinical status, whereas as the illness progresses this correlation is reversed and becomes negative. This may be the result of an adaptive response. PMID:29698400

Use of rituximab as a treatment for systemic lupus erythematosus: retrospective review

PubMed Central

Machado, Roberta Ismael Lacerda; Scheinberg, Morton Aaron; de Queiroz, Maria Yvone Carlos Formiga; de Brito, Danielle Christinne Soares Egypto; Guimarães, Maria Fernanda Brandao de Resende; Giovelli, Raquel Altoé; Freire, Eutilia Andrade Medeiros

2014-01-01

ABSTRACT Objective: To report the experience in three Brazilian institutions with the use of rituximab in patients with different clinical forms of lupus erythematosus systemic in activity. Methods: The study consisted of a sample of 17 patients with LES, who were already being treated, but that at some stage of the disease showed refractory symptoms. The patients were subdivided into groups according to the clinical manifestation, and the responses for the use of rituximab were rated as complete, partial or no response. Data were collected through a spreadsheet, and used specific parameters for each group. The treatment was carried on by using therapeutic dose of 1g, and repeating the infusion within an interval of 15 days. Results: The clinical responses to rituximab of the group only hematological and of the group only osteoarticular were complete in all cases. In the renal group there was a clinical complete response, two partial and one absent. In the renal and hematological group complete response, there was one death and a missing response. The pulmonary group presented a complete response and two partial. Conclusion: The present study demonstrated that rituximab can bring benefits to patients with lupus erythematosus systemic, with good tolerability and mild side effects; it presented, however, variable response according to the system affected. PMID:24728244

Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

PubMed Central

Jiang, Xi-Ling; Samant, Snehal; Lesko, Lawrence J.; Schmidt, Stephan

2017-01-01

Acute coronary syndromes (ACS) remain life-threatening disorders that are associated with high morbidity and mortality. Dual-antiplatelet therapy with aspirin and clopidogrel has shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in response to clopidogrel treatment in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19 that affect clopidogrel’s pharmacokinetics. While FDA has issued a boxed warning for CYP2C19 poor metabolizers due to a potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug-drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability and how they are interrelated is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence clopidogrel’s pharmacokinetics and pharmacodynamics and how they mechanistically contribute to inter-individual differences in response to clopidogrel treatment. PMID:25559342

Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients

PubMed Central

de Winter, Brenda C. M.; Masman, Anniek D.; van Dijk, Monique; Baar, Frans P. M.; Tibboel, Dick; Koch, Birgit C. P.; van Gelder, Teun; Mathot, Ron A. A.

2017-01-01

Aims Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response. Method A population PD analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check. Results The effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and interindividual variability on the overall effect. The EC50 value was 68.7 μg l–1 for a Ramsay score of 3–5 and 117.1 μg l–1 for a Ramsay score of 6. Comedication with haloperidol was the only significant covariate. The visual predictive check of the final model showed good model predictability. Conclusion We were able to describe the clinical response to midazolam accurately. As expected, there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication, as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure. PMID:28960387

Clinical and genetic characterization of a founder PKHD1 mutation in Afrikaners with ARPKD.

PubMed

Lambie, Lindsay; Amin, Rasheda; Essop, Fahmida; Cnaan, Avital; Krause, Amanda; Guay-Woodford, Lisa M

2015-02-01

Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) occurs in 1:20,000 live births. Disease expression is widely variable, with approximately 30 % of affected neonates dying perinatally, while others survive to adulthood. Mutations at the PKHD1 locus are responsible for all typical presentations. The objectives of this study were to define the clinical and genetic characteristics in a cohort of South African patients of Afrikaner origin, a population with a high prevalence of ARPKD. DNA from the cohort was analyzed for background haplotypes and the p.M627K mutation previously identified in two unrelated Afrikaner patients. The clinical phenotype of the homozygous group was characterized. Analysis of 36 Afrikaner families revealed that 27 patients, from 24 (67 %) families, were homozygous for the p.M627K substitution, occurring on a common haplotype. The clinical phenotype of the homozygous individuals was variable. Our data provide strong evidence that the p.M627K substitution is a founder mutation in the Afrikaner population and can be used for streamlined diagnostic testing for at-risk pregnancies. The observed clinical variability suggests that disease expression is modulated by other genetic loci or by gene-environment interactions.

Optimization of Answer Keys for Script Concordance Testing: Should We Exclude Deviant Panelists, Deviant Responses, or Neither?

ERIC Educational Resources Information Center

Gagnon, Robert; Lubarsky, Stuart; Lambert, Carole; Charlin, Bernard

2011-01-01

The Script Concordance Test (SCT) uses a panel-based, aggregate scoring method that aims to capture the variability of responses of experienced practitioners to particular clinical situations. The use of this type of scoring method is a key determinant of the tool's discriminatory power, but deviant answers could potentially diminish the…

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine.

PubMed

El Rouby, Nihal; Lima, John J; Johnson, Julie A

2018-04-01

Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

PubMed Central

El Rouby, Nihal; Lima, John J.; Johnson, Julie A.

2018-01-01

ABSTRACT Introduction: Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs. PMID:29620484

Understanding data requirements of retrospective studies.

PubMed

Shenvi, Edna C; Meeker, Daniella; Boxwala, Aziz A

2015-01-01

Usage of data from electronic health records (EHRs) in clinical research is increasing, but there is little empirical knowledge of the data needed to support multiple types of research these sources support. This study seeks to characterize the types and patterns of data usage from EHRs for clinical research. We analyzed the data requirements of over 100 retrospective studies by mapping the selection criteria and study variables to data elements of two standard data dictionaries, one from the healthcare domain and the other from the clinical research domain. We also contacted study authors to validate our results. The majority of variables mapped to one or to both of the two dictionaries. Studies used an average of 4.46 (range 1-12) data element types in the selection criteria and 6.44 (range 1-15) in the study variables. The most frequently used items (e.g., procedure, condition, medication) are often available in coded form in EHRs. Study criteria were frequently complex, with 49 of 104 studies involving relationships between data elements and 22 of the studies using aggregate operations for data variables. Author responses supported these findings. The high proportion of mapped data elements demonstrates the significant potential for clinical data warehousing to facilitate clinical research. Unmapped data elements illustrate the difficulty in developing a complete data dictionary. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Single nucleotide polymorphisms in multiple sclerosis: disease susceptibility and treatment response biomarkers.

PubMed

Pravica, Vera; Popadic, Dusan; Savic, Emina; Markovic, Milos; Drulovic, Jelena; Mostarica-Stojkovic, Marija

2012-04-01

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by unpredictable and variable clinical course. Etiology of MS involves both genetic and environmental factors. New technologies identified genetic polymorphisms associated with MS susceptibility among which immunologically relevant genes are significantly overrepresented. Although individual genes contribute only a small part to MS susceptibility, they might be used as biomarkers, thus helping to identify accurate diagnosis, predict clinical disease course and response to therapy. This review focuses on recent progress in research on MS genetics with special emphasis on the possibility to use single nucleotide polymorphism of candidate genes as biomarkers of susceptibility to disease and response to therapy.

Some implications for the clinical use of music facilitated imagery.

PubMed

Peach, S C

1984-01-01

In this study, Helen Bonny's Guided Imagery and Music technique provided the base experience for questionnaire responses from short-term psychiatric inpatients, students, and staff (total/n = 107). Independent measures of age range, sex, medication type, and recent relaxation practice were compared statistically with dependent responses of skin temperature, perceived ability to relax, production of images, and perceived helpfulness of the experience. Results demonstrated increases in skin temperature and relaxation perception and defined the average experience as manifesting three concurrent imagery modes. Among the man independent-dependent variable relationships, some significant differences in mean responses were present. These differences and their possible clinical implications are discussed; further research in the area, including replication, is recommended.

Predicting Treatment Response to Intra-arterial Therapies for Hepatocellular Carcinoma with the Use of Supervised Machine Learning-An Artificial Intelligence Concept.

PubMed

Abajian, Aaron; Murali, Nikitha; Savic, Lynn Jeanette; Laage-Gaupp, Fabian Max; Nezami, Nariman; Duncan, James S; Schlachter, Todd; Lin, MingDe; Geschwind, Jean-François; Chapiro, Julius

2018-06-01

To use magnetic resonance (MR) imaging and clinical patient data to create an artificial intelligence (AI) framework for the prediction of therapeutic outcomes of transarterial chemoembolization by applying machine learning (ML) techniques. This study included 36 patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization. The cohort (age 62 ± 8.9 years; 31 men; 13 white; 24 Eastern Cooperative Oncology Group performance status 0, 10 status 1, 2 status 2; 31 Child-Pugh stage A, 4 stage B, 1 stage C; 1 Barcelona Clinic Liver Cancer stage 0, 12 stage A, 10 stage B, 13 stage C; tumor size 5.2 ± 3.0 cm; number of tumors 2.6 ± 1.1; and 30 conventional transarterial chemoembolization, 6 with drug-eluting embolic agents). MR imaging was obtained before and 1 month after transarterial chemoembolization. Image-based tumor response to transarterial chemoembolization was assessed with the use of the 3D quantitative European Association for the Study of the Liver (qEASL) criterion. Clinical information, baseline imaging, and therapeutic features were used to train logistic regression (LR) and random forest (RF) models to predict patients as treatment responders or nonresponders under the qEASL response criterion. The performance of each model was validated using leave-one-out cross-validation. Both LR and RF models predicted transarterial chemoembolization treatment response with an overall accuracy of 78% (sensitivity 62.5%, specificity 82.1%, positive predictive value 50.0%, negative predictive value 88.5%). The strongest predictors of treatment response included a clinical variable (presence of cirrhosis) and an imaging variable (relative tumor signal intensity >27.0). Transarterial chemoembolization outcomes in patients with HCC may be predicted before procedures by combining clinical patient data and baseline MR imaging with the use of AI and ML techniques. Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.

Saxagliptin co-therapy in C-peptide negative Type 1 diabetes does not improve counter-regulatory responses to hypoglycaemia.

PubMed

George, P S; McCrimmon, R J

2016-09-01

To test the hypothesis that dipeptidyl peptidase-4 inhibition in C-peptide negative Type 1 diabetes would reduce glucose variability and exposure to hypoglycaemia and therefore may indirectly enhance counter-regulatory responses to subsequent hypoglycaemia. We conducted a 12-week double-blind, randomized, placebo-controlled crossover study. The study was conducted in a tertiary hospital outpatient clinic, with additional studies performed in a clinical research centre. After obtaining informed consent, we recruited 14 subjects with moderately well controlled Type 1 diabetes (HbA1c 64 ± 2 mmol/mol) of long duration (20.5 ± 2.7 years). The subjects received 12 weeks' therapy with oral saxagliptin (5 mg) or placebo. Glucose variability, assessed via continuous glucose monitoring, together with frequency of hypoglycaemia, hypoglycaemia awareness and symptomatic, cognitive and counter-regulatory hormone responses to experimental hypoglycaemia, were assessed. Additional outcome measures included HbA1c level, weight, total daily insulin dose and adverse events. Saxagliptin co-therapy did not reduce glucose variability (low blood glucose index, average daily risk range), hypoglycaemia frequency or awareness and did not improve counter-regulatory hormonal responses during experimental hypoglycaemia (area under the curve for adrenaline 25 775 vs. 24 454, for placebo vs saxagliptin, respectively; P = 0.76). No additional benefit of dipeptidyl peptidase-4 inhibition co-therapy with saxagliptin in the management of Type 1 diabetes was observed. © 2015 Diabetes UK.

Latent variables underlying the memory beliefs of Chartered Clinical Psychologists, Hypnotherapists and undergraduate students.

PubMed

Ost, James; Easton, Simon; Hope, Lorraine; French, Christopher C; Wright, Daniel B

2017-01-01

In courts in the United Kingdom, understanding of memory phenomena is often assumed to be a matter of common sense. To test this assumption 337 UK respondents, consisting of 125 Chartered Clinical Psychologists, 88 individuals who advertised their services as Hypnotherapists (HTs) in a classified directory, the Yellow Pages TM , and 124 first year undergraduate psychology students, completed a questionnaire that assessed their knowledge of 10 memory phenomena about which there is a broad scientific consensus. HTs' responses were the most inconsistent with the scientific consensus, scoring lowest on six of these ten items. Principal Components Analysis indicated two latent variables - reflecting beliefs about memory quality and malleability - underlying respondents' responses. In addition, respondents were asked to rate their own knowledge of the academic memory literature in general. There was no significant relationship between participants' self reported knowledge and their actual knowledge (as measured by their responses to the 10-item questionnaire). There was evidence of beliefs among the HTs that could give rise to some concern (e.g., that early memories from the first year of life are accurately stored and are retrievable).

Corticosteroid therapy in ulcerative colitis: Clinical response and predictors

PubMed Central

Li, Jin; Wang, Fan; Zhang, Hong-Jie; Sheng, Jian-Qiu; Yan, Wen-Feng; Ma, Min-Xing; Fan, Ru-Ying; Gu, Fang; Li, Chuan-Feng; Chen, Da-Fan; Zheng, Ping; Gu, Yu-Pei; Cao, Qian; Yang, Hong; Qian, Jia-Ming; Hu, Pin-Jin; Xia, Bing

2015-01-01

AIM: To evaluate clinical response to initial corticosteroid (CS) treatment in Chinese ulcerative colitis patients (UC) and identify predictors of clinical response. METHODS: Four hundred and twenty-three UC patients who were initially treated with oral or intravenous CS from 2007 to 2011 were retrospectively reviewed at eight inflammatory bowel disease centers in China, and 101 consecutive cases with one-year follow-up were analyzed further for clinical response and predictors. Short-term outcomes within one month were classified as primary response and primary non-response. Long-term outcomes within one year were classified as prolonged CS response, CS dependence and secondary non-response. CS refractoriness included primary and secondary non-response. Multivariate analyses were performed to identify predictors associated with clinical response. RESULTS: Within one month, 95.0% and 5.0% of the cases were classified into primary response and non-response, respectively. Within one year, 41.6% of cases were assessed as prolonged CS response, while 49.5% as CS dependence and 4.0% as secondary non-response. The rate of CS refractoriness was 8.9%, while the cumulative rate of surgery was 6.9% within one year. After multivariate analysis of all the variables, tenesmus was found to be a negative predictor of CS dependence (OR = 0.336; 95%CI: 0.147-0.768; P = 0.013) and weight loss as a predictor of CS refractoriness (OR = 5.662; 95%CI: 1.111-28.857; P = 0.040). After one-month treatment, sustained high Sutherland score (≥ 6) also predicted CS dependence (OR = 2.347; 95%CI: 0.935-5.890; P = 0.014). CONCLUSION: Tenesmus was a negative predictor of CS dependence, while weight loss and sustained high Sutherland score were strongly associated with poor CS response. PMID:25780299

Vantage sensitivity: a framework for individual differences in response to psychological intervention.

PubMed

de Villiers, Bernadette; Lionetti, Francesca; Pluess, Michael

2018-06-01

People differ significantly in their response to psychological intervention, with some benefitting more from treatment than others. According to the recently proposed theoretical framework of vantage sensitivity, some of this variability may be due to individual differences in environmental sensitivity, the inherent ability to register, and process external stimuli. In this paper, we apply the vantage sensitivity framework to the field of psychiatry and clinical psychology, proposing that some people are more responsive to the positive effects of psychological intervention due to heightened sensitivity. After presenting theoretical frameworks related to environmental sensitivity, we review a selection of recent studies reporting individual differences in the positive response to psychological intervention. A growing number of studies report that some people benefit more from psychological intervention than others as a function of genetic, physiological, and psychological characteristics. These studies support the vantage sensitivity proposition that treatment response is influenced by factors associated with heightened sensitivity to environmental influences. More recently, studies have also shown that sensitivity can be measured with a short questionnaire which appears to predict the response to psychological intervention. Vantage sensitivity is a framework with significant relevance for our understanding of widely observed heterogeneity in treatment response. It suggests that variability in response to treatment is partly influenced by people's differing capacity for environmental sensitivity, which can be measured with a short questionnaire. Application of the vantage sensitivity framework to psychiatry and clinical psychology may improve our knowledge regarding when, how, and for whom interventions work.

Predicting Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer with Textural Features Derived from Pretreatment 18F-FDG PET/CT Imaging.

PubMed

Beukinga, Roelof J; Hulshoff, Jan B; van Dijk, Lisanne V; Muijs, Christina T; Burgerhof, Johannes G M; Kats-Ugurlu, Gursah; Slart, Riemer H J A; Slump, Cornelis H; Mul, Véronique E M; Plukker, John Th M

2017-05-01

Adequate prediction of tumor response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer (EC) patients is important in a more personalized treatment. The current best clinical method to predict pathologic complete response is SUV max in 18 F-FDG PET/CT imaging. To improve the prediction of response, we constructed a model to predict complete response to nCRT in EC based on pretreatment clinical parameters and 18 F-FDG PET/CT-derived textural features. Methods: From a prospectively maintained single-institution database, we reviewed 97 consecutive patients with locally advanced EC and a pretreatment 18 F-FDG PET/CT scan between 2009 and 2015. All patients were treated with nCRT (carboplatin/paclitaxel/41.4 Gy) followed by esophagectomy. We analyzed clinical, geometric, and pretreatment textural features extracted from both 18 F-FDG PET and CT. The current most accurate prediction model with SUV max as a predictor variable was compared with 6 different response prediction models constructed using least absolute shrinkage and selection operator regularized logistic regression. Internal validation was performed to estimate the model's performances. Pathologic response was defined as complete versus incomplete response (Mandard tumor regression grade system 1 vs. 2-5). Results: Pathologic examination revealed 19 (19.6%) complete and 78 (80.4%) incomplete responders. Least absolute shrinkage and selection operator regularization selected the clinical parameters: histologic type and clinical T stage, the 18 F-FDG PET-derived textural feature long run low gray level emphasis, and the CT-derived textural feature run percentage. Introducing these variables to a logistic regression analysis showed areas under the receiver-operating-characteristic curve (AUCs) of 0.78 compared with 0.58 in the SUV max model. The discrimination slopes were 0.17 compared with 0.01, respectively. After internal validation, the AUCs decreased to 0.74 and 0.54, respectively. Conclusion: The predictive values of the constructed models were superior to the standard method (SUV max ). These results can be considered as an initial step in predicting tumor response to nCRT in locally advanced EC. Further research in refining the predictive value of these models is needed to justify omission of surgery. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

[Pain and workplace. Sociodemographic variables influence in therapeutic response and labor productivity].

PubMed

Vicente-Herrero, M T; López-González, Á A; Ramírez Iñiguez de la Torre, M V; Capdevila García, L M; Terradillos García, M J; Aguilar Jiménez, E

2016-09-01

Pain is a major cause of medical consultation. The complexity of managing it is due to its long duration and intensity, and it sometimes requires a combination of multiple drugs. The objective of this study is to assess the use of drugs for pain in workers, the clinical response obtained, its influence on estimating work productivity, its relationship to sociodemographic variables, and the type of drug used. A cross-sectional study on 1,080 workers, aged 18-65 years, during periodic surveys to monitor their health in companies in the service sector in Spain. Treatments used, clinical efficacy, influence on work productivity and sociodemographic variables (age, gender) are evaluated. The Brief Pain Inventory questionnaire, validated for Spain, was used to assess pain, and the SPSS(®) 20.0 package for the statistical analysis. NSAIDs and simple analgesics have higher percentages of improvement in pain (P=.032 and P<.0001, respectively). Men respond better to NSAIDs, and women to simple analgesics. Improved productivity is higher in men than in women (P=.042). No significant differences were observed for age, pain improvement or productivity, except in those over 55 years. The analgesic prescription pain conditions must consider the age and gender of the patient, as well as the type of drug. The choice of drug should be based on the aetiology and aspects unrelated to the clinical variables, such as sociodemographic, work or psychosocial. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Multi- and monofractal indices of short-term heart rate variability.

PubMed

Fischer, R; Akay, M; Castiglioni, P; Di Rienzo, M

2003-09-01

Indices of heart rate variability (HRV) based on fractal signal models have recently been shown to possess value as predictors of mortality in specific patient populations. To develop more powerful clinical indices of HRV based on a fractal signal model, the study investigated two HRV indices based on a monofractal signal model called fractional Brownian motion and an index based on a multifractal signal model called multifractional Brownian motion. The performance of the indices was compared with an HRV index in common clinical use. To compare the indices, 18 normal subjects were subjected to postural changes, and the indices were compared on their ability to respond to the resulting autonomic events in HRV recordings. The magnitude of the response to postural change (normalised by the measurement variability) was assessed by analysis of variance and multiple comparison testing. Four HRV indices were investigated for this study: the standard deviation of all normal R-R intervals; an HRV index commonly used in the clinic; detrended fluctuation analysis, an HRV index found to be the most powerful predictor of mortality in a study of patients with depressed left ventricular function; an HRV index developed using the maximum likelihood estimation (MLE) technique for a monofractal signal model; and an HRV index developed for the analysis of multifractional Brownian motion signals. The HRV index based on the MLE technique was found to respond most strongly to the induced postural changes (95% CI). The magnitude of its response (normalised by the measurement variability) was at least 25% greater than any of the other indices tested.

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

NASA Astrophysics Data System (ADS)

El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

2006-11-01

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

Sex and Gender Differences in the Outcomes of Vaccination over the Life Course.

PubMed

Flanagan, Katie L; Fink, Ashley L; Plebanski, Magdalena; Klein, Sabra L

2017-10-06

Both sex (i.e., biological differences) and gender (i.e., social or cultural influences) impact vaccine acceptance, responses, and outcomes. Clinical data illustrate that among children, young adults, and aged individuals, males and females differ in vaccine-induced immune responses, adverse events, and protection. Although males are more likely to receive vaccines, following vaccination, females typically develop higher antibody responses and report more adverse effects of vaccination than do males. Human, nonhuman animal, and in vitro studies reveal numerous immunological, genetic, hormonal, and environmental factors that differ between males and females and contribute to sex- and gender-specific vaccine responses and outcomes. Herein, we address the impact of sex and gender variables that should be considered in preclinical and clinical studies of vaccines.

Supraspinal Control Predicts Locomotor Function and Forecasts Responsiveness to Training after Spinal Cord Injury

PubMed Central

Field-Fote, Edelle C.; Yang, Jaynie F.; Basso, D. Michele; Gorassini, Monica A.

2017-01-01

Abstract Restoration of walking ability is an area of great interest in the rehabilitation of persons with spinal cord injury. Because many cortical, subcortical, and spinal neural centers contribute to locomotor function, it is important that intervention strategies be designed to target neural elements at all levels of the neuraxis that are important for walking ability. While to date most strategies have focused on activation of spinal circuits, more recent studies are investigating the value of engaging supraspinal circuits. Despite the apparent potential of pharmacological, biological, and genetic approaches, as yet none has proved more effective than physical therapeutic rehabilitation strategies. By making optimal use of the potential of the nervous system to respond to training, strategies can be developed that meet the unique needs of each person. To complement the development of optimal training interventions, it is valuable to have the ability to predict future walking function based on early clinical presentation, and to forecast responsiveness to training. A number of clinical prediction rules and association models based on common clinical measures have been developed with the intent, respectively, to predict future walking function based on early clinical presentation, and to delineate characteristics associated with responsiveness to training. Further, a number of variables that are correlated with walking function have been identified. Not surprisingly, most of these prediction rules, association models, and correlated variables incorporate measures of volitional lower extremity strength, illustrating the important influence of supraspinal centers in the production of walking behavior in humans. PMID:27673569

Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD).

PubMed

Chen, Tina H; Wu, Steve W; Welge, Jeffrey A; Dixon, Stephan G; Shahana, Nasrin; Huddleston, David A; Sarvis, Adam R; Sallee, Floyd R; Gilbert, Donald L

2014-12-01

Clinical trials in children with attention-deficit hyperactivity disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine. The objective of this study was to determine whether transcranial magnetic stimulation-evoked short interval cortical inhibition might be a biomarker predicting, or correlating with, clinical atomoxetine response. At baseline and after 4 weeks of atomoxetine treatment in 7- to 12-year-old children with ADHD, transcranial magnetic stimulation short interval cortical inhibition was measured, blinded to clinical improvement. Primary analysis was by multivariate analysis of covariance. Baseline short interval cortical inhibition did not predict clinical responses. However, paradoxically, after 4 weeks of atomoxetine, mean short interval cortical inhibition was reduced 31.9% in responders and increased 6.1% in nonresponders (analysis of covariance t 41 = 2.88; P = .0063). Percentage reductions in short interval cortical inhibition correlated with reductions in the ADHD Rating Scale (r = 0.50; P = .0005). In children ages 7 to 12 years with ADHD treated with atomoxetine, improvements in clinical symptoms are correlated with reductions in motor cortex short interval cortical inhibition. © The Author(s) 2014.

Gaze Response to Dyadic Bids at 2 Years Related to Outcomes at 3 Years in Autism Spectrum Disorders: A Subtyping Analysis

ERIC Educational Resources Information Center

Campbell, Daniel J.; Shic, Frederick; Macari, Suzanne; Chawarska, Katarzyna

2014-01-01

Variability in attention towards direct gaze and child-directed speech may contribute to heterogeneity of clinical presentation in toddlers with autism spectrum disorders (ASD). To evaluate this hypothesis, we clustered sixty-five 20-month-old toddlers with ASD based on their visual responses to dyadic cues for engagement, identifying three…

Inter- and Intra-individual Variability in Response to Transcranial Direct Current Stimulation (tDCS) at Varying Current Intensities.

PubMed

Chew, Taariq; Ho, Kerrie-Anne; Loo, Colleen K

2015-01-01

Translation of transcranial direct current stimulation (tDCS) from research to clinical practice is hindered by a lack of consensus on optimal stimulation parameters, significant inter-individual variability in response, and in sufficient intra-individual reliability data. Inter-individual differences in response to anodal tDCS at a range of current intensities were explored. Intra-individual reliability in response to anodal tDCS across two identical sessions was also investigated. Twenty-nine subjects participated in a crossover study. Anodal-tDCS using four different current intensities (0.2, 0.5, 1 and 2 mA), with an anode size of 16 cm2, was tested. The 0.5 mA condition was repeated to assess intra-individual variability. TMS was used to elicit 40 motor-evoked potentials (MEPs) before 10 min of tDCS, and 20 MEPs at four time-points over 30 min following tDCS. ANOVA revealed no main effect of TIME for all conditions except the first 0.5 mA condition, and no differences in response between the four current intensities. Cluster analysis identified two clusters for the 0.2 and 2 mA conditions only. Frequency distributions based on individual subject responses (excitatory, inhibitory or no response) to each condition indicate possible differential responses between individuals to different current intensities. Test-retest reliability was negligible (ICC(2,1) = -0.50). Significant inter-individual variability in response to tDCS across a range of current intensities was found. 2 mA and 0.2 mA tDCS were most effective at inducing a distinct response. Significant intra-individual variability in response to tDCS was also found. This has implications for interpreting results of single-session tDCS experiments. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling

PubMed Central

Dick, Thomas E.; Molkov, Yaroslav I.; Nieman, Gary; Hsieh, Yee-Hsee; Jacono, Frank J.; Doyle, John; Scheff, Jeremy D.; Calvano, Steve E.; Androulakis, Ioannis P.; An, Gary; Vodovotz, Yoram

2012-01-01

Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma. PMID:22783197

Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling.

PubMed

Dick, Thomas E; Molkov, Yaroslav I; Nieman, Gary; Hsieh, Yee-Hsee; Jacono, Frank J; Doyle, John; Scheff, Jeremy D; Calvano, Steve E; Androulakis, Ioannis P; An, Gary; Vodovotz, Yoram

2012-01-01

Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma.

Patient adherence to prescribed antimicrobial drug dosing regimens.

PubMed

Vrijens, Bernard; Urquhart, John

2005-05-01

The aim of this article is to review current knowledge about the clinical impact of patients' variable adherence to prescribed anti-infective drug dosing regimens, with the aim of renewing interest and exploration of this important but largely neglected area of therapeutics. Central to the estimation of a patient's adherence to a prescribed drug regimen is a reliably compiled drug dosing history. Electronic monitoring methods have emerged as the virtual 'gold standard' for compiling drug dosing histories in ambulatory patients. Reliably compiled drug dosing histories are consistently downwardly skewed, with varying degrees of under-dosing. In particular, the consideration of time intervals between protease inhibitor doses has revealed that ambulatory patients' variable execution of prescribed dosing regimens is a leading source of variance in viral response. Such analyses reveal the need for a new discipline, called pharmionics, which is the study of how ambulatory patients use prescription drugs. Properly analysed, reliable data on the time-course of patients' actual intake of prescription drugs can eliminate a major source of unallocated variance in drug responses, including the non-response that occurs and is easily misinterpreted when a patient's complete non-execution of a prescribed drug regimen is unrecognized clinically. As such, reliable compilation of ambulatory patients' drug dosing histories has the promise of being a key step in reducing unallocated variance in drug response and in improving the informational yield of clinical trials. It is also the basis for sound, measurement-guided steps taken to improve a patient's execution of a prescribed dosing regimen.

THE PEDIATRIC RHEUMATOLOGY INTERNATIONAL TRIALS ORGANIZATION PROVISIONAL CRITERIA FOR THE EVALUATION OF RESPONSE TO THERAPY IN JUVENILE DERMATOMYOSITIS

PubMed Central

Ruperto, Nicolino; Pistorio, Angela; Ravelli, Angelo; Rider, Lisa G.; Pilkington, Clarissa; Oliveira, Sheila; Wulffraat, Nico; Espada, Graciela; Garay, Stella; Cuttica, Ruben; Hofer, Michael; Quartier, Pierre; Melo-Gomes, Jose; Reed, Ann M.; Wierzbowska, Malgorzata; Feldman, Brian M.; Harjacek, Miroslav; Huppertz, Hans-Iko; Nielsen, Susan; Flato, Berit; Lahdenne, Pekka; Michels, Harmut; Murray, Kevin J.; Punaro, Lynn; Rennebohm, Robert; Russo, Ricardo; Balogh, Zsolt; Rooney, Madeleine; Pachman, Lauren M.; Wallace, Carol; Hashkes, Philip; Lovell, Daniel J.; Giannini, Edward H.; Martini, Alberto

2010-01-01

Objective To develop a provisional definition for the evaluation of response to therapy in juvenile dermatomyositis (JDM) based on the PRINTO JDM core set of variables. Methods Thirty-seven experienced pediatric rheumatologists from 27 countries, achieved consensus on 128 difficult patient profiles as clinically improved or not improved using a stepwise approach (patients rating, statistical analysis, definition selection). Using the physicians’ consensus ratings as the “gold-standard measure”, chi-square, sensitivity, specificity, false positive and negative rate, area under the ROC, and kappa agreement for candidate definitions of improvement were calculated. Definitions with kappa >0.8 were multiplied with the face validity score to select the top definitions. Results The top definition of improvement was: at least 20% improvement from baseline in 3/6 core set variables with no more than 1 of the remaining worsening by more than 30%, which cannot be muscle strength. The second highest scoring definition was at least 20% improvement from baseline in 3/6 core set variables with no more than 2 of the remaining worsening by more than 25%, which cannot be muscle strength which is definition P1 selected by the IMACS group. The third is similar to the second with the maximum amount of worsening set to 30%. This indicates convergent validity of the process. Conclusion we proposes a provisional data driven definition of improvement that reflects well the consensus rating of experienced clinicians, which incorporates clinically meaningful change in core set variables in a composite endpoint for the evaluation of global response to therapy in JDM. PMID:20583105

Attention-deficit/hyperactivity disorder children exhibit an impaired accommodative response.

PubMed

Redondo, Beatriz; Vera, Jesús; Molina, Rubén; García, José Antonio; Ouadi, Miriam; Muñoz-Hoyos, Antonio; Jiménez, Raimundo

2018-05-01

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common paediatric neurobehavioural disorders causing multiple functional impairments in children. Based on the relationship between the neural system that controls attention and ocular dynamics, the present study compares the magnitude and variability of accommodation between a group of non-medicated ADHD children and an age-matched control group. The magnitude and variability of the accommodative response were objectively measured in 36 children using the WAM-5500 autorefractometer for 90 consecutive seconds at three static viewing distances (500, 40, and 20 cm). Participants were divided into ADHD (n = 18) or control (n = 18) groups based on clinically validated criteria. Children with ADHD exhibited higher lags of accommodation (p = 0.024), increasing at closer viewing distances, in comparison to the control group. Marginal statistical differences were found for the variability of accommodation (p = 0.066), with the ADHD group showing a trend towards higher variability. Our analysis showed that the magnitude and variability of accommodation did not vary over time between groups (p > 0.05). Our data suggest that children with ADHD have a less accurate accommodative response. These results provide a new ocular index that could help to clarify the relationship between accommodative response and attentional deficits, which could have a direct impact on the academic, cognitive, and visual performance of ADHD children.

Personality and the subjective assessment of hearing aids.

PubMed

Cox, R M; Alexander, G C; Gray, G

1999-01-01

Relatively little is known about the influence of patients' personality features on the responses they make to self-assessment items used to measure the outcome of a hearing aid fitting. If the personality of the hearing aid wearer has a significant influence on self-report outcome data, it would be important to explore the relevant personality variables and to be cognizant of their effects when using subjective outcome data to justify decisions about clinical services or other matters. This investigation explored the relationship between several personality attributes and responses to the Abbreviated Profile of Hearing Aid Benefit (APHAB). It found that more extroverted patients tend to report more hearing aid benefit in all speech communication situations. In addition, patients with a more external locus of control tend to have more negative reactions to loud environmental sounds, both with and without amplification. Anxiety also played a small additional role in determining APHAB responses. Although personality variables were found to explain a relatively small amount of the variance in APHAB responses (usually around 10%), these outcomes should alert practitioners and researchers to the potential effects of personality variables in all self-report data.

Cancer-related anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond current treatment.

PubMed

Mantovani, Giovanni; Madeddu, Clelia; Macciò, Antonio; Gramignano, Giulia; Lusso, Maria Rita; Massa, Elena; Astara, Giorgio; Serpe, Roberto

2004-10-01

Cancer-related anorexia/cachexia syndrome and oxidative stress play a key role in the progression and outcome of neoplastic disease. On the basis of our previously published studies and clinical experience, we have developed an innovative approach consisting of diet with high polyphenol content (400 mg), p.o. pharmaconutritional support enriched with n - 3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) 2 cans (237 mL each) per day, medroxiprogesterone acetate 500 mg/d, antioxidant treatment with alpha-lipoic acid 300 mg/d plus carbocysteine lysine salt 2.7 g/d plus vitamin E 400 mg/d plus vitamin A 30,000 IU/d plus vitamin C 500 mg/d, and selective cyclooxygenase-2 inhibitor Celecoxib 200 mg/d. The treatment is administered for 16 weeks. The following variables are evaluated: (a) clinical variables (stage and Eastern Cooperative Oncology Group performance status); (b) nutritional variables (lean body mass, appetite, and resting energy expenditure); (c) laboratory variables (serum levels of proinflammatory cytokines, C-reactive protein, and leptin and blood levels of reactive oxygen species and antioxidant enzymes); and (d) quality of life variables (European Organization for Research and Treatment of Cancer QLQ-C30, EQ-5Dindex, and EQ-5DVAS). A phase II nonrandomized study has been designed to enroll 40 patients with advanced cancer at different sites with symptoms of cancer-related anorexia/cachexia syndrome and oxidative stress. As of January 2004, 28 patients have been enrolled: 25 patients were evaluable and 14 of them have completed the treatment (20 patients have completed 2 months of treatment). As for clinical response, five patients improved, three patients remained unchanged, and six patients worsened. The Eastern Cooperative Oncology Group performance status (grade) 1 remained unchanged. As for nutritional/functional variables, the lean body mass increased significantly at 2 and 4 months. As for laboratory variables, reactive oxygen species decreased significantly and proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha decreased significantly. As for quality of life, it comprehensively improved after treatment. The treatment has been shown to be effective for clinical response, increase of lean body mass, decrease of reactive oxygen species and proinflammatory cytokines, and improvement of quality of life. The treatment has been shown to be safe with good compliance of patients. The study is in progress (14 further patients will be included).

Response time as a discriminator between true- and false-positive responses in suprathreshold perimetry.

PubMed

Artes, Paul H; McLeod, David; Henson, David B

2002-01-01

To report on differences between the latency distributions of responses to stimuli and to false-positive catch trials in suprathreshold perimetry. To describe an algorithm for defining response time windows and to report on its performance in discriminating between true- and false-positive responses on the basis of response time (RT). A sample of 435 largely inexperienced patients underwent suprathreshold visual field examination on a perimeter that was modified to record RTs. Data were analyzed from 60,500 responses to suprathreshold stimuli and from 523 false-positive responses to catch trials. False-positive responses had much more variable latencies than responses to suprathreshold stimuli. An algorithm defining RT windows on the basis of z-transformed individual latency samples correctly identified more than 70% of false-positive responses to catch trials, whereas fewer than 3% of responses to suprathreshold stimuli were classified as false-positive responses. Latency analysis can be used to detect a substantial proportion of false-positive responses in suprathreshold perimetry. Rejection of such responses may increase the reliability of visual field screening by reducing variability and bias in a small but clinically important proportion of patients.

Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

PubMed Central

Lima, Aurea; Bernardes, Miguel; Azevedo, Rita; Medeiros, Rui; Seabra, Vitor

2015-01-01

Background: Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Methods: Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. Conclusions: This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment. PMID:26086825

Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

PubMed

Lima, Aurea; Bernardes, Miguel; Azevedo, Rita; Medeiros, Rui; Seabra, Vítor

2015-06-16

Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients' therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment.

The reliability of sensitive information provided by injecting drug users in a clinical setting: clinician-administered versus audio computer-assisted self-interviewing (ACASI).

PubMed

Islam, M Mofizul; Topp, Libby; Conigrave, Katherine M; van Beek, Ingrid; Maher, Lisa; White, Ann; Rodgers, Craig; Day, Carolyn A

2012-01-01

Research with injecting drug users (IDUs) suggests greater willingness to report sensitive and stigmatised behaviour via audio computer-assisted self-interviewing (ACASI) methods than during face-to-face interviews (FFIs); however, previous studies were limited in verifying this within the same individuals at the same time point. This study examines the relative willingness of IDUs to report sensitive information via ACASI and during a face-to-face clinical assessment administered in health services for IDUs. During recruitment for a randomised controlled trial undertaken at two IDU-targeted health services, assessments were undertaken as per clinical protocols, followed by referral of eligible clients to the trial, in which baseline self-report data were collected via ACASI. Five questions about sensitive injecting and sexual risk behaviours were administered to participants during both clinical interviews and baseline research data collection. "Percentage agreement" determined the magnitude of concordance/discordance in responses across interview methods, while tests appropriate to data format assessed the statistical significance of this variation. Results for all five variables suggest that, relative to ACASI, FFI elicited responses that may be perceived as more socially desirable. Discordance was statistically significant for four of the five variables examined. Participants who reported a history of sex work were more likely to provide discordant responses to at least one socially sensitive item. In health services for IDUs, information collection via ACASI may elicit more reliable and valid responses than FFI. Adoption of a universal precautionary approach to complement individually tailored assessment of and advice regarding health risk behaviours for IDUs may address this issue.

Reflections on gifts in the therapeutic setting: the gift from patient to therapist.

PubMed

Smolar, Andrew I

2002-01-01

Since Freud's time, psychoanalytically oriented therapists have been wary of accepting gifts from patients, although they have done so in some circumstances within the sanctum of their offices. After providing a working definition of the word "gift" for the purposes of this clinical discussion, the article reviews the relevant literature on the subject. The author presents clinical material in which he describes how gifts were presented by patients within the context of their treatment processes. The article concludes with the author's attempt to define some of the variables that affect the response of the therapist to a patient's gift, and expounds on those variables in terms of their influence on technique.

A virtual clinical trial comparing static versus dynamic PET imaging in measuring response to breast cancer therapy

NASA Astrophysics Data System (ADS)

Wangerin, Kristen A.; Muzi, Mark; Peterson, Lanell M.; Linden, Hannah M.; Novakova, Alena; Mankoff, David A.; E Kinahan, Paul

2017-05-01

We developed a method to evaluate variations in the PET imaging process in order to characterize the relative ability of static and dynamic metrics to measure breast cancer response to therapy in a clinical trial setting. We performed a virtual clinical trial by generating 540 independent and identically distributed PET imaging study realizations for each of 22 original dynamic fluorodeoxyglucose (18F-FDG) breast cancer patient studies pre- and post-therapy. Each noise realization accounted for known sources of uncertainty in the imaging process, such as biological variability and SUV uptake time. Four definitions of SUV were analyzed, which were SUVmax, SUVmean, SUVpeak, and SUV50%. We performed a ROC analysis on the resulting SUV and kinetic parameter uncertainty distributions to assess the impact of the variability on the measurement capabilities of each metric. The kinetic macro parameter, K i , showed more variability than SUV (mean CV K i   =  17%, SUV  =  13%), but K i pre- and post-therapy distributions also showed increased separation compared to the SUV pre- and post-therapy distributions (mean normalized difference K i   =  0.54, SUV  =  0.27). For the patients who did not show perfect separation between the pre- and post-therapy parameter uncertainty distributions (ROC AUC  <  1), dynamic imaging outperformed SUV in distinguishing metabolic change in response to therapy, ranging from 12 to 14 of 16 patients over all SUV definitions and uptake time scenarios (p  <  0.05). For the patient cohort in this study, which is comprised of non-high-grade ER+  tumors, K i outperformed SUV in an ROC analysis of the parameter uncertainty distributions pre- and post-therapy. This methodology can be applied to different scenarios with the ability to inform the design of clinical trials using PET imaging.

Pharmacogenomics in pediatric rheumatology.

PubMed

Becker, Mara L

2012-09-01

Despite major advancements in therapeutics, variability in drug response remains a challenge in both adults and children diagnosed with rheumatic disease. The genetic contribution to interindividual variability has emerged as a promising avenue of exploration; however, challenges remain in making this knowledge relevant in the clinical realm. New genetic associations in patients with rheumatic disease have been reported for disease modifying antirheumatic drugs, antimetabolites and biologic drugs. However, many of these findings are in need of replication, and few have taken into account the concept of ontogeny, specific to pediatrics. In the current era in which we practice, genetic variation will undoubtedly contribute to variability in therapeutic response and may be a factor that will ultimately impact individualized care. However, preliminary studies have shown that there are many hurdles that need to be overcome as we explore pharmacogenomic associations specifically in the field of pediatric rheumatology.

Intestinal lymphangiectasia in children. A favorable response to dietary modifications.

PubMed

Isa, Hasan M; Al-Arayedh, Ghadeer G; Mohamed, Afaf M

2016-02-01

Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation of intestinal lymphatics. It can be classified as primary or secondary according to the underlying etiology. The clinical presentations of IL are pitting edema, chylous ascites, pleural effusion, acute appendicitis, diarrhea, lymphocytopenia, malabsorption, and intestinal obstruction. The diagnosis is made by intestinal endoscopy and biopsies. Dietary modification is the mainstay in the management of IL with a variable response. Here we report 2 patients with IL in Bahrain who showed positive response to dietary modification.

Multiple sclerosis: individualized disease susceptibility and therapy response.

PubMed

Pravica, Vera; Markovic, Milos; Cupic, Maja; Savic, Emina; Popadic, Dusan; Drulovic, Jelena; Mostarica-Stojkovic, Marija

2013-02-01

Multiple sclerosis (MS) is a heterogeneous disease in which diverse genetic, pathological and clinical backgrounds lead to variable therapy response. Accordingly, MS care should be tailored to address disease traits unique to each person. At the core of personalized management is the emergence of new knowledge, enabling optimized treatment and disease-modifying therapies. This overview analyzes the promise of genetic and nongenetic biomarkers in advancing decision-making algorithms to assist diagnosis or in predicting the disease course and therapy response in any given MS patient.

Bladder cancer treatment response assessment with radiomic, clinical, and radiologist semantic features

NASA Astrophysics Data System (ADS)

Gordon, Marshall N.; Cha, Kenny H.; Hadjiiski, Lubomir M.; Chan, Heang-Ping; Cohan, Richard H.; Caoili, Elaine M.; Paramagul, Chintana; Alva, Ajjai; Weizer, Alon Z.

2018-02-01

We are developing a decision support system for assisting clinicians in assessment of response to neoadjuvant chemotherapy for bladder cancer. Accurate treatment response assessment is crucial for identifying responders and improving quality of life for non-responders. An objective machine learning decision support system may help reduce variability and inaccuracy in treatment response assessment. We developed a predictive model to assess the likelihood that a patient will respond based on image and clinical features. With IRB approval, we retrospectively collected a data set of pre- and post- treatment CT scans along with clinical information from surgical pathology from 98 patients. A linear discriminant analysis (LDA) classifier was used to predict the likelihood that a patient would respond to treatment based on radiomic features extracted from CT urography (CTU), a radiologist's semantic feature, and a clinical feature extracted from surgical and pathology reports. The classification accuracy was evaluated using the area under the ROC curve (AUC) with a leave-one-case-out cross validation. The classification accuracy was compared for the systems based on radiomic features, clinical feature, and radiologist's semantic feature. For the system based on only radiomic features the AUC was 0.75. With the addition of clinical information from examination under anesthesia (EUA) the AUC was improved to 0.78. Our study demonstrated the potential of designing a decision support system to assist in treatment response assessment. The combination of clinical features, radiologist semantic features and CTU radiomic features improved the performance of the classifier and the accuracy of treatment response assessment.

Principal components analysis in clinical studies.

PubMed

Zhang, Zhongheng; Castelló, Adela

2017-09-01

In multivariate analysis, independent variables are usually correlated to each other which can introduce multicollinearity in the regression models. One approach to solve this problem is to apply principal components analysis (PCA) over these variables. This method uses orthogonal transformation to represent sets of potentially correlated variables with principal components (PC) that are linearly uncorrelated. PCs are ordered so that the first PC has the largest possible variance and only some components are selected to represent the correlated variables. As a result, the dimension of the variable space is reduced. This tutorial illustrates how to perform PCA in R environment, the example is a simulated dataset in which two PCs are responsible for the majority of the variance in the data. Furthermore, the visualization of PCA is highlighted.

Response preparation and intra-individual reaction time variability in schizophrenia.

PubMed

Dankinas, Denisas; Mėlynytė, Sigita; Šiurkutė, Aldona; Dapšys, Kastytis

2016-01-01

Background. It is important to prepare response in advance to increase the efficiency of its execution. The process of response preparation is usually studied using the precueing paradigm. In this paradigm subjects have to employ the preceding information about further imperative stimulus to perform proper response preparation, which shortens the reaction time of subsequent response execution. Previous studies detected the impairment of response preparation in schizophrenia only with the help of electroencephalographic parameters, but not with the assessing of reaction time. Therefore, in this study we attempted to find a behavioural parameter that could detect impairment in response preparation of schizophrenia patients. It was recently found that appropriate response preparation not only shortens the reaction time but also increases its stability, which is measured with the intra-individual reaction time variability. It was also revealed that response stability could better find cognitive dysfunction in some studies of schizophrenia disorder than classical behavioural parameters. Hence, the main goal of this study was to verify if intra-individual reaction time variability could detect the impairment of response preparation in schizophrenia patients. Materials and methods. In order to achieve the main purpose, we carried out a study with 14 schizophrenia patients and 14 control group subjects. We used precueing paradigm in our research, in which participants had to employ information about stimulus probability for the proper response preparation. Results. Our main result showed that despite the responses of schizophrenia patients were faster to the high-probability stimulus than to the low-probability one ( F (1, 13) = 30.9, p < 0.001), intra-individual reaction time variability did not differ in this group between the responses to more and less probable stimuli ( F (1, 13) = 0.64, p = 0.44). Conclusions. Results of the study suggest that people with schizophrenia were able to use precueing probabilistic information only to shorten their reaction time, but not to increase response stability. Therefore, it was found that intra-individual reaction time variability parameter could detect response preparation impairment in schizophrenia, and could be used in clinical purposes.

Physiological and pathological clinical conditions and light scattering in brain

NASA Astrophysics Data System (ADS)

Kurata, Tsuyoshi; Iwata, Sachiko; Tsuda, Kennosuke; Kinoshita, Masahiro; Saikusa, Mamoru; Hara, Naoko; Oda, Motoki; Ohmae, Etsuko; Araki, Yuko; Sugioka, Takashi; Takashima, Sachio; Iwata, Osuke

2016-08-01

MRI of preterm infants at term commonly reveals subtle brain lesions such as diffuse white matter injury, which are linked with later cognitive impairments. The timing and mechanism of such injury remains unclear. The reduced scattering coefficient of near-infrared light (μs’) has been shown to correlate linearly with gestational age in neonates. To identify clinical variables associated with brain μs’, 60 preterm and full-term infants were studied within 7 days of birth. Dependence of μs’ obtained from the frontal head on clinical variables was assessed. In the univariate analysis, smaller μs’ was associated with antenatal glucocorticoid, emergency Caesarean section, requirement for mechanical ventilation, smaller gestational age, smaller body sizes, low 1- and 5-minute Apgar scores, higher cord blood pH and PO2, and higher blood HCO3- at the time of study. Multivariate analysis revealed that smaller gestational age, requirement for mechanical ventilation, and higher HCO3- at the time of study were correlated with smaller μs’. Brain μs’ depended on variables associated with physiological maturation and pathological conditions of the brain. Further longitudinal studies may help identify pathological events and clinical conditions responsible for subtle brain injury and subsequent cognitive impairments following preterm birth.

Clinical applications of the functional connectome

PubMed Central

Castellanos, F. Xavier; Di Martino, Adriana; Craddock, R. Cameron; Mehta, Ashesh D.; Milham, Michael P.

2013-01-01

Central to the development of clinical applications of functional connectomics for neurology and psychiatry is the discovery and validation of biomarkers. Resting state fMRI (R-fMRI) is emerging as a mainstream approach for imaging-based biomarker identification, detecting variations in the functional connectome that can be attributed to clinical variables (e.g., diagnostic status). Despite growing enthusiasm, many challenges remain. Here, we assess evidence of the readiness of R-fMRI based functional connectomics to lead to clinically meaningful biomarker identification through the lens of the criteria used to evaluate clinical tests (i.e., validity, reliability, sensitivity, specificity, and applicability). We focus on current R-fMRI-based prediction efforts, and survey R-fMRI used for neurosurgical planning. We identify gaps and needs for R-fMRI-based biomarker identification, highlighting the potential of emerging conceptual, analytical and cultural innovations (e.g., the Research Domain Criteria Project (RDoC), open science initiatives, and Big Data) to address them. Additionally, we note the need to expand future efforts beyond identification of biomarkers for disease status alone to include clinical variables related to risk, expected treatment response and prognosis. PMID:23631991

Glomerular disease: why is there a dearth of high quality clinical trials?

PubMed

Leaf, David E; Appel, Gerald B; Radhakrishnan, Jai

2010-08-01

There is a paucity of high quality clinical trials in glomerular disease, particularly in non-diabetic kidney disease. The aims of this review include quantifying the extent of this problem and exploring reasons for the scarcity of such trials in primary glomerular disease, with an emphasis on immunoglobulin A nephropathy, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy in comparison with the more common diseases of diabetic nephropathy and lupus nephritis. Reasons for the dearth of high quality clinical trials in primary glomerular disease include (1) low prevalence of disease; (2) variability in clinical presentation; (3) variability in treatment response; (4) lack of consensus in definitions; (5) difficulty in recruiting patients; (6) high costs of randomized controlled trials; and (7) lack of collaborative efforts. To facilitate greater numbers of high quality clinical trials in glomerular disease, practice guidelines should establish common classification systems of disease and common clinical end points, industry and non-industry sponsored research should find common ground and work together toward advancing science, and national registries should be created to encourage collaborations across institutions and across nations.

Parsing interindividual drug variability: an emerging role for systems pharmacology

PubMed Central

Turner, Richard M; Park, B Kevin; Pirmohamed, Munir

2015-01-01

There is notable interindividual heterogeneity in drug response, affecting both drug efficacy and toxicity, resulting in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is at the forefront of research to understand interindividual drug response variability, but although many genotype-drug response associations have been identified, translation of pharmacogenomic associations into clinical practice has been hampered by inconsistent findings and inadequate predictive values. These limitations are in part due to the complex interplay between drug-specific, human body and environmental factors influencing drug response and therefore pharmacogenomics, whilst intrinsically necessary, is by itself unlikely to adequately parse drug variability. The emergent, interdisciplinary and rapidly developing field of systems pharmacology, which incorporates but goes beyond pharmacogenomics, holds significant potential to further parse interindividual drug variability. Systems pharmacology broadly encompasses two distinct research efforts, pharmacologically-orientated systems biology and pharmacometrics. Pharmacologically-orientated systems biology utilizes high throughput omics technologies, including next-generation sequencing, transcriptomics and proteomics, to identify factors associated with differential drug response within the different levels of biological organization in the hierarchical human body. Increasingly complex pharmacometric models are being developed that quantitatively integrate factors associated with drug response. Although distinct, these research areas complement one another and continual development can be facilitated by iterating between dynamic experimental and computational findings. Ultimately, quantitative data-derived models of sufficient detail will be required to help realize the goal of precision medicine. WIREs Syst Biol Med 2015, 7:221–241. doi: 10.1002/wsbm.1302 PMID:25950758

Evaluation of Magnetic Resonance Imaging Responsiveness in Active Psoriatic Arthritis at Multiple Timepoints during the First 12 Weeks of Antitumor Necrosis Factor Therapy.

PubMed

Feletar, Marie; Hall, Stephen; Bird, Paul

2016-01-01

To assess the responsiveness of high- and low-field extremity magnetic resonance imaging (MRI) variables at multiple timepoints in the first 12 weeks post-antitumor necrosis factor (anti-TNF) therapy initiation in patients with psoriatic arthritis (PsA) and active dactylitis. Twelve patients with active PsA and clinical evidence of dactylitis involving at least 1 digit were recruited. Patients underwent sequential high-field conventional (1.5 Tesla) and extremity low-field MRI (0.2 Tesla) of the affected hand or foot, pre- and postgadolinium at baseline (pre-TNF), 2 weeks (post-TNF), 6 weeks, and 12 weeks. A blinded observer scored all images on 2 occasions using the PsA MRI scoring system. Eleven patients completed the study, but only 6 patients completed all high-field and low-field MRI assessments. MRI scores demonstrated rapid response to TNF inhibition with score reduction in tenosynovitis, synovitis, and osteitis at 2 weeks. Intraobserver reliability was good to excellent for all variables. High-field MRI demonstrated greater sensitivity to tenosynovitis, synovitis, and osteitis and greater responsiveness to change posttreatment. Treatment responses were maintained to 12 weeks. This study demonstrates the use of MRI in detecting early response to biologic therapy. MRI variables of tenosynovitis, synovitis, and osteitis demonstrated responsiveness posttherapy with high-field scores more responsive to change than low-field scores.

Response of puppies to canine-origin parvovirus vaccines.

PubMed

Carmichael, L E; Pollock, R V; Joubert, J C

1984-02-01

Pups 9-18 1/2 weeks old were given a single dose of 1 of 4 commercial, live, canine-origin parvovirus vaccines. All 4 vaccines evoked high levels of antibody in seronegative pups, but variable response in those with low levels of maternally derived antibodies. Vaccinal virus spread to unvaccinated contact controls and elicited essentially equivalent titers. No clinical signs of parvovirus infection were observed in vaccinates or controls.

Variability of plasma homovanillic acid over 13 months in patients with schizophrenia; relationship with the clinical response and the Wisconsin card sort test.

PubMed

Zumárraga, Mercedes; González-Torres, Miguel A; Arrue, Aurora; Dávila, Ricardo; Dávila, Wendy; Inchausti, Lucía; Pérez-Cabeza, Lucía; Fernández-Rivas, Aránzazu; Bustamante, Sonia; Basterreche, Nieves; Guimón, José

2011-08-01

In the present study we have measured, on a monthly basis, the concentration of plasma homovanillic acid (pHVA) in schizophrenic patients during 13 months of their pharmacological treatment. The average pHVA values of each patient were within the range of 7.30-17.70 ng/ml and the coefficients of variation for each patient (CV %) were within the range of 13-33%. Half of the patients that showed higher pHVA CV% values also showed higher scores on the Brief Psychiatric Rating Scale at the beginning of the study, and improved more after 6 months, when compared to the remaining 50% with lower CV% values. There was no significant relationship between the scores of the Wisconsin Card Sort Test and the concentration or the CV% of the pHVA of each patient. A greater variability in the pHVA may be associated with a greater plasticity of the dopaminergic system and a better clinical response.

Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis.

PubMed

León Fernández, Olga Sonia; Viebahn-Haensler, Renate; Cabreja, Gilberto López; Espinosa, Irainis Serrano; Matos, Yanet Hernández; Roche, Liván Delgado; Santos, Beatriz Tamargo; Oru, Gabriel Takon; Polo Vega, Juan Carlos

2016-10-15

Medical ozone reduced inflammation, IL-1β, TNF-α mRNA levels and oxidative stress in PG/PS-induced arthritis in rats. The aim of this study was to investigate the medical ozone effects in patients with rheumatoid arthritis treated with methotrexate and methotrexate+ozone, and to compare between them. A randomized clinical study with 60 patients was performed, who were divided into two groups: one (n=30) treated with methotrexate (MTX), folic acid and Ibuprophen (MTX group) and the second group (n=30) received the same as the MTX group+medical ozone by rectal insufflation of the gas (MTX+ozone group). The clinical response of the patients was evaluated by comparing Disease Activity Score 28 (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), Anti-Cyclic Citrullinated (Anti-CCP) levels, reactants of acute phase and biochemical markers of oxidative stress before and after 20 days of treatment. MTX+ozone reduced the activity of the disease while MTX merely showed a tendency to decrease the variables. Reactants of acute phase displayed a similar picture. MTX+ozone reduced Anti-CCP levels as well as increased antioxidant system, and decreased oxidative damage whereas MTX did not change. Glutathione correlated with all clinical variables just after MTX+ozone. MTX+ozone increased the MTX clinical response in patients with rheumatoid arthritis. No side effects were observed. These results suggest that ozone can increase the efficacy of MTX probably because both share common therapeutic targets. Medical ozone treatment is capable of being a complementary therapy in the treatment of rheumatoid arthritis. Copyright © 2016 Elsevier B.V. All rights reserved.

Clinical, histopathological and immunohistochemical characterization of a novel equine ocular disorder: heterochromic iridocyclitis with secondary keratitis in adult horses.

PubMed

Pinto, Nelson I; McMullen, Richard J; Linder, Keith E; Cullen, John M; Gilger, Brian C

2015-11-01

To describe the clinical, histopathologic and immunohistochemical characteristics of an equine ocular inflammatory disease resulting in anterior uveitis and corneal endothelial inflammation associated with iris pigment dispersion and retrocorneal fibrous membrane (RFM) formation. Retrospective study. Sixteen horses with evidence of pigmented keratic precipitates (KPs), corneal edema, and/or iris depigmentation. Information collected from the medical records included signalment, clinical signs, prereferral treatment duration and response to therapy, ophthalmic examination findings, postreferral treatment, response to therapy, and outcome. Twenty-one eyes from 16 horses were affected. Age ranged between 9 and 25 years (Average 16.1 years). Blepharospasm, epiphora, and/or corneal opacification were the first clinical signs noted. At the time of referral pigmented KPs, corneal edema, iridal depigmentation, and retrocorneal membranes were commonly seen. Treatment included topical and/or systemic anti-inflammatories and antibiotics with variable response. Reduction or cessation of anti-inflammatory therapy resulted in worsening of clinical signs and disease progression. Eight eyes ultimately required enucleation. Histopathology changes include iridal pigment loss and dispersion, RFM formation, and keratitis. Variable degrees of lymphoplasmacytic inflammation were dominated by T-cells within the corneal stroma, RFM, iris, and ciliary body with occasional multinucleated giant cells. Heterochromic iridocyclitis with secondary keratitis (HIK) is characterized by uveal inflammation with pigment dispersion and suspected corneal endothelial dysfunction. Horses being treated for HIK require diligent and frequent follow-up examinations in combination with aggressive local immune suppression to control the disease. However, HIK may not respond to therapy and enucleation may ultimately be required to ensure the horse's comfort. © 2014 American College of Veterinary Ophthalmologists.

Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study.

PubMed

Adler, Charles H; Beach, Thomas G; Hentz, Joseph G; Shill, Holly A; Caviness, John N; Driver-Dunckley, Erika; Sabbagh, Marwan N; Sue, Lucia I; Jacobson, Sandra A; Belden, Christine M; Dugger, Brittany N

2014-07-29

Determine diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard. Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to determine the predictive value of a clinical PD diagnosis, using 2 clinical diagnostic confidence levels, PossPD (never treated or not clearly responsive) and ProbPD (responsive to medications). Neuropathologic diagnosis was the gold standard. Based on first visit, 9 of 34 (26%) PossPD cases had neuropathologically confirmed PD while 80 of 97 (82%) ProbPD cases had confirmed PD. PD was confirmed in 8 of 15 (53%) ProbPD cases with <5 years of disease duration and 72 of 82 (88%) with ≥5 years of disease duration. Using final diagnosis at time of death, 91 of 107 (85%) ProbPD cases had confirmed PD. Clinical variables that improved diagnostic accuracy were medication response, motor fluctuations, dyskinesias, and hyposmia. Using neuropathologic findings of PD as the gold standard, this study establishes the novel findings of only 26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects, 53% accuracy in early PD responsive to medication (<5 years' duration), and >85% diagnostic accuracy of longer duration, medication-responsive PD. Caution is needed when interpreting clinical studies of PD, especially studies of early disease that do not have autopsy confirmation. The need for a tissue or other diagnostic biomarker is reinforced. This study provides Class II evidence that a clinical diagnosis of PD identifies patients who will have pathologically confirmed PD with a sensitivity of 88% and specificity of 68%. © 2014 American Academy of Neurology.

Key observations from the NHLBI Asthma Clinical Research Network.

PubMed

Szefler, Stanley J; Chinchilli, Vernon M; Israel, Elliot; Denlinger, Loren Clark; Lemanske, Robert F; Calhoun, William; Peters, Stephen P

2012-05-01

The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.

Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the 'common arm' approach.

PubMed

Mack, Philip C; Gandara, David R; Lara, Primo N

2012-12-01

Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer. These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding the general applicability of transnational clinical trials. Various reasons have been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics. However, without methodology to control for such variables, these hypotheses remain largely untested. The authors previously developed the 'common arm' approach in order to directly compare efficacy and toxicity results of trials simultaneously performed in different countries. By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences. In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC. In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival. Significant differences were also observed in the distribution of gender and performance status. The common arm analysis in nonSCLC included two trials from Japan and one from the USA, each containing a 'common' carboplatin/paclitaxel arm. Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia. The underlying basis for these divergent outcomes is discussed. The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.

Insights on adaptive and innate immunity in canine leishmaniosis.

PubMed

Hosein, Shazia; Blake, Damer P; Solano-Gallego, Laia

2017-01-01

Canine leishmaniosis (CanL) is caused by the parasite Leishmania infantum and is a systemic disease, which can present with variable clinical signs, and clinicopathological abnormalities. Clinical manifestations can range from subclinical infection to very severe systemic disease. Leishmaniosis is categorized as a neglected tropical disease and the complex immune responses associated with Leishmania species makes therapeutic treatments and vaccine development challenging for both dogs and humans. In this review, we summarize innate and adaptive immune responses associated with L. infantum infection in dogs, and we discuss the problems associated with the disease as well as potential solutions and the future direction of required research to help control the parasite.

Predictors and moderators of response to cognitive behavioral therapy and medication for the treatment of binge eating disorder.

PubMed

Grilo, Carlos M; Masheb, Robin M; Crosby, Ross D

2012-10-01

To examine predictors and moderators of response to cognitive behavioral therapy (CBT) and medication treatments for binge-eating disorder (BED). 108 BED patients in a randomized double-blind placebo-controlled trial testing CBT and fluoxetine treatments were assessed prior, throughout, and posttreatment. Demographic factors, psychiatric and personality disorder comorbidity, eating disorder psychopathology, psychological features, and 2 subtyping methods (negative affect, overvaluation of shape/weight) were tested as predictors and moderators for the primary outcome of remission from binge eating and 4 secondary dimensional outcomes (binge-eating frequency, eating disorder psychopathology, depression, and body mass index). Mixed-effects models analyzed all available data for each outcome variable. In each model, effects for baseline value and treatment were included with tests of both prediction and moderator effects. Several demographic and clinical variables significantly predicted and/or moderated outcomes. One demographic variable signaled a statistical advantage for medication only (younger participants had greater binge-eating reductions), whereas several demographic and clinical variables (lower self-esteem, negative affect, and overvaluation of shape/weight) signaled better improvements if receiving CBT. Overvaluation was the most salient predictor/moderator of outcomes. Overvaluation significantly predicted binge-eating remission (29% of participants with vs. 57% of participants without overvaluation remitted). Overvaluation was especially associated with lower remission rates if receiving medication only (10% vs. 42% for participants without overvaluation). Overvaluation moderated dimensional outcomes: Participants with overvaluation had significantly greater reductions in eating disorder psychopathology and depression levels if receiving CBT. Overvaluation predictor/moderator findings persisted after controlling for negative affect. Our findings have clinical utility for prescription of CBT and medication and implications for refinement of the BED diagnosis. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Predictors and Moderators of Response to Cognitive Behavioral Therapy and Medication for the Treatment of Binge Eating Disorder

PubMed Central

Grilo, Carlos. M.; Masheb, Robin M.; Crosby, Ross D.

2012-01-01

Objective To examine predictors and moderators of response to cognitive-behavioral therapy (CBT) and medication treatments for binge-eating disorder (BED). Method 108 BED patients in a randomized double-blind placebo-controlled trial testing CBT and fluoxetine treatments were assessed prior, throughout-, and post-treatment. Demographic factors, psychiatric and personality-disorder co-morbidity, eating-disorder psychopathology, psychological features, and two sub-typing methods (negative-affect, overvaluation of shape/weight) were tested as predictors and moderators for the primary outcome of remission from binge-eating and four secondary dimensional outcomes (binge-eating frequency, eating-disorder psychopathology, depression, and body mass index). Mixed-effects-models analyzed all available data for each outcome variable. In each model, effects for baseline value and treatment were included with tests of both prediction and moderator effects. Results Several demographic and clinical variables significantly predicted and/or moderated outcomes. One demographic variable signaled a statistical advantage for medication-only (younger participants had greater binge-eating reductions) whereas several demographic and clinical variables (lower self-esteem, negative-affect, and overvaluation of shape/weight) signaled better improvements if receiving CBT. Overvaluation was the most salient predictor/moderator of outcomes. Overvaluation significantly predicted binge-eating remission (29% of participants with versus 57% of participants without overvaluation remitted). Overvaluation was especially associated with lower remission rates if receiving medication-only (10% versus 42% for participants without overvaluation). Overvaluation moderated dimensional outcomes: participants with overvaluation had significantly greater reductions in eating-disorder psychopathology and depression levels if receiving CBT. Overvaluation predictor/moderator findings persisted after controlling for negative-affect. Conclusions Our findings have clinical utility for prescription of CBT and medication and implications for refinement of the BED diagnosis. PMID:22289130

A comparison of placebo response with major depressive disorder in patients recruited through newspaper advertising versus consultation referrals.

PubMed

Miller, C A; Hooper, C L; Bakish, D

1997-01-01

Recent evidence indicates few differences between patients recruited through advertising and by consultation referral, and there is some suggestion that those recruited through advertising are more representative of the target community population. However little has been reported on differences in placebo response and compliance in these two patient groups. We conducted a retrospective chart review of 49 patients with major depressive disorder (MDD), recruited through advertising or consultation, randomized to placebo in five clinical trials. Variables included demographics, clinical history, efficacy, compliance, and completion data. Homogeneity was demonstrated for most variables. Differences in placebo groups included significantly lower Hamilton Rating Scale for Depression (HAM-D) scores for the advertisement group throughout the trials. Advertisement patients were also more likely to be early placebo responders and in remission at Days 14 and 28. No differences were found in completion rates or reasons for early termination. Compliance was excellent for both groups. Early placebo response of the advertisement group reinforces the need for trials of at least 8 weeks. In addition, consultation patients may have a more severe illness and be treatment resistant, suggesting they are less generalizable to community practice populations.

Modeling Predictors of Duties Not Including Flying Status.

PubMed

Tvaryanas, Anthony P; Griffith, Converse

2018-01-01

The purpose of this study was to reuse available datasets to conduct an analysis of potential predictors of U.S. Air Force aircrew nonavailability in terms of being in "duties not to include flying" (DNIF) status. This study was a retrospective cohort analysis of U.S. Air Force aircrew on active duty during the period from 2003-2012. Predictor variables included age, Air Force Specialty Code (AFSC), clinic location, diagnosis, gender, pay grade, and service component. The response variable was DNIF duration. Nonparametric methods were used for the exploratory analysis and parametric methods were used for model building and statistical inference. Out of a set of 783 potential predictor variables, 339 variables were identified from the nonparametric exploratory analysis for inclusion in the parametric analysis. Of these, 54 variables had significant associations with DNIF duration in the final model fitted to the validation data set. The predicted results of this model for DNIF duration had a correlation of 0.45 with the actual number of DNIF days. Predictor variables included age, 6 AFSCs, 7 clinic locations, and 40 primary diagnosis categories. Specific demographic (i.e., age), occupational (i.e., AFSC), and health (i.e., clinic location and primary diagnosis category) DNIF drivers were identified. Subsequent research should focus on the application of primary, secondary, and tertiary prevention measures to ameliorate the potential impact of these DNIF drivers where possible.Tvaryanas AP, Griffith C Jr. Modeling predictors of duties not including flying status. Aerosp Med Hum Perform. 2018; 89(1):52-57.

Mandatory implementation of NICE Guidelines for the care of bipolar disorder and other conditions in England and Wales.

PubMed

Morriss, Richard

2015-09-30

Bipolar disorder is a common long-term mental health condition characterised by episodes of mania or hypomania and depression resulting in disability, early death, and high health and society costs. Public money funds the National Institute of Healthcare and Clinical Excellence (NICE) to produce clinical guidelines by systematically identifying the most up to date research evidence and costing its main recommendations for healthcare organisations and professionals to follow in England and Wales. Most governments, including those of England and Wales, need to improve healthcare but at reduced cost. There is evidence, particularly in bipolar disorder, that systematically following clinical guidelines achieves these outcomes. NICE clinical guidelines, including those regarding bipolar disorder, remain variably implemented. They give clinicians and patients a non-prescriptive basis for deciding their care. Despite the passing of the Health and Social Care Act in 2012 in England requiring all healthcare organisations to consider NICE clinical guidelines in commissioning, delivering, and inspecting healthcare services, healthcare organisations in the National Health Service may ignore them with little accountability and few consequences. There is no mechanism to ensure that healthcare professionals know or consider them. Barriers to their implementation include the lack of political and professional leadership, the complexity of the organisation of care and policy, mistrust of some processes and recommendations of clinical guidelines, and a lack of a clear implementation model, strategy, responsibility, or accountability. Mitigation to these barriers is presented herein. The variability, safety, and quality of healthcare might be improved and its cost reduced if the implementation of NICE clinical guidelines, such as those for bipolar disorder, were made the minimum starting point for clinical decision-making and mandatory responsibilities of all healthcare organisations and professionals.

Differential Regulation of Neuropeptide Y In the Amygdala and Prefrontal Cortex During Recovery from Chronic Variable Stress

DTIC Science & Technology

2011-09-01

T., Pabst, R., and Von Horsten, S. (2003). Behav- ioral effects of neuropeptide Y in F344 rat substrains with a reduced dipeptidyl- peptidase IV...studies and pre-clinical animal models supports a role for neuropeptide Y (NPY) in adaptive emotional response following stress. The long-term impact of...stress-related psychopathol- ogy. In these studies, we examined expression of NPY during recovery from a chronic variable stress (CVS) model of

Clinical chemistry and hematology values in a Caribbean population of African green monkeys.

PubMed

Liddie, Shervin; Goody, Robin J; Valles, Rodrigo; Lawrence, Matthew S

2010-12-01

Hematology and clinical chemistry (HCC) reference values are critical in veterinary practice and in vivo pre-clinical research, enabling detection of health abnormalities, response to therapeutic intervention or adverse toxicological effects, as well as monitoring of clinical management. In this report, reference ranges for 46 HCC parameters were characterized in 331 wild-caught and colony-bred African green monkeys. Effects of sex, weight and duration of captivity were determined by one-way analysis of variance. Significant sex differences were observed for several HCC parameters. Significant differences were also observed for select HCC variables between newly caught animals and those held in captivity for 1-12 months or longer. Comparison of this data with other non-human primate species and humans highlights similarities and disparities between species. Potential causes of interpopulation variability and relevance to the use of the African green monkey as a non-human primate model are discussed. © 2010 John Wiley & Sons A/S.

CLINICALLY SIGNIFICANT PSYCHOTROPIC DRUG-DRUG INTERACTIONS IN THE PRIMARY CARE SETTING

PubMed Central

English, Brett A.; Dortch, Marcus; Ereshefsky, Larry; Jhee, Stanford

2014-01-01

In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients. While life-threatening drug interactions are rare, clinically significant drug interactions impacting drug response or appearance of serious adverse drug reactions have been documented and can impact long-term outcomes. Additionally, the impact of genetic variability on the psychotropic drug’s pharmacodynamics and/or pharmacokinetics may further complicate drug therapy. Increased awareness of clinically relevant psychotropic drug interactions can aid clinicians to achieve optimal therapeutic outcomes in patients in the primary care setting. PMID:22707017

Integrated Analysis of Pharmacologic, Clinical, and SNP Microarray Data using Projection onto the Most Interesting Statistical Evidence with Adaptive Permutation Testing

PubMed Central

Pounds, Stan; Cao, Xueyuan; Cheng, Cheng; Yang, Jun; Campana, Dario; Evans, William E.; Pui, Ching-Hon; Relling, Mary V.

2010-01-01

Powerful methods for integrated analysis of multiple biological data sets are needed to maximize interpretation capacity and acquire meaningful knowledge. We recently developed Projection Onto the Most Interesting Statistical Evidence (PROMISE). PROMISE is a statistical procedure that incorporates prior knowledge about the biological relationships among endpoint variables into an integrated analysis of microarray gene expression data with multiple biological and clinical endpoints. Here, PROMISE is adapted to the integrated analysis of pharmacologic, clinical, and genome-wide genotype data that incorporating knowledge about the biological relationships among pharmacologic and clinical response data. An efficient permutation-testing algorithm is introduced so that statistical calculations are computationally feasible in this higher-dimension setting. The new method is applied to a pediatric leukemia data set. The results clearly indicate that PROMISE is a powerful statistical tool for identifying genomic features that exhibit a biologically meaningful pattern of association with multiple endpoint variables. PMID:21516175

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations

PubMed Central

Edwards, Robert R.; Dworkin, Robert H.; Turk, Dennis C.; Angst, Martin S.; Dionne, Raymond; Freeman, Roy; Hansson, Per; Haroutounian, Simon; Arendt-Nielsen, Lars; Attal, Nadine; Baron, Ralf; Brell, Joanna; Bujanover, Shay; Burke, Laurie B.; Carr, Daniel; Chappell, Amy S.; Cowan, Penney; Etropolski, Mila; Fillingim, Roger B.; Gewandter, Jennifer S.; Katz, Nathaniel P.; Kopecky, Ernest A.; Markman, John D.; Nomikos, George; Porter, Linda; Rappaport, Bob A.; Rice, Andrew S.C.; Scavone, Joseph M.; Scholz, Joachim; Simon, Lee S.; Smith, Shannon M.; Tobias, Jeffrey; Tockarshewsky, Tina; Veasley, Christine; Versavel, Mark; Wasan, Ajay D.; Wen, Warren; Yarnitsky, David

2018-01-01

There is tremendous inter-patient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine”, or personalized pain therapeutics (i.e., empirically-based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain, and the success rates for putative analgesic drugs in Phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain. PMID:27152687

Recent advances in understanding idiopathic pulmonary fibrosis

PubMed Central

Daccord, Cécile; Maher, Toby M.

2016-01-01

Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF. PMID:27303645

Optimal auxiliary-covariate-based two-phase sampling design for semiparametric efficient estimation of a mean or mean difference, with application to clinical trials.

PubMed

Gilbert, Peter B; Yu, Xuesong; Rotnitzky, Andrea

2014-03-15

To address the objective in a clinical trial to estimate the mean or mean difference of an expensive endpoint Y, one approach employs a two-phase sampling design, wherein inexpensive auxiliary variables W predictive of Y are measured in everyone, Y is measured in a random sample, and the semiparametric efficient estimator is applied. This approach is made efficient by specifying the phase two selection probabilities as optimal functions of the auxiliary variables and measurement costs. While this approach is familiar to survey samplers, it apparently has seldom been used in clinical trials, and several novel results practicable for clinical trials are developed. We perform simulations to identify settings where the optimal approach significantly improves efficiency compared to approaches in current practice. We provide proofs and R code. The optimality results are developed to design an HIV vaccine trial, with objective to compare the mean 'importance-weighted' breadth (Y) of the T-cell response between randomized vaccine groups. The trial collects an auxiliary response (W) highly predictive of Y and measures Y in the optimal subset. We show that the optimal design-estimation approach can confer anywhere between absent and large efficiency gain (up to 24 % in the examples) compared to the approach with the same efficient estimator but simple random sampling, where greater variability in the cost-standardized conditional variance of Y given W yields greater efficiency gains. Accurate estimation of E[Y | W] is important for realizing the efficiency gain, which is aided by an ample phase two sample and by using a robust fitting method. Copyright © 2013 John Wiley & Sons, Ltd.

Optimal Auxiliary-Covariate Based Two-Phase Sampling Design for Semiparametric Efficient Estimation of a Mean or Mean Difference, with Application to Clinical Trials

PubMed Central

Gilbert, Peter B.; Yu, Xuesong; Rotnitzky, Andrea

2014-01-01

To address the objective in a clinical trial to estimate the mean or mean difference of an expensive endpoint Y, one approach employs a two-phase sampling design, wherein inexpensive auxiliary variables W predictive of Y are measured in everyone, Y is measured in a random sample, and the semi-parametric efficient estimator is applied. This approach is made efficient by specifying the phase-two selection probabilities as optimal functions of the auxiliary variables and measurement costs. While this approach is familiar to survey samplers, it apparently has seldom been used in clinical trials, and several novel results practicable for clinical trials are developed. Simulations are performed to identify settings where the optimal approach significantly improves efficiency compared to approaches in current practice. Proofs and R code are provided. The optimality results are developed to design an HIV vaccine trial, with objective to compare the mean “importance-weighted” breadth (Y) of the T cell response between randomized vaccine groups. The trial collects an auxiliary response (W) highly predictive of Y, and measures Y in the optimal subset. We show that the optimal design-estimation approach can confer anywhere between absent and large efficiency gain (up to 24% in the examples) compared to the approach with the same efficient estimator but simple random sampling, where greater variability in the cost-standardized conditional variance of Y given W yields greater efficiency gains. Accurate estimation of E[Y∣W] is important for realizing the efficiency gain, which is aided by an ample phase-two sample and by using a robust fitting method. PMID:24123289

From vital signs to clinical outcomes for patients with sepsis: a machine learning basis for a clinical decision support system

PubMed Central

Gultepe, Eren; Green, Jeffrey P; Nguyen, Hien; Adams, Jason; Albertson, Timothy; Tagkopoulos, Ilias

2014-01-01

Objective To develop a decision support system to identify patients at high risk for hyperlactatemia based upon routinely measured vital signs and laboratory studies. Materials and methods Electronic health records of 741 adult patients at the University of California Davis Health System who met at least two systemic inflammatory response syndrome criteria were used to associate patients’ vital signs, white blood cell count (WBC), with sepsis occurrence and mortality. Generative and discriminative classification (naïve Bayes, support vector machines, Gaussian mixture models, hidden Markov models) were used to integrate heterogeneous patient data and form a predictive tool for the inference of lactate level and mortality risk. Results An accuracy of 0.99 and discriminability of 1.00 area under the receiver operating characteristic curve (AUC) for lactate level prediction was obtained when the vital signs and WBC measurements were analysed in a 24 h time bin. An accuracy of 0.73 and discriminability of 0.73 AUC for mortality prediction in patients with sepsis was achieved with only three features: median of lactate levels, mean arterial pressure, and median absolute deviation of the respiratory rate. Discussion This study introduces a new scheme for the prediction of lactate levels and mortality risk from patient vital signs and WBC. Accurate prediction of both these variables can drive the appropriate response by clinical staff and thus may have important implications for patient health and treatment outcome. Conclusions Effective predictions of lactate levels and mortality risk can be provided with a few clinical variables when the temporal aspect and variability of patient data are considered. PMID:23959843

Maternal care and paternal protection influence response to psychotherapy treatment for adult depression.

PubMed

Johnstone, Jeanette M; Carter, Janet D; Luty, Suzanne E; Mulder, Roger T; Frampton, Christopher M; Joyce, Peter R

2013-07-01

Adverse childhood experiences of neglect, overprotection and abuse, well-recognized risk factors for the development of adult psychopathology, were examined as predictors of response to psychotherapy treatment for adults with depression. Outpatients in a randomized clinical trial of interpersonal psychotherapy (IPT) or cognitive-behavioral therapy (CBT) completed the parental bonding instrument (PBI) at baseline to establish levels of care and protection. Childhood abuse was asked about using clinical interviews. The PBI variables were examined in tertiles while the abuse variables were categorized as "none," "some," and "severe." Associations between these childhood adversities and treatment response were examined in those who completed the trial. Of 177 outpatients with depression who were randomized, 159 completed an adequate trial of therapy. Within these 159 patients, 57% were categorized as responders to treatment. The mean percentage improvement on the MADRS was 57.7% (±31.4). Across both treatments, patients reporting intermediate levels of maternal care had the best response to treatment. Also across both treatments, the interaction effects of maternal care and paternal protection by treatment were statistically significant. Examining the two therapies independently, maternal care and paternal protection were associated with a differential response to IPT but not CBT. Reports of abuse, whether physical, emotional or sexual, did not impact treatment response. This study examined patients who completed treatment, which may have attenuated the findings. Two categories of childhood adversity were measured although a range of other adverse childhood experiences exist. The results were from exploratory analyses and require replication. Maternal care, demonstrating a robust main effect across treatments, appears to be the childhood variable most strongly associated with response to psychotherapy in this sample. In addition, maternal care and paternal protection were associated with a differential response to treatment. These results suggest that the quality of on-going intra-familial relationships has a greater impact on treatment response than experiences of abuse. The findings may aid clinicians in selecting which psychotherapy to use, depending on a patient's childhood history. Copyright © 2013 Elsevier B.V. All rights reserved.

A Case for Pharmacogenomics in Management of Cardiac Arrhythmias

PubMed Central

Kandoi, Gaurav; Nanda, Anjali; Scaria, Vinod; Sivasubbu, Sridhar

2012-01-01

Disorders of the cardiac rhythm are quite prevalent in clinical practice. Though the variability in drug response between individuals has been extensively studied, this information has not been widely used in clinical practice. Rapid advances in the field of pharmacogenomics have provided us with crucial insights on inter-individual genetic variability and its impact on drug metabolism and action. Technologies for faster and cheaper genetic testing and even personal genome sequencing would enable clinicians to optimize prescription based on the genetic makeup of the individual, which would open up new avenues in the area of personalized medicine. We have systematically looked at literature evidence on pharmacogenomics markers for anti-arrhythmic agents from the OpenPGx consortium collection and reason the applicability of genetics in the management of arrhythmia. We also discuss potential issues that need to be resolved before personalized pharmacogenomics becomes a reality in regular clinical practice. PMID:22557843

Clinical outcome of pediatric collagenous gastritis: case series and review of literature.

PubMed

Hijaz, Nadia Mazen; Septer, Seth Steven; Degaetano, James; Attard, Thomas Mario

2013-03-07

Collagenous gastritis (CG) is characterized by patchy subepithelial collagen bands. Effective treatment and the clinical and histological outcome of CG in children are poorly defined. The aim of this study is to summarize the published literature on the clinical outcome and response to therapy of pediatric CG including two new cases. We performed a search in Pubmed, OVID for related terms; articles including management and clinical and/or endo-histologic follow up information were included and abstracted. Reported findings were pooled in a dedicated database including the corresponding data extracted from chart review in our patients with CG. Twenty-four patients were included (17 females) with a mean age of 11.7 years. The clinical presentation included iron deficiency anemia and dyspepsia. The reported duration of follow up (in 18 patients) ranged between 0.2-14 years. Despite most subjects presenting with anemia including one requiring blood transfusion, oral iron therapy was only documented in 12 patients. Other treatment modalities were antisecretory measures in 13 patients; proton pump inhibitors (12), or histamine-2 blockers (3), sucralfate (5), prednisolone (6), oral budesonide in 3 patients where one received it in fish oil and triple therapy (3). Three (13%) patients showed no clinical improvement despite therapy; conversely 19 out of 22 were reported with improved symptoms including 8 with complete symptom resolution. Spontaneous clinical resolution without antisecretory, anti-inflammatory or gastroprotective agents was noted in 5 patients (4 received only supplemental iron). Follow up endo-histopathologic data (17 patients) included persistent collagen band and stable Mononuclear cell infiltrate in 12 patients with histopathologic improvement in 5 patients. Neither collagen band thickness nor mononuclear cell infiltrate correlated with clinical course. Intestinal metaplasia and endocrine cell hyperplasia were reported (1) raising the concern of long term malignant transformation. In summary, CG in children is a chronic disease, typically with a variable clinical response and an indolent course that is distinct from the adult phenotype. Long term therapy usually included iron supplementation but cannot be standardized, given the chronicity of the disease, variability of response and potential for adverse events.

Clinical outcome of pediatric collagenous gastritis: Case series and review of literature

PubMed Central

Hijaz, Nadia Mazen; Septer, Seth Steven; Degaetano, James; Attard, Thomas Mario

2013-01-01

Collagenous gastritis (CG) is characterized by patchy subepithelial collagen bands. Effective treatment and the clinical and histological outcome of CG in children are poorly defined. The aim of this study is to summarize the published literature on the clinical outcome and response to therapy of pediatric CG including two new cases. We performed a search in Pubmed, OVID for related terms; articles including management and clinical and/or endo-histologic follow up information were included and abstracted. Reported findings were pooled in a dedicated database including the corresponding data extracted from chart review in our patients with CG. Twenty-four patients were included (17 females) with a mean age of 11.7 years. The clinical presentation included iron deficiency anemia and dyspepsia. The reported duration of follow up (in 18 patients) ranged between 0.2-14 years. Despite most subjects presenting with anemia including one requiring blood transfusion, oral iron therapy was only documented in 12 patients. Other treatment modalities were antisecretory measures in 13 patients; proton pump inhibitors (12), or histamine-2 blockers (3), sucralfate (5), prednisolone (6), oral budesonide in 3 patients where one received it in fish oil and triple therapy (3). Three (13%) patients showed no clinical improvement despite therapy; conversely 19 out of 22 were reported with improved symptoms including 8 with complete symptom resolution. Spontaneous clinical resolution without antisecretory, anti-inflammatory or gastroprotective agents was noted in 5 patients (4 received only supplemental iron). Follow up endo-histopathologic data (17 patients) included persistent collagen band and stable Mononuclear cell infiltrate in 12 patients with histopathologic improvement in 5 patients. Neither collagen band thickness nor mononuclear cell infiltrate correlated with clinical course. Intestinal metaplasia and endocrine cell hyperplasia were reported (1) raising the concern of long term malignant transformation. In summary, CG in children is a chronic disease, typically with a variable clinical response and an indolent course that is distinct from the adult phenotype. Long term therapy usually inclused iron supplementation but cannot be standardized, given the chronicity of the disease, variability of response and potential for adverse events. PMID:23538318

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy: From Molecular Bases to Practical Considerations

PubMed Central

Ripellino, Paolo; Fleetwood, Thomas; Cantello, Roberto; Comi, Cristoforo

2014-01-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, in which both cellular and humoral immune responses are involved. The disease is clinically heterogeneous with some patients displaying pure motor form and others also showing a variable degree of sensory dysfunction; disease evolution may also differ from patient to patient, since monophasic, progressive, and relapsing forms are reported. Underlying such clinical variability there is probably a broad spectrum of molecular dysfunctions that are and will be the target of therapeutic strategies. In this review we first explore the biological bases of current treatments and subsequently we focus on the practical management that must also take into account pharmacoeconomic issues. PMID:24527207

Atypical Reactivity of Heart Rate Variability to Stress and Depression: Systematic Review of the Literature and Directions for Future Research

PubMed Central

Hamilton, Jessica L.; Alloy, Lauren B.

2017-01-01

Heart rate variability has received growing attention in the depression literature, with several recent meta-analyses indicating that lower resting heart rate variability is associated with depression. However, the role of fluctuations in heart rate variability (or reactivity) in response to stress in depression remains less clear. The present review provides a systematic examination of the literature on heart rate variability reactivity to a laboratory-induced stressor task and depression, including 26 studies of reactivity in heart rate variability and clinical depression, remitted (or history of) depression, and subthreshold depression (or symptom-level depression) among adults, adolescents, and children. In addition to reviewing the findings of these studies, methodological considerations and conceptual gaps in the literature are addressed. We conclude by highlighting the importance of investigating the potential transactional relationship between heart rate variability reactivity and depression and possible mechanisms underlying this relationship. PMID:27697746

Single-trial decoding of auditory novelty responses facilitates the detection of residual consciousness

PubMed Central

King, J.R.; Faugeras, F.; Gramfort, A.; Schurger, A.; El Karoui, I.; Sitt, J.D.; Rohaut, B.; Wacongne, C.; Labyt, E.; Bekinschtein, T.; Cohen, L.; Naccache, L.; Dehaene, S.

2017-01-01

Detecting residual consciousness in unresponsive patients is a major clinical concern and a challenge for theoretical neuroscience. To tackle this issue, we recently designed a paradigm that dissociates two electro-encephalographic (EEG) responses to auditory novelty. Whereas a local change in pitch automatically elicits a mismatch negativity (MMN), a change in global sound sequence leads to a late P300b response. The latter component is thought to be present only when subjects consciously perceive the global novelty. Unfortunately, it can be difficult to detect because individual variability is high, especially in clinical recordings. Here, we show that multivariate pattern classifiers can extract subject-specific EEG patterns and predict single-trial local or global novelty responses. We first validate our method with 38 high-density EEG, MEG and intracranial EEG recordings. We empirically demonstrate that our approach circumvents the issues associated with multiple comparisons and individual variability while improving the statistics. Moreover, we confirm in control subjects that local responses are robust to distraction whereas global responses depend on attention. We then investigate 104 vegetative state (VS), minimally conscious state (MCS) and conscious state (CS) patients recorded with high-density EEG. For the local response, the proportion of significant decoding scores (M = 60%) does not vary with the state of consciousness. By contrast, for the global response, only 14% of the VS patients' EEG recordings presented a significant effect, compared to 31% in MCS patients' and 52% in CS patients'. In conclusion, single-trial multivariate decoding of novelty responses provides valuable information in non-communicating patients and paves the way towards real-time monitoring of the state of consciousness. PMID:23859924

Correlates of Successful Response to a Behavioral Weight Control Clinic.

ERIC Educational Resources Information Center

And Others; Gormally, Jim

1980-01-01

Initial weight-loss success was correlated with two severity variables. Persons reporting frequent binge eating and histories of previous dieting weight loss lost the most weight. Persons who were successful at maintenance used frequent exercise. Those who relapsed reported high levels of stress during follow-up. (Author)

Enhancing Clinical Evaluation Skills: Palpation as the Principal Skill

ERIC Educational Resources Information Center

Eberman, Lindsey E.; Finn, Megan E.

2010-01-01

Context: Recognition and evaluation of injuries/illnesses accounts for the greatest percentage (24%) of an athletic trainer's responsibilities as a clinician. When teaching orthopedic evaluation, we often emphasize history taking and special/ligamentous tests to achieve a diagnosis. Because of its complexity and variability, palpation becomes an…

Update on B-cell targeted therapies for systemic lupus erythematosus.

PubMed

Mok, Chi Chiu

2014-06-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by flares and remission, leading to accrual of organ damage over time as a result of persistent tissue inflammation and treatment-related complications. Novel therapies aiming at better treatment response and fewer adverse effects are being tested in the pipeline. This review summarizes the B-cell abnormalities observed in patients with SLE, and updates recent data on the efficacy and safety of B-cell targeted therapies in the treatment of SLE. The pitfalls of clinical trial design and future directions of the development of SLE therapeutics are discussed. The variability of clinical response to treatment in SLE reflects the clinical and immunological heterogeneity of the disease. The treatment plan for patients with SLE should be individualized with the aim of eradicating disease activity, preventing flares and minimizing treatment-related complications. Despite the disappointment of recent clinical trials, B-cell remains the promising target of future SLE therapies. Results from ongoing clinical trials on B-cell targeted biological agents are eagerly awaited.

Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration

PubMed Central

Bossuyt, V.; Provenzano, E.; Symmans, W. F.; Boughey, J. C.; Coles, C.; Curigliano, G.; Dixon, J. M.; Esserman, L. J.; Fastner, G.; Kuehn, T.; Peintinger, F.; von Minckwitz, G.; White, J.; Yang, W.; Badve, S.; Denkert, C.; MacGrogan, G.; Penault-Llorca, F.; Viale, G.; Cameron, D.; Earl, Helena; Alba, Emilio; Lluch, Ana; Albanell, Joan; Amos, Keith; Biernat, Wojciech; Bonnefoi, Hervé; Buzdar, Aman; Cane, Paul; Pinder, Sarah; Carson, Lesley; Dickson-Witmer, Diana; Gong, Gyungyub; Green, Jimmy; Hsu, Chih-Yi; Tseng, Ling-Ming; Kroep, Judith; Leitch, A. Marilyn; Sarode, Venetia; Mamounas, Eleftherios; Marcom, Paul Kelly; Nuciforo, Paolo; Paik, Soonmyung; Peg, Vicente; Peston, David; Pierga, Jean-Yves; Quintela-Fandino, Miguel; Salgado, Roberto; Sikov, William; Thomas, Jeremy; Unzeitig, Gary; Wesseling, Jelle

2015-01-01

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials. PMID:26019189

Disease-modifying genetic factors in cystic fibrosis.

PubMed

Marson, Fernando A L

2018-05-01

To compile data from the past 10 years regarding the role of modifying genes in cystic fibrosis (CF). CF is a model disease for understanding of the action of modifying genes. Although it is a monogenic (CFTR) autosomal recessive disease, CF presents with wide phenotypic variability. In CF, variability occurs with different intensity among patients by each organ, being organ-specific, resulting from the mutual interaction of environmental and genetic factors, including CFTR mutations and various other genes, most of which are associated with inflammatory processes. In individuals, using precision medicine, gene modification studies have revealed individualized responses to drugs depending on particular CFTR mutations and modifying genes, most of which are alternative ion channels. Studies of modifying genes in CF allow: understanding of clinical variability among patients with the same CFTR genotype; evaluation of precision medicine; understanding of environmental and genetic effects at the organ level; understanding the involvement of genetic variants in inflammatory responses; improvements in genetic counseling; understanding the involvement of genetic variants in inflammatory responses in lung diseases, such as asthma; and understanding the individuality of the person with the disease.

Validity of Rorschach Inkblot scores for discriminating psychopaths from non-psychopaths in forensic populations: a meta-analysis.

PubMed

Wood, James M; Lilienfeld, Scott O; Nezworski, M Teresa; Garb, Howard N; Allen, Keli Holloway; Wildermuth, Jessica L

2010-06-01

Gacono and Meloy (2009) have concluded that the Rorschach Inkblot Test is a sensitive instrument with which to discriminate psychopaths from nonpsychopaths. We examined the association of psychopathy with 37 Rorschach variables in a meta-analytic review of 173 validity coefficients derived from 22 studies comprising 780 forensic participants. All studies included the Hare Psychopathy Checklist or one of its versions (Hare, 1980, 1991, 2003) and Exner's (2003) Comprehensive System for the Rorschach. Mean validity coefficients of Rorschach variables in the meta-analysis ranged from -.113 to .239, with a median validity of .070 and a mean validity of .062. Psychopathy displayed a significant and medium-sized association with the number of Aggressive Potential responses (weighted mean validity coefficient = .232) and small but significant associations with the Sum of Texture responses, Cooperative Movement = 0, the number of Personal responses, and the Egocentricity Index (weighted mean validity coefficients = .097 to .159). The remaining 32 Rorschach variables were not significantly related to psychopathy. The present findings contradict the view that the Rorschach is a clinically sensitive instrument for discriminating psychopaths from nonpsychopaths.

Beat to beat variability in cardiovascular variables: noise or music?

NASA Technical Reports Server (NTRS)

Appel, M. L.; Berger, R. D.; Saul, J. P.; Smith, J. M.; Cohen, R. J.

1989-01-01

Cardiovascular variables such as heart rate, arterial blood pressure, stroke volume and the shape of electrocardiographic complexes all fluctuate on a beat to beat basis. These fluctuations have traditionally been ignored or, at best, treated as noise to be averaged out. The variability in cardiovascular signals reflects the homeodynamic interplay between perturbations to cardiovascular function and the dynamic response of the cardiovascular regulatory systems. Modern signal processing techniques provide a means of analyzing beat to beat fluctuations in cardiovascular signals, so as to permit a quantitative, noninvasive or minimally invasive method of assessing closed loop hemodynamic regulation and cardiac electrical stability. This method promises to provide a new approach to the clinical diagnosis and management of alterations in cardiovascular regulation and stability.

Psychobiologic correlates of treatment response in schizophrenia.

PubMed

Lieberman, J A; Alvir, J M; Koreen, A; Geisler, S; Chakos, M; Sheitman, B; Woerner, M

1996-03-01

In studies conducted on largely treatment naive patients in their first episode of psychosis, we have found that treatment outcome is quite good and that most patients recover or at least achieve a substantial degree of symptom remission. However, over the course of their illness and in the context of subsequent psychotic episodes, they may experience some decrease in their treatment response from illness progression. In addition, the heterogeneity of treatment outcome is associated with specific clinical (gender, primary negative symptoms of the deficit state, duration of psychosis) and biological variables (pHVA, ventricular volume). It is unclear whether these variables represent aspects of discrete subtypes of schizophrenia or dimensional measures of pathology within the broad context of a unitary disease entity.

Endoscopic ultrasound as an adjunctive evaluation in patients with esophageal motor disorders subtyped by high-resolution manometry.

PubMed

Krishnan, K; Lin, C-Y; Keswani, R; Pandolfino, J E; Kahrilas, P J; Komanduri, S

2014-08-01

Esophageal motor disorders are a heterogeneous group of conditions identified by esophageal manometry that lead to esophageal dysfunction. The aim of this study was to assess the clinical utility of endoscopic ultrasound (EUS) in the further evaluation of patients with esophageal motor disorders categorized using the updated Chicago Classification. We performed a retrospective, single center study of 62 patients with esophageal motor disorders categorized according to the Chicago Classification. All patients underwent standard radial endosonography to assess for extra-esophageal findings or alternative explanations for esophageal outflow obstruction. Secondary outcomes included esophageal wall thickness among the different patient subsets within the Chicago Classification. EUS identified 9/62 (15%) clinically relevant findings that altered patient management and explained the etiology of esophageal outflow obstruction. We further identified substantial variability in esophageal wall thickness in a proportion of patients including some with a significantly thickened non-muscular layer. EUS findings are clinically relevant in a significant number of patients with motor disorders and can alter clinical management. Variability in esophageal wall thickness of the muscularis propria and non-muscular layers identified by EUS may also explain the observed variability in response to standard therapies for achalasia. © 2014 John Wiley & Sons Ltd.

Endoscopic ultrasound as an adjunctive evaluation in patients with esophageal motor disorders subtyped by high-resolution manometry

PubMed Central

Krishnan, Kumar; Lin, Chen-Yuan; Keswani, Rajesh; Pandolfino, John E; Kahrilas, Peter J; Komanduri, Srinadh

2015-01-01

Background and aims Esophageal motor disorders are a heterogenous group of conditions identified by esophageal manometry that lead to esophageal dysfunction. The aim of this study was to assess the clinical utility of endoscopic ultrasound in the further evaluation of patients with esophageal motor disorders categorized using the updated Chicago Classification. Methods We performed a retrospective, single center study of 62 patients with esophageal motor disorders categorized according to the Chicago Classification. All patients underwent standard radial endosonography to assess for extra esophageal findings or alternative explanations for esophageal outflow obstruction. Secondary outcomes included esophageal wall thickness among the different patient subsets within the Chicago Classification Key Results EUS identified 9/62 (15%) clinically relevant findings that altered patient management and explained the etiology of esophageal outflow obstruction. We further identified substantial variability in esophageal wall thickness in a proportion of patients including some with a significantly thickened non-muscular layer. Conclusions EUS findings are clinically relevant in a significant number of patients with motor disorders and can alter clinical management. Variability in esophageal wall thickness of the muscularis propria and non-muscular layers identified by EUS may also explain the observed variability in response to standard therapies for achalasia. PMID:25041229

Clinical and Biological Relevance of Genomic Heterogeneity in Chronic Lymphocytic Leukemia

PubMed Central

Friedman, Daphne R.; Lucas, Joseph E.; Weinberg, J. Brice

2013-01-01

Background Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients’ leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL. Methods To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups. Results Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes. Conclusions Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways. PMID:23468975

Clinical and biological relevance of genomic heterogeneity in chronic lymphocytic leukemia.

PubMed

Friedman, Daphne R; Lucas, Joseph E; Weinberg, J Brice

2013-01-01

Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients' leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL. To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups. Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes. Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways.

Predicting Fluid Responsiveness by Passive Leg Raising: A Systematic Review and Meta-Analysis of 23 Clinical Trials.

PubMed

Cherpanath, Thomas G V; Hirsch, Alexander; Geerts, Bart F; Lagrand, Wim K; Leeflang, Mariska M; Schultz, Marcus J; Groeneveld, A B Johan

2016-05-01

Passive leg raising creates a reversible increase in venous return allowing for the prediction of fluid responsiveness. However, the amount of venous return may vary in various clinical settings potentially affecting the diagnostic performance of passive leg raising. Therefore we performed a systematic meta-analysis determining the diagnostic performance of passive leg raising in different clinical settings with exploration of patient characteristics, measurement techniques, and outcome variables. PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and citation tracking of relevant articles. Clinical trials were selected when passive leg raising was performed in combination with a fluid challenge as gold standard to define fluid responders and non-responders. Trials were included if data were reported allowing the extraction of sensitivity, specificity, and area under the receiver operating characteristic curve. Twenty-three studies with a total of 1,013 patients and 1,034 fluid challenges were included. The analysis demonstrated a pooled sensitivity of 86% (95% CI, 79-92), pooled specificity of 92% (95% CI, 88-96), and a summary area under the receiver operating characteristic curve of 0.95 (95% CI, 0.92-0.98). Mode of ventilation, type of fluid used, passive leg raising starting position, and measurement technique did not affect the diagnostic performance of passive leg raising. The use of changes in pulse pressure on passive leg raising showed a lower diagnostic performance when compared with passive leg raising-induced changes in flow variables, such as cardiac output or its direct derivatives (sensitivity of 58% [95% CI, 44-70] and specificity of 83% [95% CI, 68-92] vs sensitivity of 85% [95% CI, 78-90] and specificity of 92% [95% CI, 87-94], respectively; p < 0.001). Passive leg raising retains a high diagnostic performance in various clinical settings and patient groups. The predictive value of a change in pulse pressure on passive leg raising is inferior to a passive leg raising-induced change in a flow variable.

Derivation and validation of the Personal Support Algorithm: an evidence-based framework to inform allocation of personal support services in home and community care.

PubMed

Sinn, Chi-Ling Joanna; Jones, Aaron; McMullan, Janet Legge; Ackerman, Nancy; Curtin-Telegdi, Nancy; Eckel, Leslie; Hirdes, John P

2017-11-25

Personal support services enable many individuals to stay in their homes, but there are no standard ways to classify need for functional support in home and community care settings. The goal of this project was to develop an evidence-based clinical tool to inform service planning while allowing for flexibility in care coordinator judgment in response to patient and family circumstances. The sample included 128,169 Ontario home care patients assessed in 2013 and 25,800 Ontario community support clients assessed between 2014 and 2016. Independent variables were drawn from the Resident Assessment Instrument-Home Care and interRAI Community Health Assessment that are standardised, comprehensive, and fully compatible clinical assessments. Clinical expertise and regression analyses identified candidate variables that were entered into decision tree models. The primary dependent variable was the weekly hours of personal support calculated based on the record of billed services. The Personal Support Algorithm classified need for personal support into six groups with a 32-fold difference in average billed hours of personal support services between the highest and lowest group. The algorithm explained 30.8% of the variability in billed personal support services. Care coordinators and managers reported that the guidelines based on the algorithm classification were consistent with their clinical judgment and current practice. The Personal Support Algorithm provides a structured yet flexible decision-support framework that may facilitate a more transparent and equitable approach to the allocation of personal support services.

Evaluation of the Environmental Bias on Accelerometer-Measured Total Daily Activity Counts and Owner Survey Responses in Dogs with Osteoarthritis.

PubMed

Katz, Erin M; Scott, Ruth M; Thomson, Christopher B; Mesa, Eileen; Evans, Richard; Conzemius, Michael G

2017-11-01

Objective  To determine if environmental variables affect the average daily activity counts (AC) of dogs with osteoarthritis (OA) and/or owners' perception of their dog's clinical signs or quality of life. Methods  The AC and Canine Brief Pain Inventory (CBPI) owner questionnaires of 62 dogs with OA were compared with daily environmental variables including the following: average temperature (°C), high temperature (°C), low temperature (°C), relative humidity (%), total precipitation (mm), average barometric pressure (hPa) and total daylight hours. Results  Daily AC significantly correlated with average temperature and total daylight hours, but average temperature and total daylight hours accounted for less than 1% of variation in AC. No other significant relationships were found between daily AC and daily high temperature, low temperature, relative humidity, total precipitation or average barometric pressure. No statistical relationship was found between daily AC and the CBPI, nor between environmental variables and the CBPI. Canine Brief Pain Inventory scores for pain severity and pain interference decreased significantly over the test period. Clinical Significance  The relationship between daily AC and average temperature and total daylight hours was significant, but unlikely to be clinically significant. Thus, environmental variables do not appear to have a clinically relevant bias on AC or owner CBPI questionnaires. The decrease over time in CBPI pain severity and pain interference values suggests owners completing the CBPI in this study were influenced by a caregiver placebo effect. Schattauer GmbH Stuttgart.

Pharmacogenetics in clinical practice: how far have we come and where are we going?

PubMed Central

Johnson, Julie A

2013-01-01

Recent years have seen great advances in our understanding of genetic contributors to drug response. Drug discovery and development around targeted genetic (somatic) mutations has led to a number of new drugs with genetic indications, particularly for the treatment of cancers. Our knowledge of genetic contributors to variable drug response for existing drugs has also expanded dramatically, such that the evidence now supports clinical use of genetic data to guide treatment in some situations, and across a variety of therapeutic areas. Clinical implementation of pharmacogenetics has seen substantial growth in recent years and groups are working to identify the barriers and best practices for pharmacogenetic-guided treatment. The advances and challenges in these areas are described and predictions about future use of genetics in drug therapy are discussed. PMID:23651030

Use of Cox's Cure Model to Establish Clinical Determinants of Long-Term Disease-Free Survival in Neoadjuvant-Chemotherapy-Treated Breast Cancer Patients without Pathologic Complete Response.

PubMed

Asano, Junichi; Hirakawa, Akihiro; Hamada, Chikuma; Yonemori, Kan; Hirata, Taizo; Shimizu, Chikako; Tamura, Kenji; Fujiwara, Yasuhiro

2013-01-01

In prognostic studies for breast cancer patients treated with neoadjuvant chemotherapy (NAC), the ordinary Cox proportional-hazards (PH) model has been often used to identify prognostic factors for disease-free survival (DFS). This model assumes that all patients eventually experience relapse or death. However, a subset of NAC-treated breast cancer patients never experience these events during long-term follow-up (>10 years) and may be considered clinically "cured." Clinical factors associated with cure have not been studied adequately. Because the ordinary Cox PH model cannot be used to identify such clinical factors, we used the Cox PH cure model, a recently developed statistical method. This model includes both a logistic regression component for the cure rate and a Cox regression component for the hazard for uncured patients. The purpose of this study was to identify the clinical factors associated with cure and the variables associated with the time to recurrence or death in NAC-treated breast cancer patients without a pathologic complete response, by using the Cox PH cure model. We found that hormone receptor status, clinical response, human epidermal growth factor receptor 2 status, histological grade, and the number of lymph node metastases were associated with cure.

Negative Mood and Obsessive-Compulsive Related Clinical Constructs: An Examination of Underlying Factors

PubMed Central

Britton, Gary I.; Davey, Graham C. L.

2017-01-01

Emerging evidence suggests that many of the clinical constructs used to help understand and explain obsessive-compulsive (OC) symptoms, and negative mood, may be causally interrelated. One approach to understanding this interrelatedness is a motivational systems approach. This approach suggests that rather than considering clinical constructs and negative affect as separable entities, they are all features of an integrated threat management system, and as such are highly coordinated and interdependent. The aim of the present study was to examine if clinical constructs related to OC symptoms and negative mood are best treated as separable or, alternatively, if these clinical constructs and negative mood are best seen as indicators of an underlying superordinate variable, as would be predicted by a motivational systems approach. A sample of 370 student participants completed measures of mood and the clinical constructs of inflated responsibility, intolerance of uncertainty, not just right experiences, and checking stop rules. An exploratory factor analysis suggested two plausible factor structures, one where all construct items and negative mood items loaded onto one underlying superordinate variable, and a second structure comprising of five factors, where each item loaded onto a factor representative of what the item was originally intended to measure. A confirmatory factor analysis showed that the five factor model was preferential to the one factor model, suggesting the four constructs and negative mood are best conceptualized as separate variables. Given the predictions of a motivational systems approach were not supported in the current study, other possible explanations for the causal interrelatedness between clinical constructs and negative mood are discussed. PMID:28959224

Opiate pharmacology and relief of pain.

PubMed

Pasternak, Gavril W

2014-06-01

Opioids remain the mainstay of severe pain management in patients with cancer. The hallmark of pain management is individualization of therapy. Although almost all clinically used drugs act through mu opioid receptors, they display subtle but important differences pharmacologically. Furthermore, not all patients respond equally well to all drugs. Evidence suggests that these variable responses among patients have a biologic basis and are likely to involve both biased agonism and the many mu opioid receptor subtypes that have been cloned. © 2014 by American Society of Clinical Oncology.

Variable domain glycosylation of ACPA-IgG: A missing link in the maturation of the ACPA response?

PubMed

Kempers, Ayla C; Hafkenscheid, Lise; Scherer, Hans Ulrich; Toes, René E M

2018-01-01

Anti-citrullinated Protein Antibodies (ACPA) are excellent markers for Rheumatoid arthritis (RA) and are postulated to have a pathogenic role in the disease process. A multistep model for the evolution of the ACPA response in RA was proposed in which an initial break of tolerance causes, as "first hit", "silent" production of ACPA without any clinical symptoms. The model further proposes that the ACPA immune response matures upon a certain (unknown) trigger, a "second hit", which leads to epitope spreading, an increase in ACPA titres and extended isotype usage before clinical RA manifestations. These occurrences are indicative of an expansion of the citrulline-specific B cell response, though ACPA remain of low avidity even in established disease. This persistence of low avidity is puzzling, as the typical signs of maturation of the immune response seem to be uncoupled from the classical process of affinity maturation. In fact, it suggests that B cells expressing ACPA could bypass selection mechanisms that otherwise control the expansion of auto-reactive B cells. In the established, chronic phase, we recently found that ACPA-IgG are extensively glycosylated in the variable (Fab) domain. More than 90% of ACPA-IgG molecules carry Fab glycans that are highly sialylated. This molecular feature is striking and may provide a missing link in our understanding of the maturation of the ACPA immune response. This review, therefore, describes the current knowledge about ACPA Fab glycosylation in the pathogenesis of RA. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Perceptual and response-dependent profiles of attention in children with ADHD.

PubMed

Caspersen, Ida Dyhr; Petersen, Anders; Vangkilde, Signe; Plessen, Kerstin Jessica; Habekost, Thomas

2017-05-01

Attention-deficit hyperactivity disorder (ADHD) is a complex developmental neuropsychiatric disorder, characterized by inattentiveness, impulsivity, and hyperactivity. Recent literature suggests a potential core deficit underlying these behaviors may involve inefficient processing when contextual stimulation is low. In order to specify this inefficiency, the aim of the present study was to disentangle perceptual and response-based deficits of attention by supplementing classic reaction time (RT) measures with an accuracy-only test. Moreover, it was explored whether ADHD symptom severity was systematically related to perceptual and response-based processes. We applied an RT-independent paradigm (Bundesen, 1990) and a sustained attention task (Dockree et al., 2006) to test visual attention in 24 recently diagnosed, medication-naïve children with ADHD, 14 clinical controls with pervasive developmental disorder, and 57 healthy controls. Outcome measures included perceptual processing speed, capacity of visual short-term memory, and errors of commission and omission. Children with ADHD processed information abnormally slow (d = 0.92), and performed poorly on RT variability and response stability (d's ranging from 0.60 to 1.08). In the ADHD group only, slowed visual processing speed was significantly related to response lapses (omission errors). This correlation was not explained by behavioral ratings of ADHD severity. Based on combined assessment of perceptual and response-dependent variables of attention, the present study demonstrates a specific cognitive profile in children with ADHD. This profile distinguishes the disorder at a basic level of attentional functioning, and may define subgroups of children with ADHD in a way that is more sensitive than clinical rating scales. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Furthering the Validity of a Tool to Assess Simulated Pregnancy Options Counseling Skills.

PubMed

Lupi, Carla; Ward-Peterson, Melissa; Coxe, Stefany; Minor, Suzanne; Eliacin, Irmanie; Obeso, Vivian

2016-10-01

To further the validity of a tool to assess nondirective pregnancy options counseling skills. Using a cross-sectional design, we explored four sources of construct validity evidence for an objective structured clinical examination for training and assessment of nondirective pregnancy options counseling: content, response process, internal structure, and relations to other variables. Content of the previously developed tool was enhanced through input from five family medicine educators. The objective structured clinical examination was implemented in a family medicine clerkship with third-year medical students from 2014 to 2015 using trained raters. Response process was addressed after a pilot round. Three new raters evaluated videotapes of 46 performances. Cronbach's alpha, intraclass correlation coefficients, and Spearman's rho were estimated with 95% confidence intervals. The content validity was affirmed. Cronbach's alpha was 0.71. According to Landis and Koch's criteria, all but two items unique to the clinical situation of pregnancy options counseling generated substantial to perfect agreement (0.62-1.00). Relations to other variables within the checklist were strong, ranging from 0.66 to 0.87. This tool for assessing pregnancy options counseling skills has excellent content and strong internal structure. Further work to improve the Global Rating Scale may be necessary for summative use.

Voltammetric and Mathematical Evidence for Dual Transport Mediation of Serotonin Clearance In Vivo

PubMed Central

Wood, Kevin M.; Zeqja, Anisa; Nijhout, H. Frederik; Reed, Michael C.; Best, Janet; Hashemi, Parastoo

2014-01-01

The neurotransmitter serotonin underlies many of the brain’s functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants. PMID:24702305

Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs†.

PubMed

Mullin, C M; Arkans, M A; Sammarco, C D; Vail, D M; Britton, B M; Vickery, K R; Risbon, R E; Lachowicz, J; Burgess, K E; Manley, C A; Clifford, C A

2016-12-01

Sixty-four dogs were treated with single-agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression-free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA. © 2014 John Wiley & Sons Ltd.

Predictive factors for the placebo effect in clinical trials for dry eye: a pooled analysis of three clinical trials.

PubMed

Imanaka, Takahiro; Sato, Izumi; Tanaka, Shiro; Kawakami, Koji

2017-11-01

Placebo effect is one of the methodological difficulties in dry eye clinical trials. If we could elucidate the tendencies of the placebo response and find predictors, we could reduce the placebo response in clinical trials for dry eye. In this study, we investigated the predictive factors for the placebo effect in dry eye clinical trials. A total of 205 patients with dry eye assigned to the placebo arms of three placebo-controlled randomised clinical trials were analysed by simple and multivariable regression analysis. The corneal fluorescein (FL) staining score and dry eye symptoms were studied at week 4. The variables of interest included gender, age, complications of Sjögren's syndrome, Schirmer's test I value, tear break-up time and conjunctival hyperaemia score. We also conducted a stratified analysis according to the patients' age. Among all the studied endpoints, the baseline scores were significantly related to the corresponding placebo response. In addition, for the FL score and the dryness score, age was a significant predictor of the placebo response (p=0.04 and p<0.0001, respectively). Stratified analysis by age showed that patients more than 40 years of age are more likely to have a stronger placebo response in the FL and dryness scores. The baseline scores and age were predictive factors of the placebo response in frequently used endpoints, such as FL score or dryness symptoms. These patient characteristics can be controlled by study design, and our findings enable the design of more efficient placebo-controlled studies with good statistical power. © 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.

Predictors of response to intra-articular steroid injection in psoriatic arthritis.

PubMed

Eder, Lihi; Chandran, Vinod; Ueng, Joanna; Bhella, Sita; Lee, Ker-Ai; Rahman, Proton; Pope, Angela; Cook, Richard J; Gladman, Dafna D

2010-07-01

To assess the effectiveness of IA corticosteroid (IAS) injections in PsA and to determine the association between macrophage migration inhibition factor (MIF) gene polymorphism and response to IAS injections. A cohort analysis of PsA patients who were followed prospectively was performed. Clinical response was defined as no tenderness or effusion in the injected joint at 3 months. Relapse was defined as re-occurrence of joint pain or effusion. MIF 173C > G genotyping (rs755622) was performed. Two hundred and twenty patients with 245 IAS injections were included in the study. The probability of responding at 3 months was 41.6%. Within 12 months, 25.5% of the joints relapsed. Clinical factors that were associated with response included duration of psoriasis [Odds ratio (OR) 1.03] and the use of MTX or anti-TNF agents at the time of injection (OR 2.68). Factors that were associated with relapse included injection into large joints (OR 4.58) and elevated sedimentation rate (OR 15.0), whereas absence of clinical and/or radiographic damage (OR 0.23) and duration of PsA (OR 0.92) reduced risk of relapse. MIF polymorphism was not associated with clinical response, but was associated with relapse (OR 3.2). On multivariate analysis including clinical covariates, the association between MIF polymorphism and relapse was lost. IAS injections are effective in PsA. MIF gene polymorphism is associated with relapse. However, this effect is explained by clinical variables that reflect disease activity, suggesting that MIF gene polymorphism influences inflammatory activity.

Inter- and Intra-individual variability following intermittent theta burst stimulation: implications for rehabilitation and recovery.

PubMed

Hinder, Mark R; Goss, Emily L; Fujiyama, Hakuei; Canty, Alison J; Garry, Michael I; Rodger, Jennifer; Summers, Jeffery J

2014-01-01

The continued refinement of non-invasive brain stimulation (NBS) techniques is indicative of promising clinical and rehabilitative interventions that are able to modulate cortical excitability. Intermittent theta burst stimulation (iTBS) is one such technique that can increase cortical excitability, purportedly via LTP-like mechanisms. While iTBS may have the capacity to promote recovery after neurological injury, and to combat cognitive and motor decline, recent reports observed highly variable effects across individuals, questioning the efficacy of iTBS as a clinical tool. The aim of this study was to examine intra-individual reliability and inter-individual variability in responses to iTBS. Thirty healthy participants completed two experimental sessions of the iTBS protocol 1-3 weeks apart. Motor evoked potentials in response to single pulse TMS were used to assess corticospinal excitability prior to, and up to 36 min following, iTBS. At the group level, iTBS evoked statistically significant increases in motor cortical excitability across both sessions (P < 0.001), with 22 out of 30 participants exhibiting increases in excitability in both sessions. A strong intraclass correlation demonstrated that both the direction, and magnitude of the plastic changes were reliable at the individual level. Overall, our results suggest that iTBS is capable of inducing relatively robust and consistent effects within and between young individuals. As such, the capacity for iTBS to be exploited in clinical and rehabilitative interventions should continue to be explored. Copyright © 2014 Elsevier Inc. All rights reserved.

[Normal pressure hydrocephalus: prognostic value of height in patients treated with an identical shunt system].

PubMed

Aguas, Jesús; Rodrigo, Victor; Estupiñan, Francisco; Nogues, Pere; Villalba, Gloria; Villagrasa, Javier; Caral, Luis

2013-01-01

Normal pressure hydrocephalus (NPH) is a clinical entity frequently managed by means of a cerebrospinal fluid shunt. Hydrodynamic hypotheses consider hydrostatic pressure (as well as height) a very important variable for shunt system function. However, we did not find empirical studies supporting the influence of height on clinical response in the literature. Our objective was to study the prognostic value of height, as a variable related to hydrostatic pressure, when an identical shunt system is used. A prospective series of 61 idiopathic NPH cases was analyzed. All cases were shunted by means of a ventricle-peritoneal system with a 100mmH2O opening pressure valve. Anthropometric, clinical, radiological and pressure variables were registered, as well as delay for treatment, improvement and complications. 78.7% of cases improved after shunting. This group of patients was significantly taller (P=.005) than the group without response (median value 165cm versus 152cm). There was also a significant correlation between height and ventricular size decrease after the shunt. In our series opening valve pressure was a constant (100mmHg) and we could consequently focus on the effect of hydrostatic pressure (height). Moreover, we found a positive predictive value for taller patients, probably because we had selected an opening pressure especially suitable for them. Current gravitational valve shunt systems also recommend considering patient height when customising the system. Our study empirically supports this idea. Copyright © 2012 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

Accounting for pharmacokinetic and pharmacodynamic variability: ten factors to consider before prescribing.

PubMed

O'Malley, Patricia

2007-01-01

Outcomes of pharmacological therapy are more than an accurate assessment and appropriate choice of an agent. Patient outcomes are the result of complex interactions of factors known and unknown. This study explores 10 of many factors that clinical nurse specialists should consider before writing the prescription and monitoring responses to therapy.

Comment on Hall et al. (2017), "How to Choose Between Measures of Tinnitus Loudness for Clinical Research? A Report on the Reliability and Validity of an Investigator-Administered Test and a Patient-Reported Measure Using Baseline Data Collected in a Phase IIa Drug Trial".

PubMed

Sabour, Siamak

2018-03-08

The purpose of this letter, in response to Hall, Mehta, and Fackrell (2017), is to provide important knowledge about methodology and statistical issues in assessing the reliability and validity of an audiologist-administered tinnitus loudness matching test and a patient-reported tinnitus loudness rating. The author uses reference textbooks and published articles regarding scientific assessment of the validity and reliability of a clinical test to discuss the statistical test and the methodological approach in assessing validity and reliability in clinical research. Depending on the type of the variable (qualitative or quantitative), well-known statistical tests can be applied to assess reliability and validity. The qualitative variables of sensitivity, specificity, positive predictive value, negative predictive value, false positive and false negative rates, likelihood ratio positive and likelihood ratio negative, as well as odds ratio (i.e., ratio of true to false results), are the most appropriate estimates to evaluate validity of a test compared to a gold standard. In the case of quantitative variables, depending on distribution of the variable, Pearson r or Spearman rho can be applied. Diagnostic accuracy (validity) and diagnostic precision (reliability or agreement) are two completely different methodological issues. Depending on the type of the variable (qualitative or quantitative), well-known statistical tests can be applied to assess validity.

CLINICAL APPLICATIONS OF CRYOTHERAPY AMONG SPORTS PHYSICAL THERAPISTS.

PubMed

Hawkins, Shawn W; Hawkins, Jeremy R

2016-02-01

Therapeutic modalities (TM) are used by sports physical therapists (SPT) but how they are used is unknown. To identify the current clinical use patterns for cryotherapy among SPT. Cross-sectional survey. All members (7283) of the Sports Physical Therapy Section of the APTA were recruited. A scenario-based survey using pre-participation management of an acute or sub-acute ankle sprain was developed. A Select Survey link was distributed via email to participants. Respondents selected a treatment approach based upon options provided. Follow-up questions were asked. The survey was available for two weeks with a follow-up email sent after one week. Question answers were the main outcome measures. Reliability: Cronbach's alpha=>0.9. The SPT response rate = 6.9% (503); responses came from 48 states. Survey results indicated great variability in respondents' approaches to the treatment of an acute and sub-acute ankle sprain. SPT applied cryotherapy with great variability and not always in accordance to the limited research on the TM. Continuing education, application of current research, and additional outcomes based research needs to remain a focus for clinicians. 3.

What Does Sex Have to Do with It? The Role of Sex as a Biological Variable in the Development of Posttraumatic Stress Disorder.

PubMed

Kornfield, Sara L; Hantsoo, Liisa; Epperson, C Neill

2018-05-18

This review highlights the neurobiological aspects of sex differences in posttraumatic stress disorder (PTSD), specifically focusing on the physiological responses to trauma and presents evidence supporting hormone and neurosteroid/peptide differences from both preclinical and clinical research. While others have suggested that trauma type or acute emotional reaction are responsible for women's disproportionate risk to PTSD, neither of these explanations fully accounts for the sex differences in PTSD. Sex differences in brain neurocircuitry, anatomy, and neurobiological processes, such as those involved in learning and memory, are discussed as they have been implicated in risk and resilience for the development of PTSD. Gonadal and stress hormones have been found to modulate sex differences in the neurocircuitry and neurochemistry underlying fear learning and extinction. Preclinical research has not consistently controlled for hormonal and reproductive status of rodents nor have clinical studies consistently examined these factors as potential moderators of risk for PTSD. Sex as a biological variable (SABV) should be considered, in addition to the endocrine and reproductive status of participants, in all stress physiology and PTSD research.

Individual Differences in Pain: Understanding the Mosaic that Makes Pain Personal

PubMed Central

Fillingim, Roger B.

2016-01-01

The experience of pain is characterized by tremendous inter-individual variability. Multiple biological and psychosocial variables contribute to these individual differences in pain, including demographic variables, genetic factors, and psychosocial processes. For example, sex, age and ethnic group differences in the prevalence of chronic pain conditions have been widely reported. Moreover, these demographic factors have been associated with responses to experimentally-induced pain. Similarly, both genetic and psychosocial factors contribute to clinical and experimental pain responses. Importantly, these different biopsychosocial influences interact with each other in complex ways to sculpt the experience of pain. Some genetic associations with pain have been found to vary across sex and ethnic group. Moreover, genetic factors also interact with psychosocial factors, including stress and pain catastrophizing, to influence pain. The individual and combined influences of these biological and psychosocial variables results in a unique mosaic of factors that contributes pain in each individual. Understanding these mosaics is critically important in order to provide optimal pain treatment, and future research to further elucidate the nature of these biopsychosocial interactions is needed in order to provide more informed and personalized pain care. PMID:27902569

VARIABLE SELECTION FOR REGRESSION MODELS WITH MISSING DATA

PubMed Central

Garcia, Ramon I.; Ibrahim, Joseph G.; Zhu, Hongtu

2009-01-01

We consider the variable selection problem for a class of statistical models with missing data, including missing covariate and/or response data. We investigate the smoothly clipped absolute deviation penalty (SCAD) and adaptive LASSO and propose a unified model selection and estimation procedure for use in the presence of missing data. We develop a computationally attractive algorithm for simultaneously optimizing the penalized likelihood function and estimating the penalty parameters. Particularly, we propose to use a model selection criterion, called the ICQ statistic, for selecting the penalty parameters. We show that the variable selection procedure based on ICQ automatically and consistently selects the important covariates and leads to efficient estimates with oracle properties. The methodology is very general and can be applied to numerous situations involving missing data, from covariates missing at random in arbitrary regression models to nonignorably missing longitudinal responses and/or covariates. Simulations are given to demonstrate the methodology and examine the finite sample performance of the variable selection procedures. Melanoma data from a cancer clinical trial is presented to illustrate the proposed methodology. PMID:20336190

Clinical assessment of cerebrospinal fluid dynamics in hydrocephalus. Guide to interpretation based on observational study.

PubMed

Weerakkody, R A; Czosnyka, M; Schuhmann, M U; Schmidt, E; Keong, N; Santarius, T; Pickard, J D; Czosnyka, Z

2011-08-01

The term hydrocephalus encompasses a range of disorders characterised by clinical symptoms, abnormal brain imaging and derangement of cerebrospinal fluid (CSF) dynamics. The ability to elucidate which patients would benefit from CSF diversion (a shunt or third ventriculostomy) is often unclear. Similar difficulties are often encountered in shunted patients to predict the scope for improvement by shunt re-adjustment or revision. In this study we aimed to update our knowledge of how key quantitative parameters describing CSF dynamics may be used in diagnosis of shunt-responsive hydrocephalus and in the assessment of shunt function. A number of quantitative parameters [including resistance to CSF outflow (Rcsf), pulse amplitude of intracranial pressure waveform (AMP), RAP index and slow vasogenic waves] were studies in 1423 patients with 2665 CSF infusion tests and 305 overnight intracranial pressure (ICP)-monitoring sessions over a 17 year period. We demonstrate our observations for typical values of Pb, Rcsf, AMP, slow vasogenic waves derived from infusion studies or overnight ICP monitoring in differentiating atrophy from shunt-responsive normal pressure hydrocephalus or acute hydrocephalus. From the same variables tested on shunted patients we demonstrate a standardised approach to help differentiate a properly-functioning shunt from underdrainage or overdrainage. Quantitative variables derived from CSF dynamics allow differentiation between clinically overlapping entities such as shunt-responsive normal pressure hydrocephalus and brain atrophy (not shunt responsive) as well as allowing the detection of shunt malfunction (partial or complete blockage) or overdrainage. This observational study is intended to serve as an update for our understanding of quantitative testing of CSF dynamics. © 2011 John Wiley & Sons A/S.

Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders - results from a European multicenter study.

PubMed

Dold, Markus; Bartova, Lucie; Souery, Daniel; Mendlewicz, Julien; Serretti, Alessandro; Porcelli, Stefano; Zohar, Joseph; Montgomery, Stuart; Kasper, Siegfried

2017-08-01

This naturalistic European multicenter study aimed to elucidate the association between major depressive disorder (MDD) and comorbid anxiety disorders. Demographic and clinical information of 1346 MDD patients were compared between those with and without concurrent anxiety disorders. The association between explanatory variables and the presence of comorbid anxiety disorders was examined using binary logistic regression analyses. 286 (21.2%) of the participants exhibited comorbid anxiety disorders, 10.8% generalized anxiety disorder (GAD), 8.3% panic disorder, 8.1% agoraphobia, and 3.3% social phobia. MDD patients with comorbid anxiety disorders were characterized by younger age (social phobia), outpatient status (agoraphobia), suicide risk (any anxiety disorder, panic disorder, agoraphobia, social phobia), higher depressive symptom severity (GAD), polypsychopharmacy (panic disorder, agoraphobia), and a higher proportion receiving augmentation treatment with benzodiazepines (any anxiety disorder, GAD, panic disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder). The results in terms of treatment response were conflicting (better response for panic disorder and poorer for GAD). The logistic regression analyses revealed younger age (any anxiety disorder, social phobia), outpatient status (agoraphobia), suicide risk (agoraphobia), severe depressive symptoms (any anxiety disorder, GAD, social phobia), poorer treatment response (GAD), and increased administration of benzodiazepines (any anxiety disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder) to be associated with comorbid anxiety disorders. Our findings suggest that the various anxiety disorders subtypes display divergent clinical characteristics and are associated with different variables. Especially comorbid GAD appears to be characterized by high symptom severity and poor treatment response. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clinical Outcome after Intra-Arterial Stroke Therapy in the Very Elderly: Why is it so Heterogeneous?

PubMed Central

Chandra, Ronil V.; Leslie-Mazwi, Thabele M.; Mehta, Brijesh P.; Yoo, Albert J.; Simonsen, Claus Z.

2014-01-01

Very elderly patients (i.e., ≥80 years) are disproportionally affected by acute ischemic stroke. They account for a third of hospital stroke admissions, but two-thirds of overall stroke-related morbidity and mortality. There is some evidence of clinical benefit in treating selected very elderly patients with intravenous thrombolysis (IVT). For very elderly patients ineligible or non-responsive to IVT, intra-arterial therapy (IAT) may have promise in improving clinical outcome. However, its unequivocal efficacy in the general population remains to be proven in randomized trials. Small cohort studies reveal that the rate of good clinical outcome for very elderly patients after IAT is highly variable, ranging from 0 to 28%. In addition, they experience higher rates of futile reperfusion than younger patients. Thus, it is imperative to understand the factors that impact on clinical outcome in very elderly patients after IAT. The aim of this review is to examine the factors that may be responsible for the heterogeneous clinical response of the very elderly to IAT. This will allow the reader to integrate the current available evidence to individualize intra-arterial stroke therapy in very elderly patients. Placing emphasis on pre-stroke independent living, smaller infarct core size, short procedure times, and avoiding general anesthesia where feasible, will help improve rates of good clinical outcome. PMID:24808887

Anxiety Disorders in Caucasian and African American Children: A Comparison of Clinical Characteristics, Treatment Process Variables, and Treatment Outcomes.

PubMed

Gordon-Hollingsworth, Arlene T; Becker, Emily M; Ginsburg, Golda S; Keeton, Courtney; Compton, Scott N; Birmaher, Boris B; Sakolsky, Dara J; Piacentini, John; Albano, Anne M; Kendall, Philip C; Suveg, Cynthia M; March, John S

2015-10-01

This study examined racial differences in anxious youth using data from the Child/Adolescent Anxiety Multimodal Study (CAMS) [1]. Specifically, the study aims addressed whether African American (n = 44) versus Caucasian (n = 359) children varied on (1) baseline clinical characteristics, (2) treatment process variables, and (3) treatment outcomes. Participants were ages 7-17 and met DSM-IV-TR criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder. Baseline data, as well as outcome data at 12 and 24 weeks, were obtained by independent evaluators. Weekly treatment process variables were collected by therapists. Results indicated no racial differences on baseline clinical characteristics. However, African American participants attended fewer psychotherapy and pharmacotherapy sessions, and were rated by therapists as less involved and compliant, in addition to showing lower mastery of CBT. Once these and other demographic factors were accounted for, race was not a significant predictor of response, remission, or relapse. Implications of these findings suggest African American and Caucasian youth are more similar than different with respect to the manifestations of anxiety and differences in outcomes are likely due to treatment barriers to session attendance and therapist engagement.

Anxiety Disorders in Caucasian and African American Children: A Comparison of Clinical Characteristics, Treatment Process Variables, and Treatment Outcomes

PubMed Central

Gordon-Hollingsworth, Arlene T.; Becker, Emily M.; Keeton, Courtney; Compton, Scott N.; Birmaher, Boris B.; Sakolsky, Dara J.; Piacentini, John; Albano, Anne M.; Kendall, Philip C.; Suveg, Cynthia M.; March, John S.

2014-01-01

This study examined racial differences in anxious youth using data from the Child/Adolescent Anxiety Multimodal Study (CAMS) [1]. Specifically, the study aims addressed whether African American (n = 44) versus Caucasian (n = 359) children varied on (1) baseline clinical characteristics, (2) treatment process variables, and (3) treatment outcomes. Participants were ages 7–17 and met DSM-IV-TR criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder. Baseline data, as well as outcome data at 12 and 24 weeks, were obtained by independent evaluators. Weekly treatment process variables were collected by therapists. Results indicated no racial differences on baseline clinical characteristics. However, African American participants attended fewer psychotherapy and pharmacotherapy sessions, and were rated by therapists as less involved and compliant, in addition to showing lower mastery of CBT. Once these and other demographic factors were accounted for, race was not a significant predictor of response, remission, or relapse. Implications of these findings suggest African American and Caucasian youth are more similar than different with respect to the manifestations of anxiety and differences in outcomes are likely due to treatment barriers to session attendance and therapist engagement. PMID:25293650

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia.

PubMed

Maxwell, Whitney D; Ramsey, Laura B; Johnson, Samuel G; Moore, Kate G; Shtutman, Michael; Schoonover, John H; Kawaguchi-Suzuki, Marina

2017-09-01

Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy. © 2017 Pharmacotherapy Publications, Inc.

Clinical and Vitamin Response to a Short-Term Multi-Micronutrient Intervention in Brazilian Children and Teens: From Population Data to Interindividual Responses.

PubMed

Mathias, Mariana Giaretta; Coelho-Landell, Carolina de Almeida; Scott-Boyer, Marie-Pier; Lacroix, Sébastien; Morine, Melissa J; Salomão, Roberta Garcia; Toffano, Roseli Borges Donegá; Almada, Maria Olímpia Ribeiro do Vale; Camarneiro, Joyce Moraes; Hillesheim, Elaine; de Barros, Tamiris Trevisan; Camelo-Junior, José Simon; Campos Giménez, Esther; Redeuil, Karine; Goyon, Alexandre; Bertschy, Emmanuelle; Lévêques, Antoine; Oberson, Jean-Marie; Giménez, Catherine; Carayol, Jerome; Kussmann, Martin; Descombes, Patrick; Métairon, Slyviane; Draper, Colleen Fogarty; Conus, Nelly; Mottaz, Sara Colombo; Corsini, Giovanna Zambianchi; Myoshi, Stephanie Kazu Brandão; Muniz, Mariana Mendes; Hernandes, Lívia Cristina; Venâncio, Vinícius Paula; Antunes, Lusania Maria Greggi; da Silva, Rosana Queiroz; Laurito, Taís Fontellas; Rossi, Isabela Ribeiro; Ricci, Raquel; Jorge, Jéssica Ré; Fagá, Mayara Leite; Quinhoneiro, Driele Cristina Gomes; Reche, Mariana Chinarelli; Silva, Paula Vitória Sozza; Falquetti, Letícia Lima; da Cunha, Thaís Helena Alves; Deminice, Thalia Manfrin Martins; Tambellini, Tâmara Hambúrguer; de Souza, Gabriela Cristina Arces; de Oliveira, Mariana Moraes; Nogueira-Pileggi, Vicky; Matsumoto, Marina Takemoto; Priami, Corrado; Kaput, Jim; Monteiro, Jacqueline Pontes

2018-03-01

Micronutrients are in small amounts in foods, act in concert, and require variable amounts of time to see changes in health and risk for disease. These first principles are incorporated into an intervention study designed to develop new experimental strategies for setting target recommendations for food bioactives for populations and individuals. A 6-week multivitamin/mineral intervention is conducted in 9-13 year olds. Participants (136) are (i) their own control (n-of-1); (ii) monitored for compliance; (iii) measured for 36 circulating vitamin forms, 30 clinical, anthropometric, and food intake parameters at baseline, post intervention, and following a 6-week washout; and (iv) had their ancestry accounted for as modifier of vitamin baseline or response. The same intervention is repeated the following year (135 participants). Most vitamins respond positively and many clinical parameters change in directions consistent with improved metabolic health to the intervention. Baseline levels of any metabolite predict its own response to the intervention. Elastic net penalized regression models are identified, and significantly predict response to intervention on the basis of multiple vitamin/clinical baseline measures. The study design, computational methods, and results are a step toward developing recommendations for optimizing vitamin levels and health parameters for individuals. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study.

PubMed

Johnston, Blair A; Coghill, David; Matthews, Keith; Steele, J Douglas

2015-01-01

Methylphenidate (MPH) is established as the main pharmacological treatment for patients with attention deficit hyperactivity disorder (ADHD). Whilst MPH is generally a highly effective treatment, not all patients respond, and some experience adverse reactions. Currently, there is no reliable method to predict how patients will respond, other than by exposure to a trial of medication. In this preliminary study, we sought to investigate whether an accurate predictor of clinical response to methylphenidate could be developed for individual patients, using sociodemographic, clinical and neuropsychological measures. Of the 43 boys with ADHD included in this proof-of-concept study, 30 were classed as responders and 13 as non-responders to MPH, with no significant differences in age nor verbal intelligence quotient (IQ) between the groups. Here we report the application of a multivariate analysis approach to the prediction of clinical response to MPH, which achieved an accuracy of 77% (p = 0.005). The most important variables to the classifier were performance on a 'go/no go' task and comorbid conduct disorder. This preliminary study suggested that further investigation is merited. Achieving a highly significant accuracy of 77% for the prediction of MPH response is an encouraging step towards finding a reliable and clinically useful method that could minimise the number of children needlessly being exposed to MPH. © The Author(s) 2014.

Implementation and utilization of genetic testing in personalized medicine

PubMed Central

Abul-Husn, Noura S; Owusu Obeng, Aniwaa; Sanderson, Saskia C; Gottesman, Omri; Scott, Stuart A

2014-01-01

Clinical genetic testing began over 30 years ago with the availability of mutation detection for sickle cell disease diagnosis. Since then, the field has dramatically transformed to include gene sequencing, high-throughput targeted genotyping, prenatal mutation detection, preimplantation genetic diagnosis, population-based carrier screening, and now genome-wide analyses using microarrays and next-generation sequencing. Despite these significant advances in molecular technologies and testing capabilities, clinical genetics laboratories historically have been centered on mutation detection for Mendelian disorders. However, the ongoing identification of deoxyribonucleic acid (DNA) sequence variants associated with common diseases prompted the availability of testing for personal disease risk estimation, and created commercial opportunities for direct-to-consumer genetic testing companies that assay these variants. This germline genetic risk, in conjunction with other clinical, family, and demographic variables, are the key components of the personalized medicine paradigm, which aims to apply personal genomic and other relevant data into a patient’s clinical assessment to more precisely guide medical management. However, genetic testing for disease risk estimation is an ongoing topic of debate, largely due to inconsistencies in the results, concerns over clinical validity and utility, and the variable mode of delivery when returning genetic results to patients in the absence of traditional counseling. A related class of genetic testing with analogous issues of clinical utility and acceptance is pharmacogenetic testing, which interrogates sequence variants implicated in interindividual drug response variability. Although clinical pharmacogenetic testing has not previously been widely adopted, advances in rapid turnaround time genetic testing technology and the recent implementation of preemptive genotyping programs at selected medical centers suggest that personalized medicine through pharmacogenetics is now a reality. This review aims to summarize the current state of implementing genetic testing for personalized medicine, with an emphasis on clinical pharmacogenetic testing. PMID:25206309

Clinimetrics: the science of clinical measurements.

PubMed

Fava, G A; Tomba, E; Sonino, N

2012-01-01

'Clinimetrics' is the term introduced by Alvan R. Feinstein in the early 1980s to indicate a domain concerned with indexes, rating scales and other expressions that are used to describe or measure symptoms, physical signs and other clinical phenomena. Clinimetrics has a set of rules that govern the structure of indexes, the choice of component variables, the evaluation of consistency, validity and responsiveness. This review illustrates how clinimetrics may help expanding the narrow range of information that is currently used in clinical science. It will focus on characteristics and types of clinimetric indexes and their current use. The clinimetric perspective provides an intellectual home for clinical judgment, whose implementation is likely to improve outcomes both in clinical research and practice. © 2011 Blackwell Publishing Ltd.

Intestinal lymphangiectasia in children

PubMed Central

Isa, Hasan M.; Al-Arayedh, Ghadeer G.; Mohamed, Afaf M.

2016-01-01

Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation of intestinal lymphatics. It can be classified as primary or secondary according to the underlying etiology. The clinical presentations of IL are pitting edema, chylous ascites, pleural effusion, acute appendicitis, diarrhea, lymphocytopenia, malabsorption, and intestinal obstruction. The diagnosis is made by intestinal endoscopy and biopsies. Dietary modification is the mainstay in the management of IL with a variable response. Here we report 2 patients with IL in Bahrain who showed positive response to dietary modification. PMID:26837404

The cardiac troponins: uses in routine clinical practice. Experiences from GUSTO and other clinical trials.

PubMed

Stubbs, P

1998-11-01

Recent advances in pharmacological and mechanical approaches to acute coronary syndromes have led to rapid changes in the management of patients admitted with acute coronary syndromes. These changes have been mirrored by the appearance of newer highly specific biochemical markers of myocardial damage particularly the cardiac troponins. When new biochemical markers become available it is the responsibility of the clinical chemist to evaluate them critically in terms of sensitivity, specificity, efficiency and analyzer precision, in the rigid setting of quality control that laboratories practise, and to compare them with other markers. When the data are shown to Clinical Cardiologists with supporting statements such as 'useful management tool' and 'can be used for early diagnosis of Myocardial Infarction', a different set of questions may need to be answered. The 'So what?' response is most frequent and is the most important hurdle that these newer biochemical markers have to overcome to convince physicians to change their current practice. This presentation will review the results of studies that have examined the potential clinical usefulness of the cardiac troponins with respect to diagnosis and risk stratification of patients admitted with suspected acute coronary syndromes. Any troponin variable that survives the 'so what' question has one further major hurdle to overcome. This is the requirement to inform physicians what different therapeutic strategies they should follow if the variable is present. Available clinical trial evidence about differing management options for patients according to their troponin status will be reviewed and outline management algorithms will be presented. Many questions remain unanswered and these will be included at the time points where they may be relevant.

Individual variability in clinical effect and tolerability of opioid analgesics - Importance of drug interactions and pharmacogenetics.

PubMed

Solhaug, Vigdis; Molden, Espen

2017-10-01

As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids. To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice. The article was based on unsystematic searches in PubMed to identify literature highlighting the clinical impact of drug interactions and pharmacogenetics as sources of variable response of opioid analgesics. Cytochrome P450 (CYP)-mediated metabolism is an important process for both clinically relevant interactions and pharmacogenetic variability of several opioids. Concomitant use of CYP inhibitors (e.g. paroxetine, fluoxetine and bupropion) or inducers (e.g. carbamazepine, phenobarbital and phenytoin) could counteract the clinical effect or trigger side effects of analgesics in the same manner as genetically determined differences in CYP2D6-mediated metabolism of many opioids. Moreover, combination treatment with drugs that inhibit or induce P-glycoprotein (ABCB1), a blood-brain barrier efflux transporter, may alter the amount ('dose') of opioids distributed to the brain. At the pharmacodynamic level, it is crucial to be aware of the potential risk of interaction causing serotonergic syndrome when combining opioids and serotonergic drugs, in particular antidepressants inhibiting serotonin reuptake (SSRIs and SNRIs). Regarding pharmacogenetics at the receptor level of pain treatment, the knowledge is currently scarce, but an allelic variant of the μ1 opioid receptor (OPRM1) gene has been associated with higher dosage requirement to achieve analgesia. Drug interactions and pharmacogenetic differences may lead to therapeutic failure or serious side effects of opioid analgesics. Many interactions involve combinations with antidepressants and antiepileptics, which are highly relevant drugs in patients suffering from pain. To prevent unfavourable drug interactions it is important that clinicians pay close attention and use electronic drug interaction checkers when treatments are initiated or discontinued. For the management of issues related to pharmacogenetic differences, blood-based CYP genotyping is available as routine test at many laboratories, and provide a valuable tool for proper choice of drugs and doses for treatment of pain and other diseases. Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Can we predict the blood pressure response to renal denervation?

PubMed Central

Fink, Gregory D.; Phelps, Jeremiah T.

2016-01-01

Renal denervation (RDN) is a new therapy used to treat drug-resistant hypertension in the clinical setting. Published human trials show substantial inter-individual variability in the blood pressure (BP) response to RDN, even when technical aspects of the treatment are standardized as much as possible between patients. Widespread acceptance of RDN for treating hypertension will require accurate identification of patients likely to respond to RDN with a fall in BP that is clinically significant in magnitude, well-maintained over time and does not cause adverse consequences. In this paper we review and evaluate clinical studies that address possible predictors of the BP response to RDN. We conclude that only one generally reliable predictor has been identified to date, namely pre-RDN BP level, although there is some evidence for a few other factors. Experimental interventions in laboratory animals provide the opportunity to explore potential predictors that are difficult to investigate in human patients. Therefore we also describe results (from our lab and others) with RDN in spontaneously hypertensive rats. Since virtually all patients receiving RDN are taking three or more antihypertensive drugs, a particular focus of our work was on how ongoing antihypertensive drug treatment might alter the BP response to RDN. We conclude that patient age (or duration of hypertension) and concomitant treatment with certain drugs can affect the blood pressure response to RDN and that this information could help predict a favorable clinical response. PMID:27530600

Quantitative Stratification of Diffuse Parenchymal Lung Diseases

PubMed Central

Raghunath, Sushravya; Rajagopalan, Srinivasan; Karwoski, Ronald A.; Maldonado, Fabien; Peikert, Tobias; Moua, Teng; Ryu, Jay H.; Bartholmai, Brian J.; Robb, Richard A.

2014-01-01

Diffuse parenchymal lung diseases (DPLDs) are characterized by widespread pathological changes within the pulmonary tissue that impair the elasticity and gas exchange properties of the lungs. Clinical-radiological diagnosis of these diseases remains challenging and their clinical course is characterized by variable disease progression. These challenges have hindered the introduction of robust objective biomarkers for patient-specific prediction based on specific phenotypes in clinical practice for patients with DPLD. Therefore, strategies facilitating individualized clinical management, staging and identification of specific phenotypes linked to clinical disease outcomes or therapeutic responses are urgently needed. A classification schema consistently reflecting the radiological, clinical (lung function and clinical outcomes) and pathological features of a disease represents a critical need in modern pulmonary medicine. Herein, we report a quantitative stratification paradigm to identify subsets of DPLD patients with characteristic radiologic patterns in an unsupervised manner and demonstrate significant correlation of these self-organized disease groups with clinically accepted surrogate endpoints. The proposed consistent and reproducible technique could potentially transform diagnostic staging, clinical management and prognostication of DPLD patients as well as facilitate patient selection for clinical trials beyond the ability of current radiological tools. In addition, the sequential quantitative stratification of the type and extent of parenchymal process may allow standardized and objective monitoring of disease, early assessment of treatment response and mortality prediction for DPLD patients. PMID:24676019

Contact lens deposits, adverse responses, and clinical ocular surface parameters.

PubMed

Zhao, Zhenjun; Naduvilath, Thomas; Flanagan, Judith L; Carnt, Nicole A; Wei, Xiaojia; Diec, Jennie; Evans, Vicki; Willcox, Mark D P

2010-09-01

To correlate clinical responses during contact lens wear with the amount of protein or cholesterol extracted from lenses after wear. Clinical parameters, including adverse response rates and corneal staining, and symptomatology rating during lens wear were collected from a series of clinical tests comprising four different silicone hydrogel lenses with four different multipurpose solutions. To test for correlates, the amount of total protein or cholesterol extracted from lenses after daily wear were compared statistically to clinical parameters. The amount of protein (p = 0.008) or cholesterol (p = 0.01) extracted from lenses was higher for those subjects who showed solution-induced corneal staining. Amount of protein extracted was correlated (p < 0.01) with conjunctival staining (R = -0.23), lens front surface wetting (r = 0.14), and lens fit tightness (R = -0.20). These clinical parameters accounted for 48% of lens protein deposition. The amount of cholesterol extracted from lenses was much more weakly associated with clinical variables. Amount of protein or cholesterol extracted from lenses was not associated with the production of any corneal infiltrative or mechanical adverse event during wear and was only very weakly correlated with insertion comfort of lenses. These results suggest that there may be no physiologically relevant consequence of cholesterol depositing on silicone hydrogel lenses. The amount of protein that deposits onto silicone hydrogel lenses during wear may have more affect on lens performance on-eye. However, the correlations were generally small and may still not indicate any causative relevant physiological response. Further work is required to determine whether there is any direct causative effect to support these correlative findings.

Impact of CYP2D6 polymorphisms on clinical efficacy & tolerability of metoprolol tartrate

PubMed Central

Hamadeh, Issam S.; Langaee, Taimour Y.; Dwivedi, Ruti; Garcia, Sofia; Burkley, Ben M.; Chapman, Arlene B.; Gums, John G.; Turner, Stephen T.; Gong, Yan; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.

2014-01-01

Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme, CYP2D6. Our objective was to investigate the influence of CYP2D6 polymorphisms on efficacy and tolerability of metoprolol tartrate. 281 study participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes by using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (p-value <0.0001) with poor metabolizers & intermediate metabolizers showing greater HR reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not a determinant of the variability in response or tolerability to metoprolol. PMID:24637943

Does clinical presentation predict response to a nonsurgical chronic disease management program for endstage hip and knee osteoarthritis?

PubMed

Eyles, Jillian P; Lucas, Barbara R; Patterson, Jillian A; Williams, Matthew J; Weeks, Kate; Fransen, Marlene; Hunter, David J

2014-11-01

To identify baseline characteristics of participants who will respond favorably following 6 months of participation in a chronic disease management program for hip and knee osteoarthritis (OA). This prospective cohort study assessed 559 participants at baseline and following 6 months of participation in the Osteoarthritis Chronic Care Program. Response was defined as the minimal clinically important difference of an 18% and 9-point absolute improvement in the Western Ontario and McMaster Universities Arthritis Index global score. Multivariate logistic regression modeling was used to identify predictors of response. Complete data were available for 308 participants. Those who withdrew within the study period were imputed as nonresponders. Three variables were independently associated with response: signal joint (knee vs hip), sex, and high level of comorbidity. Index joint and sex were significant in the multivariate model, but the model was not a sensitive predictor of response. Strong predictors of response to a chronic disease management program for hip and knee OA were not identified. The significant predictors that were found should be considered in future studies.

Responsiveness of clinical tests for people with neck pain.

PubMed

Jørgensen, René; Ris, Inge; Juhl, Carsten; Falla, Deborah; Juul-Kristensen, Birgit

2017-12-28

Responsiveness of a clinical test is highly relevant in order to evaluate the effect of a given intervention. However, the responsiveness of clinical tests for people with neck pain has not been adequately evaluated. The objective of the present study was to examine the responsiveness of four clinical tests which are low cost and easy to perform in a clinical setting, including the craniocervical flexion test, cervical active range of movement, test for the cervical extensors and pressure pain threshold testing. This study is a secondary analysis of data collected in a previously published randomised controlled trial. Participants were randomized to either physical training, exercises and pain education combined or pain education only. Participants were tested on the clinical tests at baseline and at 4-month follow-up. An anchor-based approach using Receiver Operator Characteristics (ROC) curves was used to evaluate responsiveness of the clinical tests. The Neck Disability Index was used to discriminate between those who had improved and those who were unchanged at the 4-month follow-up. Minimum Clinically Important Difference (MCID), together with sensitivity, specificity, positive and negative predictive values, in addition to positive and negative likelihood ratios were calculated. In total, 164 participants completed the 4 month follow up. One-hundred forty four participants were classified as unchanged whereas 20 patients were considered to be improved. Twenty-six participants didn't complete all of the clinical tests, leaving a total of 138 to be included for analyses. Area Under Curve (AUC) ranged from 0.50-0.62 for the clinical tests, and were all below an acceptable level. MCID was generally large, and the corresponding sensitivity and specificity was low with sensitivity ranging from 20 to 60%, and specificity from 54 to 86%. LR+ (0.8-2.07) and LR- (0.7-1.1) showed low diagnostic value for all variables, with PPV ranging from 12.1 to 26.1 and NPV ranging from 84.7 to 89.2. Responsiveness of the included clinical tests was generally low when using change in NDI score as the anchor from baseline to the 4-month follow up. Further investigations of responsiveness are warranted, possibly using other anchors, which to a higher degree resemble similar dimensions as the clinical tests.

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

PubMed Central

Provenzani, Alessio; Santeusanio, Andrew; Mathis, Erin; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Provenzani, Ambra; Polidori, Carlo; Vizzini, Giovanni; Polidori, Piera; D’Alessandro, Natale

2013-01-01

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing. PMID:24409044

Novel Applications of Metabolomics in Personalized Medicine: A Mini-Review.

PubMed

Li, Bingbing; He, Xuyun; Jia, Wei; Li, Houkai

2017-07-13

Interindividual variability in drug responses and disease susceptibility is common in the clinic. Currently, personalized medicine is highly valued, the idea being to prescribe the right medicine to the right patient. Metabolomics has been increasingly applied in evaluating the therapeutic outcomes of clinical drugs by correlating the baseline metabolic profiles of patients with their responses, i.e., pharmacometabonomics, as well as prediction of disease susceptibility among population in advance, i.e., patient stratification. The accelerated advance in metabolomics technology pinpoints the huge potential of its application in personalized medicine. In current review, we discussed the novel applications of metabolomics with typical examples in evaluating drug therapy and patient stratification, and underlined the potential of metabolomics in personalized medicine in the future.

[Evaluation of the radiofrequency ablation effectiveness in patients with the Wolff-Parkinson-White syndrome].

PubMed

Ushakov, I B; Ardashev, A V; Ardashev, V N; Voronkov, Iu I; Sharoĭko, M V; Akimova, O S

2012-01-01

A one-year prospective study involved 22 patients with the Wolff-Parkinson-White syndrome (WPW) and 20 healthy people. Means age of patients was 34.3 +/- 16.3 years. All 22 patients were successfully treated with radiofrequency ablation (RFA) of additional pathways. RFA effectiveness was evaluated with the help of clinical questionnaire, data of ECG, EchoCG, heart rate variability (HRV), frequency response and nonlinear dynamics. Cardiac rhythm disturbances were verified using Holter monitoring applied to all patients. Positive clinical effect was achieved in all the WPW patients, as RFA arrested cardiac arrhythmias completely. Holter monitoring did not register cardiac disturbances which points to high RFA effectiveness in WPW patients. HRV, frequency response and nonlinear dynamics reassumed their normal patterns.

Illness severity and self-efficacy as course predictors of DSM-IV alcohol dependence in a multisite clinical sample.

PubMed

Langenbucher, J; Sulesund, D; Chung, T; Morgenstern, J

1996-01-01

Illness severity and self-efficacy are two constructs of growing interest as predictors of clinical response in alcoholism. Using alternative measures of illness severity (DSM-IV symptom count, Alcohol Dependence Scale, and Addiction Severity Index) and self-efficacy (brief version of the Situational Confidence Questionnaire) rigorously controlled for theoretically important background variables, we studied their unique contribution to multiple indices of relapse, relapse latency, and use of alternative coping behaviors in a large, heterogeneous clinical sample. The Alcohol Dependence Scale contributed to the prediction of 4 of 5 relapse indicators. The SCQ failed to predict relapse behavior or its precursor, coping response. The findings emphasize the predictive validity of severity of dependence as a course specifier and underline the need for more sensitive and externally valid measures of cognitive processes such as self-efficacy for application in future studies of posttreatment behavior.

Dashboard systems: Pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies.

PubMed

Mould, Diane R; Dubinsky, Marla C

2015-03-01

Many marketed drugs exhibit high variability in exposure and response. While these drugs are efficacious in their approved indications, finding appropriate dose regimens for individual patients is not straightforward. Similar dose adjustment problems are also seen with drugs that have a complex relationship between exposure and response and/or a narrow therapeutic window. This is particularly true for monoclonal antibodies, where prolonged dosing at a sub-therapeutic dose can also elicit anti-drug antibodies which will further compromise safety and efficacy. Thus, finding appropriate doses quickly would represent a substantial improvement in healthcare. Dashboard systems, which are decision-support tools, offer an improved, convenient means of tailoring treatment for individual patients. This article reviews the clinical need for this approach, particularly with monoclonal antibodies, the design, development, and testing of such systems, and the likely benefits of dashboard systems in clinical practice. We focus on infliximab for reference. © 2015, The American College of Clinical Pharmacology.

Medicine Based Evidence for Individualized Decision Making: Case Study of Systemic Lupus Erythematosus.

PubMed

Wivel, Ashley E; Lapane, Kate; Kleoudis, Christi; Singer, Burton H; Horwitz, Ralph I

2017-11-01

To guide management decisions for an index patient, evidence is required from comparisons between approximate matches to the profile of the index case, where some matches contain responses to treatment and others act as controls. We describe a method for constructing clinically relevant histories/profiles using data collected but unreported from 2 recent phase 3 randomized controlled trials assessing belimumab in subjects with clinically active and serologically positive systemic lupus erythematosus. Outcome was the Systemic lupus erythematosus Responder Index (SRI) measured at 52 weeks. Among 1175 subjects, we constructed an algorithm utilizing 11 trajectory variables including 4 biological, 2 clinical, and 5 social/behavioral. Across all biological and social/behavioral variables, the proportion of responders based on the SRI whose value indicated clinical worsening or no improvement ranged from 27.5% to 42.3%. Kappa values suggested poor agreement, indicating that each biological and patient-reported outcome provides different information than gleaned from the SRI. The richly detailed patient profiles needed to guide decision-making in clinical practice are sharply at odds with the limited information utilized in conventional randomized controlled trial analyses. Copyright © 2017 Elsevier Inc. All rights reserved.

The complexity of interpreting genomic data in patients with acute myeloid leukemia

PubMed Central

Nazha, A; Zarzour, A; Al-Issa, K; Radivoyevitch, T; Carraway, H E; Hirsch, C M; Przychodzen, B; Patel, B J; Clemente, M; Sanikommu, S R; Kalaycio, M; Maciejewski, J P; Sekeres, M A

2016-01-01

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML). Overall, mutations in FLT3, DNMT3A, NPM1 and IDH2 were more specific for pAML whereas UTAF1, STAG2, BCORL1, BCOR, EZH2, JAK2, CBL, PRPF8, SF3B1, ASXL1 and DHX29 were more specific for sAML. However, in multivariate analysis that included clinical variables, only FLT3 and DNMT3A remained specific for pAML and EZH2, BCOR, SF3B1 and ASXL1 for sAML. When the impact of mutations on OS was evaluated in the entire cohort, mutations in DNMT3A, PRPF8, ASXL1, CBL EZH2 and TP53 had a negative impact on OS; no mutation impacted OS favorably; however, in a cox multivariate analysis that included clinical data, mutations in DNMT3A, ASXL1, CBL, EZH2 and TP53 became significant. Thus, controlling for clinical variables is important when interpreting genomic data in AML. PMID:27983727

The complexity of interpreting genomic data in patients with acute myeloid leukemia.

PubMed

Nazha, A; Zarzour, A; Al-Issa, K; Radivoyevitch, T; Carraway, H E; Hirsch, C M; Przychodzen, B; Patel, B J; Clemente, M; Sanikommu, S R; Kalaycio, M; Maciejewski, J P; Sekeres, M A

2016-12-16

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML). Overall, mutations in FLT3, DNMT3A, NPM1 and IDH2 were more specific for pAML whereas UTAF1, STAG2, BCORL1, BCOR, EZH2, JAK2, CBL, PRPF8, SF3B1, ASXL1 and DHX29 were more specific for sAML. However, in multivariate analysis that included clinical variables, only FLT3 and DNMT3A remained specific for pAML and EZH2, BCOR, SF3B1 and ASXL1 for sAML. When the impact of mutations on OS was evaluated in the entire cohort, mutations in DNMT3A, PRPF8, ASXL1, CBL EZH2 and TP53 had a negative impact on OS; no mutation impacted OS favorably; however, in a cox multivariate analysis that included clinical data, mutations in DNMT3A, ASXL1, CBL, EZH2 and TP53 became significant. Thus, controlling for clinical variables is important when interpreting genomic data in AML.

Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration.

PubMed

Bossuyt, V; Provenzano, E; Symmans, W F; Boughey, J C; Coles, C; Curigliano, G; Dixon, J M; Esserman, L J; Fastner, G; Kuehn, T; Peintinger, F; von Minckwitz, G; White, J; Yang, W; Badve, S; Denkert, C; MacGrogan, G; Penault-Llorca, F; Viale, G; Cameron, D

2015-07-01

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials. © The Author 2015. 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.

[What role for paraclinical investigations within clinical trials conducted in psychiatric patients?

PubMed

Kaladjian, A; Adida, M; Simon, N; Belzeaux, R; Blin, O; Fakra, E; Azorin, J-M

2016-12-01

As in the usual care of patients, paraclinical investigations have today only a very modest role in clinical trials in psychiatry, mainly to complete the pre-therapeutical assessments prior to inclusion of subjects or to monitor treatment tolerance. Yet, the accumulation of data in neurosciences suggests the next emergence of biomarkers, whose interest is that they are closely associated to the biological disturbances underlying psychiatric illnesses, and that they are accessible by means of technological tools such as imaging devices. These tools allow to explore the effects on brain of psychotropic medications, such as antidepressants, antipsychotics, or mood stabilizers, in relation to their therapeutic action. The obtained results allow to consider the use of such biomarkers in clinical trials in addition to more conventional approaches. In particular, they could be used as targets to measure brain response to treatment in association with clinical response, to predict a therapeutic response from the neurofunctional characteristics of patients, or to establish the safety profile of drugs on the nervous system. The use of such biomarkers in clinical trials would help to better define the explored populations and their characteristics, as well as the variables to assess, and to better measure the impact of the treatments and their potential harmful effects on the nervous system. © L’Encéphale, Paris, 2016.

Schedule-induced polydipsia: a rat model of obsessive-compulsive disorder.

PubMed

Platt, Brian; Beyer, Chad E; Schechter, Lee E; Rosenzweig-Lipson, Sharon

2008-04-01

Obsessive-compulsive disorder (OCD) is difficult to model in animals due to the involvement of both mental (obsessions) and physical (compulsions) symptoms. Due to limitations of using animals to evaluate obsessions, OCD models are limited to evaluation of the compulsive and repetitive behaviors of animals. Of these, models of adjunctive behaviors offer the most value in regard to predicting efficacy of anti-OCD drugs in the clinic. Adjunctive behaviors are those that are maintained indirectly by the variables that control another behavior, rather than directly by their own typical controlling variables. Schedule-induced polydipsia (SIP) is an adjunctive model in which rats exhibit exaggerated drinking behavior (polydipsia) when presented with food pellets under a fixed-time schedule. The polydipsic response is an excessive manifestation of a normal behavior (drinking), providing face validity to the model. Furthermore, clinically effective drugs for the treatment of OCD decrease SIP. This protocol describes a rat SIP model of OCD and provides preclinical data for drugs that decrease polydipsia and are clinically effective in the treatment of OCD.

Correlation and agreement between the bispectral index vs. state entropy during hypothermic cardio-pulmonary bypass.

PubMed

Meybohm, P; Gruenewald, M; Höcker, J; Renner, J; Graesner, J-T; Ilies, C; Scholz, J; Bein, B

2010-02-01

The bispectral index (BIS) and spectral entropy enable monitoring the depth of anaesthesia. Mild hypothermia has been shown to affect the ability of electroencephalography monitors to reflect the anaesthetic drug effect. The purpose of this study was to investigate the effect of hypothermia during a cardio-pulmonary bypass on the correlation and agreement between the BIS and entropy variables compared with normothermic conditions. This prospective clinical study included coronary artery bypass grafting patients (n=25) evaluating correlation and agreement (Bland-Altman analysis) between the BIS and both spectral and response entropy during a hypothermic cardio-pulmonary bypass (31-34 degrees C) compared with nomothermic conditions (34-37.5 degrees C). Anaesthesia was maintained with propofol and sufentanil and adjusted clinically, while the anaesthetist was blinded to the monitors. The BIS and entropy values decreased during cooling (P<0.05), but the decrease was more pronounced for entropy variables compared with BIS (P<0.05). The correlation coefficients (bias+/-SD; percentage error) between the BIS vs. spectral state entropy and response entropy were r(2)=0.56 (1+/-11; 42%) and r(2)=0.58 (-2+/-11; 43%) under normothermic conditions, and r(2)=0.17 (10+/-12; 77%) and r(2)=0.18 (9+/-11; 68%) under hypothermic conditions, respectively. Bias was significantly increased under hypothermic conditions (P<0.001 vs. normothermia). Acceptable agreement was observed between the BIS and entropy variables under normothermic but not under hypothermic conditions. The BIS and entropy variables may therefore not be interchangeable during a hypothermic cardio-pulmonary bypass.

Individual treatment selection for patients with posttraumatic stress disorder.

PubMed

Deisenhofer, Anne-Katharina; Delgadillo, Jaime; Rubel, Julian A; Böhnke, Jan R; Zimmermann, Dirk; Schwartz, Brian; Lutz, Wolfgang

2018-04-16

Trauma-focused cognitive behavioral therapy (Tf-CBT) and eye movement desensitization and reprocessing (EMDR) are two highly effective treatment options for posttraumatic stress disorder (PTSD). Yet, on an individual level, PTSD patients vary substantially in treatment response. The aim of the paper is to test the application of a treatment selection method based on a personalized advantage index (PAI). The study used clinical data for patients accessing treatment for PTSD in a primary care mental health service in the north of England. PTSD patients received either EMDR (N = 75) or Tf-CBT (N = 242). The Patient Health Questionnaire (PHQ-9) was used as an outcome measure for depressive symptoms associated with PTSD. Variables predicting differential treatment response were identified using an automated variable selection approach (genetic algorithm) and afterwards included in regression models, allowing the calculation of each patient's PAI. Age, employment status, gender, and functional impairment were identified as relevant variables for Tf-CBT. For EMDR, baseline depressive symptoms as well as prescribed antidepressant medication were selected as predictor variables. Fifty-six percent of the patients (n = 125) had a PAI equal or higher than one standard deviation. From those patients, 62 (50%) did not receive their model-predicted treatment and could have benefited from a treatment assignment based on the PAI. Using a PAI-based algorithm has the potential to improve clinical decision making and to enhance individual patient outcomes, although further replication is necessary before such an approach can be implemented in prospective studies. © 2018 Wiley Periodicals, Inc.

Predictors and Moderators of Treatment Response in Childhood Anxiety Disorders: Results from the CAMS Trial

PubMed Central

Compton, Scott N.; Peris, Tara S.; Almirall, Daniel; Birmaher, Boris; Sherrill, Joel; Kendall, Phillip C.; March, John S.; Gosch, Elizabeth A.; Ginsburg, Golda S.; Rynn, Moira A.; Piacentini, John C.; McCracken, James T.; Keeton, Courtney P.; Suveg, Cynthia M.; Aschenbrand, Sasha G.; Sakolsky, Dara; Iyengar, Satish; Walkup, John T.; Albano, Anne Marie

2014-01-01

Objective To examine predictors and moderators of treatment outcomes among 488 youth ages 7-17 years (50% female; 74% ≤ 12 years) with DSM-IV diagnoses of separation anxiety disorder, social phobia, or generalized anxiety disorder who were randomly assigned to receive either cognitive behavior therapy (CBT), sertraline (SRT), their combination (COMB), or medication management with pill placebo (PBO) in the Child/Adolescent Anxiety Multimodal Study (CAMS). Method Six classes of predictor and moderator variables (22 variables) were identified from the literature and examined using continuous (Pediatric Anxiety Ratings Scale; PARS) and categorical (Clinical Global Impression Scale-Improvement; CGI-I) outcome measures. Results Three baseline variables predicted better outcomes (independent of treatment condition) on the PARS, including low anxiety severity (as measured by parents and independent evaluators) and caregiver strain. No baseline variables were found to predict week 12 responder status (CGI-I). Participant's principal diagnosis moderated treatment outcomes, but only on the PARS. No baseline variables were found to moderate treatment outcomes on week 12 responder status (CGI-I). Discussion Overall, anxious children responded favorably to CAMS treatments. However, having more severe and impairing anxiety, greater caregiver strain, and a principal diagnosis of social phobia were associated with less favorable outcomes. Clinical implications of these findings are discussed. PMID:24417601

Rewards of bridging the divide between measurement and clinical theory: demonstration of a bifactor model for the Brief Symptom Inventory.

PubMed

Thomas, Michael L

2012-03-01

There is growing evidence that psychiatric disorders maintain hierarchical associations where general and domain-specific factors play prominent roles (see D. Watson, 2005). Standard, unidimensional measurement models can fail to capture the meaningful nuances of such complex latent variable structures. The present study examined the ability of the multidimensional item response theory bifactor model (see R. D. Gibbons & D. R. Hedeker, 1992) to improve construct validity by serving as a bridge between measurement and clinical theories. Archival data consisting of 688 outpatients' psychiatric diagnoses and item-level responses to the Brief Symptom Inventory (BSI; L. R. Derogatis, 1993) were extracted from files at a university mental health clinic. The bifactor model demonstrated superior fit for the internal structure of the BSI and improved overall diagnostic accuracy in the sample (73%) compared with unidimensional (61%) and oblique simple structure (65%) models. Consistent with clinical theory, multiple sources of item variance were drawn from individual test items. Test developers and clinical researchers are encouraged to consider model-based measurement in the assessment of psychiatric distress.

Manchester Clinical Placement Index (MCPI). Conditions for Medical Students' Learning in Hospital and Community Placements

ERIC Educational Resources Information Center

Dornan, Tim; Muijtjens, Arno; Graham, Jennifer; Scherpbier, Albert; Boshuizen, Henny

2012-01-01

The drive to quality-manage medical education has created a need for valid measurement instruments. Validity evidence includes the theoretical and contextual origin of items, choice of response processes, internal structure, and interrelationship of a measure's variables. This research set out to explore the validity and potential utility of an…

A Randomized Clinical Trial Comparison between Pivotal Response Treatment (PRT) and Structured Applied Behavior Analysis (ABA) Intervention for Children with Autism

ERIC Educational Resources Information Center

Mohammadzaheri, Fereshteh; Koegel, Lynn Kern; Rezaee, Mohammad; Rafiee, Seyed Majid

2014-01-01

Accumulating studies are documenting specific motivational variables that, when combined into a naturalistic teaching paradigm, can positively influence the effectiveness of interventions for children with autism spectrum disorder (ASD). The purpose of this study was to compare two applied behavior analysis (ABA) intervention procedures, a…

Implications of genome-wide association studies in cancer therapeutics.

PubMed

Patel, Jai N; McLeod, Howard L; Innocenti, Federico

2013-09-01

Genome wide association studies (GWAS) provide an agnostic approach to identifying potential genetic variants associated with disease susceptibility, prognosis of survival and/or predictive of drug response. Although these techniques are costly and interpretation of study results is challenging, they do allow for a more unbiased interrogation of the entire genome, resulting in the discovery of novel genes and understanding of novel biological associations. This review will focus on the implications of GWAS in cancer therapy, in particular germ-line mutations, including findings from major GWAS which have identified predictive genetic loci for clinical outcome and/or toxicity. Lessons and challenges in cancer GWAS are also discussed, including the need for functional analysis and replication, as well as future perspectives for biological and clinical utility. Given the large heterogeneity in response to cancer therapeutics, novel methods of identifying mechanisms and biology of variable drug response and ultimately treatment individualization will be indispensable. © 2013 The British Pharmacological Society.

Psychiatrists' follow-up of identified metabolic risk: a mixed-method analysis of outcomes and influences on practice.

PubMed

Patterson, Sue; Freshwater, Kathleen; Goulter, Nicole; Ewing, Julie; Leamon, Boyd; Choudhary, Anand; Moudgil, Vikas; Emmerson, Brett

2016-10-01

Aims and method To describe and explain psychiatrists' responses to metabolic abnormalities identified during screening. We carried out an audit of clinical records to assess rates of monitoring and follow-up practice. Semi-structured interviews with 36 psychiatrists followed by descriptive and thematic analyses were conducted. Results Metabolic abnormalities were identified in 76% of eligible patients screened. Follow-up, recorded for 59%, was variable but more likely with four or more abnormalities. Psychiatrists endorse guidelines but ambivalence about responsibility, professional norms, resource constraints and skills deficits as well as patient factors influences practice. Therapeutic optimism and desire to be a 'good doctor' supported comprehensive follow-up. Clinical implications Psychiatrists are willing to attend to physical healthcare, and obstacles to recommended practice are surmountable. Psychiatrists seek consensus among stakeholders about responsibilities and a systemic approach addressing the social determinants of health inequities. Understanding patients' expectations is critical to promoting best practice.

Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs?

PubMed Central

2013-01-01

Methotrexate (MTX) is the central drug in the management of rheumatoid arthritis (RA) and other immune mediated inflammatory diseases. It is widely used either in monotherapy or in association with other synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs). Although comprehensive clinical experience exists for MTX and synthetic DMARDs, to date it has not been possible to preview correctly whether or not a patient will respond to treatment with these drugs. Predicting response to MTX and other DMARDs would allow the selection of patients based on their likelihood of response, thus enabling individualized therapy and avoiding unnecessary adverse effects and elevated costs. However, studies analyzing this issue have struggled to obtain consistent, replicable results and no factor has yet been recognized to individually distinguish responders from nonresponders at treatment start. Variables possibly influencing drug effectiveness may be disease-, patient- or treatment-related, clinical or biological (genetic and nongenetic). In this review we summarize current evidence on predictors of response to MTX and other synthetic DMARDs, discuss possible causes for the heterogeneity observed and address its translation into daily clinical practice. PMID:23343013

Biophoton detection and low-intensity light therapy: a potential clinical partnership.

PubMed

Tafur, Joseph; Van Wijk, Eduard P A; Van Wijk, Roeland; Mills, Paul J

2010-02-01

Low-intensity light therapy (LILT) is showing promise in the treatment of a wide variety of medical conditions. Concurrently, our knowledge of LILT mechanisms continues to expand. We are now aware of LILT's potential to induce cellular effects through, for example, accelerated ATP production and the mitigation of oxidative stress. In clinical use, however, it is often difficult to predict patient response to LILT. It appears that cellular reduction/oxidation (redox) state may play a central role in determining sensitivity to LILT and may help explain variability in patient responsiveness. In LILT, conditions associated with elevated reactive oxygen species (ROS) production, e.g. diabetic hyperglycemia, demonstrate increased sensitivity to LILT. Consequently, assessment of tissue redox conditions in vivo may prove helpful in identifying responsive tissues. A noninvasive redox measure may be useful in advancing investigation in LILT and may one day be helpful in better identifying responsive patients. The detection of biophotons, the production of which is associated with cellular redox state and the generation of ROS, represents just such an opportunity. In this review, we will present the case for pursuing further investigation into the potential clinical partnership between biophoton detection and LILT.

Biophoton Detection and Low-Intensity Light Therapy: A Potential Clinical Partnership

PubMed Central

Van Wijk, Eduard P.A.; Van Wijk, Roeland; Mills, Paul J.

2010-01-01

Abstract Low-intensity light therapy (LILT) is showing promise in the treatment of a wide variety of medical conditions. Concurrently, our knowledge of LILT mechanisms continues to expand. We are now aware of LILT's potential to induce cellular effects through, for example, accelerated ATP production and the mitigation of oxidative stress. In clinical use, however, it is often difficult to predict patient response to LILT. It appears that cellular reduction/oxidation (redox) state may play a central role in determining sensitivity to LILT and may help explain variability in patient responsiveness. In LILT, conditions associated with elevated reactive oxygen species (ROS) production, e.g. diabetic hyperglycemia, demonstrate increased sensitivity to LILT. Consequently, assessment of tissue redox conditions in vivo may prove helpful in identifying responsive tissues. A noninvasive redox measure may be useful in advancing investigation in LILT and may one day be helpful in better identifying responsive patients. The detection of biophotons, the production of which is associated with cellular redox state and the generation of ROS, represents just such an opportunity. In this review, we will present the case for pursuing further investigation into the potential clinical partnership between biophoton detection and LILT. PMID:19754267

Heart rate variability is a trait marker of major depressive disorder: evidence from the sertraline vs. electric current therapy to treat depression clinical study.

PubMed

Brunoni, Andre Russowsky; Kemp, Andrew H; Dantas, Eduardo M; Goulart, Alessandra C; Nunes, Maria Angélica; Boggio, Paulo S; Mill, José Geraldo; Lotufo, Paulo A; Fregni, Felipe; Benseñor, Isabela M

2013-10-01

Decreased heart rate variability (HRV) is a cardiovascular predictor of mortality. Recent debate has focused on whether reductions in HRV in major depressive disorder (MDD) are a consequence of the disorder or a consequence of pharmacotherapy. Here we report on the impact of transcranial direct current stimulation (tDCS), a non-pharmacological intervention, vs. sertraline to further investigate this issue. The employed design was a double-blind, randomized, factorial, placebo-controlled trial. One hundred and eighteen moderate-to-severe, medication-free, low-cardiovascular risk depressed patients were recruited for this study and allocated to either active/sham tDCS (10 consecutive sessions plus two extra sessions every other week) or placebo/sertraline (50 mg/d) for 6 wk. Patients were age and gender-matched to healthy controls from a concurrent cohort study [the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)]. The impact of disorder, treatment and clinical response on HRV (root mean square of successive differences and high frequency) was examined. Our findings confirmed that patients displayed decreased HRV relative to controls. Furthermore, HRV scores did not change following treatment with either a non-pharmacological (tDCS) or pharmacological (sertraline) intervention, nor did HRV increase with clinical response to treatment. Based on these findings, we discuss whether reduced HRV is a trait-marker for MDD, which may predispose patients to a host of conditions and disease even after response to treatment. Our findings have important implications for our understanding of depression pathophysiology and the relationship between MDD, cardiovascular disorders and mortality.

Empirically Derived Personality Subtyping for Predicting Clinical Symptoms and Treatment Response in Bulimia Nervosa

PubMed Central

Haynos, Ann F.; Pearson, Carolyn M.; Utzinger, Linsey M.; Wonderlich, Stephen A.; Crosby, Ross D.; Mitchell, James E.; Crow, Scott J.; Peterson, Carol B.

2016-01-01

Objective Evidence suggests that eating disorder subtypes reflecting under-controlled, over-controlled, and low psychopathology personality traits constitute reliable phenotypes that differentiate treatment response. This study is the first to use statistical analyses to identify these subtypes within treatment-seeking individuals with bulimia nervosa (BN) and to use these statistically derived clusters to predict clinical outcomes. Methods Using variables from the Dimensional Assessment of Personality Pathology–Basic Questionnaire, K-means cluster analyses identified under-controlled, over-controlled, and low psychopathology subtypes within BN patients (n = 80) enrolled in a treatment trial. Generalized linear models examined the impact of personality subtypes on Eating Disorder Examination global score, binge eating frequency, and purging frequency cross-sectionally at baseline and longitudinally at end of treatment (EOT) and follow-up. In the longitudinal models, secondary analyses were conducted to examine personality subtype as a potential moderator of response to Cognitive Behavioral Therapy-Enhanced (CBT-E) or Integrative Cognitive-Affective Therapy for BN (ICAT-BN). Results There were no baseline clinical differences between groups. In the longitudinal models, personality subtype predicted binge eating (p = .03) and purging (p = .01) frequency at EOT and binge eating frequency at follow-up (p = .045). The over-controlled group demonstrated the best outcomes on these variables. In secondary analyses, there was a treatment by subtype interaction for purging at follow-up (p = .04), which indicated a superiority of CBT-E over ICAT-BN for reducing purging among the over-controlled group. Discussion Empirically derived personality subtyping is appears to be a valid classification system with potential to guide eating disorder treatment decisions. PMID:27611235

Psychotherapist countertransference in the nuclear age: Effects on therapeutic interventions

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

Oderberg, N.A.

Since the early 1980s, there has been considerable attention in the psychology literature to mental health problems related to living in a world threatened by nuclear destruction. Questionnaires were mailed to 630 psychotherapists from the Colorado Psychological Association, California Psychotherapists for Social Responsibility, California Psychologists for Social Responsibility, the US Army, and the APA Division of Military Psychology; 174 questionnaires were returned. It was hypothesized that liberalism, nuclear weapons opposition, nuclear concern, nuclear awareness, and anti-nuclear activism in psychotherapists would facilitate perception of, and openness to working with, a client's nuclear concerns and thus, would be positively correlated with intentionsmore » to discuss nuclear issues with clients in three different clinical vignettes. Results indicated that when controlling for subject group, psychotherapy orientation, age, sex, and income, all five independent variables were positively correlated with responses to all three clinical vignettes, with nuclear concern having the strongest unique effect in accounting for variance in responses to the vignettes.« less

Oral Appliance Treatment Response and Polysomnographic Phenotypes of Obstructive Sleep Apnea

PubMed Central

Sutherland, Kate; Takaya, Hisashi; Qian, Jin; Petocz, Peter; Ng, Andrew T.; Cistulli, Peter A.

2015-01-01

Study Objectives: Mandibular advancement splints (MAS) are an effective treatment for obstructive sleep apnea (OSA); however, therapeutic response is variable. Younger age, female gender, less obesity, and milder and supine-dependent OSA have variably been associated with treatment success in relatively small samples. Our objective was to utilize a large cohort of MAS treated patients (1) to compare efficacy across patients with different phenotypes of OSA and (2) to assess demographic, anthropometric, and polysomnography variables as treatment response predictors. Methods: Retrospective analysis of MAS-treated patients participating in clinical trials in sleep centers in Sydney, Australia between years 2000–2013. All studies used equivalent customized two-piece MAS devices and treatment protocols. Treatment response was defined as (1) apnea-hypopnea index (AHI) < 5/h, (2) AHI < 10/h and ≥ 50% reduction, and (3) ≥ 50% AHI reduction. Results: A total of 425 patients (109 female) were included (age 51.2 ± 10.9 years, BMI 29.2 ± 5.0 kg/m2). MAS reduced AHI by 50.3% ± 50.7% across the group. Supine-predominant OSA patients had lower treatment response rates than non-positional OSA (e.g., 36% vs. 59% for AHI < 10/h). REM-predominant OSA showed a lower response rate than either NREM or non-stage dependent OSA. In prediction modelling, age, baseline AHI, and anthropometric variables were predictive of MAS treatment outcome but not OSA phenotype. Gender was not associated with treatment outcome. Conclusions: Lower MAS treatment response rates were observed in supine and REM sleep. In a large sample, we confirm that demographic, anthropometric, and polysomnographic data only weakly inform about MAS efficacy, supporting the need for alternative objective prediction methods to reliably select patients for MAS treatment. Citation: Sutherland K, Takaya H, Qian J, Petocz P, Ng AT, Cistulli PA. Oral appliance treatment response and polysomnographic phenotypes of obstructive sleep apnea. J Clin Sleep Med 2015;11(8):861–868. PMID:25845897

Interpatient Variability in Dexmedetomidine Response: A Survey of the Literature

PubMed Central

Holliday, Samantha F.; Kane-Gill, Sandra L.; Empey, Philip E.; Buckley, Mitchell S.; Smithburger, Pamela L.

2014-01-01

Fifty-five thousand patients are cared for in the intensive care unit (ICU) daily with sedation utilized to reduce anxiety and agitation while optimizing comfort. The Society of Critical Care Medicine (SCCM) released updated guidelines for management of pain, agitation, and delirium in the ICU and recommended nonbenzodiazepines, such as dexmedetomidine and propofol, as first line sedation agents. Dexmedetomidine, an alpha-2 agonist, offers many benefits yet its use is mired by the inability to consistently achieve sedation goals. Three hypotheses including patient traits/characteristics, pharmacokinetics in critically ill patients, and clinically relevant genetic polymorphisms that could affect dexmedetomidine response are presented. Studies in patient traits have yielded conflicting results regarding the role of race yet suggest that dexmedetomidine may produce more consistent results in less critically ill patients and with home antidepressant use. Pharmacokinetics of critically ill patients are reported as similar to healthy individuals yet wide, unexplained interpatient variability in dexmedetomidine serum levels exist. Genetic polymorphisms in both metabolism and receptor response have been evaluated in few studies, and the results remain inconclusive. To fully understand the role of dexmedetomidine, it is vital to further evaluate what prompts such marked interpatient variability in critically ill patients. PMID:24558330

A Randomised, Double-blind, Placebo-controlled Trial of Trichuris suis ova in Active Crohn's Disease.

PubMed

Schölmerich, Jürgen; Fellermann, Klaus; Seibold, Frank W; Rogler, Gerhard; Langhorst, Jost; Howaldt, Stefanie; Novacek, Gottfried; Petersen, Andreas Munk; Bachmann, Oliver; Matthes, Harald; Hesselbarth, Norbert; Teich, Niels; Wehkamp, Jan; Klaus, Jochen; Ott, Claudia; Dilger, Karin; Greinwald, Roland; Mueller, Ralph

2017-04-01

To investigate the efficacy and safety of three different dosages of embryonated, viable eggs of Trichuris suis [TSO] versus placebo for induction of remission in mildly-to-moderately active ileocolonic, uncomplicated Crohn's disease [CD]. Adults with active CD [n = 252] randomly received six fortnightly doses of 250, 2500, or 7500 TSO/15 ml suspension/day [TSO 250, TSO 2500, TSO 7500], or 15 ml placebo solution/day, in a double-blind fashion, with 4 weeks' follow-up. Primary endpoint was the rate of clinical remission [Crohn's Disease Activity Index [CDAI] < 150] at end of treatment, ie at Week 12 or withdrawal. Secondary endpoints included the course of clinical remission, rate of clinical response, change in CDAI, change in markers of inflammation, mucosal healing, and Physician's Global Assessment. Clinical remission at Week 12 occurred in 38.5%, 35.2%, and 47.2% of TSO 250, TSO 2500, and TSO 7500 patients, respectively, and in 42.9% of placebo recipients. TSO induced a dose-dependent immunological response. There was no response regarding laboratory markers of inflammation. Other secondary efficacy variables also showed no advantage of TSO over placebo for treatment of active CD. Administration of TSO did not result in any serious adverse drug reaction. Review of non-serious suspected adverse drug reactions following TSO did not reveal any safety concerns. Administration of 250-7500 TSO fortnightly over 12 weeks was safe and showed a dose-dependent immunological response, but no TSO dose showed a clinically relevant effect over placebo for induction of clinical remission or response in mildly-to-moderately active, ileocolonic CD. © European Crohn’s and Colitis Organistion (ECCO) 2016.

Bayesian inference for multivariate meta-analysis Box-Cox transformation models for individual patient data with applications to evaluation of cholesterol lowering drugs

PubMed Central

Kim, Sungduk; Chen, Ming-Hui; Ibrahim, Joseph G.; Shah, Arvind K.; Lin, Jianxin

2013-01-01

In this paper, we propose a class of Box-Cox transformation regression models with multidimensional random effects for analyzing multivariate responses for individual patient data (IPD) in meta-analysis. Our modeling formulation uses a multivariate normal response meta-analysis model with multivariate random effects, in which each response is allowed to have its own Box-Cox transformation. Prior distributions are specified for the Box-Cox transformation parameters as well as the regression coefficients in this complex model, and the Deviance Information Criterion (DIC) is used to select the best transformation model. Since the model is quite complex, a novel Monte Carlo Markov chain (MCMC) sampling scheme is developed to sample from the joint posterior of the parameters. This model is motivated by a very rich dataset comprising 26 clinical trials involving cholesterol lowering drugs where the goal is to jointly model the three dimensional response consisting of Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C), and Triglycerides (TG) (LDL-C, HDL-C, TG). Since the joint distribution of (LDL-C, HDL-C, TG) is not multivariate normal and in fact quite skewed, a Box-Cox transformation is needed to achieve normality. In the clinical literature, these three variables are usually analyzed univariately: however, a multivariate approach would be more appropriate since these variables are correlated with each other. A detailed analysis of these data is carried out using the proposed methodology. PMID:23580436

Bayesian inference for multivariate meta-analysis Box-Cox transformation models for individual patient data with applications to evaluation of cholesterol-lowering drugs.

PubMed

Kim, Sungduk; Chen, Ming-Hui; Ibrahim, Joseph G; Shah, Arvind K; Lin, Jianxin

2013-10-15

In this paper, we propose a class of Box-Cox transformation regression models with multidimensional random effects for analyzing multivariate responses for individual patient data in meta-analysis. Our modeling formulation uses a multivariate normal response meta-analysis model with multivariate random effects, in which each response is allowed to have its own Box-Cox transformation. Prior distributions are specified for the Box-Cox transformation parameters as well as the regression coefficients in this complex model, and the deviance information criterion is used to select the best transformation model. Because the model is quite complex, we develop a novel Monte Carlo Markov chain sampling scheme to sample from the joint posterior of the parameters. This model is motivated by a very rich dataset comprising 26 clinical trials involving cholesterol-lowering drugs where the goal is to jointly model the three-dimensional response consisting of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) (LDL-C, HDL-C, TG). Because the joint distribution of (LDL-C, HDL-C, TG) is not multivariate normal and in fact quite skewed, a Box-Cox transformation is needed to achieve normality. In the clinical literature, these three variables are usually analyzed univariately; however, a multivariate approach would be more appropriate because these variables are correlated with each other. We carry out a detailed analysis of these data by using the proposed methodology. Copyright © 2013 John Wiley & Sons, Ltd.

Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

PubMed

Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

2015-08-01

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

A generalized partially linear mean-covariance regression model for longitudinal proportional data, with applications to the analysis of quality of life data from cancer clinical trials.

PubMed

Zheng, Xueying; Qin, Guoyou; Tu, Dongsheng

2017-05-30

Motivated by the analysis of quality of life data from a clinical trial on early breast cancer, we propose in this paper a generalized partially linear mean-covariance regression model for longitudinal proportional data, which are bounded in a closed interval. Cholesky decomposition of the covariance matrix for within-subject responses and generalized estimation equations are used to estimate unknown parameters and the nonlinear function in the model. Simulation studies are performed to evaluate the performance of the proposed estimation procedures. Our new model is also applied to analyze the data from the cancer clinical trial that motivated this research. In comparison with available models in the literature, the proposed model does not require specific parametric assumptions on the density function of the longitudinal responses and the probability function of the boundary values and can capture dynamic changes of time or other interested variables on both mean and covariance of the correlated proportional responses. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Use of generalised additive models to categorise continuous variables in clinical prediction

PubMed Central

2013-01-01

Background In medical practice many, essentially continuous, clinical parameters tend to be categorised by physicians for ease of decision-making. Indeed, categorisation is a common practice both in medical research and in the development of clinical prediction rules, particularly where the ensuing models are to be applied in daily clinical practice to support clinicians in the decision-making process. Since the number of categories into which a continuous predictor must be categorised depends partly on the relationship between the predictor and the outcome, the need for more than two categories must be borne in mind. Methods We propose a categorisation methodology for clinical-prediction models, using Generalised Additive Models (GAMs) with P-spline smoothers to determine the relationship between the continuous predictor and the outcome. The proposed method consists of creating at least one average-risk category along with high- and low-risk categories based on the GAM smooth function. We applied this methodology to a prospective cohort of patients with exacerbated chronic obstructive pulmonary disease. The predictors selected were respiratory rate and partial pressure of carbon dioxide in the blood (PCO2), and the response variable was poor evolution. An additive logistic regression model was used to show the relationship between the covariates and the dichotomous response variable. The proposed categorisation was compared to the continuous predictor as the best option, using the AIC and AUC evaluation parameters. The sample was divided into a derivation (60%) and validation (40%) samples. The first was used to obtain the cut points while the second was used to validate the proposed methodology. Results The three-category proposal for the respiratory rate was ≤ 20;(20,24];> 24, for which the following values were obtained: AIC=314.5 and AUC=0.638. The respective values for the continuous predictor were AIC=317.1 and AUC=0.634, with no statistically significant differences being found between the two AUCs (p =0.079). The four-category proposal for PCO2 was ≤ 43;(43,52];(52,65];> 65, for which the following values were obtained: AIC=258.1 and AUC=0.81. No statistically significant differences were found between the AUC of the four-category option and that of the continuous predictor, which yielded an AIC of 250.3 and an AUC of 0.825 (p =0.115). Conclusions Our proposed method provides clinicians with the number and location of cut points for categorising variables, and performs as successfully as the original continuous predictor when it comes to developing clinical prediction rules. PMID:23802742

Serial MR diffusion to predict treatment response in high-grade pediatric brain tumors: a comparison of regional and voxel-based diffusion change metrics

PubMed Central

Rodriguez Gutierrez, Daniel; Manita, Muftah; Jaspan, Tim; Dineen, Robert A.; Grundy, Richard G.; Auer, Dorothee P.

2013-01-01

Background Assessment of treatment response by measuring tumor size is known to be a late and potentially confounded response index. Serial diffusion MRI has shown potential for allowing earlier and possibly more reliable response assessment in adult patients, with limited experience in clinical settings and in pediatric brain cancer. We present a retrospective study of clinical MRI data in children with high-grade brain tumors to assess and compare the values of several diffusion change metrics to predict treatment response. Methods Eighteen patients (age range, 1.9–20.6 years) with high-grade brain tumors and serial diffusion MRI (pre- and posttreatment interval range, 1–16 weeks posttreatment) were identified after obtaining parental consent. The following diffusion change metrics were compared with the clinical response status assessed at 6 months: (1) regional change in absolute and normalized apparent diffusivity coefficient (ADC), (2) voxel-based fractional volume of increased (fiADC) and decreased ADC (fdADC), and (3) a new metric based on the slope of the first principal component of functional diffusion maps (fDM). Results Responders (n = 12) differed significantly from nonresponders (n = 6) in all 3 diffusional change metrics demonstrating higher regional ADC increase, larger fiADC, and steeper slopes (P < .05). The slope method allowed the best response prediction (P < .01, η2 = 0.78) with a classification accuracy of 83% for a slope of 58° using receiver operating characteristic (ROC) analysis. Conclusions We demonstrate that diffusion change metrics are suitable response predictors for high-grade pediatric tumors, even in the presence of variable clinical diffusion imaging protocols. PMID:23585630

IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis

PubMed Central

Wang, Jianmei; Platt, Adam; Upmanyu, Ruchi; Germer, Søren; Lei, Guiyuan; Rabe, Christina; Benayed, Ryma; Kenwright, Andrew; Hemmings, Andrew; Martin, Mitchell; Harari, Olivier

2013-01-01

Objectives To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab. Design Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response. Results Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response. Conclusions Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown. PMID:23959753

Multiple Intravenous Infusions Phase 2a: Ontario Survey

PubMed Central

Fan, Mark; Koczmara, Christine; Masino, Caterina; Cassano-Piché, Andrea; Trbovich, Patricia; Easty, Anthony

2014-01-01

Background Research conducted in earlier phases of this study prospectively identified a number of concerns related to the safe administration of multiple intravenous (IV) infusions in Ontario hospitals. Objective To investigate the potential prevalence of practices or policies that may contribute to the patient safety risks identified in Phase 1b of this study. Data Sources and Review Methods Sixty-four survey responses were analyzed from clinical units where multiple IV infusions may occur (e.g., adult intensive care units). Survey questions were organized according to the topics identified in Phase 1b as potential contributors to patient harm (e.g., labelling practices, patient transfer practices, secondary infusion policies). Results Survey results indicated suboptimal practices and policies in some clinical units, and variability in a number of infusion practices. Key areas of concern included the following: use of primary IV tubing without back check valves when administering secondary infusions administration of secondary infusions with/as high-alert continuous IV medications potential confusion about how IV tubing should be labelled to reflect replacement date and time interruptions to IV therapy due to IV pump and/or tubing changes when patients are transferred between clinical units coadministration of continuous or intermittent infusions on central venous pressure monitoring ports variability in respondents’ awareness of the infusion pump's bolus capabilities Limitations Due to the limited sample size, survey responses may not be representative of infusion practices across Ontario. Answers to some questions indicated that the intent of the questions might have been misunderstood. Due to a design error, 1 question about bolus administration methods was not shown to as many respondents as appropriate. Conclusions The Ontario survey revealed variability in IV infusion practice across the province and potential opportunities to improve safety. PMID:26257837

Indications for surgical stabilization of rib fractures in patients without flail chest: surveyed opinions of members of the Chest Wall Injury Society.

PubMed

Pieracci, Fredric M; Agarwal, Suresh; Doben, Andrew; Shiroff, Adam; Lottenberg, Larwence; Whitbeck, Sarah Ann; White, Thomas W

2018-02-01

There are currently no evidence-based indications for surgical stabilization of rib fractures (SSRF) in patients without flail chest. The purpose of this survey was to identify patients for whom there is relative equipoise (operative vs. non-operative) in order to assist in designing a randomized clinical trial. Members of the Chest Wall Injury Society were sent an online survey, in which 18 patient scenarios were presented. The baseline patient had ≥ three displaced, contiguous fractures and had no other contraindications for surgery. This default scenario was then varied based upon patient age, degree of traumatic brain injury (TBI), fracture series location, and number of abnormal pulmonary physiologic variables (oxygen requirement, respiratory rate, incentive spirometry ability, cough, and numeric pain score). Thirty respondents provided a total of 540 answers. Overall, the majority of responses were in favor of SSRF (n = 413, 84.1%). Furthermore, the vast majority of responses indicated that some degree of pulmonary compromise was necessary to recommend SSRF (n = 44, 90.4%), with ≥ two abnormal parameters being the most common threshold (n = 156, 31.8%). Decision to recommend SSRF varied significantly by number of abnormal clinical variables, age, and degree of TBI, but not by fracture series location. Patients aged 85 years old and those with moderate TBI were the least likely to be recommended for SSRF, regardless of abnormal pulmonary physiologic variables. The most appropriate cutoff for equipoise appeared to be a patient aged 21-79 years old, with no or mild TBI, ≥ two abnormal pulmonary parameters, and regardless of fracture location (44.8% consensus for SSRF). SSRF was recommended for most patients with non-flail, displaced rib fractures. However, this recommendation was contingent upon patient age, degree of TBI, and pulmonary clinical status. Results of this survey may be used to inform inclusion criteria for a future randomized, clinical trial.

Clinical Biomechanics of Wear in Total Hip Arthroplasty

PubMed Central

Callaghan, John J; Pedersen, Douglas R; Johnston, Richard C; Brown, Thomas D

2003-01-01

Complementary clinical and laboratory studies were performed to identify variables associated with polyethylene wear following total hip replacement, and to elucidate the mechanisms responsible for accelerated wear in the total hip arthroplasty construct. Observational cohort studies were performed using a prospective clinical database of more than 4000 consecutive primary total hip arthroplasties performed by a single surgeon, to identify wear-related variables. These variables included head size, acetabular/femoral component impingement, and third body debris. Novel digital edge detection techniques were developed and employed to accurately measure wear, and to determine the relationships of head size and third body debris to acceleration of wear. A novel slidingdistance-coupled finite element model was formulated and employed to examine the mechanisms responsible for wear. The long-term cohort studies demonstrated smaller head sizes to be associated with less wear. Third body debris generated from cable fretting was associated with an increase in wear, osteolysis, and acetabular loosening, especially with larger head sizes. The sliding-distance-coupled finite element model replicated the wear rates occurring in vitro and in vivo, demonstrating the importance of sliding distance on polyethylene wear following total hip arthroplasty. It also demonstrated substantial increases in wear associated with femoral head scratching from third body debris. Further extension of the finite element formulation demonstrated the potential for acetabular component rim damage from impingement wear, and the enhanced potential for third body ingress to the bearing surface with larger head sizes. Edge detection wear measurement techniques demonstrated that early wear rates were predictive of long-term wear rates. These complementary clinical and laboratory investigations have provided insight into 1) the significance of sliding distance and physiologic loci of motion as contributing factors in minimizing wear, 2) the deleterious effects of third body particulates in accelerating wear, 3) the potential for, and factors related to, impingement wear, and 4) the potential advantages and compromises related to the use of larger head sizes in the bearing surface construct. PMID:14575243

Investigating the Implications of a Variable RBE on Proton Dose Fractionation Across a Clinical Pencil Beam Scanned Spread-Out Bragg Peak

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

Marshall, Thomas I.; Chaudhary, Pankaj; Michaelidesová, Anna

2016-05-01

Purpose: To investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited. Methods and Materials: Human fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfractionmore » period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism. Results: Significant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens. Conclusions: The RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used by the modeling community for the optimization of fractionated proton therapy.« less

Future Translational Applications From the Contemporary Genomics Era

PubMed Central

Fox, Caroline S.; Hall, Jennifer L.; Arnett, Donna K.; Ashley, Euan A.; Delles, Christian; Engler, Mary B.; Freeman, Mason W.; Johnson, Julie A.; Lanfear, David E.; Liggett, Stephen B.; Lusis, Aldons J.; Loscalzo, Joseph; MacRae, Calum A.; Musunuru, Kiran; Newby, L. Kristin; O’Donnell, Christopher J.; Rich, Stephen S.; Terzic, Andre

2016-01-01

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care. PMID:25882488

Institutional Profile: University of Chicago Center for Personalized Therapeutics: research, education and implementation science.

PubMed

Dolan, M Eileen; Maitland, Michael L; O'Donnell, Peter H; Nakamura, Yusuke; Cox, Nancy J; Ratain, Mark J

2013-09-01

Pharmacogenomics is aimed at advancing our knowledge of the genetic basis of variable drug response. The Center for Personalized Therapeutics within the University of Chicago comprises basic, translational and clinical research as well as education including undergraduate, graduate, medical students, clinical/postdoctoral fellows and faculty. The Committee on Clinical Pharmacology and Pharmacogenomics is the educational arm of the Center aimed at training clinical and postdoctoral fellows in translational pharmacology and pharmacogenomics. Research runs the gamut from basic discovery and functional studies to pharmacogenomic implementation studies to evaluate physician adoption of genetic medicine. The mission of the Center is to facilitate research, education and implementation of pharmacogenomics to realize the true potential of personalized medicine and improve the lives of patients.

Using intraindividual variability to detect malingering in cognitive performance.

PubMed

Strauss, E; Hultsch, D F; Hunter, M; Slick, D J; Patry, B; Levy-Bencheton, J

1999-11-01

The utility of measures for detecting malingering was evaluated using a simulation design in which half the participants were encouraged to do their best and half were asked to feign head injury. Particular attention was focused on the utility of repeated assessment (intraindividual variability) in discriminating the groups. Participants were tested on three occasions on measures commonly used to detect malingering including a specific symptom validity test (SVT). The results indicated that multiple measures of malingering obtained in single assessment (occasion one) discriminated the groups effectively. In addition, however, intraindividual variability in performance, particularly of indicators from the SVT, provided unique information beyond level of performance. The results suggest that response inconsistency across testing sessions may be a clinically useful measure for the detection of malingering.

Obesity is associated with lack of inhibitory control and impaired heart rate variability reactivity and recovery in response to food stimuli.

PubMed

Spitoni, Grazia Fernanda; Ottaviani, Cristina; Petta, Anna Maria; Zingaretti, Pietro; Aragona, Massimiliano; Sarnicola, Antonio; Antonucci, Gabriella

2017-06-01

Recent theories compare obesity with addiction in terms of lack of inhibitory control in both clinical populations. The present study hypothesized impaired inhibition in obese patients reflected both in executive functions and reduced vagal tone (indexed by a decrease in heart rate variability; HRV) in response to food stimuli. Twenty-four inpatients with obesity (19 women) and 37 controls (24 women) underwent ECG monitoring during baseline, food stimuli viewing, and a recovery phase. Tests and questionnaires assessing inhibitory control and psychopathological dispositions were also administered. As hypothesized, patients were characterized by deficits in all the tests measuring inhibitory capacities. Results also show greater HRV reduction and impaired HRV recovery in response to food stimuli in obese patients compared to controls. The drive to eat experienced by obese patients in the absence of caloric need may rely on impairments in inhibitory and vagal functioning. Results are discussed in terms of implications for therapy. Copyright © 2017. Published by Elsevier B.V.

An assessment of burnout in graduate assistant certified athletic trainers.

PubMed

Mazerolle, Stephanie M; Monsma, Eva; Dixon, Colin; Mensch, James

2012-01-01

Graduate assistant athletic trainers (GAATs) must balance the demands of clinical care and the academic load of graduate-level students. To examine burnout among GAATs with clinical assistantships at National Collegiate Athletic Association (NCAA) Division I institutions and to identify the personal and situational variables that are related to burnout. Cross-sectional study. Division I universities offering graduate assistantship programs. Two hundred one GAATs enrolled at NCAA Division I universities with graduate assistantship positions. The Athletic Training Burnout Inventory, which assesses stress and burnout among ATs through 4 constructs: emotional exhaustion and depersonalization, administrative responsibility, time commitment, and organizational support. The 6-point Likert scale is anchored by 1 (never true) and 6 (always true). The GAATs who traveled with athletic teams (4.051 ± 0.895) and those who provided classroom instruction (4.333 ± 1.16) reported higher levels of stress due to time commitment than those who did not travel (3.713 ± 1.22) or teach (3.923 ± 0.929). We also found a difference in administrative responsibility across clinical settings (F(6,194) = 3.507, P = .003). The results showed that GAATs in NCAA Division I clinical settings (44.55 ± 13.17 hours) worked more hours than those in NCAA Division III clinical settings (33.69 ± 12.07 hours) and those in high school settings (30.51 ± 9.934 hours). Graduate assistant ATs are at risk for burnout because of the time necessary to complete their clinical and academic responsibilities and their additional administrative responsibilities. Graduate assistants who work in the Division I clinical setting are at greater risk for burnout than those in the secondary school setting because of the large number of hours required.

Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine.

PubMed

Gassó, Patricia; Rodríguez, Natalia; Blázquez, Ana; Monteagudo, Ana; Boloc, Daniel; Plana, Maria Teresa; Lafuente, Amalia; Lázaro, Luisa; Arnaiz, Joan Albert; Mas, Sergi

2017-04-03

The serotonin 1B receptor (5-HT 1B ) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B (HTR1B) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants. Copyright © 2016 Elsevier Inc. All rights reserved.

Study report on combining diagnostic and therapeutic considerations with subsystem and whole-body simulation

NASA Technical Reports Server (NTRS)

Furukawa, S.

1975-01-01

Current applications of simulation models for clinical research described included tilt model simulation of orthostatic intolerance with hemorrhage, and modeling long term circulatory circulation. Current capabilities include: (1) simulation of analogous pathological states and effects of abnormal environmental stressors by the manipulation of system variables and changing inputs in various sequences; (2) simulation of time courses of responses of controlled variables by the altered inputs and their relationships; (3) simulation of physiological responses of treatment such as isotonic saline transfusion; (4) simulation of the effectiveness of a treatment as well as the effects of complication superimposed on an existing pathological state; and (5) comparison of the effectiveness of various treatments/countermeasures for a given pathological state. The feasibility of applying simulation models to diagnostic and therapeutic research problems is assessed.

Development of a computerized assessment of clinician adherence to a treatment guideline for patients with bipolar disorder.

PubMed

Dennehy, Ellen B; Suppes, Trisha; John Rush, A; Lynn Crismon, M; Witte, B; Webster, J

2004-01-01

The adoption of treatment guidelines for complex psychiatric illness is increasing. Treatment decisions in psychiatry depend on a number of variables, including severity of symptoms, past treatment history, patient preferences, medication tolerability, and clinical response. While patient outcomes may be improved by the use of treatment guidelines, there is no agreed upon standard by which to assess the degree to which clinician behavior corresponds to those recommendations. This report presents a method to assess clinician adherence to the complex multidimensional treatment guideline for bipolar disorder utilized in the Texas Medication Algorithm Project. The steps involved in the development of this system are presented, including the reliance on standardized documentation, defining core variables of interest, selecting criteria for operationalization of those variables, and computerization of the assessment of adherence. The computerized assessment represents an improvement over other assessment methods, which have relied on laborious and costly chart reviews to extract clinical information and to analyze provider behavior. However, it is limited by the specificity of decisions that guided the adherence scoring process. Preliminary findings using this system with 2035 clinical visits conducted for the bipolar disorder module of TMAP Phase 3 are presented. These data indicate that this system of guideline adherence monitoring is feasible.

Endpoint design for future renal denervation trials - Novel implications for a new definition of treatment response to renal denervation.

PubMed

Lambert, Thomas; Nahler, Alexander; Rohla, Miklos; Reiter, Christian; Grund, Michael; Kammler, Jürgen; Blessberger, Hermann; Kypta, Alexander; Kellermair, Jörg; Schwarz, Stefan; Starnawski, Jennifer A; Lichtenauer, Michael; Weiss, Thomas W; Huber, Kurt; Steinwender, Clemens

2016-10-01

Defining an adequate endpoint for renal denervation trials represents a major challenge. A high inter-individual and intra-individual variability of blood pressure levels as well as a partial or total non-adherence on antihypertensive drugs hamper treatment evaluations after renal denervation. Blood pressure measurements at a single point in time as used as primary endpoint in most clinical trials on renal denervation, might not be sufficient to discriminate between patients who do or do not respond to renal denervation. We compared the traditional responder classification (defined as systolic 24-hour blood pressure reduction of -5mmHg six months after renal denervation) with a novel definition of an ideal respondership (based on a 24h blood pressure reduction at no point in time, one, or all follow-up timepoints). We were able to re-classify almost a quarter of patients. Blood pressure variability was substantial in patients traditionally defined as responders. On the other hand, our novel classification of an ideal respondership seems to be clinically superior in discriminating sustained from pseudo-response to renal denervation. Based on our observations, we recommend that the traditional response classification should be reconsidered and possibly strengthened by using a composite endpoint of 24h-BP reductions at different follow-up-visits. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Awareness and attitude of the public toward personalized medicine in Korea

PubMed Central

Lee, Iyn-Hyang; Kang, Hye-Young; Suh, Hae Sun; Lee, Sukhyang; Oh, Eun Sil

2018-01-01

Objectives As personalized medicine (PM) is expected to greatly improve health outcomes, efforts have recently been made for its clinical implementation in Korea. We aimed to evaluate public awareness and attitude regarding PM. Methods We performed a self-administered questionnaire survey to 703 adults, who participated in the survey on a voluntary basis. The primary outcome measures included public knowledge, attitude, and acceptance of PM. We conducted multinomial multivariate logistic analysis for outcome variables with three response categories and performed multivariate logistic regression analyses for dichotomous outcome variables. Results Only 28% of participants had knowledge that genetic factors can contribute to inter-individual variations in drug response and the definition of PM (199 out of 702). Higher family income was correlated with greater knowledge concerning PM (OR = 3.76, p = 0.034). A majority of respondents preferred integrated pharmacogenomic testing over drug-specific testing and agreed to inclusion of pharmacogenomic testing in the national health examination (64% and 77%, respectively), but only 51% were willing to pay for it. Discussion Our results identify the urgent need for public education as well as the potential health disparities in access to PM. This study helps to frame policies for implementing PM in clinical practice. PMID:29451916

An update on the genetics of usher syndrome.

PubMed

Millán, José M; Aller, Elena; Jaijo, Teresa; Blanco-Kelly, Fiona; Gimenez-Pardo, Ascensión; Ayuso, Carmen

2011-01-01

Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A.

An Update on the Genetics of Usher Syndrome

PubMed Central

Millán, José M.; Aller, Elena; Jaijo, Teresa; Blanco-Kelly, Fiona; Gimenez-Pardo, Ascensión; Ayuso, Carmen

2011-01-01

Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A. PMID:21234346

KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine | Office of Cancer Genomics

Cancer.gov

Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells.

Exploring variability of teaching & supervision at clinical clerkship teaching sites

PubMed Central

Naeem, Naghma; Elzubeir, Margaret; Al-Houqani, Mohammad; Ahmed, Luai Awad

2018-01-01

Objective: To explore undergraduate medical students’ perception of variation in teaching and supervision at different clinical teaching sites. Methods: This descriptive cross-sectional study was conducted at the College of Medicine & Health Sciences, United Arab Emirates University, UAE during 2017. Four clinical teaching sites affiliated with CMHS were evaluated namely Shaikh Khalifa Medical City (SKMC), Ambulatory Care Clinics (AC), Tawam Hospital (TH) and Al-Ain Hospital (AH). An online questionnaire was administered to year five and six students. Results: The response rate was 84.4%. Overall perception of the students about their clinical clerkship experience was positive. SKMC was rated as the best teaching site with mean rating of 3.79±0.97-4.79±0.43. The highest rated item was clinical teacher’s promotion of critical thinking in students while the lowest rated item was the opportunity to take responsibility for patient care. Ambulatory Care site had a mean rating of 2.33±1.23-4.13±1.19. The highest rated item at this site was the clinical teacher encouraging students to ask questions and participate actively. At Tawam Hospital, the mean ratings ranged between 2.65±1.64-4.31±0.86 with highest rated item being ability of the students to see cases with positive clinical findings. At the Al-Ain Hospital, the mean rating was in the range of 2.79±1.45-3.81±1.11. The item rated highest here was the ability of students to see cases with positive clinical findings. The lowest rated item at all three sites was the availability of on-call rooms and lockers. Significant variability was seen across training sites in the clinical teacher’s ability to act as professional role models, the opportunity for students to apply their previous knowledge to patient care and to independently assess patients before discussion with teachers. Conclusion: This study tool highlights variation in clinical teaching and supervision at four clinical teaching sites. It provides specific, actionable information which can be utilized to deliver equitable learning experiences across clinical clerkships and teaching sites. It places emphasis on the fact that lack of physical facilities hampers clinical teaching and supervision, hence, on call rooms, lockers and separate rooms for independent student interaction with patients should be provided at all clinical teaching sites. PMID:29805410

Exploring variability of teaching & supervision at clinical clerkship teaching sites.

PubMed

Naeem, Naghma; Elzubeir, Margaret; Al-Houqani, Mohammad; Ahmed, Luai Awad

2018-01-01

To explore undergraduate medical students' perception of variation in teaching and supervision at different clinical teaching sites. This descriptive cross-sectional study was conducted at the College of Medicine & Health Sciences, United Arab Emirates University, UAE during 2017. Four clinical teaching sites affiliated with CMHS were evaluated namely Shaikh Khalifa Medical City (SKMC), Ambulatory Care Clinics (AC), Tawam Hospital (TH) and Al-Ain Hospital (AH). An online questionnaire was administered to year five and six students. The response rate was 84.4%. Overall perception of the students about their clinical clerkship experience was positive. SKMC was rated as the best teaching site with mean rating of 3.79±0.97-4.79±0.43. The highest rated item was clinical teacher's promotion of critical thinking in students while the lowest rated item was the opportunity to take responsibility for patient care. Ambulatory Care site had a mean rating of 2.33±1.23-4.13±1.19. The highest rated item at this site was the clinical teacher encouraging students to ask questions and participate actively. At Tawam Hospital, the mean ratings ranged between 2.65±1.64-4.31±0.86 with highest rated item being ability of the students to see cases with positive clinical findings. At the Al-Ain Hospital, the mean rating was in the range of 2.79±1.45-3.81±1.11. The item rated highest here was the ability of students to see cases with positive clinical findings. The lowest rated item at all three sites was the availability of on-call rooms and lockers. Significant variability was seen across training sites in the clinical teacher's ability to act as professional role models, the opportunity for students to apply their previous knowledge to patient care and to independently assess patients before discussion with teachers. This study tool highlights variation in clinical teaching and supervision at four clinical teaching sites. It provides specific, actionable information which can be utilized to deliver equitable learning experiences across clinical clerkships and teaching sites. It places emphasis on the fact that lack of physical facilities hampers clinical teaching and supervision, hence, on call rooms, lockers and separate rooms for independent student interaction with patients should be provided at all clinical teaching sites.

Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.

PubMed

Parker, Nicole R; Hudson, Amanda L; Khong, Peter; Parkinson, Jonathon F; Dwight, Trisha; Ikin, Rowan J; Zhu, Ying; Cheng, Zhangkai Jason; Vafaee, Fatemeh; Chen, Jason; Wheeler, Helen R; Howell, Viive M

2016-03-04

Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies.

Metabolic and anthropometric parameters contribute to ART-mediated CD4+ T cell recovery in HIV-1-infected individuals: an observational study.

PubMed

Azzoni, Livio; Foulkes, Andrea S; Firnhaber, Cynthia; Yin, Xiangfan; Crowther, Nigel J; Glencross, Deborah; Lawrie, Denise; Stevens, Wendy; Papasavvas, Emmanouil; Sanne, Ian; Montaner, Luis J

2011-07-29

The degree of immune reconstitution achieved in response to suppressive ART is associated with baseline individual characteristics, such as pre-treatment CD4 count, levels of viral replication, cellular activation, choice of treatment regimen and gender. However, the combined effect of these variables on long-term CD4 recovery remains elusive, and no single variable predicts treatment response. We sought to determine if adiposity and molecules associated with lipid metabolism may affect the response to ART and the degree of subsequent immune reconstitution, and to assess their ability to predict CD4 recovery. We studied a cohort of 69 (48 females and 21 males) HIV-infected, treatment-naïve South African subjects initiating antiretroviral treatment (d4T, 3Tc and lopinavir/ritonavir). We collected information at baseline and six months after viral suppression, assessing anthropometric parameters, dual energy X-ray absorptiometry and magnetic resonance imaging scans, serum-based clinical laboratory tests and whole blood-based flow cytometry, and determined their role in predicting the increase in CD4 count in response to ART. We present evidence that baseline CD4+ T cell count, viral load, CD8+ T cell activation (CD95 expression) and metabolic and anthropometric parameters linked to adiposity (LDL/HDL cholesterol ratio and waist/hip ratio) significantly contribute to variability in the extent of CD4 reconstitution (ΔCD4) after six months of continuous ART. Our final model accounts for 44% of the variability in CD4+ T cell recovery in virally suppressed individuals, representing a workable predictive model of immune reconstitution.

The nature of placebo response in clinical studies of major depressive disorder.

PubMed

Papakostas, George I; Østergaard, Søren D; Iovieno, Nadia

2015-04-01

To review factors influencing placebo response and clinical trial outcome in depression, and suggest ways to optimize trial success in mood disorders. PubMed searches were conducted by cross-referencing the terms depression, depressive with placebo, clinical trial, and clinical trials for studies published in English between 1970 and September 2013. Relevant abstracts were identified in PubMed, including clinical trials, quantitative studies, and qualitative research. We obtained and reviewed relevant articles and utilized their information to synthesize the present review. Included articles were grouped in the following areas of relevance: (1) biological validity of illness, (2) baseline severity of illness, (3) chronicity of the index episode of depression, (4) age of participants, (5) medical and psychiatric comorbidity, (6) probability of receiving placebo, (7) use of prospective treatment phases (lead-in) (8) dosing schedule, (9) trial duration, (10) frequency of follow-up assessments, and (11) study outcome measure. Several key elements emerge as critical to the ultimate success of a clinical trial, including the probability of receiving placebo, study duration, dosing schedule, visit frequency, the use of blinded lead-in phases, the use of centralized raters, illness severity and duration, and comorbid anxiety. Our increasing understanding of the placebo response in clinical trials of major depressive disorder lends to a, gradually, more predictable phenomenon and, hopefully, to one that becomes lesser in magnitude and variability. Several elements have emerged that seem to play a critical role in trial success, gradually reshaping the design of clinical, translational, as well as mechanistic studies in depression. © Copyright 2015 Physicians Postgraduate Press, Inc.

The roles of host and pathogen factors and the innate immune response in the pathogenesis of Clostridium difficile infection

PubMed Central

Sun, Xingmin; Hirota, Simon A.

2014-01-01

Clostridium difficile (C. difficile) is the most common cause of nosocomial antibiotic-associated diarrhea and the etiologic agent of pseudomembranous colitis. The clinical manifestation of Clostridium difficile infection (CDI) is highly variable, from asymptomatic carriage, to mild self-limiting diarrhea, to the more severe pseudomembranous colitis. Furthermore, in extreme cases, colonic inflammation and tissue damage can lead to toxic megacolon, a condition requiring surgical intervention. C. difficile expresses two key virulence factors; the exotoxins, toxin A (TcdA) and toxin B (TcdB), which are glucosyltransferases that target host-cell monomeric GTPases. In addition, some hypervirulent strains produce a third toxin, binary toxin or C. difficile transferase (CDT), which may contribute to the pathogenesis of CDI. More recently, other factors such as surface layer proteins (SLPs) and flagellin have also been linked to the inflammatory responses observed in CDI. Although the adaptive immune response can influence the severity of CDI, the innate immune responses to C. difficile and its toxins play crucial roles in CDI onset, progression, and overall prognosis. Despite this, the innate immune responses in CDI have drawn relatively little attention from clinical researchers. Targeting these responses may prove useful clinically as adjuvant therapies, especially in refractory and/or recurrent CDI. This review will focus on recent advances in our understanding of how C. difficile and its toxins modulate innate immune responses that contribute to CDI pathogenesis. PMID:25242213

Interaction between FKBP5 gene and childhood trauma on psychosis, depression and anxiety symptoms in a non-clinical sample.

PubMed

de Castro-Catala, Marta; Peña, Elionora; Kwapil, Thomas R; Papiol, Sergi; Sheinbaum, Tamara; Cristóbal-Narváez, Paula; Ballespí, Sergi; Barrantes-Vidal, Neus; Rosa, Araceli

2017-11-01

Childhood trauma has been associated with a heightened risk for presenting clinical and non-clinical psychopathology in adulthood. Genes related with the stress response, such as the FK506 binding protein 51 (FKBP5), are plausible candidates moderating the effects of childhood trauma on the emergence of such symptoms later on. The present study aimed to explore the moderating role of FKBP5 genetic variability on the association of different types of childhood trauma with subclinical psychosis, depression and anxiety in a non-clinical sample. Schizotypy, psychotic-like experiences, depression and anxiety symptoms and childhood trauma were assessed in 808 young adults. Two FKBP5 haplotypic blocks were detected: block 1 (rs3800373 - rs9296158 - rs1360780) and block 2 (rs9470080 - rs4713916). Subjects were classified in two groups according to whether they carried or not the risk haplotype previously described in the literature (block 1: CAT and block 2: TA). Linear regression analyses were used to study (i) the main effects of childhood trauma and FKBP5 haplotype blocks and (ii) their interaction effects on the mentioned forms of psychopathology. All childhood trauma scales, except sexual abuse, were associated with schizotypy, psychotic-like experiences, depression and anxiety symptoms. None of the analysed symptoms was associated with the main effects of FKBP5 genetic variability. However an interaction effect between block 1 and physical abuse was observed on anxiety, with lower scores in CAT carriers. This effect was driven by SNP 1 and 2. Moreover, an interaction effect between block 2 and physical abuse was identified on the variables tapping depressive and anxiety symptoms. Specifically, non-TA carrier subjects who were exposed to physical abuse were found to be at higher risk for depressive and anxiety symptoms. These effects were driven by SNP 5. No interaction effect was observed for the other variables. Our data suggest that exposure to childhood physical abuse may increase the risk for sub-clinical depressive and anxiety symptoms depending on FKBP5 genetic variability. Further research is needed to better elucidate the role of FKBP5 on mental health in clinical and non-clinical cohorts. Copyright © 2017 Elsevier Ltd. All rights reserved.

Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.

PubMed

Nader, Ahmed; Zahran, Noran; Alshammaa, Aya; Altaweel, Heba; Kassem, Nancy; Wilby, Kyle John

2017-04-01

Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice. A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII ® . A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics. Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c ) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively). Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

Effects of autogenic training on stress response and heart rate variability in nursing students.

PubMed

Lim, Seung-Joo; Kim, Chunmi

2014-12-01

This study was undertaken to confirm the effects of autogenic training (AT) on stress response and heart rate variability in nursing school students experiencing stress related to clinical training. The study was carried out from September 2012 to April 2013 in a quasi-experimental nonequivalent control group using a pretest-posttest design. The participants were 40 nursing students in their third year at either of two nursing colleges. All consented to participate. Nineteen nursing students at one college were assigned to the experimental group and underwent the 8-week AT program, and the other 21 were assigned to the control group and did not undergo any training. Stress response was assessed by questionnaire and HRV was measured three times, that is, before the program, at the end of the program, and 6 months after the end of the AT program. A significant time/group interaction was found for stress response (F = 4.68, p = .012), a subjective indicator. However, no significant interaction was found for the objective indicators of heart rate variability, normalized low frequency (F = 2.59, p = .090), normalized high frequency (F = 2.59, p = .090), or low frequency to high frequency ratio (F = 1.38, p = .257). The results suggest that AT provides an acceptable approach to stress reduction in nursing students. Copyright © 2014. Published by Elsevier B.V.

Validity and clinical utility of the DSM-5 severity specifier for bulimia nervosa: results from a multisite sample of patients who received evidence-based treatment.

PubMed

Dakanalis, Antonios; Bartoli, Francesco; Caslini, Manuela; Crocamo, Cristina; Zanetti, Maria Assunta; Riva, Giuseppe; Clerici, Massimo; Carrà, Giuseppe

2017-12-01

A new "severity specifier" for bulimia nervosa (BN), based on the frequency of inappropriate weight compensatory behaviours (IWCBs), was added to the DSM-5 as a means of documenting heterogeneity and variability in the severity of the disorder. Yet, evidence for its validity in clinical populations, including prognostic significance for treatment outcome, is currently lacking. Existing data from 281 treatment-seeking patients with DSM-5 BN, who received the best available treatment for their disorder (manual-based cognitive behavioural therapy; CBT) in an outpatient setting, were re-analysed to examine whether these patients subgrouped based on the DSM-5 severity levels would show meaningful and consistent differences on (a) a range of clinical variables assessed at pre-treatment and (b) post-treatment abstinence from IWCBs. Results highlight that the mild, moderate, severe, and extreme severity groups were statistically distinguishable on 22 variables assessed at pre-treatment regarding eating disorder pathological features, maintenance factors of BN, associated (current) and lifetime psychopathology, social maladjustment and illness-specific functional impairment, and abstinence outcome. Mood intolerance, a maintenance factor of BN but external to eating disorder pathological features (typically addressed within CBT), emerged as the primary clinical variable distinguishing the severity groups showing a differential treatment response. Overall, the findings speak to the concurrent and predictive validity of the new DSM-5 severity criterion for BN and are important because a common benchmark informing patients, clinicians, and researchers about severity of the disorder and allowing severity fluctuation and patient's progress to be tracked does not exist so far. Implications for future research are outlined.

Assessing national provision of care: variability in bariatric clinical care pathways.

PubMed

Telem, Dana A; Majid, Saniea F; Powers, Kinga; DeMaria, Eric; Morton, John; Jones, Daniel B

2017-02-01

The American Society for Metabolic and Bariatric Surgery (ASMBS) Quality Improvement and Patient Safety (QIPS) Committee hypothesized that collecting and sharing clinical pathways could provide a valuable resource to new and existing bariatric programs. To shed light on the variability in practice patterns across the country by analyzing pathways. United States Centers of Excellence METHODS: From June 2014 to April 2015, clinical pathways pertaining to preoperative, intraoperative, and postoperative management of bariatric patients were solicited from the ASMBS executive council (EC), QIPS committee members, and state chapter presidents. Pathways were de-identified and then analyzed based on predetermined metrics pertaining to preoperative, intraoperative, and postoperative care. Concordance and discordance were then analyzed. In total, 31 pathways were collected; response rate was 80% from the EC, 77% from the QIPS committee, and 21% from state chapter presidents. The number of pathways sent in ranged from 1 to 10 with a median of 3 pathways per individual or institution. The majority of pathways centered on perioperative care (80%). Binary assessment (presence or absence) of variables found a high concordance (defined by greater than 65% of pathways accounting for that parameter) in only 6 variables: nutritional evaluation, psychological evaluation, intraoperative venous thromboembolism (VTE) prophylaxis, utilization of antiemetics in the postoperative period, a dedicated pain pathway, and postoperative laboratory evaluation. There is considerable national variation in clinical pathways among practicing bariatric surgeons. Most pathways center on Metabolic and Bariatric Surgery Accredited Quality Improvement Program (MBSAQIP) accreditation parameters, patient satisfaction, or Surgical Care Improvement Protocol (SCIP) measures. These pathways provide a path toward standardization of improved care. Copyright © 2016. Published by Elsevier Inc.

Phenotypic Variability Among Café-au-lait Macules in NF1

PubMed Central

Boyd, Kevin P.; Gao, Liyan; Feng, Rui; Beasley, Mark; Messiaen, Ludwine; Korf, Bruce R.; Theos, Amy

2009-01-01

Background Cafe-au-lait macules (CALMs) in NF1 are an early and accessible phenotype in NF1, but have not been extensively studied. Objective To more fully characterize the phenotype of CALMs in patients with NF1. Methods Twenty-four patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the Genetics Department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin (M) based on its absorption of visible light. The major response was defined as the difference between the mean M from the CALM and the mean M from the surrounding skin. The major response for each spot was compared to spots within an individual and across individuals in the study population. Results There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, <0.0001) and secondly to interpersonal variability (33.0%, <0.0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. Limitations The study was performed on a small population of patients and the method utilized has not yet been used extensively for this purpose. Conclusions CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1. PMID:20605257

Epidemiological, clinical, microbiological and therapeutic differences in tuberculosis disease in patients with and without HIV infection.

PubMed

Martínez-Sanz, Javier; Lago-Gómez, María Rosa; Rodríguez-Zurita, María Elena; Martín-Echevarría, Esteban; Torralba, Miguel

2018-04-23

Our objective is to analyze the incidence of tuberculosis (TB) in our population and to compare the characteristics of patients with and without HIV infection. Clinical-epidemiological retrospective cohort study that included patients diagnosed with TB with and without HIV infection between 2005-2016 in the province of Guadalajara (Spain). Epidemiological, clinical, microbiological and therapeutic variables were assessed, including microbiological resistances. TB was diagnosed in 261 patients. There were 25 patients (9.6%) who had HIV infection. Patients with HIV infection were predominantly males, had higher incidence of hepatitis C virus, a higher percentage of extrapulmonary TB, a higher prevalence of resistance to isoniazid and rifampicin, a greater paradoxical response and a longer average hospital stay. On the other hand, they had a lower percentage of positive tuberculin skin test and positive sputum smear (microscopy). A significant percentage of TB patients had no serology for HIV. Patients with HIV infection show remarkable differences in epidemiological, clinical and resistance variables to antituberculosis drugs. A high percentage of patients with TB were not tested for HIV. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Female Pattern Hair Loss: a clinical and pathophysiological review*

PubMed Central

Ramos, Paulo Müller; Miot, Hélio Amante

2015-01-01

Female Pattern Hair Loss or female androgenetic alopecia is the main cause of hair loss in adult women and has a major impact on patients' quality of life. It evolves from the progressive miniaturization of follicles that lead to a subsequent decrease of the hair density, leading to a non-scarring diffuse alopecia, with characteristic clinical, dermoscopic and histological patterns. In spite of the high frequency of the disease and the relevance of its psychological impact, its pathogenesis is not yet fully understood, being influenced by genetic, hormonal and environmental factors. In addition, response to treatment is variable. In this article, authors discuss the main clinical, epidemiological and pathophysiological aspects of female pattern hair loss. PMID:26375223

Predictors of short-term outcome to exercise and manual therapy for people with hip osteoarthritis.

PubMed

French, Helen P; Galvin, Rose; Cusack, Tara; McCarthy, Geraldine M

2014-01-01

Physical therapy for hip osteoarthritis (OA) has shown short-term effects but limited long-term benefit. There has been limited research, with inconsistent results, in identifying prognostic factors associated with a positive response to physical therapy. The purpose of this study was to identify potential predictors of response to physical therapy (exercise therapy [ET] with or without adjunctive manual therapy [MT]) for hip OA based on baseline patient-specific and clinical characteristics. A prognostic study was conducted. Secondary analysis of data from a multicenter randomized controlled trial (RCT) (N=131) that evaluated the effectiveness of ET and ET+MT for hip OA was undertaken. Treatment response was defined using OMERACT/OARSI responder criteria. Ten baseline measures were used as predictor variables. Regression analyses were undertaken to identify predictors of outcome. Discriminative ability (sensitivity, specificity, and likelihood ratios) of significant variables was calculated. The RCT results showed no significant difference in most outcomes between ET and ET+MT at 9 and 18 weeks posttreatment. Forty-six patients were classified as responders at 9 weeks, and 36 patients were classified as responders at 18 weeks. Four baseline variables were predictive of a positive outcome at 9 weeks: male sex, pain with activity (<6/10), Western Ontario and McMaster Universities Osteoarthritis Index physical function subscale score (<34/68), and psychological health (Hospital Anxiety and Depression Scale score <9/42). No predictor variables were identified at the 18-week follow-up. Prognostic accuracy was fair for all 4 variables (sensitivity=0.5-0.58, specificity=0.57-0.72, likelihood ratios=1.25-1.77), indicating fair discriminative ability at predicting treatment response. The short-term follow-up limits the interpretation of results, and the low number of identified responders may have resulted in possible overfitting of the predictor model. The authors were unable to identify baseline variables in patients with hip OA that indicate those most likely to respond to treatment due to low discriminative ability. Further validation studies are needed to definitively define the best predictors of response to physical therapy in people with hip OA.

Physical performance measures that predict faller status in community-dwelling older adults.

PubMed

Macrae, P G; Lacourse, M; Moldavon, R

1992-01-01

Falls are a leading cause of fatal and nonfatal injuries among the elderly. Accurate determination of risk factors associated with falls in older adults is necessary, not only for individual patient management, but also for the development of fall prevention programs. The purpose of this study was to evaluate the effectiveness of clinical measures, such as the one-legged stance test (OLST), sit-to-stand test (STST), manual muscle tests (MMT), and response speed in predicting faller status in community-dwelling older adults (N = 94, age 60-89 years). The variables assessed were single-leg standing (as measured by OLST), STST, and MMT of 12 different muscle groups (hip flexors, hip abductors, hip adductors, knee flexors, knee extensors, ankle dorsiflexors, ankle plantarflexors, shoulder flexors, shoulder abductors, elbow flexors, elbow extensors, and finger flexors), and speed of response (as measured by a visual hand reaction and movement time task). Of the 94 older adults assessed, 28 (29.7%) reported at least one fall within the previous year. The discriminant analysis revealed that there were six variables that significantly discriminated between fallers and nonfallers. These variables included MMT of the ankle dorsiflexors, knee flexors, hip abductors, and knee extensors, as well as time on the OLST and the STST. The results indicate that simple clinical measures of musculoskeletal function can discriminate fallers from nonfallers in community-dwelling older adults. J Orthop Sports Phys Ther 1992;16(3):123-128.

Safety and effectiveness of olanzapine in monotherapy: a multivariate analysis of a naturalistic study.

PubMed

Ciudad, Antonio; Gutiérrez, Miguel; Cañas, Fernando; Gibert, Juan; Gascón, Josep; Carrasco, José-Luis; Bobes, Julio; Gómez, Juan-Carlos; Alvarez, Enrique

2005-07-01

This study investigated safety and effectiveness of olanzapine in monotherapy compared with conventional antipsychotics in treatment of acute inpatients with schizophrenia. This was a prospective, comparative, nonrandomized, open-label, multisite, observational study of Spanish inpatients with an acute episode of schizophrenia. Data included safety assessments with an extrapyramidal symptoms (EPS) questionnaire and the report of spontaneous adverse events, plus clinical assessments with the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impressions-Severity of Illness (CGI-S). A multivariate methodology was used to more adequately determine which factors can influence safety and effectiveness of olanzapine in monotherapy. 339 patients treated with olanzapine in monotherapy (OGm) and 385 patients treated with conventional antipsychotics (CG) were included in the analysis. Treatment-emergent EPS were significantly higher in the CG (p<0.0001). Response rate was significantly higher in the OGm (p=0.005). Logistic regression analyses revealed that the only variable significantly correlated with treatment-emergent EPS and clinical response was treatment strategy, with patients in OGm having 1.5 times the probability of obtaining a clinical response and patients in CG having 5 times the risk of developing EPS. In this naturalistic study olanzapine in monotherapy was better-tolerated and at least as effective as conventional antipsychotics.

Empirically derived personality subtyping for predicting clinical symptoms and treatment response in bulimia nervosa.

PubMed

Haynos, Ann F; Pearson, Carolyn M; Utzinger, Linsey M; Wonderlich, Stephen A; Crosby, Ross D; Mitchell, James E; Crow, Scott J; Peterson, Carol B

2017-05-01

Evidence suggests that eating disorder subtypes reflecting under-controlled, over-controlled, and low psychopathology personality traits constitute reliable phenotypes that differentiate treatment response. This study is the first to use statistical analyses to identify these subtypes within treatment-seeking individuals with bulimia nervosa (BN) and to use these statistically derived clusters to predict clinical outcomes. Using variables from the Dimensional Assessment of Personality Pathology-Basic Questionnaire, K-means cluster analyses identified under-controlled, over-controlled, and low psychopathology subtypes within BN patients (n = 80) enrolled in a treatment trial. Generalized linear models examined the impact of personality subtypes on Eating Disorder Examination global score, binge eating frequency, and purging frequency cross-sectionally at baseline and longitudinally at end of treatment (EOT) and follow-up. In the longitudinal models, secondary analyses were conducted to examine personality subtype as a potential moderator of response to Cognitive Behavioral Therapy-Enhanced (CBT-E) or Integrative Cognitive-Affective Therapy for BN (ICAT-BN). There were no baseline clinical differences between groups. In the longitudinal models, personality subtype predicted binge eating (p = 0.03) and purging (p = 0.01) frequency at EOT and binge eating frequency at follow-up (p = 0.045). The over-controlled group demonstrated the best outcomes on these variables. In secondary analyses, there was a treatment by subtype interaction for purging at follow-up (p = 0.04), which indicated a superiority of CBT-E over ICAT-BN for reducing purging among the over-controlled group. Empirically derived personality subtyping appears to be a valid classification system with potential to guide eating disorder treatment decisions. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:506-514). © 2016 Wiley Periodicals, Inc.

Study of variables affecting critical value notification in a laboratory catering to tertiary care hospital.

PubMed

Agarwal, Rachna; Chhillar, Neelam; Tripathi, Chandra B

2015-01-01

During post-analytical phase, critical value notification to responsible caregiver in a timely manner has potential to improve patient safety which requires cooperative efforts between laboratory personnel and caregivers. It is widely accepted by hospital accreditors that ineffective notification can lead to diagnostic errors that potentially harm patients and are preventable. The objective of the study was to assess the variables affecting critical value notification, their role in affecting it's quality and approaches to improve it. In the present study 1,187 critical values were analysed in the Clinical Chemistry Laboratory catering to tertiary care hospital for neuropsychiatric diseases. During 25 months of study period, we evaluated critical value notification with respect to clinical care area, caregiver to whom it was notified and timeliness of notification. During the study period (25 months), the laboratory obtained 1,279 critical values in clinical chemistry. The analytes most commonly notified were sodium and potassium (20.97 & 20.8 % of total critical results). Analysis of critical value notification versus area of care showed that critical value notification was high in ICU and emergency area followed by inpatients and 64.61 % critical values were notified between 30 and 120 min after receiving the samples. It was found that failure to notify the responsible caregiver in timely manner represent an important patient safety issue and may lead to diagnostic errors. The major area of concern are notification of critical value for outpatient samples, incompleteness of test requisition forms regarding illegible writing, lack of information of treating physician and location of test ordering and difficulty in contacting the responsible caregiver.

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability.

PubMed

Clarke, John D; Cherrington, Nathan J

2015-07-01

There are numerous factors in individual variability that make the development and implementation of precision medicine a challenge in the clinic. One of the main goals of precision medicine is to identify the correct dose for each individual in order to maximize therapeutic effect and minimize the occurrence of adverse drug reactions. Many promising advances have been made in identifying and understanding how factors such as genetic polymorphisms can influence drug pharmacokinetics (PK) and contribute to variable drug response (VDR), but it is clear that there remain many unidentified variables. Underlying liver diseases such as nonalcoholic steatohepatitis (NASH) alter absorption, distribution, metabolism, and excretion (ADME) processes and must be considered in the implementation of precision medicine. There is still a profound need for clinical investigation into how NASH-associated changes in ADME mediators, such as metabolism enzymes and transporters, affect the pharmacokinetics of individual drugs known to rely on these pathways for elimination. This review summarizes the key PK factors in individual variability and VDR and highlights NASH as an essential underlying factor that must be considered as the development of precision medicine advances. A multifactorial approach to precision medicine that considers the combination of two or more risk factors (e.g. genetics and NASH) will be required in our effort to provide a new era of benefit for patients. Copyright © 2015 Elsevier Inc. All rights reserved.

The state of ophthalmology medical student education in the United States and Canada, 2012 through 2013.

PubMed

Shah, Manjool; Knoch, Daniel; Waxman, Evan

2014-06-01

To characterize the state of ophthalmology medical student education in the United States and Canada. Survey of United States and Canadian medical schools. One hundred thirty-five Association of University Professors of Ophthalmology (AUPO) member institutions were surveyed, along with 30 osteopathic medical schools in the United States and 40 non-AUPO-affiliated allopathic medical schools in the United States. A survey characterizing preclinical, clinical, and extracurricular exposures to ophthalmology was used. Response rate, presence of, and types of preclinical and clinical exposures. Response rates to the survey were lower from non-AUPO institutions. Preclinical exposures largely consisted of basic lectures and examination skills, and most responding institutions had some sort of required preclinical ophthalmology experience. Clinical exposures were more variable, with an overall rate of required clinical rotations diminishing. There continues to be a gradual erosion of the role of ophthalmic medical education in the standard medical school curriculum. Clearly, there is room for improvement across all types of medical educational institutions. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Does nutrition support have a role in managing cancer cachexia?

PubMed

Laviano, Alessandro; Di Lazzaro Giraldi, Gianluca; Koverech, Angela

2016-12-01

Cachexia is a negative prognostic factor in cancer patients. The pathogenesis is related to a variable combination of reduced food intake and metabolic changes. However, whether nutritional support may contribute to effectively prevent and treat cachexia remains a debated issue. Consistent evidence demonstrates that anabolic windows of opportunity occur during the clinical trajectory of cancer patients. Also, the use of specific nutrients, namely omega-3 fatty acids, may enhance the efficacy of nutritional support when tumor-driven inflammatory response is high. Of greater interest, it is now becoming clearer that the use of nutritional support at key time points in the clinical journey of cancer patients (i.e., perioperative period) may extend its clinical benefits beyond those on nutritional status. Nutritional support plays a role in managing cancer cachexia, when it is timely delivered, when it provides adequate amounts of calories and proteins, and when it is part of a concurrent palliative care approach. Specific nutrients, that is, omega-3 fatty acids, may help in those cancer patients with high-inflammatory response, and may also contribute to positively influence long-term clinical outcomes.

[Analysis of clinical phenotype and CGH1 gene mutations in a family affected with dopa-responsive dystonia].

PubMed

Yan, Yaping; Chen, Xiaohong; Luo, Wei

2017-04-10

To explore genetic mutations and clinical features of a pedigree affected with dopa-responsive dystonia. PCR and Sanger sequencing were applied to detect mutations of the GCH1 gene among 7 members from the pedigree. The family was detected to have a known heterozygous mutation of the GCH1 gene (c.550C>T). For the 7 members from the pedigree, the age of onset has ranged from 13 to 60 years. The mother of the proband has carried the same mutation but was still healthy at 80. The symptoms of the other three patients were in slow progression, with diurnal fluctuation which can be improved with sleeping, dystonias of lower limbs, and tremor of both hands. Treatment with small dose of levodopa has resulted in significant improvement of clinical symptoms. By database analysis, the c.550C>T mutation was predicted as probably pathological. The c.550C>T mutation probably underlies the disease in this pedigree. The clinical phenotypes of family members may be variable for their ages of onset. Some may even be symptom free.

Successful Identification of Clinical Dermatophyte and Neoscytalidium Species by Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry

PubMed Central

Alshawa, Kinda; Beretti, Jean-Luc; Lacroix, Claire; Feuilhade, Martine; Dauphin, Brunhilde; Quesne, Gilles; Hassouni, Noura; Nassif, Xavier

2012-01-01

Dermatophytes are keratinolytic fungi responsible for a wide variety of diseases of glabrous skin, nails, and hair. Their identification, currently based on morphological criteria, is hindered by intraspecies morphological variability and the atypical morphology of some clinical isolates. The aim of this study was to evaluate matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) as a routine tool for identifying dermatophyte and Neoscytalidium species, both of which cause dermatomycoses. We first developed a spectral database of 12 different species of common and unusual dermatophytes and two molds responsible for dermatomycoses (Neoscytalidium dimidiatum and N. dimidiatum var. hyalinum). We then prospectively tested the performance of the database on 381 clinical dermatophyte and Neoscytalidium isolates. Correct identification of the species was obtained for 331/360 dermatophytes (91.9%) and 18/21 Neoscytalidium isolates (85.7%). The results of MALDI-TOF MS and standard identification disagreed for only 2 isolates. These results suggest that MALDI-TOF MS could be a useful tool for routine and fast identification of dermatophytes and Neoscytalidium spp. in clinical mycology laboratories. PMID:22535981

Visual evoked potentials in the horse.

PubMed

Ström, L; Ekesten, B

2016-06-21

Electrical potentials generated in the central nervous system in response to brief visual stimuli, flash visual evoked potentials (FVEPs), can be recorded non-invasively over the occipital cortex. FVEPs are used clinically in human medicine and also experimentally in a number of animal species, but the method has not yet been evaluated in the horse. The method would potentially allow the ophthalmologist and equine clinician to evaluate visual impairment caused by disorders affecting post-retinal visual pathways. The aim was to establish a method for recording of FVEPs in horses in a clinical setting and to evaluate the waveform morphology in the normal horse. Ten horses were sedated with a continuous detomidine infusion. Responses were recorded from electrodes placed on the scalp. Several positions were evaluated to determine suitable electrode placement. Flash electroretinograms (FERGs) were recorded simultaneously. To evaluate potential contamination of the FVEP from retinal potentials, a retrobulbar nerve block was performed in two horses and transection of the optic nerve was performed in one horse as a terminal procedure. A series of positive (P) and negative (N) peaks in response to light stimuli was recorded in all horses. Reproducible wavelets with mean times-to-peaks of 26 (N1), 55 (P2), 141 (N2) and 216 ms (P4) were seen in all horses in all recordings. Reproducible results were obtained when the active electrode was placed in the midline rostral to the nuchal crest. Recording at lateral positions gave more variable results, possibly due to ear muscle artifacts. Averaging ≥100 responses reduced the impact of noise and artifacts. FVEPs were reproducible in the same horse during the same recording session and between sessions, but were more variable between horses. Retrobulbar nerve block caused a transient loss of the VEP whereas transection of the optic nerve caused an irreversible loss. We describe the waveform of the equine FVEP and our results show that it is possible to record FVEPs in sedated horses in a clinical setting. The potentials recorded were shown to be of post-retinal origin. Further studies are needed to provide normative data and assess potential clinical use.

Clinical Reasoning: Survey of Teaching Methods, Integration, and Assessment in Entry-Level Physical Therapist Academic Education.

PubMed

Christensen, Nicole; Black, Lisa; Furze, Jennifer; Huhn, Karen; Vendrely, Ann; Wainwright, Susan

2017-02-01

Although clinical reasoning abilities are important learning outcomes of physical therapist entry-level education, best practice standards have not been established to guide clinical reasoning curricular design and learning assessment. This research explored how clinical reasoning is currently defined, taught, and assessed in physical therapist entry-level education programs. A descriptive, cross-sectional survey was administered to physical therapist program representatives. An electronic 24-question survey was distributed to the directors of 207 programs accredited by the Commission on Accreditation in Physical Therapy Education. Descriptive statistical analysis and qualitative content analysis were performed. Post hoc demographic and wave analyses revealed no evidence of nonresponse bias. A response rate of 46.4% (n=96) was achieved. All respondents reported that their programs incorporated clinical reasoning into their curricula. Only 25% of respondents reported a common definition of clinical reasoning in their programs. Most respondents (90.6%) reported that clinical reasoning was explicit in their curricula, and 94.8% indicated that multiple methods of curricular integration were used. Instructor-designed materials were most commonly used to teach clinical reasoning (83.3%). Assessment of clinical reasoning included practical examinations (99%), clinical coursework (94.8%), written examinations (87.5%), and written assignments (83.3%). Curricular integration of clinical reasoning-related self-reflection skills was reported by 91%. A large number of incomplete surveys affected the response rate, and the program directors to whom the survey was sent may not have consulted the faculty members who were most knowledgeable about clinical reasoning in their curricula. The survey construction limited some responses and application of the results. Although clinical reasoning was explicitly integrated into program curricula, it was not consistently defined, taught, or assessed within or between the programs surveyed-resulting in significant variability in clinical reasoning education. These findings support the need for the development of best educational practices for clinical reasoning curricula and learning assessment. © 2017 American Physical Therapy Association

The National Clinical Trials Network: Conducting Successful Clinical Trials of New Therapies for Rare Cancers

PubMed Central

Schott, Anne F.; Welch, John J.; Verschraegen, Claire F.; Kurzrock, Razelle

2015-01-01

Rare cancers account for 27% of neoplasms diagnosed each year, and 25% of cancer-related deaths in the United States. However, rare cancers show some of the highest response rates to targeted therapies, probably due to identification of oncogenic drivers with little inter-patient variability. Although the low incidence of rare cancers make large scale randomized trials involving single histologies difficult to perform, drugs have been successfully developed in rare cancers utilizing clinical trial designs that combine microscopic anatomies. Such trials are being pursued within the National Clinical Trials Network (NCTN), which possesses unique qualifications to perform widespread molecular screening of tumors for patient enrollment onto therapeutic clinical trials. When larger clinical trials are needed to determine optimum treatment strategies in rare cancers, the NCTN's broad reach in North America and internationally, and ability to partner with both US-based and international research organizations, can make these challenging studies feasible. PMID:26433554

Interactive Book Reading to Accelerate Word Learning by Kindergarten Children With Specific Language Impairment: Identifying an Adequate Intensity and Variation in Treatment Response.

PubMed

Storkel, Holly L; Voelmle, Krista; Fierro, Veronica; Flake, Kelsey; Fleming, Kandace K; Romine, Rebecca Swinburne

2017-01-01

This study sought to identify an adequate intensity of interactive book reading for new word learning by children with specific language impairment (SLI) and to examine variability in treatment response. An escalation design adapted from nontoxic drug trials (Hunsberger, Rubinstein, Dancey, & Korn, 2005) was used in this Phase I/II preliminary clinical trial. A total of 27 kindergarten children with SLI were randomized to 1 of 4 intensities of interactive book reading: 12, 24, 36, or 48 exposures. Word learning was monitored through a definition task and a naming task. An intensity response curve was examined to identify the adequate intensity. Correlations and classification accuracy were used to examine variation in response to treatment relative to pretreatment and early treatment measures. Response to treatment improved as intensity increased from 12 to 24 to 36 exposures, and then no further improvements were observed as intensity increased to 48 exposures. There was variability in treatment response: Children with poor phonological awareness, low vocabulary, and/or poor nonword repetition were less likely to respond to treatment. The adequate intensity for this version of interactive book reading was 36 exposures, but further development of the treatment is needed to increase the benefit for children with SLI.

Interactive Book Reading to Accelerate Word Learning by Kindergarten Children With Specific Language Impairment: Identifying an Adequate Intensity and Variation in Treatment Response

PubMed Central

Voelmle, Krista; Fierro, Veronica; Flake, Kelsey; Fleming, Kandace K.; Romine, Rebecca Swinburne

2017-01-01

Purpose This study sought to identify an adequate intensity of interactive book reading for new word learning by children with specific language impairment (SLI) and to examine variability in treatment response. Method An escalation design adapted from nontoxic drug trials (Hunsberger, Rubinstein, Dancey, & Korn, 2005) was used in this Phase I/II preliminary clinical trial. A total of 27 kindergarten children with SLI were randomized to 1 of 4 intensities of interactive book reading: 12, 24, 36, or 48 exposures. Word learning was monitored through a definition task and a naming task. An intensity response curve was examined to identify the adequate intensity. Correlations and classification accuracy were used to examine variation in response to treatment relative to pretreatment and early treatment measures. Results Response to treatment improved as intensity increased from 12 to 24 to 36 exposures, and then no further improvements were observed as intensity increased to 48 exposures. There was variability in treatment response: Children with poor phonological awareness, low vocabulary, and/or poor nonword repetition were less likely to respond to treatment. Conclusion The adequate intensity for this version of interactive book reading was 36 exposures, but further development of the treatment is needed to increase the benefit for children with SLI. PMID:28036410

Exposure-Response Relationship for Ombitasvir and Paritaprevir/Ritonavir in Hepatitis C Virus Subgenotype 1b-Infected Japanese Patients in the Phase 3 Randomized GIFT-I Study.

PubMed

Gopalakrishnan, Sathej; Khatri, Amit; Mensing, Sven; Redman, Rebecca; Menon, Rajeev; Zha, Jiuhong

2016-04-01

The all-oral 2 direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once a day has been evaluated in hepatitis C virus subgenotype 1b-infected Japanese adults in the GIFT-I study. The aim of this analysis was to evaluate potential relationships between DAA exposures and laboratory abnormalities/adverse events of peripheral edema in patients in GIFT-I. The GIFT-I study consisted of a randomized, double-blind, placebo-controlled substudy in patients without cirrhosis and an open-label substudy in patients with compensated cirrhosis. Patients received ombitasvir/paritaprevir/ritonavir for 12 weeks. Exposure-response relationships between individual components of the ombitasvir/paritaprevir/ritonavir regimen and clinical parameters of interest were explored using pharmacokinetic and clinical data from patients in the study. Graphical analyses were performed. For events that occurred in at least 10 patients (total bilirubin elevation ≥grade 2 and peripheral edema ≥grade 1), multivariate logistic regression analyses were used to identify significant relationships between predictor variables (drug exposures) and response variables (probability of adverse events or laboratory abnormalities), with consideration for the effect of potential covariates and baseline status of response variables. Data from 321 noncirrhotic and 42 compensated cirrhotic patients were analyzed. There were 14 events of peripheral edema (10 at grade 1 and 4 at grade 2) in patients who received concomitant administration of calcium channel blockers and ombitasvir/paritaprevir/ritonavir. There was no apparent relationship between the incidences of peripheral edema and exposures of paritaprevir, ombitasvir, or ritonavir. There was a shallow relationship between total bilirubin elevation and exposures of paritaprevir which is an inhibitor of bilirubin transporter organic anion-transporting polypeptide 1B. Based on graphical analyses, exposures of paritaprevir, ombitasvir, or ritonavir were weakly associated with hemoglobin decrease, but not associated with post baseline alanine aminotransferase or aspartate aminotransferase elevations. In Japanese patients, there were no associations or only shallow relationships between DAA exposures and peripheral edema or laboratory abnormalities. Consequently, therapeutic drug monitoring is not expected to be beneficial in managing patients on the 2-DAA regimen. ClinicalTrials.gov identifier, NCT02023099. AbbVie Inc.

Use of Wearable Sensors and Biometric Variables in an Artificial Pancreas System.

PubMed

Turksoy, Kamuran; Monforti, Colleen; Park, Minsun; Griffith, Garett; Quinn, Laurie; Cinar, Ali

2017-03-07

An artificial pancreas (AP) computes the optimal insulin dose to be infused through an insulin pump in people with Type 1 Diabetes (T1D) based on information received from a continuous glucose monitoring (CGM) sensor. It has been recognized that exercise is a major challenge in the development of an AP system. The use of biometric physiological variables in an AP system may be beneficial for prevention of exercise-induced challenges and better glucose regulation. The goal of the present study is to find a correlation between biometric variables such as heart rate (HR), heat flux (HF), skin temperature (ST), near-body temperature (NBT), galvanic skin response (GSR), and energy expenditure (EE), 2D acceleration-mean of absolute difference (MAD) and changes in glucose concentrations during exercise via partial least squares (PLS) regression and variable importance in projection (VIP) in order to determine which variables would be most useful to include in a future artificial pancreas. PLS and VIP analyses were performed on data sets that included seven different types of exercises. Data were collected from 26 clinical experiments. Clinical results indicate ST to be the most consistently important (important for six out of seven tested exercises) variable over all different exercises tested. EE and HR are also found to be important variables over several types of exercise. We also found that the importance of GSR and NBT observed in our experiments might be related to stress and the effect of changes in environmental temperature on glucose concentrations. The use of the biometric measurements in an AP system may provide better control of glucose concentration.

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms

PubMed Central

Monsma, David J; Cherba, David M; Eugster, Emily E; Dylewski, Dawna L; Davidson, Paula T; Peterson, Chelsea A; Borgman, Andrew S; Winn, Mary E; Dykema, Karl J; Webb, Craig P; MacKeigan, Jeffrey P; Duesbery, Nicholas S; Nickoloff, Brian J; Monks, Noel R

2015-01-01

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAFV600E models showed acquired drug resistance, one BRAFV600E model had a complete and durable response, and a BRAFV600V model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations. PMID:26101714

Implementing the undergraduate mini-CEX: a tailored approach at Southampton University.

PubMed

Hill, Faith; Kendall, Kathleen; Galbraith, Kevin; Crossley, Jim

2009-04-01

The mini-clinical evaluation exercise (mini-CEX) is widely used in the UK to assess clinical competence, but there is little evidence regarding its implementation in the undergraduate setting. This study aimed to estimate the validity and reliability of the undergraduate mini-CEX and discuss the challenges involved in its implementation. A total of 3499 mini-CEX forms were completed. Validity was assessed by estimating associations between mini-CEX score and a number of external variables, examining the internal structure of the instrument, checking competency domain response rates and profiles against expectations, and by qualitative evaluation of stakeholder interviews. Reliability was evaluated by overall reliability coefficient (R), estimation of the standard error of measurement (SEM), and from stakeholders' perceptions. Variance component analysis examined the contribution of relevant factors to students' scores. Validity was threatened by various confounding variables, including: examiner status; case complexity; attachment specialty; patient gender, and case focus. Factor analysis suggested that competency domains reflect a single latent variable. Maximum reliability can be achieved by aggregating scores over 15 encounters (R = 0.73; 95% confidence interval [CI] +/- 0.28 based on a 6-point assessment scale). Examiner stringency contributed 29% of score variation and student attachment aptitude 13%. Stakeholder interviews revealed staff development needs but the majority perceived the mini-CEX as more reliable and valid than the previous long case. The mini-CEX has good overall utility for assessing aspects of the clinical encounter in an undergraduate setting. Strengths include fidelity, wide sampling, perceived validity, and formative observation and feedback. Reliability is limited by variable examiner stringency, and validity by confounding variables, but these should be viewed within the context of overall assessment strategies.

Neuroblastoma in children: Update on clinicopathologic and genetic prognostic factors.

PubMed

Ahmed, Atif A; Zhang, Lei; Reddivalla, Naresh; Hetherington, Maxine

2017-04-01

Neuroblastoma is the most common extracranial solid tumor in childhood accounting for 8-10% of all childhood malignancies. The tumor is characterized by a spectrum of histopathologic features and a heterogeneous clinical phenotype. Modern multimodality therapy results in variable clinical response ranging from cure in localized tumors to limited response in aggressive metastatic disease. Accurate clinical staging and risk assessment based on clinical, surgical, biologic and pathologic criteria are of pivotal importance in assigning prognosis and planning effective treatment approaches. Numerous studies have analyzed the presence of several clinicopathologic and biologic factors in association with the patient's prognosis and outcome. Although patient's age, tumor stage, histopathologic classification, and MYCN amplification are the most commonly validated prognostic markers, several new gene mutations have been identified in sporadic and familial neuroblastoma cases that show association with an adverse outcome. Novel molecular studies have also added data on chromosomal segmental aberrations in MYCN nonamplified tumors. In this review, we provide an updated summary of the clinical, serologic and genetic prognostic indicators in neuroblastoma including classic factors that have consistently played a role in risk stratification of patients as well as newly discovered biomarkers that may show a potential significance in patients' management.

Professional ethics: beyond the clinical competency.

PubMed

Vanaki, Zohreh; Memarian, Robabeh

2009-01-01

Assessment of clinical competency in professional roles especially in crucial situations can improve the nursing profession. This qualitative research was conducted to determine the process of acquiring clinical competency by nurses in its cultural context and within the health care delivery system in Iran. This study, using grounded theory methodology, took place in universities and hospitals in Tehran. Nurses (36) included nurse managers, tutors, practitioners, and members of the Iranian Nursing Organization. Simultaneous data collection and analysis took place using participant semistructured interviews. Three categories emerged: (a) personal characteristics such as philanthropy, strong conscience, being attentive, accepting responsibility, being committed to and respecting self and others; (b) care environment including appropriate management systems, in-service training provision, employment laws, and control mechanisms, suitable and adequate equipment; and (c) provision of productive work practices including love of the profession, critical thinking, nursing knowledge, and professional expertise. Professional ethics has emerged as the core variable that embodies concepts such as commitment, responsibility, and accountability. Professional ethics guarantees clinical competency and leads to the application of specialized knowledge and skill by nurses. The results can be used to form the basis of guiding the process of acquiring clinical competency by nurses using a systematic process.

Hydroxyurea responses in clinically varied beta, HbE-beta thalassaemia and sickle cell anaemia patients of Eastern India.

PubMed

Chatterjee, Tridip; Chakravarty, Amit; Chakravarty, Sudipa

2018-05-01

The haematological and clinical response to hydroxyurea was estimated in HbE-beta, beta thalassaemia and sickle cell anaemia patients of Eastern India, with variable clinical severity and transfusion requirement to determine whether hydroxyurea can help these patients to maintain their steady haemoglobin level without blood transfusions. Three hundred patients (189 HbE-beta thalassaemia, 95 beta thalassaemia and 16 other haemoglobinopathies including sickle cell anaemia) were selected for hydroxyurea therapy and were followed up for 48-60 months. Results suggest significant response to hydroxyurea therapy in 19 beta and 99 HbE-beta patients in the transfusion-dependent group (GR-I). All of them became transfusion-independent while on hydroxyurea therapy. The majority of responding patients were IVS1-5(G-C) in one of their alleles in HbE-beta cases (83 out of 119). Though IVS1-5(G-C) was found to be the commonest mutation in our selected patients, the mutational background of the patients does not found to have any significant correlation with the response category towards hydroxyurea as per the results observed in our study. But, the drug works pretty well in most of the transfusion-dependent patients, as these patients were withdrawn from regular blood transfusion. At the same time, partial or no response to the drug hydroxyurea was also recorded in our study.

Antipsychotic Response Worsens With Postmenopausal Duration in Women With Schizophrenia.

PubMed

González-Rodríguez, Alexandre; Catalán, Rosa; Penadés, Rafael; Ruiz Cortés, Victoria; Torra, Mercè; Seeman, Mary V; Bernardo, Miquel

2016-12-01

The loss of estrogens in the menopause may lead to increased vulnerability for psychotic relapse, poor clinical outcome, and a need for increased antipsychotic dose. However, confounders such as cumulative estrogen exposure and time since menopause have been inadequately studied. Our aim was to investigate potential variables capable of influencing antipsychotic response in a sample of postmenopausal women with schizophrenia. Sixty-four postmenopausal schizophrenic women were followed in a 12-week prospective treatment-by-clinical requirement study. Duration of reproductive years was considered an indirect measure of lifetime cumulative estrogens exposure. Psychopathological assessment included the following: Positive and Negative Syndrome Scale, Personal and Social Performance, and Clinical Global Impression-Schizophrenia Scale. Response was defined as a reduction of 30% or more of Positive and Negative Syndrome Scale total scores. Antipsychotic adherence was assessed by plasma level monitoring at 4 weeks. Regression analyses were performed to investigate the association between potential confounding factors and antipsychotic response. Forty-two participants (66%) were found to be antipsychotic responders. Time since menopause was significantly and negatively associated with overall antipsychotic response, explaining almost 42% of the variance of the model used. Smoking and cumulative estrogen exposures were associated with improvement in negative symptoms. Smoking and time since menopause were associated with improvement in excitement symptoms, and smoking was positively associated with improvement in depressive and cognitive symptoms. Time since menopause was significantly negatively associated with antipsychotic response in postmenopausal schizophrenic women, suggesting a decline in antipsychotic response after menopause. The neurobiological basis for antipsychotic response may include a role for estrogen and nicotine receptors.

Model-Free Conditional Independence Feature Screening For Ultrahigh Dimensional Data.

PubMed

Wang, Luheng; Liu, Jingyuan; Li, Yong; Li, Runze

2017-03-01

Feature screening plays an important role in ultrahigh dimensional data analysis. This paper is concerned with conditional feature screening when one is interested in detecting the association between the response and ultrahigh dimensional predictors (e.g., genetic makers) given a low-dimensional exposure variable (such as clinical variables or environmental variables). To this end, we first propose a new index to measure conditional independence, and further develop a conditional screening procedure based on the newly proposed index. We systematically study the theoretical property of the proposed procedure and establish the sure screening and ranking consistency properties under some very mild conditions. The newly proposed screening procedure enjoys some appealing properties. (a) It is model-free in that its implementation does not require a specification on the model structure; (b) it is robust to heavy-tailed distributions or outliers in both directions of response and predictors; and (c) it can deal with both feature screening and the conditional screening in a unified way. We study the finite sample performance of the proposed procedure by Monte Carlo simulations and further illustrate the proposed method through two real data examples.

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

PubMed Central

Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

2012-01-01

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

[Occipital neuralgia: clinical and therapeutic characteristics of a series of 14 patients].

PubMed

Pedraza, María Isabel; Ruiz, Marina; Rodríguez, Cristina; Muñoz, Irene; Barón, Johanna; Mulero, Patricia; Herrero-Velázquez, Sonia; Guerrero-Peral, Ángel L

2013-09-01

INTRODUCTION. Occipital neuralgia is a pain in the distribution of the occipital nerves, accompanied by hypersensitivity to touch in the corresponding territory. AIMS. We present the occipital neuralgia series from the specialised headache unit at a tertiary hospital and analyse its clinical characteristics and its response to therapy. PATIENTS AND METHODS. Variables were collected from the cases of occipital neuralgia diagnosed in the above-mentioned headache unit between January 2008 and April 2013. RESULTS. A series of 14 patients (10 females, 4 males) with occipital neuralgia was obtained out of a total of 2338 (0.59%). Age at onset of the clinical signs and symptoms: 53.4 ± 20.3 years (range: 17-81 years) and time elapsed to diagnosis was 35.5 ± 58.8 months (range: 1-230 months). An intracranial or cervical pathology was ruled out by suitable means in each case. Baseline pain of a generally oppressive nature and an intensity of 5.3 ± 1.3 (4-8) on the verbal analogue scale was observed in 13 of them (92.8%). Eleven (78.5%) presented exacerbations, generally stabbing pains, a variable frequency (4.6 ± 7 a day) and an intensity of 7.8 ± 1.7 (range: 4-10) on the verbal analogue scale. Anaesthetic blockade was not performed in four of them (two due to a remitting pattern and two following the patient's wishes); in the others, blockade was carried out and was completely effective for between two and seven months. Four cases had previously received preventive treatment (amitriptyline in three and gabapentin in one), with no response. CONCLUSIONS. In this series from a specialised headache unit, occipital neuralgia is an infrequent condition that mainly affects patients over 50 years of age. Given its poor response to preventive treatment, the full prolonged response to anaesthetic blockades must be taken into account.

Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer.

PubMed

Castellanos, Emily; Feld, Emily; Horn, Leora

2017-04-01

EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Achilles Tendinopathy: Current Concepts about the Basic Science and Clinical Treatments

PubMed Central

Li, Hong-Yun

2016-01-01

Achilles tendinopathy is one of the most frequently ankle and foot overuse injuries, which is a clinical syndrome characterized by the combination of pain, swelling, and impaired performance. The two main categories of Achilles tendinopathy are classified according to anatomical location and broadly include insertional and noninsertional tendinopathy. The etiology of Achilles tendinopathy is multifactorial including both intrinsic and extrinsic factors. Failed healing response and degenerative changes were found in the tendon. The failed healing response includes three different and continuous stages (reactive tendinopathy, tendon disrepair, and degenerative tendinopathy). The histological studies have demonstrated an increased number of tenocytes and concentration of glycosaminoglycans in the ground substance, disorganization and fragmentation of the collagen, and neovascularization. There are variable conservative and surgical treatment options for Achilles tendinopathy. However, there has not been a gold standard of these treatments because of the controversial clinical results between various studies. In the future, new level I researches will be needed to prove the effect of these treatment options. PMID:27885357

Future translational applications from the contemporary genomics era: a scientific statement from the American Heart Association.

PubMed

Fox, Caroline S; Hall, Jennifer L; Arnett, Donna K; Ashley, Euan A; Delles, Christian; Engler, Mary B; Freeman, Mason W; Johnson, Julie A; Lanfear, David E; Liggett, Stephen B; Lusis, Aldons J; Loscalzo, Joseph; MacRae, Calum A; Musunuru, Kiran; Newby, L Kristin; O'Donnell, Christopher J; Rich, Stephen S; Terzic, Andre

2015-05-12

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care. © 2015 American Heart Association, Inc.

Parent Training on Generalized Use of Behavior Analytic Strategies for Decreasing the Problem Behavior of Children with Autism Spectrum Disorder: A Data-Based Case Study

ERIC Educational Resources Information Center

Crone, Regina M.; Mehta, Smita Shukla

2016-01-01

Setting variables such as location of parent training, programming with common stimuli, generalization of discrete responses to non-trained settings, and subsequent reduction in child problem behavior may influence the effectiveness of interventions. The purpose of this study was to evaluate the effectiveness of home-versus clinic-based training…

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

Pearlberg, J.; Haggar, A.M.; Saravolatz, L.

Hemophilus influenzae septicemia is an important cause of life-threatening pneumonia in an immunocompromised patient. Eleven cases proved by blood culture were analyzed. Multilobar involvement with lobar or segmental consolidation pleural effusion were common radiographic findings, but there were no signs of lobar expansion, bulging fissures, or cavitation. In general, predisposing factors such as alcoholism and chemotherapy place patients at risk. Radiographic response to therapy is variable but often lags behind clinical improvement.

Intolerance of uncertainty and transdiagnostic group cognitive behavioral therapy for anxiety.

PubMed

Talkovsky, Alexander M; Norton, Peter J

2016-06-01

Recent evidence suggests intolerance of uncertainty (IU) is a transdiagnostic variable elevated across anxiety disorders. No studies have investigated IU's response to transdiagnostic group CBT for anxiety (TGCBT). This study evaluated IU outcomes following TGCBT across anxiety disorders. 151 treatment-seekers with primary diagnoses of social anxiety disorder, panic disorder, or GAD were evaluated before and after 12 weeks of TGCBT and completed self-report questionnaires at pre-, mid-, and post-treatment. IU decreased significantly following treatment. Decreases in IU predicted improvements in clinical presentation across diagnoses. IU interacted with time to predict improvement in clinical presentation irrespective of primary diagnosis. IU also interacted with time to predict improvement in clinical presentation although interactions of time with diagnosis-specific measures did not. IUS interacted with time to predict reduction in anxiety and fear symptoms, and inhibitory IU interacted with time to predicted reductions in anxiety symptoms but prospective IU did not. IU appears to be an important transdiagnostic variable in CBT implicated in both initial presentation and treatment change. Further implications are discussed. Published by Elsevier Ltd.

[Prenatal care in public and private health services: a population-based survey in Rio Grande, Rio Grande do Sul State, Brazil].

PubMed

Cesar, Juraci A; Sutil, Andréa T; Santos, Gabriela B dos; Cunha, Carolina F; Mendoza-Sassi, Raúl A

2012-11-01

This study aimed to evaluate public and private prenatal care for women in Rio Grande, Rio Grande do Sul State, Brazil. Women who gave birth at the two local maternity hospitals from January 1 to December 31, 2010, answered a standardized questionnaire. The interview sites in the public sector were primary health care units with and without the Family Health Strategy (FHS) and outpatient clinics; the private sector included clinics operated by health plans and private physicians' offices. The chi-square test was used to compare proportions. The response rate was 97.2% (2,395 out of 2,464). Among the 23 target variables and indicators, seven showed a clear advantage for mothers who had received prenatal care under the FHS and six for health plan clinics and private offices. Four variables showed virtually universal coverage at all five study sites. Prenatal care showed better coverage for pregnant women treated in the private sector. Pregnant women treated under the FHS showed similar coverage to that in the private sector.

Missing Data in Clinical Studies: Issues and Methods

PubMed Central

Ibrahim, Joseph G.; Chu, Haitao; Chen, Ming-Hui

2012-01-01

Missing data are a prevailing problem in any type of data analyses. A participant variable is considered missing if the value of the variable (outcome or covariate) for the participant is not observed. In this article, various issues in analyzing studies with missing data are discussed. Particularly, we focus on missing response and/or covariate data for studies with discrete, continuous, or time-to-event end points in which generalized linear models, models for longitudinal data such as generalized linear mixed effects models, or Cox regression models are used. We discuss various classifications of missing data that may arise in a study and demonstrate in several situations that the commonly used method of throwing out all participants with any missing data may lead to incorrect results and conclusions. The methods described are applied to data from an Eastern Cooperative Oncology Group phase II clinical trial of liver cancer and a phase III clinical trial of advanced non–small-cell lung cancer. Although the main area of application discussed here is cancer, the issues and methods we discuss apply to any type of study. PMID:22649133

Acute clinical recovery from sport-related concussion.

PubMed

Nelson, Lindsay D; Janecek, Julie K; McCrea, Michael A

2013-12-01

Concussion is a highly prevalent injury in contact and collision sports that has historically been poorly understood. An influx of sport-concussion research in recent years has led to a dramatic improvement in our understanding of the injury's defining characteristics and natural history of recovery. In this review, we discuss the current state of knowledge regarding the characteristic features of concussion and typical acute course of recovery, with an emphasis on the aspects of functioning most commonly assessed by clinicians and researchers (e.g., symptoms, cognitive deficits, postural stability). While prototypical clinical recovery is becoming better understood, questions remain regarding what factors (e.g., injury severity, demographic variables, history of prior concussions, psychological factors) may explain individual variability in recovery. Although research concerning individual differences in response to concussion is relatively new, and in many cases limited methodologically, we discuss the evidence about several potential moderators of concussion recovery and point out areas for future research. Finally, we describe how increased knowledge about the negative effects of and recovery following concussion has been translated into clinical guidelines for managing concussed athletes.

Policy to implementation: evidence-based practice in community mental health – study protocol

PubMed Central

2013-01-01

Background Evidence-based treatments (EBTs) are not widely available in community mental health settings. In response to the call for implementation of evidence-based treatments in the United States, states and counties have mandated behavioral health reform through policies and other initiatives. Evaluations of the impact of these policies on implementation are rare. A systems transformation about to occur in Philadelphia, Pennsylvania, offers an important opportunity to prospectively study implementation in response to a policy mandate. Methods/design Using a prospective sequential mixed-methods design, with observations at multiple points in time, we will investigate the responses of staff from 30 community mental health clinics to a policy from the Department of Behavioral Health encouraging and incentivizing providers to implement evidence-based treatments to treat youth with mental health problems. Study participants will be 30 executive directors, 30 clinical directors, and 240 therapists. Data will be collected prior to the policy implementation, and then at two and four years following policy implementation. Quantitative data will include measures of intervention implementation and potential moderators of implementation (i.e., organizational- and leader-level variables) and will be collected from executive directors, clinical directors, and therapists. Measures include self-reported therapist fidelity to evidence-based treatment techniques as measured by the Therapist Procedures Checklist-Revised, organizational variables as measured by the Organizational Social Context Measurement System and the Implementation Climate Assessment, leader variables as measured by the Multifactor Leadership Questionnaire, attitudes towards EBTs as measured by the Evidence-Based Practice Attitude Scale, and knowledge of EBTs as measured by the Knowledge of Evidence- Based Services Questionnaire. Qualitative data will include semi-structured interviews with a subset of the sample to assess the implementation experience of high-, average-, and low-performing agencies. Mixed methods will be integrated through comparing and contrasting results from the two methods for each of the primary hypotheses in this study. Discussion Findings from the proposed research will inform both future policy mandates around implementation and the support required for the success of these policies, with the ultimate goal of improving the quality of treatment provided to youth in the public sector. PMID:23522556

Policy to implementation: evidence-based practice in community mental health--study protocol.

PubMed

Beidas, Rinad S; Aarons, Gregory; Barg, Frances; Evans, Arthur; Hadley, Trevor; Hoagwood, Kimberly; Marcus, Steven; Schoenwald, Sonja; Walsh, Lucia; Mandell, David S

2013-03-24

Evidence-based treatments (EBTs) are not widely available in community mental health settings. In response to the call for implementation of evidence-based treatments in the United States, states and counties have mandated behavioral health reform through policies and other initiatives. Evaluations of the impact of these policies on implementation are rare. A systems transformation about to occur in Philadelphia, Pennsylvania, offers an important opportunity to prospectively study implementation in response to a policy mandate. Using a prospective sequential mixed-methods design, with observations at multiple points in time, we will investigate the responses of staff from 30 community mental health clinics to a policy from the Department of Behavioral Health encouraging and incentivizing providers to implement evidence-based treatments to treat youth with mental health problems. Study participants will be 30 executive directors, 30 clinical directors, and 240 therapists. Data will be collected prior to the policy implementation, and then at two and four years following policy implementation. Quantitative data will include measures of intervention implementation and potential moderators of implementation (i.e., organizational- and leader-level variables) and will be collected from executive directors, clinical directors, and therapists. Measures include self-reported therapist fidelity to evidence-based treatment techniques as measured by the Therapist Procedures Checklist-Revised, organizational variables as measured by the Organizational Social Context Measurement System and the Implementation Climate Assessment, leader variables as measured by the Multifactor Leadership Questionnaire, attitudes towards EBTs as measured by the Evidence-Based Practice Attitude Scale, and knowledge of EBTs as measured by the Knowledge of Evidence- Based Services Questionnaire. Qualitative data will include semi-structured interviews with a subset of the sample to assess the implementation experience of high-, average-, and low-performing agencies. Mixed methods will be integrated through comparing and contrasting results from the two methods for each of the primary hypotheses in this study. Findings from the proposed research will inform both future policy mandates around implementation and the support required for the success of these policies, with the ultimate goal of improving the quality of treatment provided to youth in the public sector.

Uncovering Clinical Features of De Novo Philadelphia Positive Myelodysplasia.

PubMed

Armas, Aristides; Chen, Chen; Mims, Martha; Rivero, Gustavo

2017-01-01

Myelodysplastic syndrome (MDS) is cytogenetically heterogeneous and retains variable risk for acute myeloid leukemia transformation. Though not yet fully understood, there is an association between genetic abnormalities and defects in gene expression. The functional role for infrequent cytogenetic alteration remains unclear. An uncommon chromosomic abnormality is the presence of the Philadelphia (Ph) chromosome. Here, we report a patient with Ph+ MDS treated with low dose Dasatinib who achieved hematologic response for 7 months. In addition, we also examined the English literature on all de novo Ph + MDS cases between 1996 and 2015 to gain insight into clinical features and outcome.

Uncovering Clinical Features of De Novo Philadelphia Positive Myelodysplasia

PubMed Central

Armas, Aristides; Chen, Chen; Mims, Martha

2017-01-01

Myelodysplastic syndrome (MDS) is cytogenetically heterogeneous and retains variable risk for acute myeloid leukemia transformation. Though not yet fully understood, there is an association between genetic abnormalities and defects in gene expression. The functional role for infrequent cytogenetic alteration remains unclear. An uncommon chromosomic abnormality is the presence of the Philadelphia (Ph) chromosome. Here, we report a patient with Ph+ MDS treated with low dose Dasatinib who achieved hematologic response for 7 months. In addition, we also examined the English literature on all de novo Ph + MDS cases between 1996 and 2015 to gain insight into clinical features and outcome. PMID:28321349

Return to preinjury sports participation following anterior cruciate ligament reconstruction: contributions of demographic, knee impairment, and self-report measures.

PubMed

Lentz, Trevor A; Zeppieri, Giorgio; Tillman, Susan M; Indelicato, Peter A; Moser, Michael W; George, Steven Z; Chmielewski, Terese L

2012-11-01

Cross-sectional cohort. (1) To examine differences in clinical variables (demographics, knee impairments, and self-report measures) between those who return to preinjury level of sports participation and those who do not at 1 year following anterior cruciate ligament reconstruction, (2) to determine the factors most strongly associated with return-to-sport status in a multivariate model, and (3) to explore the discriminatory value of clinical variables associated with return to sport at 1 year postsurgery. Demographic, physical impairment, and psychosocial factors individually prohibit return to preinjury levels of sports participation. However, it is unknown which combination of factors contributes to sports participation status. Ninety-four patients (60 men; mean age, 22.4 years) 1 year post-anterior cruciate ligament reconstruction were included. Clinical variables were collected and included demographics, knee impairment measures, and self-report questionnaire responses. Patients were divided into "yes return to sports" or "no return to sports" groups based on their answer to the question, "Have you returned to the same level of sports as before your injury?" Group differences in demographics, knee impairments, and self-report questionnaire responses were analyzed. Discriminant function analysis determined the strongest predictors of group classification. Receiver-operating-characteristic curves determined the discriminatory accuracy of the identified clinical variables. Fifty-two of 94 patients (55%) reported yes return to sports. Patients reporting return to preinjury levels of sports participation were more likely to have had less knee joint effusion, fewer episodes of knee instability, lower knee pain intensity, higher quadriceps peak torque-body weight ratio, higher score on the International Knee Documentation Committee Subjective Knee Evaluation Form, and lower levels of kinesiophobia. Knee joint effusion, episodes of knee instability, and score on the International Knee Documentation Committee Subjective Knee Evaluation Form were identified as the factors most strongly associated with self-reported return-to-sport status. The highest positive likelihood ratio for the yes-return-to-sports group classification (14.54) was achieved when patients met all of the following criteria: no knee effusion, no episodes of instability, and International Knee Documentation Committee Subjective Knee Evaluation Form score greater than 93. In multivariate analysis, the factors most strongly associated with return-to-sport status included only self-reported knee function, episodes of knee instability, and knee joint effusion.

Variability in Immunization Practices for Preterm Infants.

PubMed

Gopal, Srirupa Hari; Edwards, Kathryn M; Creech, Buddy; Weitkamp, Joern-Hendrik

2018-06-08

 The Advisory Committee on Immunization Practices and the American Academy of Pediatrics (AAP) recommend the same immunization schedule for preterm and term infants. However, significant delays in vaccination of premature infants have been reported.  The objective of this study was to assess the variability of immunization practices in preterm infants.  We conducted an online survey of 2,443 neonatologists in the United States, who are members of the Section for Neonatal-Perinatal Medicine of the AAP. Questions were targeted at immunization practices in the neonatal intensive care unit (NICU).  Of the 420 responses (17%) received, 55% of providers administer the first vaccine at >2-month chronological age. Most providers (83%) surveyed reported delaying vaccines in the setting of clinical illness. Sixty percent reported increasing frequency of apnea-bradycardia events following immunization. More than half administer the initial vaccines over several days despite lack of supporting data. Reported considerations in delaying or spreading out 2-month vaccines were clinical instability, provider preference, lower gestational age, and lower birth weight.  This survey substantiates the variability of immunizations practices in the NICU and identifies reasons for this variability. Future studies should inform better practice guidance for immunization of preterm NICU patients based on vaccine safety and effectiveness. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Is electromyography a predictive test of patient response to biofeedback in the treatment of fecal incontinence?

PubMed

Lacima, Gloria; Pera, Miguel; González-Argenté, Xavier; Torrents, Abiguei; Valls-Solé, Josep; Espuña-Pons, Montserrat

2016-03-01

Biofeedback is effective in more than 70% of patients with fecal incontinence. However, reliable predictors of successful treatment have not been identified. The aim was to identify clinical variables and diagnostic tests, particularly electromyography, that could predict a successful outcome. We included 135 consecutive women with fecal incontinence treated with biofeedback. Clinical evaluation, manometry, ultrasonography, electromyography, and pudendal nerve terminal motor latency were performed before therapy. Treatment outcome was assessed using a symptoms diary, Wexner incontinence score and the patient's subjective perception. According to the symptoms diaries, 106 (78.5%) women had a good clinical result and 29 (21.5%) had a poor result. There were no differences in age, severity and type of fecal incontinence. Maximum resting pressure (39.3 ± 19.1 mmHg vs. 33.7 ± 20.2 mmHg; P = 0.156) and maximum squeeze pressure (91.8 ± 33.2 mmHg vs. 79.8 ± 31.2 mmHg; P = 0.127) were higher in patients having good clinical outcome although the difference was not significant. There were no differences in the presence of sphincter defects or abnormalities in electromyographic recordings. Logistic regression analysis found no independent predictive factor for good clinical outcome. Biofeedback is effective in more than 75% of patients with fecal incontinence. Clinical characteristics of patients and results of baseline tests have no predictive value of response to therapy. Specifically, we found no association between severity of electromyographic deficit and clinical response. © 2015 Wiley Periodicals, Inc.

Emotional Variability and Clarity in Depression and Social Anxiety

PubMed Central

Thompson, Renee J.; Boden, Matthew Tyler; Gotlib, Ian H.

2016-01-01

Recent research has underscored the importance of elucidating specific patterns of emotion that characterize mental disorders. We examined two emotion traits, emotional variability and emotional clarity, in relation to both categorical (diagnostic interview) and dimensional (self-report) measures of Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) in women diagnosed with MDD only (n=35), SAD only (n=31), MDD and SAD (n=26), or no psychiatric disorder (n=38). Results of the categorical analyses suggest that elevated emotional variability and diminished emotional clarity are transdiagnostic of MDD and SAD. More specifically, emotional variability was elevated for MDD and SAD diagnoses compared to no diagnosis, showing an additive effect for co-occurring MDD and SAD. Similarly diminished levels of emotional clarity characterized all three clinical groups compared to the healthy control group. Dimensional findings suggest that whereas emotional variability is associated more consistently with depression than with social anxiety, emotional clarity is associated more consistently with social anxiety than with depression. Results are interpreted using a threshold- and dose-response framework. PMID:26371579

Multilevel analysis of ADHD, anxiety and depression symptoms aggregation in families.

PubMed

Segenreich, Daniel; Paez, Marina Silva; Regalla, Maria Angélica; Fortes, Dídia; Faraone, Stephen V; Sergeant, Joseph; Mattos, Paulo

2015-05-01

A strong genetic role in the etiology of attention-deficit hyperactivity disorder (ADHD) has been demonstrated by several studies using different methodologies. Shortcomings of genetic studies often include the lack of golden standard practices for diagnosis for ADHD, the use of categorical instead of a dimensional approach, and the disregard for assortative mating phenomenon in parents. The current study aimed to overcome these shortcomings and analyze data through a novel statistical approach, using multilevel analyses with Bayesian procedures and a specific mathematical model, which takes into account data with an elevated number of zero responses (expected in samples with few or no ADHD symptoms). Correlations of parental clinical variables (ADHD, anxiety and depression) to offspring psychopathology may vary according to gender and type of symptoms. We aimed to investigate how those variables interact within each other. One hundred families, comprising a proband child or adolescent with ADHD or a typically developing child or adolescent were included and all family members (both biological parents, the proband child or adolescent and their sibling) were examined through semi-structured interviews using DSM-IV criteria. Results indicated that: (a) maternal clinical variables (ADHD, anxiety and depression) were more correlated with offspring variables than paternal ones; (b) maternal inattention (but not hyperactivity) was correlated with both inattention and hyperactivity in the offspring; (c) maternal anxiety was correlated with offspring inattention; on the other hand, maternal inattention was correlated with anxiety in the offspring. Although a family study design limits the possibility of revealing causality and cannot disentangle genetic and environmental factors, our findings suggest that ADHD, anxiety and depression are variables that correlate in families and should be addressed together. Maternal variables significantly correlated with offspring variables, but the paternal variables did not.

Differential Expression of Immunogenic Proteins on Virulent Mycobacterium tuberculosis Clinical Isolates

PubMed Central

Klepp, Laura; Vazquez, Camila; Rocha, Roxana Valeria; Blanco, Federico Carlos; López, Beatriz; Bigi, Fabiana; Sasiain, María del Carmen

2014-01-01

Molecular epidemiology has revealed that Mycobacterium tuberculosis (Mtb), formerly regarded as highly conserved species, displays a considerable degree of genetic variability that can influence the outcome of the disease as well as the innate and adaptive immune response. Recent studies have demonstrated that Mtb families found worldwide today differ in pathology, transmissibility, virulence, and development of immune response. By proteomic approaches seven proteins that were differentially expressed between a local clinical isolate from Latin-American-Mediterranean (LAM) and from Haarlem (H) lineages were identified. In order to analyze the immunogenic ability, recombinant Rv2241, Rv0009, Rv0407, and Rv2624c proteins were produced for testing specific antibody responses. We found that these proteins induced humoral immune responses in patients with drug-sensitive and drug-resistant tuberculosis with substantial cross-reactivity among the four proteins. Moreover, such reactivity was also correlated with anti-Mtb-cell surface IgM, but not with anti-ManLAM, anti-PPD, or anti-Mtb-surface IgG antibodies. Therefore, the present results describe new Mtb antigens with potential application as biomarkers of TB. PMID:25105140

Weight reduction is not a major reason for improvement in rheumatoid arthritis from lacto-vegetarian, vegan or Mediterranean diets

PubMed Central

Sköldstam, Lars; Brudin, Lars; Hagfors, Linda; Johansson, Gunnar

2005-01-01

Objectives Several investigators have reported that clinical improvements of patients with rheumatoid arthritis (RA), from participating in therapeutic diet intervention studies, have been accompanied by loss of body weight. This has raised the question whether weight reduction per se can improve RA. In order to test this hypothesis, three previously conducted diet intervention studies, comprising 95 patients with RA, were pooled. Together with Age, Gender, and Disease Duration, change during the test period in body weight, characterised dichotomously as reduction or no reduction (dichoΔBody Weight), as well as Diet (dichotomously as ordinary diet or test diet), were the independent variables. Dependent variables were the difference (Δ) from baseline to conclusion of the study in five different disease outcome measures. ΔESR and ΔPain Score were both characterised numerically and dichotomously (improvement or no improvement). ΔAcute Phase Response, ΔPhysical Function, and ΔTender Joint Count were characterised dichotomously only. Multiple logistic regression was used to analyse associations between the independent and the disease outcome variables. Results Statistically significant correlations were found between Diet and three disease outcome variables i.e. ΔAcute-Phase Response, ΔPain Score, and ΔPhysical Function. Δ Body Weight was univariately only correlated to ΔAcute-Phase Response but not significant when diet was taken into account. Conclusion Body weight reduction did not significantly contribute to the improvement in rheumatoid arthritis when eating lacto-vegetarian, vegan or Mediterranean diets. PMID:15871736

Clinical characterization and treatment outcome of patients with burning mouth syndrome.

PubMed

Hakeem, Abdulaziz; Fitzpatrick, Sarah G; Bhattacharyya, Indraneel; Islam, Mohammed N; Cohen, Donald M

2018-01-01

Burning mouth syndrome (BMS) is a complex condition that affects the oral cavity, and data regarding effective treatment are limited. The purpose of this study was to explore the demographic and clinical information along with treatment outcomes for patients with BMS treated in a large referral center. Clinical records of the Oral Medicine Clinic at the University of Florida College of Dentistry were retrospectively searched for patients diagnosed between 2009 and 2014. Clinical data and treatment effectiveness were recorded. The records of 64 patients were included in this study. Women represented the majority of patients (81.2%), and the average age of all patients was 65 years. The most common systemic diseases were hypertension (59.4%), psycho-logical disorders (51.6%), and gastroesophageal reflux disease (50.0%). The majority of patients were taking 5 or more medications (70.3%). Treatment frequency and efficacy were as follows: a-lipoic acid, 47.5% frequency (57 prescribed treatments of 120 total treatments) and lasting improvement reported with 45.6% of prescribed treatments; clonazepam, 17.5% frequency (21/120) and improvement reported with 33.0% of prescribed treatments; oral disintegrating clonazepam, 15.8% frequency (19/120) and improvement reported with 52.6% of prescribed treatments; and topical vitamin E, 5.0% frequency (6/120) and improvement reported with 33.0% of prescribed treatments. Chi-square analysis indicated that a significantly better response to treatment was reported by women (P = 0.010) and patients who reported involvement limited to the tongue rather than multifocal oral involvement (P = 0.040); however, the significant relationships did not persist when the variables were evaluated together using logistic regression analysis. No other clinical or demographic features showed significant differences in response to treatment. Although treatment effectiveness in this study was variable and limited for some regimens due to infrequent usage, many of the patients reported alleviation of symptoms.

Localization of genes involved in the metabolic syndrome using multivariate linkage analysis.

PubMed

Olswold, Curtis; de Andrade, Mariza

2003-12-31

There are no well accepted criteria for the diagnosis of the metabolic syndrome. However, the metabolic syndrome is identified clinically by the presence of three or more of these five variables: larger waist circumference, higher triglyceride levels, lower HDL-cholesterol concentrations, hypertension, and impaired fasting glucose. We use sets of two or three variables, which are available in the Framingham Heart Study data set, to localize genes responsible for this syndrome using multivariate quantitative linkage analysis. This analysis demonstrates the applicability of using multivariate linkage analysis and how its use increases the power to detect linkage when genes are involved in the same disease mechanism.

Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study

PubMed Central

Stevens, Adam; Murray, Philip; Wojcik, Jerome; Raelson, John; Koledova, Ekaterina; Chatelain, Pierre

2016-01-01

Objective Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations. Design and methods Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification. Results The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes – SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR). Conclusions The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use. PMID:27651465

Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.

PubMed

Stevens, Adam; Murray, Philip; Wojcik, Jerome; Raelson, John; Koledova, Ekaterina; Chatelain, Pierre; Clayton, Peter

2016-12-01

Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations. Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification. The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes - SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR). The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use. © 2016 European Society of Endocrinology.

Predicting outcome of Internet-based treatment for depressive symptoms.

PubMed

Warmerdam, Lisanne; Van Straten, Annemieke; Twisk, Jos; Cuijpers, Pim

2013-01-01

In this study we explored predictors and moderators of response to Internet-based cognitive behavioral therapy (CBT) and Internet-based problem-solving therapy (PST) for depressive symptoms. The sample consisted of 263 participants with moderate to severe depressive symptoms. Of those, 88 were randomized to CBT, 88 to PST and 87 to a waiting list control condition. Outcomes were improvement and clinically significant change in depressive symptoms after 8 weeks. Higher baseline depression and higher education predicted improvement, while higher education, less avoidance behavior and decreased rational problem-solving skills predicted clinically significant change across all groups. No variables were found that differentially predicted outcome between Internet-based CBT and Internet-based PST. More research is needed with sufficient power to investigate predictors and moderators of response to reveal for whom Internet-based therapy is best suited.

Systems integration of innate and adaptive immunity.

PubMed

Zak, Daniel E; Aderem, Alan

2015-09-29

The pathogens causing AIDS, malaria, and tuberculosis have proven too complex to be overcome by classical approaches to vaccination. The complexities of human immunology and pathogen-induced modulation of the immune system mandate new approaches to vaccine discovery and design. A new field, systems vaccinology, weds holistic analysis of innate and adaptive immunity within a quantitative framework to enable rational design of new vaccines that elicit tailored protective immune responses. A key step in the approach is to discover relationships between the earliest innate inflammatory responses to vaccination and the subsequent vaccine-induced adaptive immune responses and efficacy. Analysis of these responses in clinical studies is complicated by the inaccessibility of relevant tissue compartments (such as the lymph node), necessitating reliance upon peripheral blood responses as surrogates. Blood transcriptomes, although indirect to vaccine mechanisms, have proven very informative in systems vaccinology studies. The approach is most powerful when innate and adaptive immune responses are integrated with vaccine efficacy, which is possible for malaria with the advent of a robust human challenge model. This is more difficult for AIDS and tuberculosis, given that human challenge models are lacking and efficacy observed in clinical trials has been low or highly variable. This challenge can be met by appropriate clinical trial design for partially efficacious vaccines and by analysis of natural infection cohorts. Ultimately, systems vaccinology is an iterative approach in which mechanistic hypotheses-derived from analysis of clinical studies-are evaluated in model systems, and then used to guide the development of new vaccine strategies. In this review, we will illustrate the above facets of the systems vaccinology approach with case studies. Copyright © 2015. Published by Elsevier Ltd.

The Prognostic Influence of BRAF Mutation and other Molecular, Clinical and Laboratory Parameters in Stage IV Colorectal Cancer.

PubMed

Karadima, Maria L; Saetta, Angelica A; Chatziandreou, Ilenia; Lazaris, Andreas C; Patsouris, Efstratios; Tsavaris, Nikolaos

2016-10-01

Our aim was to evaluate the predictive and prognostic influence of BRAF mutation and other molecular, clinical and laboratory parameters in stage IV colorectal cancer (CRC). 60 patients were included in this retrospective analysis, and 17 variables were examined for their relation with treatment response and survival. KRAS mutation was identified in 40.3 % of cases, BRAF and PIK3CA in 8.8 % and 10.5 % respectively. 29.8 % of patients responded to treatment. Median survival time was 14.3 months. Weight loss, fever, abdominal metastases, blood transfusion, hypoalbuminaimia, BRAF and PIK3CA mutations, CRP and DNA Index were associated with survival. In multivariate analysis, male patients had 3.8 times higher probability of response, increased DNA Index was inversely correlated with response and one unit raise of DNA Index augmented 6 times the probability of death. Our findings potentiate the prognostic role of BRAF, PIK3CA mutations and ploidy in advanced CRC.

Psychiatrists' follow-up of identified metabolic risk: a mixed-method analysis of outcomes and influences on practice

PubMed Central

Patterson, Sue; Freshwater, Kathleen; Goulter, Nicole; Ewing, Julie; Leamon, Boyd; Choudhary, Anand; Moudgil, Vikas; Emmerson, Brett

2016-01-01

Aims and method To describe and explain psychiatrists' responses to metabolic abnormalities identified during screening. We carried out an audit of clinical records to assess rates of monitoring and follow-up practice. Semi-structured interviews with 36 psychiatrists followed by descriptive and thematic analyses were conducted. Results Metabolic abnormalities were identified in 76% of eligible patients screened. Follow-up, recorded for 59%, was variable but more likely with four or more abnormalities. Psychiatrists endorse guidelines but ambivalence about responsibility, professional norms, resource constraints and skills deficits as well as patient factors influences practice. Therapeutic optimism and desire to be a ‘good doctor’ supported comprehensive follow-up. Clinical implications Psychiatrists are willing to attend to physical healthcare, and obstacles to recommended practice are surmountable. Psychiatrists seek consensus among stakeholders about responsibilities and a systemic approach addressing the social determinants of health inequities. Understanding patients' expectations is critical to promoting best practice. PMID:27752343

Five year follow-up of a smoking withdrawal clinic population.

PubMed Central

West, D W; Graham, S; Swanson, M; Wilkinson, G

1977-01-01

Eight hundred volunteers who attended smoking clinics at Roswell Park Memorial Institute from 1964-1965 were followed up five years later to ascertain their current smoking status. From three waves of a mailed questionnaire, plus a telephone campaign, we obtained 559 usable responses. The relationship between smoking status at the five-year follow-up and clinic protocols and selected social and psychological characteristics as determined during the clinics were examined. Of those individuals contacted five years after the clinic, 17.8 per cent were not smoking. Variations in clinic protocol in terms of drugs and education methods had no relation to long-term smoking withdrawal. Several social and psychological variables, however, were related to smoking behavior five years after the clinics. Non-smokers were more likely than smokers to be males, to be older, to have smoked less before the clinic, to have started smoking at a later age, to have a milieu that was supportive of their stopping, and to have fewer indices of neurosis and fewer psychosomatic symptoms. PMID:869086

Hemodynamic responses to etomidate versus ketamine-thiopental sodium combination for anesthetic induction in coronary artery bypass graft surgery patients with low ejection fraction: a double-blind, randomized, clinical trial.

PubMed

Habibi, Mohammad Reza; Baradari, Afshin Gholipour; Soleimani, Aria; Emami Zeydi, Amir; Nia, Hamid Sharif; Habibi, Ali; Onagh, Naser

2014-10-01

During induction of anesthesia and intubation, hemodynamic changes are very important; especially in patients with coronary artery disease (CAD) and left ventricular dysfunction. A little information is available on the hemodynamic effects of a combination of ketamine-thiopental for induction of anesthesia in patients undergoing coronary artery bypass graft (CABG) surgery, with impaired ventricular function. The aim of this study was to compare the hemodynamic responses to etomidate versus ketamine-thiopental sodium combination for anesthetic induction in CABG surgery patients with low ejection fraction (EF<45%). In a double blind randomized clinical trial, a total of 100 patients, scheduled for elective CABG surgery were randomly assigned into two groups. These patients received either etomidate or ketamine-thiopental sodium combination at induction of anesthesia. Hemodynamics variable were measured and recorded at baseline, immediately before and after laryngoscopy and intubation, one, two and three minutes after intubation. Also, muscle twitching incidence among patients in two groups was evaluated. No significant differences between the two groups regarding the changes of hemodynamic variables including systolic and diastolic arterial blood pressure, mean arterial pressure and heart rate, were notice (p>0.05). Muscle twitching was not observed in the two groups. Hemodynamic stability after administration of ketamine-thiopental sodium combination for induction of anesthesia in patients undergoing CABG surgery, with impaired ventricular function, supports the clinical impression that this combination is safe in CABG surgery patients with low EF.

Correlation between clinical response to sorafenib in hepatocellular carcinoma treatment and polymorphisms of P-glycoprotein (ABCB1) and of breast cancer resistance protein (ABCG2): monocentric study.

PubMed

Tandia, Mahamadou; Mhiri, Asma; Paule, Bernard; Saffroy, Raphaël; Cailliez, Valérie; Noé, Gaëlle; Farinotti, Robert; Bonhomme-Faivre, Laurence

2017-04-01

We studied the relation between the polymorphism of P-glycoprotein (P-gp) and of breast cancer resistance protein (BCRP), encoded by ABCB1 and ABCG2 genes, respectively, and the pharmacokinetic variability and clinical response during the treatment with sorafenib of hepatocellular carcinoma. At the Paul Brousse Hospital in Villejuif, France, 47 consecutive patients with advanced HCC treated with a single agent sorafenib, were enrolled. Sorafenib exposure was measured by its plasma concentration 3 h after oral administration of 400 mg (bid) by liquid chromatography. All enrolled patients were genotyped for ABCB1 (rs2032582; rs1045642) and ABCG2 (rs2231137; rs2231142; rs2622604) by blood genomic DNA extraction and Mass ARRAY genotyping. The clinical response was evaluated after 3months of treatment according to the RECIST criteria. Significant associations between sorafenib exposure and the studied polymorphisms were observed for ABCB1 3435C>T, ABCG2 34G>A, ABCG2 1143C>T and ABCG2 421C>A, but not for ABCB1 2677G>TA SNP. In heterozygous patients for ABCB1 3435 C>T, ABCG2 34 G>A and ABCG2 1143 C>T polymorphisms were significantly associated with the lowest sorafenib plasma levels. Those patients presented a tendency to have the best clinical evolution. Heterozygous forms of the studied polymorphisms could be associated with a better therapeutic response.

Dose-response relationships for the onset of avoidance of sonar by free-ranging killer whales.

PubMed

Miller, Patrick J O; Antunes, Ricardo N; Wensveen, Paul J; Samarra, Filipa I P; Alves, Ana Catarina; Tyack, Peter L; Kvadsheim, Petter H; Kleivane, Lars; Lam, Frans-Peter A; Ainslie, Michael A; Thomas, Len

2014-02-01

Eight experimentally controlled exposures to 1-2 kHz or 6-7 kHz sonar signals were conducted with four killer whale groups. The source level and proximity of the source were increased during each exposure in order to reveal response thresholds. Detailed inspection of movements during each exposure session revealed sustained changes in speed and travel direction judged to be avoidance responses during six of eight sessions. Following methods developed for Phase-I clinical trials in human medicine, response thresholds ranging from 94 to 164 dB re 1 μPa received sound pressure level (SPL) were fitted to Bayesian dose-response functions. Thresholds did not consistently differ by sonar frequency or whether a group had previously been exposed, with a mean SPL response threshold of 142 ± 15 dB (mean ± s.d.). High levels of between- and within-individual variability were identified, indicating that thresholds depended upon other undefined contextual variables. The dose-response functions indicate that some killer whales started to avoid sonar at received SPL below thresholds assumed by the U.S. Navy. The predicted extent of habitat over which avoidance reactions occur depends upon whether whales responded to proximity or received SPL of the sonar or both, but was large enough to raise concerns about biological consequences to the whales.

Obesity and Its Potential Effects on Antidepressant Treatment Outcomes in Patients with Depressive Disorders: A Literature Review

PubMed Central

Woo, Young Sup; Seo, Hye-Jin; McIntyre, Roger S.; Bahk, Won-Myong

2016-01-01

Accumulating evidence regarding clinical, neurobiological, genetic, and environmental factors suggests a bidirectional link between obesity and depressive disorders. Although a few studies have investigated the link between obesity/excess body weight and the response to antidepressants in depressive disorders, the effect of weight on treatment response remains poorly understood. In this review, we summarized recent data regarding the relationship between the response to antidepressants and obesity/excess body weight in clinical studies of patients with depressive disorders. Although several studies indicated an association between obesity/excess body weight and poor antidepressant responses, it is difficult to draw definitive conclusions due to the variability of subject composition and methodological differences among studies. Especially, differences in sex, age and menopausal status, depressive symptom subtypes, and antidepressants administered may have caused inconsistencies in the results among studies. The relationship between obesity/excess body weight and antidepressant responses should be investigated further in high-powered studies addressing the differential effects on subject characteristics and treatment. Moreover, future research should focus on the roles of mediating factors, such as inflammatory markers and neurocognitive performance, which may alter the antidepressant treatment outcome in patients with comorbid obesity and depressive disorder. PMID:26771598

A multiscale modeling approach to inflammation: A case study in human endotoxemia

NASA Astrophysics Data System (ADS)

Scheff, Jeremy D.; Mavroudis, Panteleimon D.; Foteinou, Panagiota T.; An, Gary; Calvano, Steve E.; Doyle, John; Dick, Thomas E.; Lowry, Stephen F.; Vodovotz, Yoram; Androulakis, Ioannis P.

2013-07-01

Inflammation is a critical component in the body's response to injury. A dysregulated inflammatory response, in which either the injury is not repaired or the inflammatory response does not appropriately self-regulate and end, is associated with a wide range of inflammatory diseases such as sepsis. Clinical management of sepsis is a significant problem, but progress in this area has been slow. This may be due to the inherent nonlinearities and complexities in the interacting multiscale pathways that are activated in response to systemic inflammation, motivating the application of systems biology techniques to better understand the inflammatory response. Here, we review our past work on a multiscale modeling approach applied to human endotoxemia, a model of systemic inflammation, consisting of a system of compartmentalized differential equations operating at different time scales and through a discrete model linking inflammatory mediators with changing patterns in the beating of the heart, which has been correlated with outcome and severity of inflammatory disease despite unclear mechanistic underpinnings. Working towards unraveling the relationship between inflammation and heart rate variability (HRV) may enable greater understanding of clinical observations as well as novel therapeutic targets.

Rapid response predicts 12-month post-treatment outcomes in binge-eating disorder: theoretical and clinical implications

PubMed Central

Grilo, C. M.; White, M. A.; Wilson, G. T.; Gueorguieva, R.; Masheb, R. M.

2011-01-01

Background We examined rapid response in obese patients with binge-eating disorder (BED) in a clinical trial testing cognitive behavioral therapy (CBT) and behavioral weight loss (BWL). Method Altogether, 90 participants were randomly assigned to CBT or BWL. Assessments were performed at baseline, throughout and post-treatment and at 6- and 12-month follow-ups. Rapid response, defined as ≥70% reduction in binge eating by week four, was determined by receiver operating characteristic curves and used to predict outcomes. Results Rapid response characterized 57% of participants (67% of CBT, 47% of BWL) and was unrelated to most baseline variables. Rapid response predicted greater improvements across outcomes but had different prognostic significance and distinct time courses for CBT versus BWL. Patients receiving CBT did comparably well regardless of rapid response in terms of reduced binge eating and eating disorder psychopathology but did not achieve weight loss. Among patients receiving BWL, those without rapid response failed to improve further. However, those with rapid response were significantly more likely to achieve binge-eating remission (62% v. 13%) and greater reductions in binge-eating frequency, eating disorder psychopathology and weight loss. Conclusions Rapid response to treatment in BED has prognostic significance through 12-month follow-up, provides evidence for treatment specificity and has clinical implications for stepped-care treatment models for BED. Rapid responders who receive BWL benefit in terms of both binge eating and short-term weight loss. Collectively, these findings suggest that BWL might be a candidate for initial intervention in stepped-care models with an evaluation of progress after 1 month to identify non-rapid responders who could be advised to consider a switch to a specialized treatment. PMID:21923964

Metabolic and anthropometric parameters contribute to ART-mediated CD4+ T cell recovery in HIV-1-infected individuals: an observational study

PubMed Central

2011-01-01

Background The degree of immune reconstitution achieved in response to suppressive ART is associated with baseline individual characteristics, such as pre-treatment CD4 count, levels of viral replication, cellular activation, choice of treatment regimen and gender. However, the combined effect of these variables on long-term CD4 recovery remains elusive, and no single variable predicts treatment response. We sought to determine if adiposity and molecules associated with lipid metabolism may affect the response to ART and the degree of subsequent immune reconstitution, and to assess their ability to predict CD4 recovery. Methods We studied a cohort of 69 (48 females and 21 males) HIV-infected, treatment-naïve South African subjects initiating antiretroviral treatment (d4T, 3Tc and lopinavir/ritonavir). We collected information at baseline and six months after viral suppression, assessing anthropometric parameters, dual energy X-ray absorptiometry and magnetic resonance imaging scans, serum-based clinical laboratory tests and whole blood-based flow cytometry, and determined their role in predicting the increase in CD4 count in response to ART. Results We present evidence that baseline CD4+ T cell count, viral load, CD8+ T cell activation (CD95 expression) and metabolic and anthropometric parameters linked to adiposity (LDL/HDL cholesterol ratio and waist/hip ratio) significantly contribute to variability in the extent of CD4 reconstitution (ΔCD4) after six months of continuous ART. Conclusions Our final model accounts for 44% of the variability in CD4+ T cell recovery in virally suppressed individuals, representing a workable predictive model of immune reconstitution. PMID:21801351

Qualitative Analysis of Attitudes Toward Adult-Child Sexual Activity Among Minor-Attracted Persons.

PubMed

Spriggs, Sharron A; Cohen, Lisa J; Valencia, Ashley; S Zimri, Yaseen; Galynker, Igor I

2018-05-09

This study uses qualitative methodology to explore narrative responses to a question regarding the harmful versus beneficial effects of adult-child sex on children. Data were gathered from a survey of self-identified minor-attracted persons (MAPs). Two hundred and sixty-seven survey participants provided narrative responses. Results indicated a significant amount of variability in perceptions of harm and of mitigating or aggravating factors. Understanding the subjective perspectives of MAPs, the range of their attitudes, and the issues that they identify as pertinent is critically important for clinical efficacy in the treatment of pedophilia.

A general theoretical framework for interpreting patient-reported outcomes estimated from ordinally scaled item responses.

PubMed

Massof, Robert W

2014-10-01

A simple theoretical framework explains patient responses to items in rating scale questionnaires. Fixed latent variables position each patient and each item on the same linear scale. Item responses are governed by a set of fixed category thresholds, one for each ordinal response category. A patient's item responses are magnitude estimates of the difference between the patient variable and the patient's estimate of the item variable, relative to his/her personally defined response category thresholds. Differences between patients in their personal estimates of the item variable and in their personal choices of category thresholds are represented by random variables added to the corresponding fixed variables. Effects of intervention correspond to changes in the patient variable, the patient's response bias, and/or latent item variables for a subset of items. Intervention effects on patients' item responses were simulated by assuming the random variables are normally distributed with a constant scalar covariance matrix. Rasch analysis was used to estimate latent variables from the simulated responses. The simulations demonstrate that changes in the patient variable and changes in response bias produce indistinguishable effects on item responses and manifest as changes only in the estimated patient variable. Changes in a subset of item variables manifest as intervention-specific differential item functioning and as changes in the estimated person variable that equals the average of changes in the item variables. Simulations demonstrate that intervention-specific differential item functioning produces inefficiencies and inaccuracies in computer adaptive testing. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Duration of untreated illness as a predictor of treatment response and clinical course in generalized anxiety disorder.

PubMed

Altamura, A C; Dell'osso, Bernardo; D'Urso, Nazario; Russo, Michela; Fumagalli, Sara; Mundo, Emanuela

2008-05-01

The aim of the present study was to investigate the impact of the duration of untreated illness (DUI)-defined as the time elapsing between the onset of generalized anxiety disorder (GAD) and the first adequate pharmacologic treatment-on treatment response and clinical course in a sample of subjects with GAD. One hundred patients with GAD, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria, were enrolled and their main demographic and clinical features collected. Patients were then treated with selective serotonin reuptake inhibitors or venlafaxine for 8 weeks in open-label conditions. Treatment response and other clinical variables were analyzed after dividing the sample into two groups according to DUI (DUI 12 months). When the DUI was computed with respect to the first antidepressant treatment (DUI-AD), a higher improvement (Clinical Global Impressions-Severity of Illness scale) after the pharmacologic treatment was found in the group with a shorter DUI (analysis of variance with repeated measures: time effect F=654.975, P<.001; group effect: F=4.369, P=.039). When computed with respect to the first treatment with benzodiazepines (DUI-BDZ), the two groups did not show any significant difference in treatment response (time effect: F=652.183, P<.001; group effect: F=0.009, P=.924). In addition, patients with a longer DUI (DUI-BDZ or DUI-AD) showed an earlier age at onset, a longer duration of illness and a higher rate of comorbid psychiatric disorders with onset later than GAD. Results from this preliminary study seem to suggest that a shorter DUI-AD may determine a better response to pharmacologic treatment in patients with GAD, and that a longer DUI (DUI-BDZ and DUI-AD) may be associated to a worse clinical course. Further investigation on the relationship between DUI and GAD is needed.

Naltrexone and Cognitive Behavioral Therapy for the Treatment of Alcohol Dependence

PubMed Central

Baros, AM; Latham, PK; Anton, RF

2008-01-01

Background Sex differences in regards to pharmacotherapy for alcoholism is a topic of concern following publications suggesting naltrexone, one of the longest approved treatments of alcoholism, is not as effective in women as in men. This study was conducted by combining two randomized placebo controlled clinical trials utilizing similar methodologies and personnel in which the data was amalgamated to evaluate sex effects in a reasonable sized sample. Methods 211 alcoholics (57 female; 154 male) were randomized to the naltrexone/CBT or placebo/CBT arm of the two clinical trials analyzed. Baseline variables were examined for differences between sex and treatment groups via analysis of variance (ANOVA) for continuous variable or chi-square test for categorical variables. All initial outcome analysis was conducted under an intent-to-treat analysis plan. Effect sizes for naltrexone over placebo were determined by Cohen’s D (d). Results The effect size of naltrexone over placebo for the following outcome variables was similar in men and women (%days abstinent (PDA) d=0.36, %heavy drinking days (PHDD) d=0.36 and total standard drinks (TSD) d=0.36). Only for men were the differences significant secondary to the larger sample size (PDA p=0.03; PHDD p=0.03; TSD p=0.04). There were a few variables (GGT at wk-12 change from baseline to week-12: men d=0.36, p=0.05; women d=0.20, p=0.45 and drinks per drinking day: men d=0.36, p=0.05; women d=0.28, p=0.34) where the naltrexone effect size for men was greater than women. In women, naltrexone tended to increase continuous abstinent days before a first drink (women d-0.46, p=0.09; men d=0.00, p=0.44). Conclusions The effect size of naltrexone over placebo appeared similar in women and men in our hands suggesting the findings of sex differences in naltrexone response might have to do with sample size and/or endpoint drinking variables rather than any inherent pharmacological or biological differences in response. PMID:18336635

Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency.

PubMed

Loewenthal, Neta; Haim, Alon; Parvari, Ruti; Hershkovitz, Eli

2015-12-01

Phosphoglucomutase 1 (PGM1, EC 5.4.2.2) plays a critical role in glucose homeostasis and is also essential for protein N-glycosylation. The main clinical manifestations of PGM1 deficiency (MIM 614921) reported in 19 patients from different ethnic backgrounds include the following: cleft uvula/palate, Pierre Robin sequence, muscle weakness, dilated cardiomyopathy, growth retardation, elevated serum transaminases, hypoglycemia, and various endocrine abnormalities. We report the variable clinical picture of seven patients with PGM1 deficiency from a consanguineous family. Medical records of the patients were reviewed for clinical details and endocrine evaluation. Whole exome sequencing (WES) was performed. Seven patients aged 2-29 years were included, one patient died at 13 years old when getting off the school bus. All patients have an abnormal palatine structure (cleft palate, bifid uvula) and elevated serum transaminases, 4/7 have short stature (<-2 SDS) and one was diagnosed with growth hormone deficiency. Recurrent episodes of ketotic hypoglycemia were present in 6/7 patients. In two patients, hypoglycemic episodes have spontaneously resolved later on. Four out of seven patients have deteriorating adrenal function with abnormally low cortisol and ACTH levels during hypoglycemia and subnormal response of cortisol to low dose ACTH test . Serum electrolytes were within normal range. Hydrocortisone replacement therapy improved, but not entirely eliminated hypoglycemic episodes. WES revealed a previously described homozygous mutation c.112A>T, p.Asn38Tyr in the PGM1 gene. The clinical picture of PGM1 deficiency is variable among patients with the same mutation and genetic background. ACTH deficiency should be considered in any PGM1 deficient patient with hypoglycemia. © 2015 Wiley Periodicals, Inc.

Profiles in fibromyalgia: algometry, auditory evoked potentials and clinical characterization of different subtypes.

PubMed

Triñanes, Yolanda; González-Villar, Alberto; Gómez-Perretta, Claudio; Carrillo-de-la-Peña, María T

2014-11-01

The heterogeneity found in fibromyalgia (FM) patients has led to the investigation of disease subgroups, mainly based on clinical features. The aim of this study was to test the hypothesis that clinical FM subgroups are associated with different underlying pathophysiological mechanisms. Sixty-three FM patients were classified in type I or type II, according to the Fibromyalgia Impact Questionnaire (FIQ), and in mild/moderate versus severe FM, according to the severity of three cardinal symptoms considered in the American College of Rheumatology (ACR) 2010 criteria (unrefreshed sleep, cognitive problems and fatigue). To validate the subgroups obtained by these two classifications, we calculated the area under the receiver operating characteristic curves for various clinical variables and for two potential biomarkers of FM: Response to experimental pressure pain (algometry) and the amplitude/intensity slopes of the auditory evoked potentials (AEPs) obtained to stimuli of increasing intensity. The variables that best discriminated type I versus type II were those related to depression, while the indices of clinical or experimental pain (threshold or tolerance) did not significantly differ between them. The variables that best discriminated the mild/moderate versus severe subgroups were those related to the algometry. The AEPs did not allow discrimination among the generated subsets. The FIQ-based classification allows the identification of subgroups that differ in psychological distress, while the index based on the ACR 2010 criteria seems to be useful to characterize the severity of FM mainly based on hyperalgesia. The incorporation of potential biomarkers to generate or validate classification criteria is crucial to advance in the knowledge of FM and in the understanding of pathophysiological pathways.

Interindividual differences in the clinical effectiveness of liraglutide in Type 2 diabetes: a real-world retrospective study conducted in Spain.

PubMed

Gomez-Peralta, F; Lecube, A; Fernández-Mariño, A; Alonso Troncoso, I; Morales, C; Morales-Pérez, F M; Guler, I; Cadarso-Suárez, C

2018-06-26

To study the response of clinical variables (HbA 1c , body weight, lipid profile and blood pressure) over 24 months of liraglutide treatment in a real-world clinical setting, and to describe the evolution of HbA 1c and body weight reduction in response to liraglutide treatment by employing generalized additive mixed models (GAMMs). We included people aged ≥ 18 years with Type 2 diabetes mellitus that initiated liraglutide treatment between November 2011 and May 2015. Demographic and clinical data were retrieved retrospectively over 24 months from electronic medical records with a median duration of observation of 7.0 (IQR 3.0-12.0) months. Individuals that initiated liraglutide therapy were obese (BMI 39.1 kg/m 2 ), with inadequate HbA 1c (68 mmol/mol [8.4%)], blood pressure and lipid levels. Upon liraglutide treatment, HbA 1c , body weight, mean systolic and diastolic blood pressure, and lipid levels decreased gradually. GAMMs demonstrated that longer treatment with liraglutide was a predictor of improved HbA 1c response, whereas higher baseline HbA 1c , longer Type 2 diabetes duration and treatment with insulin were predictors of worse HbA 1c response. Higher baseline weight, longer treatment with liraglutide and the interaction between metformin and time were predictors of improved weight response. In this real-world study, we showed the effectiveness of liraglutide in improving body weight, HbA 1c , mean systolic and diastolic blood pressure, and lipid levels. GAMMs indicated that baseline HbA 1c and weight, time of treatment with liraglutide, diabetes duration and the use of metformin or insulin are predictors of clinical response to liraglutide. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Role of Pharmacogenomics in the Management of Traditional and Novel Oral Anticoagulants

PubMed Central

Cavallari, Larisa H.; Shin, Jaekyu; Perera, Minoli A.

2013-01-01

Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration–cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotype-guided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available. PMID:22122181

Skin denervation and its clinical significance in late-stage chronic kidney disease.

PubMed

Chao, Chi-Chao; Wu, Vin-Cent; Tan, Chun-Hsiang; Wang, Yi-Mei; Tseng, Ming-Tsung; Wu, Pei-Chen; Lin, Yea-Huey; Lin, Whei-Min; Wu, Kwan-Dun; Hsieh, Sung-Tsang

2011-02-01

To investigate the skin innervation and its clinical significance in late-stage chronic kidney disease (CKD). Case series. National Taiwan University Hospital, Taipei, Taiwan. Forty consecutive nondiabetic patients with late-stage CKD (14 female and 26 male; mean [SD] age, 60.7 [12.3] years), including 2 cases with stage 3 CKD, 6 with stage 4 CKD, and 32 with stage 5 CKD, ie, end-stage kidney disease. Clinical evaluation of neurological deficits, nerve conduction study, autonomic function tests, and a 3-mm-diameter skin biopsy specimen taken from the distal leg. Quantitation of epidermal innervation, parameters of nerve conduction study, R-R interval variability, and sympathetic skin response. Clinically, 21 patients (52.5%) were symptomatic with paresthesia over the limbs or autonomic symptoms. The intraepidermal nerve fiber (IENF) density was markedly reduced in patients with CKD compared with age- and sex-matched controls (mean [SD], 2.8 [2.0] vs 8.6 [2.8] fibers/mm; P < .001). Skin denervation was observed in 27 patients (67.5%). Fifteen patients (37.5%) had abnormalities on nerve conduction studies, and 29 patients (72.5%) had abnormal results on autonomic function tests. By analysis with multiple regression models, the IENF density was negatively correlated with the duration of renal disease (P = .02). Additionally, the R-R interval variability at rest was linearly correlated with the IENF density (P = .02) and the absence of sympathetic skin responses at the soles was associated with reduced IENF density (P = .03). Small-fiber sensory and autonomic neuropathies constitute the major form of neuropathy in late-stage CKD. Furthermore, skin denervation was associated with the duration of renal disease.

The effect of clinical academic service contracts on surgeon satisfaction.

PubMed

Clifton, Joanne; Bradley, Christine; Cadeliña, Rachel; Hsiang, York

2007-06-01

The purpose of this study was to determine the satisfaction of members of an academic department who are funded by a Clinical Academic Service Contract (CASC), compared with those who are not. We mailed a satisfaction questionnaire designed to examine surgeons' perceived effect of CASCs on their participation in their division or department and on professional activities (research, teaching, clinical) to members of the surgery department who perform operative interventions. We analyzed responses from CASC and non-CASC members, using t tests for continuous variables and chi-square tests for categorical variables. Four of 9 operative divisions (cardiac, thoracic, neurosurgery, pediatric surgery) are CASC-funded, and 5 are not (general, plastic, otolaryngology, urology, vascular). The response rate after 3 mailings was 59%. CASC responders agreed on the need for the following: improved focus and resolution of issues (p < 0.001, p < 0.02); focus on developmental and future planning (p < 0.001); flexibility to change the level of participation in research, teaching and clinical activities (p < 0.001); recognition for academic and administrative activities (p < 0.002); opportunities to achieve career path goals (p < 0.002); more autonomy in research (p < 0.04); compensation for professional activities (p < 0.001); and increased leisure time (p < 0.004). Responders disagreed that morale was low (p < 0.001). They were satisfied with the following: professional activities (p < 0.019), increased research activities (p < 0.001), quality of research (p < 0.001), more presentations (p < 0.025), increased teaching time (p < 0.004) and ability to care for their patients (p < 0.001). CASC responders were significantly more satisfied with their professional activities and more optimistic in their divisional roles than were non-CASC responders. Based on these results, all departmental members who perform operative interventions should consider being on a CASC.

Sub-Optimal Treatment of Bacterial Biofilms

PubMed Central

Song, Tianyan; Duperthuy, Marylise; Wai, Sun Nyunt

2016-01-01

Bacterial biofilm is an emerging clinical problem recognized in the treatment of infectious diseases within the last two decades. The appearance of microbial biofilm in clinical settings is steadily increasing due to several reasons including the increased use of quality of life-improving artificial devices. In contrast to infections caused by planktonic bacteria that respond relatively well to standard antibiotic therapy, biofilm-forming bacteria tend to cause chronic infections whereby infections persist despite seemingly adequate antibiotic therapy. This review briefly describes the responses of biofilm matrix components and biofilm-associated bacteria towards sub-lethal concentrations of antimicrobial agents, which may include the generation of genetic and phenotypic variabilities. Clinical implications of bacterial biofilms in relation to antibiotic treatments are also discussed. PMID:27338489

Phenotypic variability among café-au-lait macules in neurofibromatosis type 1.

PubMed

Boyd, Kevin P; Gao, Liyan; Feng, Rui; Beasley, Mark; Messiaen, Ludwine; Korf, Bruce R; Theos, Amy

2010-09-01

Café-au-lait macules (CALMs) in neurofibromatosis type 1 (NF1) are an early and accessible phenotype in NF1, but have not been extensively studied. We sought to more fully characterize the phenotype of CALMs in patients with NF1. In all, 24 patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the genetics department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin based on its absorption of visible light. The major response was defined as the difference between the mean melanin from the CALM and the mean melanin from the surrounding skin. The major response for each spot was compared with spots within an individual and across individuals in the study population. There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, P < .0001) and secondly to interpersonal variability (33.0%, P < .0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. The study was performed on a small population of patients and the method has not yet been used extensively for this purpose. CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1. Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Deciphering Sources of Variability in Clinical Pathology.

PubMed

Tripathi, Niraj K; Everds, Nancy E; Schultze, A Eric; Irizarry, Armando R; Hall, Robert L; Provencher, Anne; Aulbach, Adam

2017-01-01

The objectives of this session were to explore causes of variability in clinical pathology data due to preanalytical and analytical variables as well as study design and other procedures that occur in toxicity testing studies. The presenters highlighted challenges associated with such variability in differentiating test article-related effects from the effects of experimental procedures and its impact on overall data interpretation. These presentations focused on preanalytical and analytical variables and study design-related factors and their influence on clinical pathology data, and the importance of various factors that influence data interpretation including statistical analysis and reference intervals. Overall, these presentations touched upon potential effect of many variables on clinical pathology parameters, including animal physiology, sample collection process, specimen handling and analysis, study design, and some discussion points on how to manage those variables to ensure accurate interpretation of clinical pathology data in toxicity studies. This article is a brief synopsis of presentations given in a session entitled "Deciphering Sources of Variability in Clinical Pathology-It's Not Just about the Numbers" that occurred at the 35th Annual Symposium of the Society of Toxicologic Pathology in San Diego, California.

Diurnal and nocturnal cardiovascular variability and heart rate arousal response in idiopathic hypersomnia.

PubMed

Sforza, Emilia; Roche, Frédéric; Barthélémy, Jean Claude; Pichot, Vincent

2016-08-01

Autonomic nervous system dysfunction has been described in narcolepsy with cataplexy affecting sympathetic functions. In this study we analyzed whether altered diurnal and nocturnal cardiovascular control is present in idiopathic hypersomnia (IH). Fourteen drug-free patients aged 26.2 ± 7 years and 14 age-matched controls were examined. Clinical data, 24-h polysomnography, heart rate (HR) variability, and the HR response to spontaneous arousal were available. Sleep macrostructure was comparable between controls and patients, with the latter having significantly longer sleep time, a higher number of sleep cycles (p < 0.0001), and low sleep efficiency (p < 0.01). The HR variability indices did not differ between groups, except for the rise of high frequency (HF) and HFnu in patients (p < 0.05) associated with blunted sympathetic indices (p < 0.01). These parasympathetic alterations were present for light, slow wave, and rapid eye-movement sleep and persisted for all sleep cycles. Compared to controls, the HR arousal response was significantly higher (p < 0.01) in patients starting before the arousal onset and persisting into the post-arousal period. In IH patients a dysfunction of the parasympathetic activity during awake and sleep and an altered autonomic response to arousals are present. These findings suggest an impaired parasympathetic function that may explain some vegetative symptoms present in this type of central hypersomnia. Copyright © 2016 Elsevier B.V. All rights reserved.

Differences between naïve and expert observers’ vergence and accommodative responses to a range of targets

PubMed Central

Horwood, Anna M; Riddell, Patricia M

2015-01-01

Purpose Vergence and accommodation studies often use adult participants with experience of vision science. Reports of infant and clinical responses are generally more variable and of lower gain, with the implication that differences lie in immaturity or sub-optimal clinical characteristics but expert /naïve differences are rarely considered or quantified. Methods Sixteen undergraduates, naïve to vision science were individually matched by age, visual acuity, refractive error, heterophoria, stereoacuity and near point of accommodation to 2nd & 3rd year orthoptics and optometry undergraduates (“experts”). Accommodation and vergence responses were assessed to targets moving between 33cm, 50 cm, 1m and 2m using a haploscopic device incorporating a PlusoptiX SO4 autorefractor. Disparity, blur and looming cues were separately available or minimised in all combinations. Instruction set was minimal. Results In all cases, vergence and accommodation response slopes (gain) were steeper and closer to 1.0 in the expert group (p=0.001), with the largest expert /naïve differences for both vergence and accommodation being for near targets (p=0.012). For vergence, the differences between expert and naïve response slopes increased with increasingly open-loop targets (linear trend p=0.025). Although we predicted that proximal cues would drive additional response in the experts, the proximity-only cue was the only condition that showed no statistical effect of experience. Conclusions Expert observers provide more accurate responses to near target demand than closely matched naïve observers. We suggest that attention, practice, voluntary and proprioceptive effects may enhance responses in experienced participants when compared to a more typical general population. Differences between adult reports and the developmental and clinical literature may partially reflect expert / naïve effects, as well as developmental change. If developmental and clinical studies are to be compared to adult normative data, uninstructed naïve adult data should be used. PMID:20444119

Army Nurse Corps Personnel Management Practices (Executive Summary).

DTIC Science & Technology

1984-09-01

among the three groups . c. Results of the discriminant analysis, using gender as the dependent variable, revealed that it was not possible to classify...subjects’ gender by their responses. Men and women ANC members responded in a like manner. d. Further discriminant analyses using grouped years of...Associate Investigator US Army Health Care Studies and Clinical Investigation Activity Fort Sam Houston, TX 78234 Final Report #83-005A September 1984

Response to depression treatment in the Aging Brain Care Medical Home model.

PubMed

LaMantia, Michael A; Perkins, Anthony J; Gao, Sujuan; Austrom, Mary G; Alder, Cathy A; French, Dustin D; Litzelman, Debra K; Cottingham, Ann H; Boustani, Malaz A

2016-01-01

To evaluate the effect of the Aging Brain Care (ABC) Medical Home program's depression module on patients' depression severity measurement over time. Retrospective chart review. Public hospital system. Patients enrolled in the ABC Medical Home program between October 1, 2012 and March 31, 2014. The response of 773 enrolled patients who had multiple patient health questionnaire-9 (PHQ-9) scores recorded in the ABC Medical Home program's depression care protocol was evaluated. Repeatedly measured PHQ-9 change scores were the dependent variables in the mixed effects models, and demographic and comorbid medical conditions were tested as potential independent variables while including random effects for time and intercept. Among those patients with baseline PHQ-9 scores >10, there was a significant decrease in PHQ-9 scores over time ( P <0.001); however, the effect differed by gender ( P =0.015). On average, women's scores (4.5 point drop at 1 month) improved faster than men's scores (1 point drop at 1 month). Moreover, both men and women had a predicted drop of 7 points (>50% decline from baseline) on the PHQ-9 at 6 months. These analyses demonstrate evidence for the sustained effectiveness of the ABC Medical Home program at inducing depression remission outcomes while employing clinical staff who required less formal training than earlier clinical trials.

Primer in Genetics and Genomics, Article 2-Advancing Nursing Research With Genomic Approaches.

PubMed

Lee, Hyunhwa; Gill, Jessica; Barr, Taura; Yun, Sijung; Kim, Hyungsuk

2017-03-01

Nurses investigate reasons for variable patient symptoms and responses to treatments to inform how best to improve outcomes. Genomics has the potential to guide nursing research exploring contributions to individual variability. This article is meant to serve as an introduction to the novel methods available through genomics for addressing this critical issue and includes a review of methodological considerations for selected genomic approaches. This review presents essential concepts in genetics and genomics that will allow readers to identify upcoming trends in genomics nursing research and improve research practice. It introduces general principles of genomic research and provides an overview of the research process. It also highlights selected nursing studies that serve as clinical examples of the use of genomic technologies. Finally, the authors provide suggestions about how to apply genomic technology in nursing research along with directions for future research. Using genomic approaches in nursing research can advance the understanding of the complex pathophysiology of disease susceptibility and different patient responses to interventions. Nurses should be incorporating genomics into education, clinical practice, and research as the influence of genomics in health-care research and practice continues to grow. Nurses are also well placed to translate genomic discoveries into improved methods for patient assessment and intervention.

Effects of vibration therapy on hormone response and stress in severely disabled patients: a double-blind randomized placebo-controlled clinical trial.

PubMed

Seco, J; Rodríguez-Pérez, V; López-Rodríguez, A F; Torres-Unda, J; Echevarria, E; Díez-Alegre, M I; Ortega, A; Morán, P; Mendoza-Laíz, N; Abecia Inchaurregui, L C

2015-01-01

To assess the effects of vibration therapy (VT) on quality of life and hormone response in severely disabled patients compared with placebo. A longitudinal prospective, double-blind, randomized placebo-controlled trial, with pre and postintervention assessments. A total of 20 severely disabled individuals were recruited from a National Reference Centre in Spain: 13 (65%) men and 7 (35%) women, 45.5 ± 9.32 years of age (range 41: 22-63). We evaluated their physical stress and state anxiety. No statistically significant changes were found in the socio-psychological variables studied, while in the experimental group state anxiety decreased significantly with p < 0.01 (Z = 2.38; one-tailed p = .009) and, among the biological variables, the level of cortisol fell (p = 0.03). Short periods of exposure to low-frequency and low-amplitude local vibration are a safe and effective mechanical stimulus that can have a positive effect in terms of hormone response. VT can be considered to have an anti-stress effect. © 2013 Association of Rehabilitation Nurses.

Predictors of Iranian women's intention to first papanicolaou test practice: An application of protection motivation theory.

PubMed

Dehdari, T; Hassani, L; Shojaeizadeh, D; Hajizadeh, E; Nedjat, S; Abedini, M

2016-01-01

Given the importance of papanicolaou (Pap) test in the early detection and timely treatment of cervical cancer, present study was designed to determine predictors of a sample of Iranian women's intention to first Pap test practice based on the protection motivation theory (PMT) variables. In this cross-sectional study, a total of 240 women referral to the 30 primary health care clinics were selected. They completed a developed scale based on PMT variables including intention, perceived vulnerability and severity, fear, response costs, response efficacy and self-efficacy. Path analysis was used to determine the association between predictive factors and intention. The results showed that PMT had goodness of fit with a χ2/df = 2.37, df = 28, P= 0.001 and RMSEA = 0.076. PMT explained 42% of the variance in women's intention to get first Pap smear test. Self-efficacy (b = 0.55, P< 0.001) and response efficacy (b = 0.19, P< 0.001) were found to be the predictors of intention. These findings may be used to develop tailored, theory-based educational interventions associated with Pap testing among women.

Clinical features of avian vacuolar myelinopathy in American coots

USGS Publications Warehouse

Larsen, R.S.; Nutter, F.B.; Augspurger, T.; Rocke, T.E.; Tomlinson, L.; Thomas, N.J.; Stoskopf, M.K.

2002-01-01

Objectivea??To characterize clinical features of avian vacuolar myelinopathy (AVM) in American coots. Designa??Case-control study. Animalsa??26 AVM-affected American coots and 12 unaffected coots. Proceduresa??Complete physical, neurologic, hematologic, and plasma biochemical evaluations were performed. Affected coots received supportive care. All coots died or were euthanatized, and AVM status was confirmed via histopathologic findings. Resultsa??3 severely affected coots were euthanatized immediately after examination. Seventeen affected coots were found dead within 7 days of admission, but 5 affected coots survived > 21 days and had signs of clinical recovery. Abnormal physical examination findings appeared to be related to general debilitation. Ataxia (88%), decreased withdrawal reflexes (88%), proprioceptive deficits (81%), decreased vent responses (69%), beak or tongue weakness (42%), and head tremors (31%), as well as absent pupillary light responses (46%), anisocoria (15%), apparent blindness (4%), nystagmus (4%), and strabismus (4%) were detected. Few gross abnormalities were detected at necropsy, but histologically, all AVM-affected coots had severe vacuolation of white matter of the brain. None of the control coots had vacuolation. Conclusions and Clinical Relevancea??Although there was considerable variability in form and severity of clinical neurologic abnormalities, clinical signs common in AVM-affected birds were identified. Clinical recovery of some AVM-affected coots can occur when supportive care is administered. Until the etiology is identified, caution should be exercised when rehabilitating and releasing coots thought to be affected by AVM.

An analysis of variability in the manufacturing of dexosomes: implications for development of an autologous therapy.

PubMed

Patel, Sanjay; Mehta-Damani, Anita; Shu, Helen; Le Pecq, Jean-Bernard

2005-10-20

Dexosomes are nanometer-size vesicles released by dendritic-cells, possessing much of the cellular machinery required to stimulate an immune response (i.e. MHC Class I and II). The ability of patient-derived dexosomes loaded with tumor antigens to elicit anti-tumor activity is currently being evaluated in clinical trials. Unlike conventional biologics, where variability between lots of product arises mostly from the manufacturing process, an autologous product has inherent variability in the starting material due to heterogeneity in the human population. In an effort to assess the variability arising from the dexosome manufacturing process versus the human starting material, 144 dexosome preparations from normal donors (111) and cancer patients (33) from two Phase I clinical trials were analyzed. A large variability in the quantity of dexosomes (measured as the number of MHC Class II molecules) produced between individual lots was observed ( > 50-fold). An analysis of intra-lot variability shows that the manufacturing process introduces relatively little of this variability. To identify the source(s) of variability arising from the human starting material, distributions of the key parameters involved in dexosome production were established, and a model created. Computer simulations using this model were performed, and compared to the actual data observed. The main conclusion from these simulations is that the number of cells collected per individual and the productivity of these cells of are the principal sources of variability in the production of Class II. The approach described here can be extended to other autologous therapies in general to evaluate control of manufacturing processes. Moreover, this analysis of process variability is directly applicable to production at a commercial scale, since the large scale manufacture of autologous products entails an exact process replication rather than scale-up in volume, as is the case with traditional drugs or biologics. Copyright 2005 Wiley Periodicals, Inc.

Datamining approaches for modeling tumor control probability.

PubMed

Naqa, Issam El; Deasy, Joseph O; Mu, Yi; Huang, Ellen; Hope, Andrew J; Lindsay, Patricia E; Apte, Aditya; Alaly, James; Bradley, Jeffrey D

2010-11-01

Tumor control probability (TCP) to radiotherapy is determined by complex interactions between tumor biology, tumor microenvironment, radiation dosimetry, and patient-related variables. The complexity of these heterogeneous variable interactions constitutes a challenge for building predictive models for routine clinical practice. We describe a datamining framework that can unravel the higher order relationships among dosimetric dose-volume prognostic variables, interrogate various radiobiological processes, and generalize to unseen data before when applied prospectively. Several datamining approaches are discussed that include dose-volume metrics, equivalent uniform dose, mechanistic Poisson model, and model building methods using statistical regression and machine learning techniques. Institutional datasets of non-small cell lung cancer (NSCLC) patients are used to demonstrate these methods. The performance of the different methods was evaluated using bivariate Spearman rank correlations (rs). Over-fitting was controlled via resampling methods. Using a dataset of 56 patients with primary NCSLC tumors and 23 candidate variables, we estimated GTV volume and V75 to be the best model parameters for predicting TCP using statistical resampling and a logistic model. Using these variables, the support vector machine (SVM) kernel method provided superior performance for TCP prediction with an rs=0.68 on leave-one-out testing compared to logistic regression (rs=0.4), Poisson-based TCP (rs=0.33), and cell kill equivalent uniform dose model (rs=0.17). The prediction of treatment response can be improved by utilizing datamining approaches, which are able to unravel important non-linear complex interactions among model variables and have the capacity to predict on unseen data for prospective clinical applications.

Who wants feedback? An investigation of the variables influencing residents' feedback-seeking behavior in relation to night shifts.

PubMed

Teunissen, Pim W; Stapel, Diederik A; van der Vleuten, Cees; Scherpbier, Albert; Boor, Klarke; Scheele, Fedde

2009-07-01

The literature on feedback in clinical medical education has predominantly treated trainees as passive recipients. Past research has focused on how clinical supervisors can use feedback to improve a trainee's performance. On the basis of research in social and organizational psychology, the authors reconceptualized residents as active seekers of feedback. They investigated what individual and situational variables influence residents' feedback-seeking behavior on night shifts. Early in 2008, the authors sent obstetrics-gynecology residents in the Netherlands--both those in their first two years of graduate training and those gaining experience between undergraduate and graduate training--a questionnaire that assessed four predictor variables (learning and performance goal orientation, and instrumental and supportive leadership), two mediator variables (perceived feedback benefits and costs), and two outcome variables (frequency of feedback inquiry and monitoring). They used structural equation modeling software to test a hypothesized model of relationships between variables. The response rate was 76.5%. Results showed that residents who perceive more feedback benefits report a higher frequency of feedback inquiry and monitoring. More perceived feedback costs result mainly in more feedback monitoring. Residents with a higher learning goal orientation perceive more feedback benefits and fewer costs. Residents with a higher performance goal orientation perceive more feedback costs. Supportive physicians lead residents to perceive more feedback benefits and fewer costs. This study showed that some residents actively seek feedback. Residents' feedback-seeking behavior partially depends on attending physicians' supervisory style. Residents' goal orientations influence their perceptions of the benefits and costs of feedback-seeking.

Clinical findings associated with cardiovascular autonomic dysfunction in adult sickle cell anaemia patients.

PubMed

Oguanobi, Nelson I; Onwubere, Basden J C; Anisiuba, Benedict C; Ike, Samuel O; Ejim, Emmanuel C; Ibegbulam, Obike G

2012-04-01

Involvement of the cardiovascular autonomic nervous system in various diseases is often associated with increased morbidity and mortality. The objective of this study was to examine the clinical features associated with cardiovascular autonomic neuropathy (CAN) in adult Nigerians with sickle cell anaemia. A cross-sectional study was carried out on 62 steady state sickle cell anaemia patients recruited from the adult out-patient clinic. Cardiovascular autonomic dysfunction was determined based on abnormal values in at least two of five non-invasive tests: Valsalva manoeuvre, heart rate variation during deep breathing, heart rate response to standing, blood pressure response to sustained handgrip, and blood pressure response to standing. All the subjects were initially evaluated in the clinic for symptoms of cardiovascular disease and peripheral vascular disease, and then clinically examined to assess their cardiovascular and neurological status at rest. Out of the 44 patients with cardiovascular autonomic neuropathy 23 were males, while 21 were females. The mean ages were 28.3 +/- 5.8 y for patients with CAN and 28.0 +/- 5.0 y for patients without CAN (P = 0.817). Sickle cell anaemia patients with CAN had significantly lower ankle systolic blood pressure, reduced ankle brachial blood pressure index, mean arterial blood pressure and haematocrit than patients without CAN. Of all the variables evaluated leg ulcers, postural dizziness, erectile dysfunction in men, and history of recurrent acute chest syndromes were found significantly more in patients with CAN than without. Clinical abnormalities tend to worsen with increasing degree of cardiovascular autonomic dysfunction. Significant cardiac morbidity is associated with abnormal cardiovascular autonomic function in sickle cell anaemia.

Immune mechanisms regulating pharmacokinetics and pharmacodynamics of PEGylated liposomal anticancer agents

NASA Astrophysics Data System (ADS)

Song, Gina

Nanotechnology has made significant advances in drug delivery system for the treatment of cancer. Among various nanoparticle (NP) platforms, liposomes have been most widely used as a NP drug carrier for cancer therapy. High variation in pharmacokinetics (PK) and pharmacodynamics (PD) of liposome-based therapeutics has been reported. However, the interaction of liposome-based therapeutics with the immune system, specifically the mononuclear phagocyte system (MPS), and underlying molecular mechanisms for variable responses to liposomal drugs remain poorly understood. The objective of this dissertation was to elucidate immune mechanisms for the variable responses to PEGylated liposomal doxorubicin (PLD; DoxilRTM), a clinically relevant NP, in animal models and in patients. In vitro, in vivo and clinical systems were investigated to evaluate the effects of chemokines (CCL2 and CCL5), heterogeneity of the tumor microenvironment, and genetic variations on PK and PD of PLD. Results showed that there was a significantly positive linear relationship between PLD exposure (AUC) and total amount of CCL2 and CCL5, most prevalent chemokines in plasma, in patients with recurrent ovarian cancer. Consistent with these findings, preclinical studies using mice bearing SKOV3 orthotopic ovarian cancer xenografts demonstrated that PLD induced the production and secretion of chemokines into plasma. In addition, in vitro studies using human monocytic THP-1 cells demonstrated that PLD altered monocyte migration towards CCL2 and CCL5. The PK and efficacy studies of PLD in murine models of breast cancer showed that heterogeneous tumor microenvironment was associated with significantly different tumor delivery and efficacy of PLD, but not small molecule doxorubicin between two breast tumor models. A candidate genetic locus that was associated with clearance of PLD in 23 inbred mouse strains contains a gene that encodes for engulfment adapter PTB domain containing 1 (Gulp1). By using integrated approaches, we were able to identify the immunological mechanisms at the molecular, tissue, and clinical levels that may contribute to inter-individual variability in PK and PD of PLD. This dissertation research has a potential to make an impact on development of future NP-based anticancer therapeutics as well as on clinical use of PLD (DoxilRTM) and other PEGylated liposomal anticancer agents.

Use of Wearable Sensors and Biometric Variables in an Artificial Pancreas System

PubMed Central

Turksoy, Kamuran; Monforti, Colleen; Park, Minsun; Griffith, Garett; Quinn, Laurie; Cinar, Ali

2017-01-01

An artificial pancreas (AP) computes the optimal insulin dose to be infused through an insulin pump in people with Type 1 Diabetes (T1D) based on information received from a continuous glucose monitoring (CGM) sensor. It has been recognized that exercise is a major challenge in the development of an AP system. The use of biometric physiological variables in an AP system may be beneficial for prevention of exercise-induced challenges and better glucose regulation. The goal of the present study is to find a correlation between biometric variables such as heart rate (HR), heat flux (HF), skin temperature (ST), near-body temperature (NBT), galvanic skin response (GSR), and energy expenditure (EE), 2D acceleration-mean of absolute difference (MAD) and changes in glucose concentrations during exercise via partial least squares (PLS) regression and variable importance in projection (VIP) in order to determine which variables would be most useful to include in a future artificial pancreas. PLS and VIP analyses were performed on data sets that included seven different types of exercises. Data were collected from 26 clinical experiments. Clinical results indicate ST to be the most consistently important (important for six out of seven tested exercises) variable over all different exercises tested. EE and HR are also found to be important variables over several types of exercise. We also found that the importance of GSR and NBT observed in our experiments might be related to stress and the effect of changes in environmental temperature on glucose concentrations. The use of the biometric measurements in an AP system may provide better control of glucose concentration. PMID:28272368

Patient predictors of response to cognitive behaviour therapy and schema therapy for depression.

PubMed

Carter, Janet D; McIntosh, Virginia Vw; Jordan, Jennifer; Porter, Richard J; Douglas, Katie; Frampton, Christopher M; Joyce, Peter R

2018-01-01

Few studies have examined differential predictors of response to psychotherapy for depression. Greater understanding about the factors associated with therapeutic response may better enable therapists to optimise response by targeting therapy for the individual. The aim of the current exploratory study was to examine patient characteristics associated with response to cognitive behaviour therapy and schema therapy for depression. Participants were 100 outpatients in a clinical trial randomised to either cognitive behaviour therapy or schema therapy. Potential predictors of response examined included demographic, clinical, functioning, cognitive, personality and neuropsychological variables. Individuals with chronic depression and increased levels of pre-treatment negative automatic thoughts had a poorer response to both cognitive behaviour therapy and schema therapy. A treatment type interaction was found for verbal learning and memory. Lower levels of verbal learning and memory impairment markedly impacted on response to schema therapy. This was not the case for cognitive behaviour therapy, which was more impacted if verbal learning and memory was in the moderate range. Study findings are consistent with the Capitalisation Model suggesting that therapy that focuses on the person's strengths is more likely to contribute to a better outcome. Limitations were that participants were outpatients in a randomised controlled trial and may not be representative of other depressed samples. Examination of a variety of potential predictors was exploratory and requires replication.

Nerve stimulator-guided sciatic-femoral nerve block in raptors undergoing surgical treatment of pododermatitis.

PubMed

d'Ovidio, Dario; Noviello, Emilio; Adami, Chiara

2015-07-01

To describe the nerve stimulator-guided sciatic-femoral nerve block in raptors undergoing surgical treatment of pododermatitis. Prospective clinical trial. Five captive raptors (Falco peregrinus) aged 6.7 ± 1.3 years. Anaesthesia was induced and maintained with isoflurane in oxygen. The sciatic-femoral nerve block was performed with 2% lidocaine (0.05 mL kg(-1) per nerve) as the sole intra-operative analgesic treatment. Intraoperative physiological variables were recorded every 10 minutes from endotracheal intubation until the end of anaesthesia. Assessment of intraoperative nociception was based on changes in physiological variables above baseline values, while evaluation of postoperative pain relied on species-specific behavioural indicators. The sciatic-femoral nerve block was feasible in raptors and the motor responses following electrical stimulation of both nerves were consistent with those reported in mammalian species. During surgery no rescue analgesia was required. The anaesthesia plane was stable and cardiorespiratory variables did not increase significantly in response to surgical stimulation. Iatrogenic complications, namely nerve damage and local anaesthetic toxicity, did not occur. Recovery was smooth and uneventful. The duration (mean ± SD) of the analgesic effect provided by the nerve block was 130 ± 20 minutes. The sciatic-femoral nerve block as described in dogs and rabbits can be performed in raptors as well. Further clinical trials with a control groups are required to better investigate the analgesic efficacy and the safety of this technique in raptors. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Multicollinearity in prognostic factor analyses using the EORTC QLQ-C30: identification and impact on model selection.

PubMed

Van Steen, Kristel; Curran, Desmond; Kramer, Jocelyn; Molenberghs, Geert; Van Vreckem, Ann; Bottomley, Andrew; Sylvester, Richard

2002-12-30

Clinical and quality of life (QL) variables from an EORTC clinical trial of first line chemotherapy in advanced breast cancer were used in a prognostic factor analysis of survival and response to chemotherapy. For response, different final multivariate models were obtained from forward and backward selection methods, suggesting a disconcerting instability. Quality of life was measured using the EORTC QLQ-C30 questionnaire completed by patients. Subscales on the questionnaire are known to be highly correlated, and therefore it was hypothesized that multicollinearity contributed to model instability. A correlation matrix indicated that global QL was highly correlated with 7 out of 11 variables. In a first attempt to explore multicollinearity, we used global QL as dependent variable in a regression model with other QL subscales as predictors. Afterwards, standard diagnostic tests for multicollinearity were performed. An exploratory principal components analysis and factor analysis of the QL subscales identified at most three important components and indicated that inclusion of global QL made minimal difference to the loadings on each component, suggesting that it is redundant in the model. In a second approach, we advocate a bootstrap technique to assess the stability of the models. Based on these analyses and since global QL exacerbates problems of multicollinearity, we therefore recommend that global QL be excluded from prognostic factor analyses using the QLQ-C30. The prognostic factor analysis was rerun without global QL in the model, and selected the same significant prognostic factors as before. Copyright 2002 John Wiley & Sons, Ltd.

[Alcohol consumption in men punished for intimate partner violence: individual and contextual factors].

PubMed

Catalá-Miñana, Alba; Lila, Marisol; Oliver, Amparo

2013-01-01

Alcohol consumption is often associated with violence against women. The aim of this paper is to analyze the relationship between alcohol and other relevant variables in the intervention with men convicted of intimate partner violence, both at the individual and contextual spheres. Clinical symptomatology, Drug abuse, Impulsivity, Self-esteem, Assumption of responsibility, Intimate support perception, Social rejection perception, Accumulation of stressful life events, Income perception and Social support in community are assessed in a sample of 291 participants in an intervention program for men condemned for intimate partner violence. Data were analyzed using bivariate correlations and ANOVAs. Statistically significant differences were obtained among Risk consumers and Not risk consumers in Clinical symptomatology, Drug abuse, Impulsivity, Self-esteem and Attribution of blame to personal context as individual variables and Intimate support perception, Social rejection and Accumulation of stressful life events as contextual variables. Results of previous work are confirmed and the importance of considering social factors in the participants' environment when considering decreasing alcohol consumption and intimate partner violence is demonstrated. New tools for enhancing interventions in rehabilitation programs with men convicted for violence against women is provided.

A Description of Weekend Physiotherapy Services in Three Tertiary Hospitals in the Greater Toronto Area

PubMed Central

Hill, Kylie

2010-01-01

ABSTRACT Purpose: The aims of this study were (1) to describe the cardiorespiratory physiotherapy weekend service (PWS) at three tertiary hospitals in the Greater Toronto Area (GTA) and (2) to compare measures of staff burden among the clinical service areas in one of the hospitals that had a programme-based management structure. Method: Two focus-group meetings were held with physiotherapists from hospitals within the GTA. Thereafter, variables characterizing the PWS were collected over 8 months, using a standardized data-collection form. Results: A total of 632 data-collection forms were received. Response rates exceeded 75% at each hospital. Workload variables, including the number of patient visits, new referrals per hour, and the proportion of staff completing unpaid overtime, differed between the hospitals (p<0.002). There was no difference in any variable when data were compared between Saturday, Sunday, and statutory holidays (p>0.13). Workload measures varied between clinical service areas at the hospital that provided PWS using a programme-based approach. Conclusions: These findings highlight the important shortcomings of a programme-based management approach to providing PWS and may constitute a catalyst for change. PMID:21359048

Systemic Corticosteroid Responses in Children with Severe Asthma: Phenotypic and Endotypic Features.

PubMed

Fitzpatrick, Anne M; Stephenson, Susan T; Brown, Milton R; Nguyen, Khristopher; Douglas, Shaneka; Brown, Lou Ann S

Severe asthma in children is a heterogeneous disorder associated with variable responses to corticosteroid treatment. Criterion standards for corticosteroid responsiveness assessment in children are lacking. This study sought to characterize systemic corticosteroid responses in children with severe asthma after treatment with intramuscular triamcinolone and to identify phenotypic and molecular predictors of an intramuscular triamcinolone response. Asthma-related quality of life, exhaled nitric oxide, blood eosinophils, lung function, and inflammatory cytokine and chemokine mRNA gene expression in peripheral blood mononuclear cells were assessed in 56 children with severe asthma at baseline and 14 days after intramuscular triamcinolone injection. The Asthma Control Questionnaire was used to classify children with severe asthma into corticosteroid response groups. Three groups of children with severe asthma were identified: controlled severe asthma, children who achieved control after triamcinolone, and children who did not achieve control. At baseline, these groups were phenotypically similar. After triamcinolone, discordance between symptoms, lung function, exhaled nitric oxide, and blood eosinophils was noted. Clinical phenotypic predictors were of limited utility in predicting the triamcinolone response, whereas systemic mRNA expression of inflammatory cytokines and chemokines related to IL-2, IL-10, and TNF signaling pathways, namely, AIMP1, CCR2, IL10RB, and IL5, strongly differentiated children who failed to achieve control with triamcinolone administration. Systemic corticosteroid responsiveness in children with severe asthma is heterogeneous. Alternative prediction models that include molecular endotypic as well as clinical phenotypic features are needed to identify which children derive the most clinical benefit from systemic corticosteroid step-up therapy given the potential side effects. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

PubMed Central

Ye, Zheng; Rae, Charlotte L.; Nombela, Cristina; Ham, Timothy; Rittman, Timothy; Jones, Peter Simon; Rodríguez, Patricia Vázquez; Coyle‐Gilchrist, Ian; Regenthal, Ralf; Altena, Ellemarije; Housden, Charlotte R.; Maxwell, Helen; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2016-01-01

Abstract Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016. © 2016 Wiley Periodicals, Inc. PMID:26757216

Phenobarbital for Neonatal Seizures: Response Rate and Predictors of Refractoriness.

PubMed

Spagnoli, Carlotta; Seri, Stefano; Pavlidis, Elena; Mazzotta, Silvia; Pelosi, Annalisa; Pisani, Francesco

2016-10-01

Background Phenobarbital is the first-line choice for neonatal seizures treatment, despite a response rate of approximately 45%. Failure to respond to acute anticonvulsants is associated with poor neurodevelopmental outcome, but knowledge on predictors of refractoriness is limited. Objective To quantify response rate to phenobarbital and to establish variables predictive of its lack of efficacy. Methods We retrospectively evaluated newborns with electrographically confirmed neonatal seizures admitted between January 1999 and December 2012 to the neonatal intensive care unit of Parma University Hospital (Italy), excluding neonates with status epilepticus. Response was categorized as complete (cessation of clinical and electrographic seizures after phenobarbital administration), partial (reduction but not cessation of electrographic seizures with the first bolus, response to the second bolus), or absent (no response after the second bolus). Multivariate analysis was used to identify independent predictors of refractoriness. Results Out of 91 newborns receiving phenobarbital, 57 (62.6%) responded completely, 15 (16.5%) partially, and 19 (20.9%) did not respond. Seizure type (p = 0.02), background electroencephalogram (EEG; p ≤ 0.005), and neurologic examination (p  ≤  0.005) correlated with response to phenobarbital. However, EEG (p  ≤  0.02) and seizure type (p  ≤  0.001) were the only independent predictors. Conclusion Our results suggest a prominent role of neurophysiological variables (background EEG and electrographic-only seizure type) in predicting the absence of response to phenobarbital in high-risk newborns. Georg Thieme Verlag KG Stuttgart · New York.

Sterilization of granulomas is common in both active and latent tuberculosis despite extensive within-host variability in bacterial killing

PubMed Central

Lin, Philana Ling; Ford, Christopher B.; Coleman, M. Teresa; Myers, Amy J.; Gawande, Richa; Ioerger, Thomas; Sacchettini, James; Fortune, Sarah M.; Flynn, JoAnne L.

2013-01-01

Over 30% of the world’s population is infected with Mycobacterium tuberculosis (Mtb), yet only ~5–10% will develop clinical disease1. Despite considerable effort, we understand little about what distinguishes individuals who progress to active tuberculosis (TB) from those who remain latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb2. Active disease in macaques is defined by clinical, microbiologic and immunologic signs and occurs in ~45% of animals, while the remaining are clinically asymptomatic2,3. Here, we use barcoded Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lesions are likely founded by a single bacterium and reach similar maximum burdens. Despite common origins, the fate of individual lesions varies substantially within the same host. Strikingly, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be important in developing effective interventions to prevent active TB. PMID:24336248

Quality controls in cellular immunotherapies: rapid assessment of clinical grade dendritic cells by gene expression profiling.

PubMed

Castiello, Luciano; Sabatino, Marianna; Zhao, Yingdong; Tumaini, Barbara; Ren, Jiaqiang; Ping, Jin; Wang, Ena; Wood, Lauren V; Marincola, Francesco M; Puri, Raj K; Stroncek, David F

2013-02-01

Cell-based immunotherapies are among the most promising approaches for developing effective and targeted immune response. However, their clinical usefulness and the evaluation of their efficacy rely heavily on complex quality control assessment. Therefore, rapid systematic methods are urgently needed for the in-depth characterization of relevant factors affecting newly developed cell product consistency and the identification of reliable markers for quality control. Using dendritic cells (DCs) as a model, we present a strategy to comprehensively characterize manufactured cellular products in order to define factors affecting their variability, quality and function. After generating clinical grade human monocyte-derived mature DCs (mDCs), we tested by gene expression profiling the degrees of product consistency related to the manufacturing process and variability due to intra- and interdonor factors, and how each factor affects single gene variation. Then, by calculating for each gene an index of variation we selected candidate markers for identity testing, and defined a set of genes that may be useful comparability and potency markers. Subsequently, we confirmed the observed gene index of variation in a larger clinical data set. In conclusion, using high-throughput technology we developed a method for the characterization of cellular therapies and the discovery of novel candidate quality assurance markers.

Reporting of research quality characteristics of studies published in 6 major clinical dental specialty journals.

PubMed

Pandis, Nikolaos; Polychronopoulou, Argy; Madianos, Phoebus; Makou, Margarita; Eliades, Theodore

2011-06-01

The objective of this article was to record reporting characteristics related to study quality of research published in major specialty dental journals with the highest impact factor (Journal of Endodontics, Journal of Oral and Maxillofacial Surgery, American Journal of Orthodontics and Dentofacial Orthopedics; Pediatric Dentistry, Journal of Clinical Periodontology, and International Journal of Prosthetic Dentistry). The included articles were classified into the following 3 broad subject categories: (1) cross-sectional (snap-shot), (2) observational, and (3) interventional. Multinomial logistic regression was conducted for effect estimation using the journal as the response and randomization, sample calculation, confounding discussed, multivariate analysis, effect measurement, and confidence intervals as the explanatory variables. The results showed that cross-sectional studies were the dominant design (55%), whereas observational investigations accounted for 13%, and interventions/clinical trials for 32%. Reporting on quality characteristics was low for all variables: random allocation (15%), sample size calculation (7%), confounding issues/possible confounders (38%), effect measurements (16%), and multivariate analysis (21%). Eighty-four percent of the published articles reported a statistically significant main finding and only 13% presented confidence intervals. The Journal of Clinical Periodontology showed the highest probability of including quality characteristics in reporting results among all dental journals. Copyright © 2011 Elsevier Inc. All rights reserved.

An Assessment of Burnout in Graduate Assistant Certified Athletic Trainers

PubMed Central

Mazerolle, Stephanie M.; Monsma, Eva; Dixon, Colin; Mensch, James

2012-01-01

Context: Graduate assistant athletic trainers (GAATs) must balance the demands of clinical care and the academic load of graduate-level students. Objective: To examine burnout among GAATs with clinical assistantships at National Collegiate Athletic Association (NCAA) Division I institutions and to identify the personal and situational variables that are related to burnout. Design: Cross-sectional study. Setting: Division I universities offering graduate assistantship programs. Patients or Other Participants: Two hundred one GAATs enrolled at NCAA Division I universities with graduate assistantship positions. Main Outcome Measures(s): The Athletic Training Burnout Inventory, which assesses stress and burnout among ATs through 4 constructs: emotional exhaustion and depersonalization, administrative responsibility, time commitment, and organizational support. The 6-point Likert scale is anchored by 1 (never true) and 6 (always true). Results: The GAATs who traveled with athletic teams (4.051 ± 0.895) and those who provided classroom instruction (4.333 ± 1.16) reported higher levels of stress due to time commitment than those who did not travel (3.713 ± 1.22) or teach (3.923 ± 0.929). We also found a difference in administrative responsibility across clinical settings (F6,194  =  3.507, P  =  .003). The results showed that GAATs in NCAA Division I clinical settings (44.55 ± 13.17 hours) worked more hours than those in NCAA Division III clinical settings (33.69 ± 12.07 hours) and those in high school settings (30.51 ± 9.934 hours). Conclusions: Graduate assistant ATs are at risk for burnout because of the time necessary to complete their clinical and academic responsibilities and their additional administrative responsibilities. Graduate assistants who work in the Division I clinical setting are at greater risk for burnout than those in the secondary school setting because of the large number of hours required. PMID:22892414

Medical school clinical placements - the optimal method for assessing the clinical educational environment from a graduate entry perspective.

PubMed

Hyde, Sarah; Hannigan, Ailish; Dornan, Tim; McGrath, Deirdre

2018-01-05

Educational environment is a strong determinant of student satisfaction and achievement. The learning environments of medical students on clinical placements are busy workplaces, composed of many variables. There is no universally accepted method of evaluating the clinical learning environment, nor is there consensus on what concepts or aspects should be measured. The aims of this study were to compare the Dundee ready educational environment measure (DREEM - the current de facto standard) and the more recently developed Manchester clinical placement index (MCPI) for the assessment of the clinical learning environment in a graduate entry medical student cohort by correlating the scores of each and analysing free text comments. This study also explored student perceptionof how the clinical educational environment is assessed. An online, anonymous survey comprising of both the DREEM and MCPI instruments was delivered to students on clinical placement in a graduate entry medical school. Additional questions explored students' perceptions of instruments for giving feedback. Numeric variables (DREEM score, MCPI score, ratings) were tested for normality and summarised. Pearson's correlation coefficient was used to measure the strength of the association between total DREEM score and total MCPI scores. Thematic analysis was used to analyse the free text comments. The overall response rate to the questionnaire was 67% (n = 180), with a completed response rate for the MCPI of 60% (n = 161) and for the DREEM of 58% (n = 154). There was a strong, positive correlation between total DREEM and MCPI scores (r = 0.71, p < 0.001). On a scale of 0 to 7, the mean rating for how worthwhile students found completing the DREEM was 3.27 (SD 1.41) and for the MCPI was 3.49 (SD 1.57). 'Finding balance' and 'learning at work' were among the themes to emerge from analysis of free text comments. The present study confirms that DREEM and MCPI total scores are strongly correlated. Graduate entry students tended to favour this method of evaluation over the DREEM with the MCPI prompting rich description of the clinical learning environment. Further study is warranted to determine if this finding is transferable to all clinical medical student cohorts.

Corneal Deformation Response and Ocular Geometry: A Noninvasive Diagnostic Strategy in Marfan Syndrome.

PubMed

Beene, Lauren C; Traboulsi, Elias I; Seven, Ibrahim; Ford, Matthew R; Sinha Roy, Abhijit; Butler, Robert S; Dupps, William J

2016-01-01

To evaluate corneal air-puff deformation responses and ocular geometry as predictors of Marfan syndrome. Prospective observational clinical study. Sixteen investigator-derived, 4 standard Ocular Response Analyzer (ORA), and geometric variables from corneal tomography and optical biometry using Oculus Pentacam and IOL Master were assessed for discriminative value in Marfan syndrome, measuring right eyes of 24 control and 13 Marfan syndrome subjects. Area under the receiver operating characteristic (AUROC) curve was assessed in univariate and multivariate analyses. Six investigator-derived ORA variables successfully discriminated Marfan syndrome. The best lone disease predictor was Concavity Min (Marfan syndrome 47.5 ± 20, control 69 ± 14, P = .003; AUROC = 0.80). Corneal hysteresis (CH) and corneal resistance factor (CRF) were decreased (Marfan syndrome CH 9.45 ± 1.62, control CH 11.24 ± 1.21, P = .01; Marfan syndrome CRF 9.77 ± 1.65, control CRF 11.03 ± 1.72, P = .01) and corneas were flatter in Marfan syndrome (Marfan syndrome Kmean 41.25 ± 2.09 diopter, control Kmean 42.70 ± 1.81 diopter, P = .046). No significant differences were observed in central corneal thickness, axial eye length, or intraocular pressure. A multivariate regression model incorporating corneal curvature and hysteresis loop area (HLA) provided the best predictive value for Marfan syndrome (AUROC = 0.85). This study describes novel biodynamic features of corneal deformation responses in Marfan syndrome, including increased deformation, decreased bending resistance, and decreased energy dissipation capacity. A predictive model incorporating HLA and corneal curvature shows greatest potential for noninvasive clinical diagnosis of Marfan syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Corneal Deformation Response and Ocular Geometry: A Non-invasive Diagnostic Strategy in Marfan Syndrome

PubMed Central

Beene, Lauren C.; Traboulsi, Elias I.; Seven, Ibrahim; Ford, Matthew R.; Roy, Abhijit Sinha; Butler, Robert S.; Dupps, William J.

2015-01-01

Purpose To evaluate corneal air-puff deformation responses and ocular geometry as predictors of Marfan syndrome. Design Prospective observational clinical study Methods Sixteen investigator-derived, 4 standard Ocular Response Analyzer (ORA), and geometric variables from corneal tomography and optical biometry using Oculus Pentacam and IOL Master were assessed for discriminative value in Marfan syndrome, measuring right eyes of 24 control and 13 Marfan syndrome subjects. Area under the receiver operating characteristic (AUROC) curve was assessed in univariate and multivariate analyses Results Six investigator-derived ORA variables successfully discriminated Marfan syndrome. The best lone disease predictor was Concavity Min (Marfan syndrome 47.5 ± 20, control 69 ± 14, p = 0.003; AUROC = 0.80). Corneal hysteresis and corneal resistance factor were decreased (Marfan syndrome CH 9.45 ± 1.62, control CH 11.24 ± 1.21, p = 0.01; Marfan syndrome CRF 9.77 ± 1.65, control CRF 11.03 ± 1.72, p = 0.01) and corneas were flatter in Marfan syndrome (Marfan syndrome Kmean 41.25 ± 2.09 D, control Kmean 42.70 ± 1.81 D, p = 0.046). No significant differences were observed in central corneal thickness, axial eye length, or intraocular pressure. A multivariate regression model incorporating corneal curvature and hysteresis loop area (HLA) provided the best predictive value for Marfan syndrome (AUROC = 0.85). Conclusions This study describes novel biodynamic features of corneal deformation responses in Marfan syndrome, including increased deformation, decreased bending resistance, and decreased energy dissipation capacity. A predictive model incorporating HLA and corneal curvature shows greatest potential for non-invasive clinical diagnosis of Marfan syndrome. PMID:26432567

Comparison of the prognostic value of pretreatment measurements of systemic inflammatory response in patients undergoing curative resection of clear cell renal cell carcinoma.

PubMed

Lucca, Ilaria; de Martino, Michela; Hofbauer, Sebastian L; Zamani, Nura; Shariat, Shahrokh F; Klatte, Tobias

2015-12-01

Pretreatment measurements of systemic inflammatory response, including the Glasgow prognostic score (GPS), the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR) and the prognostic nutritional index (PNI) have been recognized as prognostic factors in clear cell renal cell carcinoma (CCRCC), but there is at present no study that compared these markers. We evaluated the pretreatment GPS, NLR, MLR, PLR and PNI in 430 patients, who underwent surgery for clinically localized CCRCC (pT1-3N0M0). Associations with disease-free survival were assessed with Cox models. Discrimination was measured with the C-index, and a decision curve analysis was used to evaluate the clinical net benefit. On multivariable analyses, all measures of systemic inflammatory response were significant prognostic factors. The increase in discrimination compared with the stage, size, grade and necrosis (SSIGN) score alone was 5.8 % for the GPS, 1.1-1.4 % for the NLR, 2.9-3.4 % for the MLR, 2.0-3.3 % for the PLR and 1.4-3.0 % for the PNI. On the simultaneous multivariable analysis of all candidate measures, the final multivariable model contained the SSIGN score (HR 1.40, P < 0.001), the GPS (HR 2.32, P < 0.001) and the MLR (HR 5.78, P = 0.003) as significant variables. Adding both the GPS and the MLR increased the discrimination of the SSIGN score by 6.2 % and improved the clinical net benefit. In patients with clinically localized CCRCC, the GPS and the MLR appear to be the most relevant prognostic measures of systemic inflammatory response. They may be used as an adjunct for patient counseling, tailoring management and clinical trial design.

Strategies of experiment standardization and response optimization in a rat model of hemorrhagic shock and chronic hypertension.

PubMed

Reynolds, Penny S; Tamariz, Francisco J; Barbee, Robert Wayne

2010-04-01

Exploratory pilot studies are crucial to best practice in research but are frequently conducted without a systematic method for maximizing the amount and quality of information obtained. We describe the use of response surface regression models and simultaneous optimization methods to develop a rat model of hemorrhagic shock in the context of chronic hypertension, a clinically relevant comorbidity. Response surface regression model was applied to determine optimal levels of two inputs--dietary NaCl concentration (0.49%, 4%, and 8%) and time on the diet (4, 6, 8 weeks)--to achieve clinically realistic and stable target measures of systolic blood pressure while simultaneously maximizing critical oxygen delivery (a measure of vulnerability to hemorrhagic shock) and body mass M. Simultaneous optimization of the three response variables was performed though a dimensionality reduction strategy involving calculation of a single aggregate measure, the "desirability" function. Optimal conditions for inducing systolic blood pressure of 208 mmHg, critical oxygen delivery of 4.03 mL/min, and M of 290 g were determined to be 4% [NaCl] for 5 weeks. Rats on the 8% diet did not survive past 7 weeks. Response surface regression model and simultaneous optimization method techniques are commonly used in process engineering but have found little application to date in animal pilot studies. These methods will ensure both the scientific and ethical integrity of experimental trials involving animals and provide powerful tools for the development of novel models of clinically interacting comorbidities with shock.

A Novel Methodology to Estimate the Treatment Effect in Presence of Highly Variable Placebo Response

PubMed Central

Gomeni, Roberto; Goyal, Navin; Bressolle, Françoise; Fava, Maurizio

2015-01-01

One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the ‘true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach. The new method for estimating TE was based on a nonlinear longitudinal modeling of clinical scores (NLMMRM). NLMMRM estimates TE by associating a weighting factor to the data collected in each center. The weight was defined by the posterior probability of detecting a clinically relevant difference between active treatment and placebo at that center. Data from five RCTs in depression were used to compare the performance of MMRM with NLMMRM. The results of the analyses showed an average improvement of ~15% in the TE estimated with NLMMRM when the center effect was included in the analyses. Opposite results were observed with MMRM: TE estimate was reduced by ~4% when the center effect was considered as covariate in the analysis. The novel NLMMRM approach provides a tool for controlling the confounding effect of high placebo response, to increase signal detection and to provide a more reliable estimate of the ‘true' TE by controlling false negative results associated with excessively high placebo response. PMID:25895454

The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch Syndrome: from bench to bedside

PubMed Central

Koi, Minoru; Chang, Dong K.; Carethers, John M.

2010-01-01

Lynch syndrome is an inherited disease caused by a germline mutation in one of four DNA mismatch repair (MMR) genes. The clinical manifestations can be somewhat variable depending upon which gene is involved, and where the mutation occurs. Moreover, the approach to the diagnosis of Lynch syndrome is becoming more complex as more is learned about the disease, and one needs to understand how the DNA MMR proteins function, and what makes them malfunction, to have an optimal appreciation of how to interpret diagnostic studies such as microsatellite instability and immunohistochemistry of the DNA MMR proteins. Finally, an understanding of the role of the DNA MMR system in regulation of the cell cycle and the response to DNA damage helps illuminate the differences in natural history and response to chemotherapeutic agents seen in Lynch syndrome. PMID:17636426

Reduction in clinical response to empiric antimicrobial therapy of febrile granulocytopenic patients receiving TMP/SMX infection prophylaxis

PubMed Central

Bow, Eric J; Pater, Joseph L; Louie, Thomas J; Feld, Ronald; Mandell, Lionel; Robson, Hugh G; Chow, Anthony; Belch, Andrew; Miedzinski, Lilly; Paul, Nancy; Elliott, Catherine R; Willan, Andrew R

1992-01-01

In the course of a multicentre clinical trial evaluating two antibacterial regimens for the empiric treatment of suspected infection in febrile neutropenic cancer patients, a suboptimal response was noted among recipients of antibacterial prophylaxis with trimethoprim/sulphamethoxazole (TMP/SMX). Multivariate analysis identified TMP/SMX prophylaxis as a predictor of poor outcome independent of other variables such as classification of infection, marrow recovery, neutrophil count at first fever, indwelling central venous catheter use, and underlying disease. This effect appeared to be restricted to recipients of tobramycin plus ticarcillin (TT). TMP/SMX suppresses potentially pathogenic aerobic Gram-negative bacilli and allows colonization and subsequent infection by Gram-positive microorganisms against which TT-like regimens have limited activity. Recognition of this phenomenon may permit a more appropriate selection of antibacterial agents for the therapy of suspected infection in the neutropenic patient. PMID:22416197

A study on the clinical characteristics of treating nevus of Ota by Q-switched Nd:YAG laser.

PubMed

Yan, Liu; Di, Li; Weihua, Wang; Feng, Liu; Ruilian, Li; Jun, Zhou; Hui, Su; Zhaoxia, Ying; Weihui, Zeng

2018-01-01

The purpose of this study was to retrospectively analyze the clinical characteristics of treating nevus of Ota by Q-switched Nd:YAG laser in Laser Cosmetology Center of Department of Dermatology, the Second Hospital, Xi'an Jiaotong University. The data of 1168 patients of nevus of Ota were analyzed retrospectively, which included the correlation among lesion color, treatment sessions, sex, age, lesion types, and effect. The Q-switched (QS) Nd:YAG laser system had a higher number of treatment sessions which were positively associated with a better response to treatment. Other variables, including gender, age, the categorization of the lesion according to Tanino's classification, and the color of the lesion, were not associated with the response to treatment. The treatment of nevus of Ota with QS Nd:YAG laser is safe and effective, with rare complications.

Dissociation predicts treatment response in eye-movement desensitization and reprocessing for posttraumatic stress disorder.

PubMed

Bae, Hwallip; Kim, Daeho; Park, Yong Chon

2016-01-01

Using clinical data from a specialized trauma clinic, this study investigated pretreatment clinical factors predicting response to eye-movement desensitization and reprocessing (EMDR) among adult patients diagnosed with posttraumatic stress disorder (PTSD). Participants were evaluated using the Clinician-Administered PTSD Scale (CAPS), the Symptom Checklist-90-Revised, the Beck Depression Inventory, and the Dissociative Experiences Scale before treatment and were reassessed using the CAPS after treatment and at 6-month follow-up. A total of 69 patients underwent an average of 4 sessions of EMDR, and 60 (87%) completed the posttreatment evaluation, including 8 participants who terminated treatment prematurely. Intent-to-treat analysis revealed that 39 (65%) of the 60 patients were classified as responders and 21 (35%) as nonresponders when response was defined as more than a 30% decrease in total CAPS score. The nonresponders had higher levels of dissociation (depersonalization and derealization) and numbing symptoms, but other PTSD symptoms, such as avoidance, hyperarousal, and intrusion, were not significantly different. The number of psychiatric comorbidities was also associated with treatment nonresponse. The final logistic regression model yielded 2 significant variables: dissociation (p < .001) and more than 2 comorbidities compared to none (p < .05). These results indicate that complex symptom patterns in PTSD may predict treatment response and support the inclusion of the dissociative subtype of PTSD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

Machine learning for predicting the response of breast cancer to neoadjuvant chemotherapy

PubMed Central

Mani, Subramani; Chen, Yukun; Li, Xia; Arlinghaus, Lori; Chakravarthy, A Bapsi; Abramson, Vandana; Bhave, Sandeep R; Levy, Mia A; Xu, Hua; Yankeelov, Thomas E

2013-01-01

Objective To employ machine learning methods to predict the eventual therapeutic response of breast cancer patients after a single cycle of neoadjuvant chemotherapy (NAC). Materials and methods Quantitative dynamic contrast-enhanced MRI and diffusion-weighted MRI data were acquired on 28 patients before and after one cycle of NAC. A total of 118 semiquantitative and quantitative parameters were derived from these data and combined with 11 clinical variables. We used Bayesian logistic regression in combination with feature selection using a machine learning framework for predictive model building. Results The best predictive models using feature selection obtained an area under the curve of 0.86 and an accuracy of 0.86, with a sensitivity of 0.88 and a specificity of 0.82. Discussion With the numerous options for NAC available, development of a method to predict response early in the course of therapy is needed. Unfortunately, by the time most patients are found not to be responding, their disease may no longer be surgically resectable, and this situation could be avoided by the development of techniques to assess response earlier in the treatment regimen. The method outlined here is one possible solution to this important clinical problem. Conclusions Predictive modeling approaches based on machine learning using readily available clinical and quantitative MRI data show promise in distinguishing breast cancer responders from non-responders after the first cycle of NAC. PMID:23616206

Photodynamic dosimetry in the treatment of periodontitis

NASA Astrophysics Data System (ADS)

Andersen, Roger C.; Loebel, Nicolas G.; Andersen, Dane M.

2009-06-01

Photodynamic therapy has been demonstrated to effectively kill human periopathogens in vitro. However, the translation of in vitro work to in vivo clinical efficacy has been difficult due to the number of variables present in any given patient. Parameters such as photosensitizer concentration, duration of light therapy and amount of light delivered to the target tissue all play a role in the dose response of PDT in vivo. In this 121 patient study we kept all parameters the same except for light dose which was delivered at either 150 mW or 220 mW. This clearly demonstrated the clinical benefits of a higher light dose in the treatment of periodontitis.

Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study

PubMed Central

Erdman, Laura K.; D’Acremont, Valérie; Hayford, Kyla; Kilowoko, Mary; Kyungu, Esther; Hongoa, Philipina; Alamo, Leonor; Streiner, David L.; Genton, Blaise; Kain, Kevin C.

2015-01-01

Background Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO) has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance. Methods We studied children with WHO-defined clinical pneumonia (n = 155) within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30), other infiltrates (n = 31), or normal chest x-ray (n = 94). Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis. Results Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5–98.8), 80.8% specificity (72.6–87.1), positive likelihood ratio 4.9 (3.4–7.1), negative likelihood ratio 0.083 (0.022–0.32), and misclassification rate 0.20 (standard error 0.038). Conclusions In Tanzanian children with WHO-defined clinical pneumonia, combinations of host biomarkers distinguished between end-point pneumonia, other infiltrates, and normal chest x-ray, whereas clinical variables did not. These findings generate pathophysiological hypotheses and may have potential research and clinical utility. PMID:26366571

Innovative biomarkers in psychiatric disorders: a major clinical challenge in psychiatry.

PubMed

Lozupone, Madia; Seripa, Davide; Stella, Eleonora; La Montagna, Maddalena; Solfrizzi, Vincenzo; Quaranta, Nicola; Veneziani, Federica; Cester, Alberto; Sardone, Rodolfo; Bonfiglio, Caterina; Giannelli, Gianluigi; Bisceglia, Paola; Bringiotti, Roberto; Daniele, Antonio; Greco, Antonio; Bellomo, Antonello; Logroscino, Giancarlo; Panza, Francesco

2017-09-01

Currently, the diagnosis of psychiatric illnesses is based upon DSM-5 criteria. Although endophenotype-specificity for a particular disorder is discussed, the identification of objective biomarkers is ongoing for aiding diagnosis, prognosis, or clinical response to treatment. We need to improve the understanding of the biological abnormalities in psychiatric illnesses across conventional diagnostic boundaries. The present review investigates the innovative post-genomic knowledge used for psychiatric illness diagnostics and treatment response, with a particular focus on proteomics. Areas covered: This review underlines the contribution that psychiatric innovative biomarkers have reached in relation to diagnosis and theragnosis of psychiatric illnesses. Furthermore, it encompasses a reliable representation of their involvement in disease through proteomics, metabolomics/pharmacometabolomics and lipidomics techniques, including the possible role that gut microbiota and CYP2D6 polimorphisms may play in psychiatric illnesses. Expert opinion: Etiologic heterogeneity, variable expressivity, and epigenetics may impact clinical manifestations, making it difficult for a single measurement to be pathognomonic for multifaceted psychiatric disorders. Academic, industry, or government's partnerships may successfully identify and validate new biomarkers so that unfailing clinical tests can be developed. Proteomics, metabolomics, and lipidomics techniques are considered to be helpful tools beyond neuroimaging and neuropsychology for the phenotypic characterization of brain diseases.

Pharmacogenetics of neurological and psychiatric diseases at older age: has the time come?

PubMed

Lozupone, Madia; Panza, Francesco; Stella, Eleonora; La Montagna, Maddalena; Bisceglia, Paola; Miscio, Giuseppe; Galizia, Ilaria; Daniele, Antonio; di Mauro, Lazzaro; Bellomo, Antonello; Logroscino, Giancarlo; Greco, Antonio; Seripa, Davide

2017-03-01

In recent years, a number of pharmacological approaches for treating neuropsychiatric conditions at older age have proven to be inadequate. The resulting increased prevalence of therapeutic failures (TF) and a worsening of clinical symptoms often linked to adverse reactions (ADRs), are perhaps among the major causes of the increasing rate of hospitalizations and institutionalizations observed in these patients. Areas covered: This review underlines the importance of pharmacogenetic data to fingerprint the pharmacological treatment of neuropsychiatric late-life conditions throughout the analysis of metabolizing enzymes and transporters of psychotropic drugs, mainly those of the cytochrome P450 (CYP) family. Pharmacodynamic response measures as treatment effects mediated through targets (i.e., receptors in the brain) may also contribute to this image. Expert opinion: CYP genetics is the basis of a continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice with advancing age. Furthermore, other specific polymorphic genes influence drug response through differential effects of their functional genetic variants. The known genotypes associated with an altered metabolizer status and drug transporters may help clinical decision-making to avoid concomitant treatments, reduce therapeutic attempts and increase drug safety in neuropsychiatric conditions in older age, after controlling for other clinical variables.

Assessing pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review.

PubMed

Ryan, J E; Warrier, S K; Lynch, A C; Heriot, A G

2015-10-01

Pathological complete response to neoadjuvant chemoradiotherapy is found in 20% of patients with rectal cancer undergoing long-course chemoradiotherapy. Some authors have suggested that these patients do not need to undergo surgery and can be managed with careful follow-up, with surgery only used in the event of clinical failure. Widespread adoption of this regimen is limited by the accuracy of methods to confirm a pathological complete response (pCR). A systematic search of PubMed, Medline and Cochrane databases was conducted to identify clinical, histological and radiological features in those patients with rectal cancer who achieved a pCR following chemoradiotherapy. Searches were conducted with the following keywords and MeSH search terms: 'rectal neoplasm', 'response', 'neoadjuvant', 'preoperative chemoradiation' and 'tumour response'. After review of title and abstracts, 89 articles addressing the assessment of pCR were identified. Histology and clinical assessment are the most effective methods of assessment of pCR, with histology considered the gold standard. Clinical assessment is limited to low rectal tumours and is open to significant inter-rater variability, while histological examination requires a surgical specimen. Diffusion-weighted MRI and (18) F-fluorodeoxyglucose positron emission tomography/CT demonstrate the greatest potential for the assessment of pCR, but both modalities have limited accuracy. Determination of a pCR is crucial if a nonoperative approach is to be undertaken proactively. Various methods are available, but currently they lack sufficient sensitivity and specificity to define management. This is likely to be an area of further research in the future. Colorectal Disease © 2015 The Association of Coloproctology of Great Britain and Ireland.

Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn's Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN/ADHERE Trials.

PubMed

Panaccione, Remo; Sandborn, William J; D'Haens, Geert; Wolf, Douglas C; Berg, Sofie; Maa, Jen-Fue; Petersson, Joel; Robinson, Anne M

2018-04-25

In the 4-week GAIN clinical trial, adalimumab was efficacious in inducing remission in patients with moderate to severe Crohn's disease (CD) who had prior loss of response/intolerance to infliximab. The efficacy and safety of adalimumab in these patients are reported here up to 96 weeks or for 3 years, respectively, in ADHERE open-label extension study. Patients who completed GAIN could enrol in ADHERE and receive open-label adalimumab 40 mg every other week. Efficacy variables included clinical response (Crohn's Disease Activity Index [CDAI] decrease from baseline ≥70/≥100 points [CR-70/CR-100]) and remission (CDAI<150), steroid discontinuation and fistula remission (absence of drainage). Data were reported using hybrid non-responder imputation (hNRI), last observation carried forward and as-observed analysis. Subgroup analyses were performed by randomised group in GAIN and by Week 4 efficacy in GAIN. Safety was also assessed. A total of 310 patients from GAIN enrolled in ADHERE. CR-70, CR-100 and remission rates at Week 96 were 39.0%, 35.5% and 26.5% (hNRI), respectively. Of the patients with CR-70 response or remission at Week 4 of GAIN, 45.5% and 44.4% (hNRI), respectively, maintained effect at Week 96. Steroid discontinuation and steroid-free remission rates increased from Week 12 to 96 in patients using corticosteroids at GAIN baseline. Long-term adalimumab maintenance therapy led to sustained clinical remission and response, and steroid discontinuation in a considerable proportion of patients with CD previously treated with infliximab. No new safety signals were observed in this patient population.

Spinal manipulation force and duration affect vertebral movement and neuromuscular responses.

PubMed

Colloca, Christopher J; Keller, Tony S; Harrison, Deed E; Moore, Robert J; Gunzburg, Robert; Harrison, Donald D

2006-03-01

Previous study in human subjects has documented biomechanical and neurophysiological responses to impulsive spinal manipulative thrusts, but very little is known about the neuromechanical effects of varying thrust force-time profiles. Ten adolescent Merino sheep were anesthetized and posteroanterior mechanical thrusts were applied to the L3 spinous process using a computer-controlled, mechanical testing apparatus. Three variable pulse durations (10, 100, 200 ms, force = 80 N) and three variable force amplitudes (20, 40, 60 N, pulse duration = 100 ms) were examined for their effect on lumbar motion response (L3 displacement, L1, L2 acceleration) and normalized multifidus electromyographic response (L3, L4) using a repeated measures analysis of variance. Increasing L3 posteroanterior force amplitude resulted in a fourfold linear increase in L3 posteroanterior vertebral displacement (p < 0.001) and adjacent segment (L1, L2) posteroanterior acceleration response (p < 0.001). L3 displacement was linearly correlated (p < 0.001) to the acceleration response over the 20-80 N force range (100 ms). At constant force, 10 ms thrusts resulted in nearly fivefold lower L3 displacements and significantly increased segmental (L2) acceleration responses compared to the 100 ms (19%, p = 0.005) and 200 ms (16%, p = 0.023) thrusts. Normalized electromyographic responses increased linearly with increasing force amplitude at higher amplitudes and were appreciably affected by mechanical excitation pulse duration. Changes in the biomechanical and neuromuscular response of the ovine lumbar spine were observed in response to changes in the force-time characteristics of the spinal manipulative thrusts and may be an underlying mechanism in related clinical outcomes.

Clinical evaluation of the Jay Sensitivity Sensor Probe: a new microprocessor-controlled instrument to evaluate dentin hypersensitivity.

PubMed

Sowinski, Joseph A; Kakar, Ashish; Kakar, Kanupriya

2013-05-01

To compare the Jay Sensitivity Sensor Probe (Jay Probe), a new microprocessor-based, pre-calibrated instrument, with well accepted methods used to evaluate sensitivity, i.e. tactile response to the Yeaple Probe, air blast (Schiff scale), and patient responses by Visual Analog Score (VAS). Jay Probe assessments were accomplished using several approaches. With a cohort of 12 subjects, two clinical examiners compared the repeatability of the Jay and Yeaple Probes. A second evaluation of both probes was conducted during two independent parallel design clinical studies each enrolling 100 adults with dentin hypersensitivity (DH). In each study, subjects were evaluated for DH responses after twice daily oral hygiene with a negative control fluoride dentifrice or a positive control dentifrice formulated with ingredients proven to reduce sensitivity, i.e. potassium nitrate or 8.0% arginine with calcium carbonate. Tactile evaluations by the Jay and Yeaple Probes were conducted at baseline and recall visits over the 8-week duration of each study. Also evaluated at each visit were responses to air blast and to patient reported DH assessment by VAS. Low inter-examiner variability with no significant differences between replicate measurements (P > 0.05) was observed with the Jay Probe. Consistent with results from previous studies, subjects assigned dentifrices formulated with potassium nitrate or 8% arginine/calcium carbonate demonstrated improvements in Yeaple, air blast and VAS responses in comparison to those assigned the fluoride dentifrice (P < 0.05). Jay Probe responses correlated significantly with all other sensitivity measures (P < 0.05). Differences between these treatments were observed at all post-treatment evaluations using these methods.

Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses.

PubMed

García-Conesa, María-Teresa; Chambers, Karen; Combet, Emilie; Pinto, Paula; Garcia-Aloy, Mar; Andrés-Lacueva, Cristina; de Pascual-Teresa, Sonia; Mena, Pedro; Konic Ristic, Alekxandra; Hollands, Wendy J; Kroon, Paul A; Rodríguez-Mateos, Ana; Istas, Geoffrey; Kontogiorgis, Christos A; Rai, Dilip K; Gibney, Eileen R; Morand, Christine; Espín, Juan Carlos; González-Sarrías, Antonio

2018-02-28

Understanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total-cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation.

Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses

PubMed Central

Chambers, Karen; Andrés-Lacueva, Cristina; Konic Ristic, Aleksandra; Hollands, Wendy J.; Kroon, Paul A.; Rodríguez-Mateos, Ana; Istas, Geoffrey; Kontogiorgis, Christos A.; Morand, Christine; Espín, Juan Carlos

2018-01-01

Understanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total-cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation. PMID:29495642

Cytochrome P450 and ABCB1 genetics: association with quetiapine and norquetiapine plasma and cerebrospinal fluid concentrations and with clinical response in patients suffering from schizophrenia. A pilot study.

PubMed

Nikisch, Georg; Baumann, Pierre; Oneda, Beatrice; Kiessling, Bernhard; Weisser, Heike; Mathé, Aleksander A; Yoshitake, Takashi; Kehr, Jan; Wiedemann, Georg; Eap, Chin B

2011-07-01

Variability in response to atypical antipsychotic drugs is due to genetic and environmental factors. Cytochrome P450 (CYP) isoforms are implicated in the metabolism of drugs, while the P-glycoprotein transporter (P-gp), encoded by the ABCB1 gene, may influence both the blood and brain drug concentrations. This study aimed to identify the possible associations of CYP and ABCB1 genetic polymorphisms with quetiapine and norquetiapine plasma and cerebrospinal fluid (CSF) concentrations and with response to treatment. Twenty-two patients with schizophrenia receiving 600 mg of quetiapine daily were genotyped for four CYP isoforms and ABCB1 polymorphisms. Quetiapine and norquetiapine peak plasma and CSF concentrations were measured after 4 weeks of treatment. Stepwise multiple regression analysis revealed that ABCB1 3435C > T (rs1045642), 2677G > T (rs2032582) and 1236C > T (rs1128503) polymorphisms predicted plasma quetiapine concentrations, explaining 41% of the variability (p = 0.001). Furthermore, the ABCB1 polymorphisms predicted 48% (p = 0.024) of the variability of the Δ PANSS total score, with the non-carriers of the 3435TT showing higher changes in the score. These results suggest that ABCB1 genetic polymorphisms may be a predictive marker of quetiapine treatment in schizophrenia.

64Cu-MM-302 Positron Emission Tomography Quantifies Variability of Enhanced Permeability and Retention of Nanoparticles in Relation to Treatment Response in Patients with Metastatic Breast Cancer.

PubMed

Lee, Helen; Shields, Anthony F; Siegel, Barry A; Miller, Kathy D; Krop, Ian; Ma, Cynthia X; LoRusso, Patricia M; Munster, Pamela N; Campbell, Karen; Gaddy, Daniel F; Leonard, Shannon C; Geretti, Elena; Blocker, Stephanie J; Kirpotin, Dmitri B; Moyo, Victor; Wickham, Thomas J; Hendriks, Bart S

2017-08-01

Purpose: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. Experimental Design: We assessed the EPR effect in patients using a 64 Cu-labeled nanoparticle, 64 Cu-MM-302 ( 64 Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by PET/CT. Nineteen patients with HER2-positive metastatic breast cancer underwent 2 to 3 PET/CT scans postadministration of 64 Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Results: Significant background uptake of 64 Cu-MM-302 was observed in liver and spleen. Tumor accumulation of 64 Cu-MM-302 at 24 to 48 hours varied 35-fold (0.52-18.5 %ID/kg), including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24 to 48 hours. Patients were classified on the basis of 64 Cu-MM-302 lesion deposition using a cut-off point that is comparable with a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high 64 Cu-MM-302 deposition was associated with more favorable treatment outcomes (HR = 0.42). Conclusions: These findings provide important evidence and quantification of the EPR effect in human metastatic tumors and support imaging nanoparticle deposition in tumors as a potential means to identify patients well suited for treatment with therapeutic nanoparticles. Clin Cancer Res; 23(15); 4190-202. ©2017 AACR . ©2017 American Association for Cancer Research.

A design of experiments approach to validation sampling for logistic regression modeling with error-prone medical records.

PubMed

Ouyang, Liwen; Apley, Daniel W; Mehrotra, Sanjay

2016-04-01

Electronic medical record (EMR) databases offer significant potential for developing clinical hypotheses and identifying disease risk associations by fitting statistical models that capture the relationship between a binary response variable and a set of predictor variables that represent clinical, phenotypical, and demographic data for the patient. However, EMR response data may be error prone for a variety of reasons. Performing a manual chart review to validate data accuracy is time consuming, which limits the number of chart reviews in a large database. The authors' objective is to develop a new design-of-experiments-based systematic chart validation and review (DSCVR) approach that is more powerful than the random validation sampling used in existing approaches. The DSCVR approach judiciously and efficiently selects the cases to validate (i.e., validate whether the response values are correct for those cases) for maximum information content, based only on their predictor variable values. The final predictive model will be fit using only the validation sample, ignoring the remainder of the unvalidated and unreliable error-prone data. A Fisher information based D-optimality criterion is used, and an algorithm for optimizing it is developed. The authors' method is tested in a simulation comparison that is based on a sudden cardiac arrest case study with 23 041 patients' records. This DSCVR approach, using the Fisher information based D-optimality criterion, results in a fitted model with much better predictive performance, as measured by the receiver operating characteristic curve and the accuracy in predicting whether a patient will experience the event, than a model fitted using a random validation sample. The simulation comparisons demonstrate that this DSCVR approach can produce predictive models that are significantly better than those produced from random validation sampling, especially when the event rate is low. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Novel approach to characterising individuals with low back-related leg pain: cluster identification with latent class analysis and 12-month follow-up.

PubMed

Stynes, Siobhán; Konstantinou, Kika; Ogollah, Reuben; Hay, Elaine M; Dunn, Kate M

2018-04-01

Traditionally, low back-related leg pain (LBLP) is diagnosed clinically as referred leg pain or sciatica (nerve root involvement). However, within the spectrum of LBLP, we hypothesised that there may be other unrecognised patient subgroups. This study aimed to identify clusters of patients with LBLP using latent class analysis and describe their clinical course. The study population was 609 LBLP primary care consulters. Variables from clinical assessment were included in the latent class analysis. Characteristics of the statistically identified clusters were compared, and their clinical course over 1 year was described. A 5 cluster solution was optimal. Cluster 1 (n = 104) had mild leg pain severity and was considered to represent a referred leg pain group with no clinical signs, suggesting nerve root involvement (sciatica). Cluster 2 (n = 122), cluster 3 (n = 188), and cluster 4 (n = 69) had mild, moderate, and severe pain and disability, respectively, and response to clinical assessment items suggested categories of mild, moderate, and severe sciatica. Cluster 5 (n = 126) had high pain and disability, longer pain duration, and more comorbidities and was difficult to map to a clinical diagnosis. Most improvement for pain and disability was seen in the first 4 months for all clusters. At 12 months, the proportion of patients reporting recovery ranged from 27% for cluster 5 to 45% for cluster 2 (mild sciatica). This is the first study that empirically shows the variability in profile and clinical course of patients with LBLP including sciatica. More homogenous groups were identified, which could be considered in future clinical and research settings.

Long-Term Post-CABG Survival: Performance of Clinical Risk Models Versus Actuarial Predictions.

PubMed

Carr, Brendan M; Romeiser, Jamie; Ruan, Joyce; Gupta, Sandeep; Seifert, Frank C; Zhu, Wei; Shroyer, A Laurie

2016-01-01

Clinical risk models are commonly used to predict short-term coronary artery bypass grafting (CABG) mortality but are less commonly used to predict long-term mortality. The added value of long-term mortality clinical risk models over traditional actuarial models has not been evaluated. To address this, the predictive performance of a long-term clinical risk model was compared with that of an actuarial model to identify the clinical variable(s) most responsible for any differences observed. Long-term mortality for 1028 CABG patients was estimated using the Hannan New York State clinical risk model and an actuarial model (based on age, gender, and race/ethnicity). Vital status was assessed using the Social Security Death Index. Observed/expected (O/E) ratios were calculated, and the models' predictive performances were compared using a nested c-index approach. Linear regression analyses identified the subgroup of risk factors driving the differences observed. Mortality rates were 3%, 9%, and 17% at one-, three-, and five years, respectively (median follow-up: five years). The clinical risk model provided more accurate predictions. Greater divergence between model estimates occurred with increasing long-term mortality risk, with baseline renal dysfunction identified as a particularly important driver of these differences. Long-term mortality clinical risk models provide enhanced predictive power compared to actuarial models. Using the Hannan risk model, a patient's long-term mortality risk can be accurately assessed and subgroups of higher-risk patients can be identified for enhanced follow-up care. More research appears warranted to refine long-term CABG clinical risk models. © 2015 The Authors. Journal of Cardiac Surgery Published by Wiley Periodicals, Inc.

Long‐Term Post‐CABG Survival: Performance of Clinical Risk Models Versus Actuarial Predictions

PubMed Central

Carr, Brendan M.; Romeiser, Jamie; Ruan, Joyce; Gupta, Sandeep; Seifert, Frank C.; Zhu, Wei

2015-01-01

Abstract Background/aim Clinical risk models are commonly used to predict short‐term coronary artery bypass grafting (CABG) mortality but are less commonly used to predict long‐term mortality. The added value of long‐term mortality clinical risk models over traditional actuarial models has not been evaluated. To address this, the predictive performance of a long‐term clinical risk model was compared with that of an actuarial model to identify the clinical variable(s) most responsible for any differences observed. Methods Long‐term mortality for 1028 CABG patients was estimated using the Hannan New York State clinical risk model and an actuarial model (based on age, gender, and race/ethnicity). Vital status was assessed using the Social Security Death Index. Observed/expected (O/E) ratios were calculated, and the models' predictive performances were compared using a nested c‐index approach. Linear regression analyses identified the subgroup of risk factors driving the differences observed. Results Mortality rates were 3%, 9%, and 17% at one‐, three‐, and five years, respectively (median follow‐up: five years). The clinical risk model provided more accurate predictions. Greater divergence between model estimates occurred with increasing long‐term mortality risk, with baseline renal dysfunction identified as a particularly important driver of these differences. Conclusions Long‐term mortality clinical risk models provide enhanced predictive power compared to actuarial models. Using the Hannan risk model, a patient's long‐term mortality risk can be accurately assessed and subgroups of higher‐risk patients can be identified for enhanced follow‐up care. More research appears warranted to refine long‐term CABG clinical risk models. doi: 10.1111/jocs.12665 (J Card Surg 2016;31:23–30) PMID:26543019

Electronic stethoscope with frequency shaping and infrasonic recording capabilities.

PubMed

Gordon, E S; Lagerwerff, J M

1976-03-01

A small electronic stethoscope with variable frequency response characteristics has been developed for aerospace and research applications. The system includes a specially designed piezoelectric pickup and amplifier with an overall frequency response from 0.7 to 5,000 HZ (-3 dB points) and selective bass and treble boost or cut of up to 15 dB. A steep slope, high pass filter can be switched in for ordinary clinical auscultation without overload distortion from strong infrasonic signal inputs. A commercial stethoscope-type headset, selected for best overall response, is used which can adequately handle up to 100 mW of audio power delivered from the amplifier. The active components of the amplifier consist of only four opamp-type integrated circuits.

Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

PubMed Central

Aslibekyan, Stella; Straka, Robert J.; Irvin, Marguerite R.; Claas, Steven A.; Arnett, Donna K.

2017-01-01

High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 genes have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts. PMID:23469915

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

Bradshaw, Tyler J.; Bowen, Stephen R.; Deveau, Michael A.

Purpose: Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy. Methods and Materials: Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapymore » and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV{sub max}; SUV{sub mean}) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R{sup 2}. Results: The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV{sub mean} (P=.018), and midtreatment FLT SUV{sub max} (P=.006). Large decreases in FLT SUV{sub mean} from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV{sub max} (P=.022) in combination with large FLT response from pretreatment to midtreatment (P=.041). Conclusions: In addition to tumor volume, pronounced tumor proliferative response quantified using FLT PET, especially when associated with high residual FLT PET at midtreatment, is a negative prognostic biomarker of outcome in canine tumors following radiation therapy. Neither FDG PET nor Cu-ATSM PET were predictive of outcome.« less

Molecular imaging biomarkers of resistance to radiation therapy for spontaneous nasal tumors in canines.

PubMed

Bradshaw, Tyler J; Bowen, Stephen R; Deveau, Michael A; Kubicek, Lyndsay; White, Pamela; Bentzen, Søren M; Chappell, Richard J; Forrest, Lisa J; Jeraj, Robert

2015-03-15

Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy. Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapy and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV(max); SUV(mean)) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R(2). The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV(mean) (P=.018), and midtreatment FLT SUV(max) (P=.006). Large decreases in FLT SUV(mean) from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV(max) (P=.022) in combination with large FLT response from pretreatment to midtreatment (P=.041). In addition to tumor volume, pronounced tumor proliferative response quantified using FLT PET, especially when associated with high residual FLT PET at midtreatment, is a negative prognostic biomarker of outcome in canine tumors following radiation therapy. Neither FDG PET nor Cu-ATSM PET were predictive of outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Time for a neonatal–specific consensus definition for sepsis

PubMed Central

Wynn, James L.; Wong, Hector R.; Shanley, Thomas P.; Bizzarro, Matthew J.; Saiman, Lisa; Polin, Richard A.

2014-01-01

Objective To review the accuracy of the pediatric consensus definition of sepsis in term neonates and to determine the definition of neonatal sepsis used. Study selection The review focused primarily on pediatric literature relevant to the topic of interest. Conclusions Neonatal sepsis is variably defined based on a number of clinical and laboratory criteria that make the study of this common and devastating condition very difficult. Diagnostic challenges and uncertain disease epidemiology necessarily result from a variable definition of disease. In 2005, intensivists caring for children recognized that as new drugs became available, children would be increasingly studied and thus, pediatric-specific consensus definitions were needed. Pediatric sepsis criteria are not accurate for term neonates and have not been examined in preterm neonates for whom the developmental stage influences aberrations associated with host immune response. Thus, specific consensus definitions for both term and preterm neonates are needed. Such definitions are critical for the interpretation of observational studies, future training of scientists and practitioners, and implementation of clinical trials in neonates. PMID:24751791

Complex and Simple Clinical Reaction Times Are Associated with Gait, Balance, and Major Fall Injury in Older Subjects with Diabetic Peripheral Neuropathy

PubMed Central

Richardson, James K.; Eckner, James T.; Allet, Lara; Kim, Hogene; Ashton-Miller, James

2016-01-01

Objective To identify relationships between complex and simple clinical measures of reaction time (RTclin), and indicators of balance in older subjects with and without diabetic peripheral neuropathy (DPN). Design Prospective cohort design. Complex RTclin Accuracy, Simple RTclin Latency, and their ratio were determined using a novel device in 42 subjects (age = 69.1 ± 8.3 yrs), 26 with DPN and 16 without. Dependent variables included unipedal stance time (UST), step width variability and range on an uneven surface, and major fall-related injury over 12 months. Results In the DPN subjects the ratio of Complex RTclin Accuracy:Simple RTclin Latency was strongly associated with longer UST (r/p = .653/.004), and decreased step width variability and range (r/p = −.696/.001 and −.782/<.001, respectively) on an uneven surface. Additionally, the two DPN subjects sustaining major injuries had lower Complex RTclin Accuracy:Simple: RTclin Latency than those without. Conclusions The ratio of Complex RTclin Accuracy:Simple RTclin Latency is a potent predictor of UST and frontal plane gait variability in response to perturbations, and may predict major fall injury in older subjects with DPN. These short latency neurocognitive measures may compensate for lower limb neuromuscular impairments, and provide a more comprehensive understanding of balance and fall risk. PMID:27552354

Sources of Variance in Baseline Gene Expression in the Rodent Liver

PubMed Central

Corton, J. Christopher; Bushel, Pierre R.; Fostel, Jennifer; O'Lone, Raegan B.

2012-01-01

The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver. PMID:22230429

Effects of an educational intervention based on the protection motivation theory and implementation intentions on first and second pap test practice in Iran.

PubMed

Dehdari, Tahereh; Hassani, Laleh; Hajizadeh, Ebrahim; Shojaeizadeh, Davoud; Nedjat, Saharnaz; Abedini, Mehrandokht

2014-01-01

Few Iranian women take the Papanicolaou test despite its important role in preventing cervical cancer. This study aimed to determine the effectiveness of an educational intervention based on the protection motivation theory (PMT) variables and implementation intentions in the first and second Pap test practice among Iranian women. In this quasi-randomized controlled trial, 200 women who were referred to 30 primary health care clinics in Tehran were randomly selected. PMT variables and Pap test practice were measured at baseline and again after 3 and 15 months. The 4-week educational intervention program was conducted for the intervention group. Following the intervention, the mean scores of self-efficacy, perceived vulnerability, and behavior intention variables were significantly higher in the intervention group when compared to the control group (p<0.05). No significant differences were found in the perceived severity, response efficacy, response cost, and fear between the two groups following the intervention. Higher percent of women in the intervention group had obtained first and second Pap test compared to the controls. The PMT and implementation intentions provide a suitable theory-based framework for developing educational interventions regarding Pap test practice in Iran.

Clinical judgement and antibiotic use in general practice.

PubMed Central

Howie, J G

1976-01-01

Illustrated booklets that contained standard physical but variable social and psychological information relating to 16 patients with sore throats were posted to 1000 general practitioners. The doctors were asked whether they would prescribed antibiotics in each of the cases presented. Replies were received from 634 doctors and it was found that the variations in social and psychological history provided had significantly affected the doctor's responses. Images FIG 1 p1064-a PMID:990762

Proverb and idiom comprehension in Alzheimer disease.

PubMed

Kempler, D; Van Lancker, D; Read, S

1988-01-01

Twenty-nine patients diagnosed with Probable Alzheimer Disease were administered tests of word, familiar phrases (idioms and proverbs), and novel phrase comprehension. From the early stage of the disease, patients performed worse at understanding familiar phrases than single words or novel phrases. The results uphold common observations that AD patients have difficulty interpreting abstract meanings. Cognitive variables responsible for poor idiom/proverb comprehension and the clinical implications of this new protocol are discussed.

[Clinical Management: Basics and organization].

PubMed

Torres, Juan; Mingo, Carlos

2015-01-01

Many strategies have been proposed over the last years to ensure the Health Care System sustainability, mainly after the recent global economic crisis. One of the most attractive approaches is clinical management, which is a way of organizing health care units based on active participation of professionals who receive the transference of responsibilities dispoto achieve the objectives with the mission of ensuring a proper patient centered care, taking into consideration the rational use of resources (Efficiency) For the start up of Health Care structures based on clinical management, it is necessary a previous management culture within the departments involved and the center's executive board. Furthermore, to achieve the objectives proposed various tools must be used, such as evidence based medicine, clinical practice variability analysis, process management, in addition of quality and safety strategies. The units involved have to propose a management plan that will result in a management contract with the center's executive board. This agreement will establish some activity, expense and quality objectives that will be quantifiable through various indicators. Risk transference to the unit must include certain budget allocation and incentive decision capacity. Clinical management must not be employed as a savings tool from the part of macro and meso management. There is not a health care structure based on clinical management that have a general character for all health care organizations, existing a great variability in the adoption of various organizational formulas, so that every center must perform its own analysis and decide the most adequate model. In our country there are many clinical management experiences, although there is a long way to go.

Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic.

PubMed

Diamond, Peter R; Farmery, Andrew D; Atkinson, Stephanie; Haldar, Jag; Williams, Nicola; Cowen, Phil J; Geddes, John R; McShane, Rupert

2014-06-01

Ketamine has a rapid antidepressant effect in treatment-resistant depression (TRD). The effects on cognitive function of multiple ketamine infusions and of concurrent antidepressant medication on response rate and duration are not known. Twenty-eight patients with uni- or bipolar TRD were treated over three weeks with either three or six ketamine infusions (0.5 mg/kg over 40 minutes) in the recovery room of a routine ECT clinic. Post-treatment memory assessments were conducted on day 21 (4-7 days after the final infusion). Patients were followed up for six months where possible, with severity of depression and side effects monitored throughout. Eight (29%) patients responded of whom four remitted. Only three (11%) patients had responded within six hours after a single infusion, but in all responders, the response had developed before the third infusion. The duration of response from the final infusion was variable (median 70, range 25-168 days). Discontinuations included two (7%) because of acute adverse reactions during the infusion and five (18%) because of failure to benefit and increasing anxiety. Ketamine was not associated with memory impairment. The ECT clinic was rated suitable by patients and offered appropriate levels of monitoring. This small, open label naturalistic study shows that up to six low dose ketamine infusions can safely be given within an existing NHS clinical structure to patients who continue their antidepressants. The response rate was comparable to that found in RCTs of single doses of ketamine in antidepressant-free patients but took slightly longer to develop. © The Author(s) 2014.

Vital signs monitoring to detect patient deterioration: An integrative literature review.

PubMed

Mok, Wen Qi; Wang, Wenru; Liaw, Sok Ying

2015-05-01

Vital signs monitoring is an important nursing assessment. Yet, nurses seem to be doing it as part of a routine and often overlooking their significance in detecting patient deterioration. An integrative literature review was conducted to explore factors surrounding ward nursing practice of vital signs monitoring in detecting and reporting deterioration. Twenty papers were included. The structural component of a Nursing Role Effectiveness Model framework, which comprises of patient, nurse and organizational variables, was used to synthesize the review. Patient variables include signs of deterioration displayed by patients which include physical cues and abnormal vital signs. Nursing variables include clinical knowledge, roles and responsibilities, and reporting of deteriorating vital signs. Organizational variables include heavy workload, technology, and observation chart design. This review has highlighted current nursing practice in vital signs monitoring. A myriad of factors were found to surround ward practice of vital signs monitoring in detecting and reporting deterioration. © 2015 Wiley Publishing Asia Pty Ltd.

Methods for measuring, enhancing, and accounting for medication adherence in clinical trials.

PubMed

Vrijens, B; Urquhart, J

2014-06-01

Adherence to rationally prescribed medications is essential for effective pharmacotherapy. However, widely variable adherence to protocol-specified dosing regimens is prevalent among participants in ambulatory drug trials, mostly manifested in the form of underdosing. Drug actions are inherently dose and time dependent, and as a result, variable underdosing diminishes the actions of trial medications by various degrees. The ensuing combination of increased variability and decreased magnitude of trial drug actions reduces statistical power to discern between-group differences in drug actions. Variable underdosing has many adverse consequences, some of which can be mitigated by the combination of reliable measurements of ambulatory patients' adherence to trial and nontrial medications, measurement-guided management of adherence, statistically and pharmacometrically sound analyses, and modifications in trial design. Although nonadherence is prevalent across all therapeutic areas in which the patients are responsible for treatment administration, the significance of the adverse consequences depends on the characteristics of both the disease and the medications.

A 7-item version of the fatigue severity scale has better psychometric properties among HIV-infected adults: an application of a Rasch model.

PubMed

Lerdal, Anners; Kottorp, Anders; Gay, Caryl; Aouizerat, Bradley E; Portillo, Carmen J; Lee, Kathryn A

2011-11-01

To examine the psychometric properties of the 9-item Fatigue Severity Scale (FSS) using a Rasch model application. A convenience sample of HIV-infected adults was recruited, and a subset of the sample was assessed at 6-month intervals for 2 years. Socio-demographic, clinical, and symptom data were collected by self-report questionnaires. CD4 T-cell count and viral load measures were obtained from medical records. The Rasch analysis included 316 participants with 698 valid questionnaires. FSS item 2 did not advanced monotonically, and items 1 and 2 did not show acceptable goodness-of-fit to the Rasch model. A reduced FSS 7-item version demonstrated acceptable goodness-of-fit and explained 61.2% of the total variance in the scale. In the FSS-7 item version, no uniform Differential Item Functioning was found in relation to time of evaluation or to any of the socio-demographic or clinical variables. This study demonstrated that the FSS-7 has better psychometric properties than the FSS-9 in this HIV sample and that responses to the different items are comparable over time and unrelated to socio-demographic and clinical variables.

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs.

PubMed

Censi, Roberta; Di Martino, Piera

2015-10-15

Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations.

Dietary interventions in overweight and obese pregnant women: a systematic review of the content, delivery, and outcomes of randomized controlled trials.

PubMed

Flynn, Angela C; Dalrymple, Kathryn; Barr, Suzanne; Poston, Lucilla; Goff, Louise M; Rogozińska, Ewelina; van Poppel, Mireille N M; Rayanagoudar, Girish; Yeo, SeonAe; Barakat Carballo, Ruben; Perales, Maria; Bogaerts, Annick; Cecatti, Jose G; Dodd, Jodie; Owens, Julie; Devlieger, Roland; Teede, Helena; Haakstad, Lene; Motahari-Tabari, Narges; Tonstad, Serena; Luoto, Riitta; Guelfi, Kym; Petrella, Elisabetta; Phelan, Suzanne; Scudeller, Tânia T; Hauner, Hans; Renault, Kristina; Sagedal, Linda Reme; Stafne, Signe N; Vinter, Christina; Astrup, Arne; Geiker, Nina R W; McAuliffe, Fionnuala M; Mol, Ben W; Thangaratinam, Shakila

2016-05-01

Interventions targeting maternal obesity are a healthcare and public health priority. The objective of this review was to evaluate the adequacy and effectiveness of the methodological designs implemented in dietary intervention trials for obesity in pregnancy. A systematic review of the literature, consistent with PRISMA guidelines, was performed as part of the International Weight Management in Pregnancy collaboration. Thirteen randomized controlled trials, which aimed to modify diet and physical activity in overweight and obese pregnant women, were identified. There was significant variability in the content, delivery, and dietary assessment methods of the dietary interventions examined. A number of studies demonstrated improved dietary behavior in response to diet and/or lifestyle interventions. Nine studies reduced gestational weight gain. This review reveals large methodological variability in dietary interventions to control gestational weight gain and improve clinical outcomes in overweight and obese pregnant women. This lack of consensus limits the ability to develop clinical guidelines and apply the evidence in clinical practice. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Evaluation of dental pulp sensibility tests in a clinical setting.

PubMed

Jespersen, James J; Hellstein, John; Williamson, Anne; Johnson, William T; Qian, Fang

2014-03-01

The goal of this project was to evaluate the performance of dental pulp sensibility testing with Endo Ice (1,1,1,2-tetrafluoroethane) and an electric pulp tester (EPT) and to determine the effect of several variables on the reliability of these tests. Data were collected from 656 patients seen in the University of Iowa College of Dentistry Endodontic graduate clinic. The results of pulpal sensibility tests, along with the tooth number, age, sex, number of restored surfaces, presence or absence of clinical or radiographic caries, and reported recent use of analgesic medications, were recorded. The presence of vital tissue within the pulp chamber was used to verify the diagnosis. The Endo Ice results showed accuracy, 0.904; sensitivity, 0.916; specificity, 0.896; positive predictive value, 0.862; and negative predictive value, 0.937. The EPT results showed accuracy, 0.75; sensitivity, 0.84; specificity, 0.74; positive predictive value, 0.58; and negative predictive value, 0.90. Patients aged 21-50 years exhibited a more accurate response to cold testing (P = .0043). Vital teeth with caries responded more accurately to cold testing (P = .0077). There was no statistically significant difference noted with any other variable examined. Pulpal sensibility testing with Endo Ice and EPT are accurate and reliable methods of determining pulpal vitality. Patients aged 21-50 exhibited a more accurate response to cold. Sex, tooth type, number of restored surfaces, presence of caries, and recent analgesic use did not significantly alter the results of pulpal sensibility testing in this study. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability.

PubMed

Aller, E; Jaijo, T; Oltra, S; Alió, J; Galán, F; Nájera, C; Beneyto, M; Millán, J M

2004-12-01

Usher syndrome type III is an autosomal recessive disorder clinically characterized by the association of retinitis pigmentosa (RP), variable presence of vestibular dysfunction and progressive hearing loss, being the progression of the hearing impairment the critical parameter classically used to distinguish this form from Usher syndrome type I and Usher syndrome type II. Usher syndrome type III clinical subtype is the rarest form of Usher syndrome in Spain, accounting only for 6% of all Usher syndrome Spanish cases. The gene responsible for Usher syndrome type III is named clarin-1 and it is thought to be involved in hair cell and photoreceptor cell synapses. Here, we report a screening for mutations in clarin-1 gene among our series of Usher syndrome Spanish patients. Clarin-1 has been found to be responsible for the disease in only two families: the first one is a previously reported family homozygous for Y63X mutation and the second one, described here, is homozygous for C40G. This accounts for 1.7% of Usher syndrome Spanish families. It is noticeable that, whereas C40G family is clinically compatible with Usher syndrome type III due to the progression of the hearing loss, Y63X family could be diagnosed as Usher syndrome type I because the hearing impairment is profound and stable. Thus, we consider that the progression of hearing loss is not the definitive key parameter to distinguish Usher syndrome type III from Usher syndrome type I and Usher syndrome type II.

Validation of a Host Response Assay, Septicyte™ LAB, for Discriminating Sepsis from SIRS in the ICU.

PubMed

Miller Iii, Russell R; Lopansri, Bert K; Burke, John P; Levy, Mitchell; Opal, Steven; Rothman, Richard E; D'Alessio, Franco R; Sidhaye, Venkataramana K; Aggarwal, Neil R; Balk, Robert; Greenberg, Jared A; Yoder, Mark; Patel, Gourang; Gilbert, Emily; Afshar, Majid; Parada, Jorge P; Martin, Greg S; Esper, Annette M; Kempker, Jordan A; Narasimhan, Mangala; Tsegaye, Adey; Hahn, Stella; Mayo, Paul; van der Poll, Tom; Schultz, Marcus J; Scicluna, Brendon P; Klein Klouwenberg, Peter; Rapisarda, Antony; Seldon, Therese A; McHugh, Leo C; Yager, Thomas D; Cermelli, Silvia; Sampson, Dayle; Rothwell, Victoria; Newman, Richard; Bhide, Shruti; Kirk, James T; Navalkar, Krupa; Davis, Roy F; Brandon, Roslyn A; Brandon, Richard B

2018-04-06

A molecular test to distinguish between sepsis and systemic inflammation of non-infectious etiology could potentially have clinical utility. This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte™ LAB) designed to distinguish between sepsis and non-infectious systemic inflammation in critically ill adults. The study employed a prospective, observational, non-interventional design, and recruited a heterogeneous cohort of adult critical care patients from seven sites in the USA (N=249). An additional group of 198 patients, recruited in the large MARS consortium trial in the Netherlands (clinicaltrials.gov identifier: NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. Performance of SeptiCyte™ LAB was compared to retrospective physician diagnosis by a panel of three experts. In receiver operating characteristic curve analysis, SeptiCyte™ LAB had an estimated area under curve of 0.82-0.89 for discriminating sepsis from non-infectious systemic inflammation. The relative likelihood of sepsis versus non-infectious systemic inflammation was found to increase with increasing test score (range 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables including procalcitonin. Performance of the assay was not significantly affected by demographic variables including age, sex, or race/ethnicity. SeptiCyte™ LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registrations available at clinicaltrials.gov, IDs NCT02127502 and NCT01905033.

Meaning and challenges in the practice of multiple therapeutic massage modalities: a combined methods study.

PubMed

Porcino, Antony J; Boon, Heather S; Page, Stacey A; Verhoef, Marja J

2011-09-20

Therapeutic massage and bodywork (TMB) practitioners are predominantly trained in programs that are not uniformly standardized, and in variable combinations of therapies. To date no studies have explored this variability in training and how this affects clinical practice. Combined methods, consisting of a quantitative, population-based survey and qualitative interviews with practitioners trained in multiple therapies, were used to explore the training and practice of TMB practitioners in Alberta, Canada. Of the 5242 distributed surveys, 791 were returned (15.1%). Practitioners were predominantly female (91.7%), worked in a range of environments, primarily private (44.4%) and home clinics (35.4%), and were not significantly different from other surveyed massage therapist populations. Seventy-seven distinct TMB therapies were identified. Most practitioners were trained in two or more therapies (94.4%), with a median of 8 and range of 40 therapies. Training programs varied widely in number and type of TMB components, training length, or both. Nineteen interviews were conducted. Participants described highly variable training backgrounds, resulting in practitioners learning unique combinations of therapy techniques. All practitioners reported providing individualized patient treatment based on a responsive feedback process throughout practice that they described as being critical to appropriately address the needs of patients. They also felt that research treatment protocols were different from clinical practice because researchers do not usually sufficiently acknowledge the individualized nature of TMB care provision. The training received, the number of therapies trained in, and the practice descriptors of TMB practitioners are all highly variable. In addition, clinical experience and continuing education may further alter or enhance treatment techniques. Practitioners individualize each patient's treatment through a highly adaptive process. Therefore, treatment provision is likely unique to each practitioner. These results may be of interest to researchers considering similar practice issues in other professions. The use of a combined-methods design effectively captured this complexity of TMB practice. TMB research needs to consider research approaches that can capture or adapt to the individualized nature of practice.

Simulation and qualitative analysis of glucose variability, mean glucose, and hypoglycemia after subcutaneous insulin therapy for stress hyperglycemia.

PubMed

Strilka, Richard J; Stull, Mamie C; Clemens, Michael S; McCaver, Stewart C; Armen, Scott B

2016-01-27

The critically ill can have persistent dysglycemia during the "subacute" recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial. Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation. Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, "rebound hyperglycemia" was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes. Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose variability; its linear dose-response curve rendered the preparation better suited for a sliding-scale protocol. The longer duration of action of subcutaneous regular insulin resulted in better glycemic-control metrics for patients who were continuously postprandial. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units; if present, their clinical effects should be evaluated.

[Intra-articular injections of triamcinolone hexacetonide in rheumatoid arthritis: short and long-term improvement predictors].

PubMed

Furtado, Rita Nely Vilar; Machado, Flavia Soares; Luz, Karine Rodrigues da; Santos, Marla Francisca dos; Konai, Monique Sayuri; Lopes, Roberta Vilela; Natour, Jamil

2015-01-01

Identify good response predictors to intra-articular injection (IAI) with triamcinolone hexacetonide (TH). This study was carried out in rheumatoid arthritis (RA) patients (American College of Rheumatology criteria) submitted to IAI (mono, pauci or polyarticular injection). A "blinded" observer prospectively evaluated joints at one week (T1), four weeks (T4), twelve weeks (T12) and 24 weeks (T24) after IAI. Outcome measurements included Visual Analogue Scale (0-10 cm) at rest, in movement and for swollen joints. Clinical, demographic and variables related to injection at baseline were analyzed according to IAI response. We studied 289 patients with RA (635 joints) with a mean age of 48.7 years (±10.68), 48.5% of them Caucasians, VAS for global pain=6.52 (±1.73). Under univariate analysis, the variables relating the best responses following IAI (improvement > 70%) were: "elbow and metacarpophalangeal (MCP) IAI, and functional class II". Under multivariate analysis, "males" and "non-whites" were the predictors with the best response to IAI at T4, while "elbow and MCP IAI", "polyarticular injection", "use of methotrexate" and "higher total dose of TH" obtained the best response at T24. Several predictors of good response to IAI in patients with RA were identified. The best-response predictors for TH IAI of long term were "apply elbow and MCP IAI" and "apply polyarticular injection". Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis.

PubMed

Zampeli, Evanthia; Gizis, Michalis; Siakavellas, Spyros I; Bamias, Giorgos

2014-08-15

Ulcerative colitis (UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor (anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve (primary non-response) or lose response after a period of improvement (secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters that may predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular (immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.

The use of personalized biomarkers and liquid biopsies to monitor treatment response and disease recurrence in locally advanced rectal cancer after neoadjuvant chemoradiation.

PubMed

Carpinetti, Paola; Donnard, Elisa; Bettoni, Fabiana; Asprino, Paula; Koyama, Fernanda; Rozanski, Andrei; Sabbaga, Jorge; Habr-Gama, Angelita; Parmigiani, Raphael B; Galante, Pedro A F; Perez, Rodrigo O; Camargo, Anamaria A

2015-11-10

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the mainstay treatment for locally advanced rectal cancer. Variable degrees of tumor regression are observed after nCRT and alternative treatment strategies, including close surveillance without immediate surgery, have been investigated to spare patients with complete tumor regression from potentially adverse outcomes of radical surgery. However, clinical and radiological assessment of response does not allow accurate identification of patients with complete response. In addition, surveillance for recurrence is similarly important for these patients, as early detection of recurrence allows salvage resections and adjuvant interventions. We report the use of liquid biopsies and personalized biomarkers for monitoring treatment response to nCRT and detecting residual disease and recurrence in patients with rectal cancer. We sequenced the whole-genome of four rectal tumors to identify patient-specific chromosomal rearrangements that were used to monitor circulating tumor DNA (ctDNA) in liquid biopsies collected at diagnosis and during nCRT and follow-up. We compared ctDNA levels to clinical, radiological and pathological response to nCRT. Our results indicate that personalized biomarkers and liquid biopsies may not be sensitive for the detection of microscopic residual disease. However, it can be efficiently used to monitor treatment response to nCRT and detect disease recurrence, preceding increases in CEA levels and radiological diagnosis. Similar good results were observed when assessing tumor response to systemic therapy and disease progression. Our study supports the use of personalized biomarkers and liquid biopsies to tailor the management of rectal cancer patients, however, replication in a larger cohort is necessary to introduce this strategy into clinical practice.

Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus.

PubMed

Pena, Michelle J; Heinzel, Andreas; Rossing, Peter; Parving, Hans-Henrik; Dallmann, Guido; Rossing, Kasper; Andersen, Steen; Mayer, Bernd; Heerspink, Hiddo J L

2016-07-05

Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response to ARBs in patients with diabetes mellitus and micro- or macroalbuminuria. Liquid chromatography-tandem mass spectrometry metabolomics was performed on serum samples. Data from patients with type 2 diabetes and microalbuminuria (n = 49) treated with irbesartan 300 mg/day were used for discovery. LASSO and ridge regression were performed to develop the classifier. Improvement in albuminuria response prediction was assessed by calculating differences in R(2) between a reference model of clinical parameters and a model with clinical parameters and the classifier. The classifier was externally validated in patients with type 1 diabetes and macroalbuminuria (n = 50) treated with losartan 100 mg/day. Molecular process analysis was performed to link metabolites to molecular mechanisms contributing to ARB response. In discovery, median change in urinary albumin excretion (UAE) was -42 % [Q1-Q3: -69 to -8]. The classifier, consisting of 21 metabolites, was significantly associated with UAE response to irbesartan (p < 0.001) and improved prediction of UAE response on top of the clinical reference model (R(2) increase from 0.10 to 0.70; p < 0.001). In external validation, median change in UAE was -43 % [Q1-Q35: -63 to -23]. The classifier improved prediction of UAE response to losartan (R(2) increase from 0.20 to 0.59; p < 0.001). Specifically ADMA impacting eNOS activity appears to be a relevant factor in ARB response. A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus.

Insulin delivery and nocturnal glucose control in children and adolescents with type 1 diabetes.

PubMed

Tauschmann, Martin; Hovorka, Roman

2017-12-01

Nocturnal glucose control remains challenging in children and adolescents with type 1 diabetes due to highly variable overnight insulin requirements. The issue may be addressed by glucose responsive insulin delivery based on real-time continuous glucose measurements. Areas covered: This review outlines recent developments of glucose responsive insulin delivery systems from a paediatric perspective. We cover threshold-based suspend application, predictive low glucose suspend, and more advanced single hormone and dual-hormone closed-loop systems. Approaches are evaluated in relation to nocturnal glucose control particularly during outpatient randomised controlled trials. Expert opinion: Significant progress translating research from controlled clinical centre settings to free-living unsupervised home studies have been achieved over the past decade. Nocturnal glycaemic control can be improved whilst reducing the risk of hypoglycaemia with closed-loop systems. Following the US regulatory approval of the first hybrid closed-loop system in non-paediatric population, large multinational closed-loop clinical trials and pivotal studies including paediatric populations are underway or in preparation to facilitate the use of closed-loop systems in clinical practice.

Exploring the Crosstalk between Adipose Tissue and the Cardiovascular System.

PubMed

Akoumianakis, Ioannis; Akawi, Nadia; Antoniades, Charalambos

2017-09-01

Obesity is a clinical entity critically involved in the development and progression of cardiovascular disease (CVD), which is characterised by variable expansion of adipose tissue (AT) mass across the body as well as by phenotypic alterations in AT. AT is able to secrete a diverse spectrum of biologically active substances called adipocytokines, which reach the cardiovascular system via both endocrine and paracrine routes, potentially regulating a variety of physiological and pathophysiological responses in the vasculature and heart. Such responses include regulation of inflammation and oxidative stress as well as cell proliferation, migration and hypertrophy. Furthermore, clinical observations such as the "obesity paradox," namely the fact that moderately obese patients with CVD have favourable clinical outcome, strongly indicate that the biological "quality" of AT may be far more crucial than its overall mass in the regulation of CVD pathogenesis. In this work, we describe the anatomical and biological diversity of AT in health and metabolic disease; we next explore its association with CVD and, importantly, novel evidence for its dynamic crosstalk with the cardiovascular system, which could regulate CVD pathogenesis.

Exploring the Crosstalk between Adipose Tissue and the Cardiovascular System

PubMed Central

2017-01-01

Obesity is a clinical entity critically involved in the development and progression of cardiovascular disease (CVD), which is characterised by variable expansion of adipose tissue (AT) mass across the body as well as by phenotypic alterations in AT. AT is able to secrete a diverse spectrum of biologically active substances called adipocytokines, which reach the cardiovascular system via both endocrine and paracrine routes, potentially regulating a variety of physiological and pathophysiological responses in the vasculature and heart. Such responses include regulation of inflammation and oxidative stress as well as cell proliferation, migration and hypertrophy. Furthermore, clinical observations such as the “obesity paradox,” namely the fact that moderately obese patients with CVD have favourable clinical outcome, strongly indicate that the biological “quality” of AT may be far more crucial than its overall mass in the regulation of CVD pathogenesis. In this work, we describe the anatomical and biological diversity of AT in health and metabolic disease; we next explore its association with CVD and, importantly, novel evidence for its dynamic crosstalk with the cardiovascular system, which could regulate CVD pathogenesis. PMID:28955384

A Danish population-based analysis of 105 mantle cell lymphoma patients: incidences, clinical features, response, survival and prognostic factors.

PubMed

Andersen, N S; Jensen, M K; de Nully Brown, P; Geisler, C H

2002-02-01

This study presents the first large clinical analysis of 105 unselected mantle cell lymphoma (MCL) patients diagnosed from 1992 to 2000 in a well-defined Danish population. The annual incidences were 0.7/100000 for men and 0.2/100000 for women, with no significant change during the study period. Of 97 evaluable cases, 43% achieved a complete response (CR) after initial therapy. The median disease-free (DFS) and overall survival (OS) rates were 15 and 30 months, respectively. In multivariate analysis, splenomegaly (P=0.002), anaemia (P=0.0001) and age (P=0.002), but not the international prognostic index (IPI) and the Ann Arbor staging system, had an independent impact on survival. Moreover, in a sub-analysis of 45 younger MCL patients (<65 years), a trend towards an OS plateau of 58% was observed in cases without splenomegaly and anaemia (n=29). Thus, in contrast to previously suggested prognostic factors, these variables may prove useful for clinical decisions in a significant subset of MCL patients.

When to trust our learners? Clinical teachers' perceptions of decision variables in the entrustment process.

PubMed

Duijn, Chantal C M A; Welink, Lisanne S; Bok, Harold G J; Ten Cate, Olle T J

2018-06-01

Clinical training programs increasingly use entrustable professional activities (EPAs) as focus of assessment. However, questions remain about which information should ground decisions to trust learners. This qualitative study aimed to identify decision variables in the workplace that clinical teachers find relevant in the elaboration of the entrustment decision processes. The findings can substantiate entrustment decision-making in the clinical workplace. Focus groups were conducted with medical and veterinary clinical teachers, using the structured consensus method of the Nominal Group Technique to generate decision variables. A ranking was made based on a relevance score assigned by the clinical teachers to the different decision variables. Field notes, audio recordings and flip chart lists were analyzed and subsequently translated and, as a form of axial coding, merged into one list, combining the decision variables that were similar in their meaning. A list of 11 and 17 decision variables were acknowledged as relevant by the medical and veterinary teacher groups, respectively. The focus groups yielded 21 unique decision variables that were considered relevant to inform readiness to perform a clinical task on a designated level of supervision. The decision variables consisted of skills, generic qualities, characteristics, previous performance or other information. We were able to group the decision variables into five categories: ability, humility, integrity, reliability and adequate exposure. To entrust a learner to perform a task at a specific level of supervision, a supervisor needs information to support such a judgement. This trust cannot be credited on a single case at a single moment of assessment, but requires different variables and multiple sources of information. This study provides an overview of decision variables giving evidence to justify the multifactorial process of making an entrustment decision.

The dose-response ratio in electroconvulsive therapy a preliminary study.

PubMed

Price, T R; Mackenzie, T B; Tucker, G J; Culver, C

1978-09-01

To investigate pretreatment patient variables that might correlate with dose-response characteristics of electroconvulsive therapy (ECT) and treatment outcomes, 14 patients were assessed on a daily basis, before and during treatment, using self-report affective scales, three simple paper-and-pencil tests of cognitive function,and finger-tapping speed. From these data, dose-response ratios and treatment outcome measures were derived. The dose-response ratio of ECT was found to correlate with age--the younger the patient, the more favorable the ratio. This finding is discussed in terms of the known relationships between brain monoamine oxidase levels and age, and the established relationship between seizure duration and treatment efficacy. The dose-response ratio over the first two electroconvulsive treatments as well as lesser degrees of initial congnitive and greater degrees of initial affective impairment correlated strongly with greater overall affective improvement. Some clinical and research implications of these findings are discussed.

The nonlinear, complex sequential organization of behavior in schizophrenic patients: neurocognitive strategies and clinical correlations.

PubMed

Paulus, M P; Perry, W; Braff, D L

1999-09-01

Thought disorder is a hallmark of schizophrenia and can be inferred from disorganized behavior. Measures of the sequential organization of behavior are important because they reflect the cognitive processes of the selection and sequencing of behavioral elements, which generate observable and analyzable behavioral patterns. In this context, sequences of choices generated by schizophrenic patients in a two-choice guessing task fluctuate significantly, which reflects an "oscillating dysregulation" between highly predictable and highly unpredictable subsequences within a single test session. In this study, we aimed to clarify the significance of dysregulation by seeing whether demographic, clinical, neuropsychological, and psychological measures predict the degree of dysregulation observed on this two-choice task. Thirty schizophrenic patients repeatedly performed a LEFT or RIGHT key press that was followed by a stimulus, which occurred randomly on the left or right side of the computer screen. Thus, the stimulus location had nothing to do with the key press behavior. The range of key press sequence predictabilities as measured by the dynamical entropy was used to quantify the dysregulation of response sequences and reflects the range of fixity and randomness of the responses. A factor analysis was performed and step-wise multiple regression analyses were used to relate the factor scores to demographic, clinical, symptomatic, Wisconsin Card Sorting Test (WCST), and Rorschach variables. The LEFT/RIGHT key press sequences were determined by three factors: 1) the degree of win-stay/lose-shift strategy; 2) the degree of contextual influence on the current choice; and 3) the degree of dysregulation on the choice task. Demographic and clinical variables did not predict any of the three response patterns on the choice task. In contrast, the WCST and Rorschach test predicted performance on various factors of choice task response patterns. Schizophrenic patients employ several rules, i.e., "win-stay/lose-shift" and "decide according to the previous choice," that fluctuate significantly when generating sequences on this task, confirming that a basic behavioral dysregulation occurs in a single schizophrenic subject across a single test session. The organization or the "temporal architecture" of the behavioral sequences is not related to symptoms per se, but is related to deficits in executive functioning, problem solving, and perceptual organizational abilities.

[Visit-to-visit blood pressure variability: clinical and prognostic significance].

PubMed

Kotovskaia, Iu V; Troitskaia, E A; Kobalava, Zh D

2014-01-01

The phenomenon of variability of blood pressure (BP) was studied for a long time, but recently it has received increased attention, with the focus shifted from short-term BP variability, estimated at daily monitoring for clinical blood pressure variability from visit to visit, which can be regarded as one of the indicators quality control of blood pressure with prolonged treatment. In light of the recent years of clinical data from visit to visit BP variability seems a promising new target for antihypertensive therapy.

Pharmacogenetics of asthma: toward precision medicine.

PubMed

Kersten, Elin T G; Koppelman, Gerard H

2017-01-01

Although currently available drugs to treat asthma are effective in most patients, a proportion of patients do not respond or experience side-effects; which is partly genetically determined. Pharmacogenetics is the study of how genetic variations influence drug response. In this review, we summarize prior results and recent studies in pharmacogenetics to determine if we can use genetic profiles for personalized treatment of asthma. The field of pharmacogenetics has moved from candidate gene studies in single populations toward genome-wide association studies and meta-analysis of multiple studies. New technologies have been used to enrich results, and an expanding number of genetic loci have been associated with therapeutic responses to asthma drugs. Prospective, genotype-stratified treatment studies have been conducted for β2-agonists, showing attenuated response in children carrying the Arg16 variant in the β2-adrenoreceptor gene. Although there has been much progress, many findings have not been replicated and currently known genetic loci only account for a fraction of variability in drug response. More research is necessary to translate into clinical practice. A polygenic predictive approach integrated in complex networks with other 'omics' technologies could aid to achieve this goal. Finally, to change clinical practice, studies that compare precision medicine with traditional medicine are needed.

Orientation program for hospital-based nurse practitioners.

PubMed

Bahouth, Mona N; Esposito-Herr, Mary Beth

2009-01-01

The transition from student to practicing clinician is often a challenging and difficult period for many nurse practitioners. Newly graduated nurse practitioners commonly describe feelings of inadequacy in assuming clinical responsibilities, lack of support by team members, unclear expectations for the orientation period, and role isolation. This article describes the formal nurse practitioner orientation program implemented at the University of Maryland Medical Center, a large urban academic medical center, to facilitate the transition of new nurse practitioners into the workforce. This comprehensive program incorporates streamlined administrative activities, baseline didactic and simulation-based critical care education, ongoing and focused peer support, access to formalized resources, and individualized clinical preceptor programs. This formalized orientation program has proven to be one of the key variables to successful integration of nurse practitioners into our acute care clinical teams.

Exercise Dose in Clinical Practice

PubMed Central

Wasfy, Meagan; Baggish, Aaron L.

2016-01-01

There is wide variability in the physical activity patterns of the patients in contemporary clinical cardiovascular practice. This review is designed to address the impact of exercise dose on key cardiovascular risk factors and on mortality. We begin by examining the body of literature that supports a dose-response relationship between exercise and cardiovascular disease risk factors including plasma lipids, hypertension, diabetes mellitus, and obesity. We next explore the relationship between exercise dose and mortality by reviewing the relevant epidemiological literature underlying current physical activity guideline recommendations. We then expand this discussion to critically examine recent data pertaining to the impact of exercise dose at the lowest and highest ends of the spectrum. Finally, we provide a framework for how the key concepts of exercise dose can be integrated into clinical practice. PMID:27267537

Exercise Dose in Clinical Practice.

PubMed

Wasfy, Meagan M; Baggish, Aaron L

2016-06-07

There is wide variability in the physical activity patterns of the patients in contemporary clinical cardiovascular practice. This review is designed to address the impact of exercise dose on key cardiovascular risk factors and on mortality. We begin by examining the body of literature that supports a dose-response relationship between exercise and cardiovascular disease risk factors, including plasma lipids, hypertension, diabetes mellitus, and obesity. We next explore the relationship between exercise dose and mortality by reviewing the relevant epidemiological literature underlying current physical activity guideline recommendations. We then expand this discussion to critically examine recent data pertaining to the impact of exercise dose at the lowest and highest ends of the spectrum. Finally, we provide a framework for how the key concepts of exercise dose can be integrated into clinical practice. © 2016 American Heart Association, Inc.

Pharmacogenetics in cardiovascular diseases: State of the art and implementation-recommendations of the French National Network of Pharmacogenetics (RNPGx).

PubMed

Lamoureux, Fabien; Duflot, Thomas

2017-04-01

The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Perceived parental rearing behaviours, responsibility attitudes and life events as predictors of obsessive compulsive symptomatology: test of a cognitive model.

PubMed

Haciomeroglu, Bikem; Karanci, A Nuray

2014-11-01

It is important to investigate the role of cognitive, developmental and environmental factors in the development and maintenance of Obsessive Compulsive Symptomatology (OCS). The main objective of this study was to examine the vulnerability factors of OCS in a non-clinical sample. On the basis of Salkovskis' cognitive model of OCD, the study aimed to investigate the role of perceived parental rearing behaviours, responsibility attitudes, and life events in predicting OCS. Furthermore, the mediator role of responsibility attitudes in the relationship between perceived parental rearing behaviours and OCS was examined. Finally, the specificity of these variables to OCS was evaluated by examining the relationship of the same variables with depression and trait anxiety. A total of 300 university students (M = 19.55±1.79) were administered the Padua Inventory-Washington State University Revision, Responsibility Attitudes Scale, s-EMBU (My memories of upbringing), Life Events Inventory for University Students, Beck Depression Inventory, and State-Trait Anxiety Inventory-Trait Form. Regression analysis revealed that perceived mother overprotection, responsibility attitudes and life events significantly predicted OCS. Furthermore, responsibility attitudes mediated the relationship between perceived mother overprotection and OCS. The predictive role of perceived mother overprotection and the mediator role responsibility attitudes were OCS specific. The findings of the present study supported that perceived mother over-protection as a developmental vulnerability factor significantly contributed to the explanation of a cognitive vulnerability factor (namely responsibility attitudes), and perceived maternal overprotection had its predictive role for OCS through responsibility attitudes.

Night Blood Pressure Responses to Atenolol and Hydrochlorothiazide in Black and White Patients With Essential Hypertension

PubMed Central

2014-01-01

BACKGROUND Night blood pressure (BP) predicts patient outcomes. Variables associated with night BP response to antihypertensive agents have not been fully evaluated in essential hypertension. METHODS We sought to measure night BP responses to hydrochlorothiazide (HCTZ), atenolol (ATEN), and combined therapy using ambulatory blood pressure (ABP) monitoring in 204 black and 281 white essential hypertensive patients. Initial therapy was randomized; HCTZ and ATEN once daily doses were doubled after 3 weeks and continued for 6 more weeks with the alternate medication added for combined therapy arms. ABP was measured at baseline and after completion of each drug. Night, day, and night/day BP ratio responses (treatment − baseline) were compared in race/sex subgroups. RESULTS Baseline night systolic BP and diastolic BP, and night/day ratios were greater in blacks than whites (P < 0.01, all comparisons). Night BP responses to ATEN were absent and night/day ratios increased significantly in blacks (P < 0.05). At the end of combined therapy, women, blacks, and those starting with HCTZ as opposed to ATEN had significantly greater night BP responses (P < 0.01). Variables that significantly associated with ATEN response differed from those that associated with HCTZ response and those that associated with night BP response differed from those that associated with day BP response. CONCLUSIONS In summary, after completion of HCTZ and ATEN therapy, women, blacks, and those who started with HCTZ had greater night BP responses. Reduced night BP response and increased night/day BP ratios occured with ATEN in blacks. Given the prognostic significance of night BP, strategies for optimizing night BP antihypertensive therapy should be considered. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov identifier NCT00246519 PMID:23886594

Baseline Factors Predicting Placebo Response to Treatment in Children and Adolescents With Autism Spectrum Disorders

PubMed Central

King, Bryan H.; Dukes, Kimberly; Donnelly, Craig L.; Sikich, Linmarie; McCracken, James T.; Scahill, Lawrence; Hollander, Eric; Bregman, Joel D.; Anagnostou, Evdokia; Robinson, Fay; Sullivan, Lisa; Hirtz, Deborah

2016-01-01

IMPORTANCE The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population. OBJECTIVE To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression–Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children’s Yale-Brown Obsessive-Compulsive Scale. INTERVENTIONS Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d). MAIN OUTCOMES AND MEASURES A positive response was defined as having a score of at least much improved on the Clinical Global Impression–Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale–Revised, and the Children’s Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire. RESULTS Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders. CONCLUSIONS AND RELEVANCE This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00086645 PMID:24061784

Diagnosis and Management of Subacute Ruminal Acidosis in Dairy Herds.

PubMed

Oetzel, Garrett R

2017-11-01

Subacute ruminal acidosis (SARA) is a common problem in lactating dairy cows that causes chronic health problems, impairs feed efficiency, and increases the environmental impact of milk production. Low ruminal pH appears to be the main instigator of the pathophysiology of SARA, although other metabolites produced in the rumen may be involved. Inflammatory responses to SARA are variable but important determinants of a cow's response to SARA. SARA can be diagnosed at the herd level by integrating information about clinical signs and on-farm measures of ruminal pH. Prevention of SARA requires excellent feeding management and proper diet formulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Relationship between clinical fieldwork educator performance and health professional students' perceptions of their practice education learning environments.

PubMed

Brown, Ted; Williams, Brett; Lynch, Marty

2013-12-01

The Dundee Ready Education Environment Measure, Clinical Teaching Effectiveness Instrument, and Clinical Learning Environment Inventory were completed by 548 undergraduate students (54.5% response rate) enrolled in eight health professional bachelor degree courses. Regression analysis was used to investigate the significant predictors of the Clinical Teaching Effectiveness Instrument with the Dundee Ready Education Environment Measure and Clinical Learning Environment Inventory subscales as independent variables. The results indicated that the Dundee Ready Education Environment Measure and Clinical Learning Environment Inventory Actual version subscale scores explained 44% of the total variance in the Clinical Teaching Effectiveness Instrument score. The Dundee Ready Education Environment Measure subscale Academic Self-Perception explained 1.1% of the variance in the Clinical Teaching Effectiveness Instrument score. The Clinical Learning Environment Inventory Actual subscales accounted for the following variance percentages in the Clinical Teaching Effectiveness Instrument score: personalization, 1.1%; satisfaction, 1.7%; task orientation, 5.1%; and innovation, 6.2%. Aspects of the clinical learning environment appear to be predictive of the effectiveness of the clinical teaching that students experience. Fieldwork educator performance might be a significant contributing factor toward student skill development and practitioner success. © 2013 Wiley Publishing Asia Pty Ltd.

Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group.

PubMed

Provenzano, Elena; Bossuyt, Veerle; Viale, Giuseppe; Cameron, David; Badve, Sunil; Denkert, Carsten; MacGrogan, Gaëtan; Penault-Llorca, Frédérique; Boughey, Judy; Curigliano, Giuseppe; Dixon, J Michael; Esserman, Laura; Fastner, Gerd; Kuehn, Thorsten; Peintinger, Florentia; von Minckwitz, Gunter; White, Julia; Yang, Wei; Symmans, W Fraser

2015-09-01

Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor-Node-Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.

Role of genetic testing in patients undergoing percutaneous coronary intervention.

PubMed

Moon, Jae Youn; Franchi, Francesco; Rollini, Fabiana; Rivas Rios, Jose R; Kureti, Megha; Cavallari, Larisa H; Angiolillo, Dominick J

2018-02-01

Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y 12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y 12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.

Role of Genetic Testing in Patients undergoing Percutaneous Coronary Intervention

PubMed Central

Moon, Jae Youn; Franchi, Francesco; Rollini, Fabiana; Rios, Jose R. Rivas; Kureti, Megha; Cavallari, Larisa H.; Angiolillo, Dominick J.

2017-01-01

Introduction Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert Commentary The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes. PMID:28689434

Validity of the Instrumented Push and Release Test to Quantify Postural Responses in Persons With Multiple Sclerosis.

PubMed

El-Gohary, Mahmoud; Peterson, Daniel; Gera, Geetanjali; Horak, Fay B; Huisinga, Jessie M

2017-07-01

To test the validity of wearable inertial sensors to provide objective measures of postural stepping responses to the push and release clinical test in people with multiple sclerosis. Cross-sectional study. University medical center balance disorder laboratory. Total sample N=73; persons with multiple sclerosis (PwMS) n=52; healthy controls n=21. Stepping latency, time and number of steps required to reach stability, and initial step length were calculated using 3 inertial measurement units placed on participants' lumbar spine and feet. Correlations between inertial sensor measures and measures obtained from the laboratory-based systems were moderate to strong and statistically significant for all variables: time to release (r=.992), latency (r=.655), time to stability (r=.847), time of first heel strike (r=.665), number of steps (r=.825), and first step length (r=.592). Compared with healthy controls, PwMS demonstrated a longer time to stability and required a larger number of steps to reach stability. The instrumented push and release test is a valid measure of postural responses in PwMS and could be used as a clinical outcome measures for patient care decisions or for clinical trials aimed at improving postural control in PwMS. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Looking for the Perfect Mentor.

PubMed

Sá, Ana Pinheiro; Teixeira-Pinto, Cristina; Veríssimo, Rafaela; Vilas-Boas, Andreia; Firmino-Machado, João

2015-01-01

The authors established the profile of the Internal Medicine clinical teachers in Portugal aiming to define a future interventional strategy plan as adequate as possible to the target group and to the problems identified by the residents. Observational, transversal, analytic study. An online anonymous questionnaire was defined, evaluating the demographic characteristics of the clinical teachers, their path in Internal Medicine and their involvement in the residents learning process. We collected 213 valid questionnaires, making for an estimated response rate of 28.4%. Median global satisfaction with the clinical teacher was 4.52 (± 1.33 points) and the classification of the relationship between resident and clinical teacher was 4.86 ± 1.04 points. The perfect clinical teacher is defined by high standards of dedication and responsibility (4.9 ± 1.37 points), practical (4.8 ± 1.12 points) and theoretical skills (4.8 ± 1.07 points). The multiple linear regression model allowed to determine predictors of the residentâs satisfaction with their clinical teacher, justifying 82,5% of the variation of satisfaction with the clinical teacher (R2 = 0.83; R2 a = 0.82). Postgraduate medical education consists of an interaction between several areas of knowledge and intervening variables in the learning process having the clinical teacher in the central role. Overall, the pedagogical abilities were the most valued by the Internal Medicine residents regarding their clinical teacher, as determinants of a quality residentship. This study demonstrates the critical relevance of the clinical teacher in the satisfaction of residents with their residentship. The established multiple linear regression model highlights the impact of the clinical and pedagogical relantionship with the clinical teacher in a relevant increase in the satisfaction with the latter.

Carbon Nanomaterial Based Biosensors for Non-Invasive Detection of Cancer and Disease Biomarkers for Clinical Diagnosis

PubMed Central

Tung, Thanh Tran

2017-01-01

The early diagnosis of diseases, e.g., Parkinson’s and Alzheimer’s disease, diabetes, and various types of cancer, and monitoring the response of patients to the therapy plays a critical role in clinical treatment; therefore, there is an intensive research for the determination of many clinical analytes. In order to achieve point-of-care sensing in clinical practice, sensitive, selective, cost-effective, simple, reliable, and rapid analytical methods are required. Biosensors have become essential tools in biomarker sensing, in which electrode material and architecture play critical roles in achieving sensitive and stable detection. Carbon nanomaterials in the form of particle/dots, tube/wires, and sheets have recently become indispensable elements of biosensor platforms due to their excellent mechanical, electronic, and optical properties. This review summarizes developments in this lucrative field by presenting major biosensor types and variability of sensor platforms in biomedical applications. PMID:28825646

Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis.

PubMed

Nathan, Steven D; Albera, Carlo; Bradford, Williamson Z; Costabel, Ulrich; du Bois, Roland M; Fagan, Elizabeth A; Fishman, Robert S; Glaspole, Ian; Glassberg, Marilyn K; Glasscock, Kenneth F; King, Talmadge E; Lancaster, Lisa; Lederer, David J; Lin, Zhengning; Pereira, Carlos A; Swigris, Jeffrey J; Valeyre, Dominique; Noble, Paul W; Wells, Athol U

2016-05-01

The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months. A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, -0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. NCT01366209, NCT00287729, NCT00287716. 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/

Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis

PubMed Central

Nathan, Steven D; Albera, Carlo; Bradford, Williamson Z; Costabel, Ulrich; du Bois, Roland M; Fagan, Elizabeth A; Fishman, Robert S; Glaspole, Ian; Glassberg, Marilyn K; King, Talmadge E; Lancaster, Lisa; Lederer, David J; Lin, Zhengning; Pereira, Carlos A; Swigris, Jeffrey J; Valeyre, Dominique; Noble, Paul W; Wells, Athol U

2016-01-01

Background The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. Methods The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months. Results A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, −0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). Conclusions Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. Trial registration numbers NCT01366209, NCT00287729, NCT00287716. PMID:26968970

Pharmacogenetics in obstetric anesthesia.

PubMed

Landau, Ruth; Kraft, John C

2010-06-01

Genomic research in pain, anesthesia and analgesia generated some hope that pharmacogenetics may guide anesthesiologists to provide effective medicine in a 'tailored' manner. Within the field of obstetric anesthesia, relatively few studies have evaluated the effect of polymorphisms on the perception of labor or postcesarean pain or the response to analgesics for childbirth. Because of the multifactorial nature of labor and delivery pain and particularly challenging clinical context, many consider that 'titration of drugs to the desired effect works just fine'. With recent evidence highlighting an association between severe postdelivery pain and persistent pain, early recognition of an increased susceptibility for acute pain has become particularly relevant. Neuraxial labor analgesia is influenced by a common polymorphism of the mu-opioid receptor gene. This polymorphism also affects the analgesic response to systemic opioids for postcesarean pain and other types of surgeries. Finally, the risk for persistent pain after cesarean deliveries may be associated with a certain genetic profile. Although still premature to anticipate clinical implications and a change in practice based on these recent discoveries, genetic variability clearly appears to affect pain perception, response to analgesics and predisposition for the development of chronic pain.

Item Response Theory to Quantify Longitudinal Placebo and Paliperidone Effects on PANSS Scores in Schizophrenia.

PubMed

Krekels, Ehj; Novakovic, A M; Vermeulen, A M; Friberg, L E; Karlsson, M O

2017-08-01

As biomarkers are lacking, multi-item questionnaire-based tools like the Positive and Negative Syndrome Scale (PANSS) are used to quantify disease severity in schizophrenia. Analyzing composite PANSS scores as continuous data discards information and violates the numerical nature of the scale. Here a longitudinal analysis based on Item Response Theory is presented using PANSS data from phase III clinical trials. Latent disease severity variables were derived from item-level data on the positive, negative, and general PANSS subscales each. On all subscales, the time course of placebo responses were best described with Weibull models, and dose-independent functions with exponential models to describe the onset of the full effect were used to describe paliperidone's effect. Placebo and drug effect were most pronounced on the positive subscale. The final model successfully describes the time course of treatment effects on the individual PANSS item-levels, on all PANSS subscale levels, and on the total score level. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins.

PubMed

Ternant, David; Paintaud, Gilles

2005-09-01

Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell's receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration-effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration-effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose-response relationships must be studied by PK-PD modelling.

Clinical and non-clinical depression and anxiety in young people: A scoping review on heart rate variability.

PubMed

Paniccia, Melissa; Paniccia, David; Thomas, Scott; Taha, Tim; Reed, Nick

2017-12-01

Heart rate variability (HRV), a measure of cardiac autonomic nervous system functioning, has emerged as a physiological indicator for emotional regulation and psychological well-being. HRV is understudied in the context of depression and anxiety in young people (10-24years old). Main objectives: (1) describe the nature and breadth of reviewed studies; and (2) synthesize main findings in the context of clinical and non-clinical populations of young people with depression and/or anxiety. The Arksey and O'Malley methodology was utilized for this scoping review. CINHAL, EMBASE, Medline, PsychInfo, Scopus, Web of Science, as well as grey literature, were searched. Two reviewers screened titles, abstracts and full papers for inclusion. A total of 20 citations were included in the final review (19 citations peer-reviewed journal articles, 1 journal abstract). Numerical and thematic analysis was used to summarize study findings. In clinical populations of either depression or anxiety, HRV was lower compared to controls. In non-clinical populations of either depression or anxiety, HRV was found to be lower in those who reported more depression or anxiety symptoms. The quality of the reviewed articles was not assessed which limits the ability to generate conclusions regarding study findings. Changes in HRV were found across the spectrum of clinical and non-clinical populations of young people with depression or anxiety. Neurophysiological research on depression and anxiety in young people can act as a first step to understanding how physiological flexibility (i.e. HRV) is related to psychological flexibility (i.e. adaptive or maladaptive responses to life events). Copyright © 2017 Elsevier B.V. All rights reserved.

Association of medical home team-based care functions and perceived improvements in patient-centered care at VHA primary care clinics.

PubMed

Helfrich, Christian D; Dolan, Emily D; Fihn, Stephan D; Rodriguez, Hector P; Meredith, Lisa S; Rosland, Ann-Marie; Lempa, Michele; Wakefield, Bonnie J; Joos, Sandra; Lawler, Lauren H; Harvey, Henry B; Stark, Richard; Schectman, Gordon; Nelson, Karin M

2014-12-01

Team-based care is central to the patient-centered medical home (PCMH), but most PCMH evaluations measure team structure exclusively. We assessed team-based care in terms of team structure, process and effectiveness, and the association with improvements in teams׳ abilities to deliver patient-centered care. We fielded a cross-sectional survey among 913 VA primary care clinics implementing a PCMH model in 2012. The dependent variable was clinic-level respondent-reported improvements in delivery of patient-centered care. Independent variables included three sets of measures: (1) team structure, (2) team process, and (3) team effectiveness. We adjusted for clinic workload and patient comorbidity. 4819 surveys were returned (25% estimated response rate). The highest ratings were for team structure (median of 89% of respondents being assigned to a teamlet, i.e., a PCP working with the same clinical associate, nurse care manager and clerk) and lowest for team process (median of 10% of respondents reporting the lowest level of stress/chaos). In multivariable regression, perceived improvements in patient-centered care were most strongly associated with participatory decision making (β=32, P<0.0001) and history of change in the clinic (β=18, P=0008) (both team processes). A stressful/chaotic clinic environment was associated with higher barriers to patient centered care (β=0.16-0.34, P=<0.0001), and lower improvements in patient-centered care (β=-0.19, P=0.001). Team process and effectiveness measures, often omitted from PCMH evaluations, had stronger associations with perceived improvements in patient-centered care than team structure measures. Team process and effectiveness measures may facilitate synthesis of evaluation findings and help identify positive outlier clinics. Published by Elsevier Inc.

The responsiveness of novel, dynamic, contrast-enhanced magnetic resonance measures of total knee synovitis after intra-articular corticosteroid for painful osteoarthritis.

PubMed

Wenham, C Y J; Balamoody, S; Grainger, A J; Hensor, E M A; Draycott, S; Hodgson, R; Conaghan, P G

2014-10-01

Sensitive biomarkers are needed to understand synovial response to therapy in osteoarthritis (OA). Dynamic, contrast-enhanced magnetic resonance imaging (DCE MRI) provides quantitative, novel measures of synovial inflammation. This exploratory study examined DCE-assessed synovial response to intra-articular corticosteroid (IACS). People with ACR clinical criteria OA knee underwent 3 T MRI pre- and 2 weeks post-IACS. Five MRI variables were assessed blindly: total synovial volume (semi-automated computer program), early enhancement rate (EER) and late enhancement ratio of the entire knee, synovial volume × late enhancement and a semi-quantitative (SQ) score (six sites scored 0-3). Clinical symptoms were assessed using pain visual analogue score (VAS) and WOMAC. 13 participants (5 male, mean age 63, mean pain VAS 66 mm mean body mass index (BMI) 31.3 kg/m(2)) were included. The majority of MRIs demonstrated no change in SQ score although the DCE variables changed to some extent in all. There was generally a reduction in synovial volume ((Wilcoxon test) median (interquartile range (IQR)) reduction 14 cm(3) (-1, 29)), EER (0.2% (-0.3, 0.6)) and late enhancement ratio (8% (-0.5, 41)). Synovial volume × late enhancement ratio demonstrated a substantive reduction (2250 (-930, 5630)) as well as the largest effect size, r = 0.45. There was a median 26% reduction in EER in participants with good symptomatic response to IACS, contrasting with a 23% increase in those who responded poorly. DCE MRI may be more sensitive than a SQ score at detecting post-therapy synovial changes. The association between EER and symptomatic response to IACS may reflect a closer relation of this biomarker to synovial inflammation than with volumetric assessment. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

The efficacy of inhibiting tumour necrosis factor alpha and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons.

PubMed

Nixon, R; Bansback, N; Brennan, A

2007-07-01

New treatments that inhibit the cytokines tumour necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1) in the treatment of rheumatoid arthritis have proven clinical effect against placebo and methotrexate (MTX) in several clinical trials in early and late-stage disease and different severity groups. Since there are no head-to-head randomized controlled trials directly comparing the currently available treatments, etanercept, adalimumab, infliximab or anakinra, we perform a meta-analysis that adjusts for differences between study characteristics, and allows indirect comparisons between treatments. Thirteen trials of cytokine antagonists were included from a systematic review of the literature. They reported the primary outcome of American College of Rheumatology (ACR) response criteria at 6 months or beyond. Meta-analytical methods are used to quantify relative treatment effects, using the log odds ratio of an ACR20 or ACR50 response at 6 months, whilst adjusting for study-level variables. In each of the trials, cytokine treatment was efficacious in comparison with placebo or MTX. For each treatment, the inclusion of MTX in combination improved the response. After adjustment for study-level variables, we found TNFalpha antagonists to be more efficacious compared with anakinra (P < 0.05). Indirect comparisons between the three TNFalpha antagonists indicated no difference in efficacy. Sensitivity analysis using a different statistical model structure confirmed these results. When the outcome of interest is the probability of an ACR20 or ACR50 response at 6 months we found: (i) treatment with the IL-1 antagonist anakinra is better than placebo; (ii) for each treatment, the use of combination MTX improves the probability of response; (iii) treatment with any of the TNFalpha antagonists is better than with the IL-1 antagonist anakinra; and (iv) all drugs in the TNFalpha antagonist class are no different from each other.

Translational applications of evaluating physiologic variability in human endotoxemia

PubMed Central

Scheff, Jeremy D.; Mavroudis, Panteleimon D.; Calvano, Steve E.; Androulakis, Ioannis P.

2012-01-01

Dysregulation of the inflammatory response is a critical component of many clinically challenging disorders such as sepsis. Inflammation is a biological process designed to lead to healing and recovery, ultimately restoring homeostasis; however, the failure to fully achieve those beneficial results can leave a patient in a dangerous persistent inflammatory state. One of the primary challenges in developing novel therapies in this area is that inflammation is comprised of a complex network of interacting pathways. Here, we discuss our approaches towards addressing this problem through computational systems biology, with a particular focus on how the presence of biological rhythms and the disruption of these rhythms in inflammation may be applied in a translational context. By leveraging the information content embedded in physiologic variability, ranging in scale from oscillations in autonomic activity driving short-term heart rate variability (HRV) to circadian rhythms in immunomodulatory hormones, there is significant potential to gain insight into the underlying physiology. PMID:23203205

The placebo effect in sports performance: a brief review.

PubMed

Beedie, Christopher J; Foad, Abigail J

2009-01-01

The placebo effect, with its central role in clinical trials, is acknowledged as a factor in sports medicine, although until recently little has been known about the likely magnitude and extent of the effect in any specific research setting. Even less is known about the prevalence of the effect in competitive sport. The present paper reviews 12 intervention studies in sports performance. All examine placebo effects associated with the administration of an inert substance believed by subjects to be an ergogenic aid. Placebo effects of varying magnitudes are reported in studies addressing sports from weightlifting to endurance cycling. Findings suggest that psychological variables such as motivation, expectancy and conditioning, and the interaction of these variables with physiological variables, might be significant factors in driving both positive and negative outcomes. Programmatic research involving the triangulation of data, and investigation of contextual and personality factors in the mediation of placebo responses may help to advance knowledge in this area.

[Customizing dosage drugs what contribution in therapeutic drug monitoring?].

PubMed

Abdessadek, Mohammed; Magoul, Rabia; Amarti, Afaf; El Ouezzani, Seloua; Khabbal, Youssef

2014-01-01

Drug response is often variable from an individual to another: the same dose of drug administered to different patients could cause variable pharmacological effects in nature and intensity. Those effects are often the result of variability in drugs pharmacokinetics (absorption, distribution, metabolism and elimination) which alter their bioavailability. In fact, two factors should be taken into account: the disease(s) from which the patient suffers, and the associated drugs, because many drug interactions may alter their pharmacokinetics causing consequently quite enough of different therapeutic effects. The choice of the assay of the drug subject in monitoring is crucial, it allows quantifying the in vivo dose of the drug and the quality of compliance thereof, the pharmacokinetic characteristics allows the clinician to adjust the dosage by different approaches so that plasma concentrations are included in the therapeutic range. Therapeutic monitoring aims to increase clinical efficacy and to minimize toxicity.

Utility of Time and Frequency Domain Parameters of Heart Rate Variability in the Context of Autonomic Disorders Characterized by Orthostatic Dysfunction.

PubMed

Baker, Jacquie; Racosta, Juan M; Balint, Brittany; Kimpinski, Kurt

2018-03-01

The clinical significance of heart rate variability in the context of autonomic dysfunction continues to be a matter of debate. A consensus is lacking on the best heart rate variability measures for clinical purposes. Therefore, the purpose of this study was to investigate the utility of heart rate variability parameters in healthy versus autonomic dysfunction. Healthy young (n = 134), healthy older (n = 32), and patients with mild (postural tachycardia syndrome; n = 25) and severe (neurogenic orthostatic hypotension; n = 34) autonomic dysfunction were included. Time and frequency parameters during baseline, head-up tilt (HUT), and heart rate response to deep breathing (HRDB) were compared. Cardiovagal time parameters were significantly reduced during HUT in healthy young and postural tachycardia syndrome (P < 0.001). Healthy young had significantly higher time parameters during baseline, HUT, and HRDB (P < 0.01). This was reflected by a significantly lower resting heart rate (HR) (61.4 ± 9.0 bpm vs. 76.8 ± 13.6 bpm; P < 0.001) and a smaller [INCREMENT]HR during HUT (32.8 ± 10.5 bpm vs. 44.4 ± 13.3 bpm; P < 0.001). Time parameters increased in young and postural tachycardia syndrome during HRDB, which was characterized by a nonsignificant difference in [INCREMENT]HR between both groups. Time parameters were significantly higher in healthy old versus neurogenic orthostatic hypotension at rest and during HRDB (P < 0.05). During HUT, only the SD of all normal RR intervals remained significantly higher. Heart rate changes corroborated these findings. Resting HR was significantly lower in healthy older (62.6 ± 11.0 bpm vs. 70.7 ± 12.4 bpm), and [INCREMENT]HR during HRDB was significantly higher (15.9 ± 9.2 bpm vs. 3.9 ± 4.2 bpm; P < 0.001). During HUT, [INCREMENT]HR showed no significant differences. Time domain parameters of heart rate variability have a greater utility than frequency parameters in clinical autonomic disorders.

Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis.

PubMed

Harmatz, Paul; Cattaneo, Federica; Ardigò, Diego; Geraci, Silvia; Hennermann, Julia B; Guffon, Nathalie; Lund, Allan; Hendriksz, Christian J; Borgwardt, Line

2018-06-01

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of a spontaneous canine model of immunoglobulin E-mediated food hypersensitivity: dynamic changes in serum and fecal allergen-specific immunoglobulin E values relative to dietary change.

PubMed

Jackson, Hilary A; Hammerberg, Bruce

2002-08-01

The purpose of the pilot study reported here was to evaluate serum and fecal total and allergen-specific immunoglobulin E (IgE) responses to dietary change in five Maltese x beagle dogs with suspected food hypersensitivity, compared with those of five clinically normal dogs. Clinical parameters (pruritus, otitis, and diarrhea) improved in the Maltese x beagle dogs during feeding of a novel diet, and signs were exacerbated by oral allergen provocation. Relative concentrations of serum and fecal wheat-, corn-, and milk-specific IgE were determined by use of an ELISA. The onset of clinical signs of disease was accompanied by an increase in serum allergen-specific IgE concentrations. In contrast, changes in clinical signs of disease or allergen-specific IgE values were not seen in the control group undergoing the same regimen. Total serum IgE concentration was measured by use of the ELISA, and comparison with known quantities of a monoclonal IgE allowed absolute values to be reported. Values were high in the Maltese x beagle colony (7 to 34 microg/ml), compared with those in the control dogs (0.7 to 6 microg/ml). Total serum and total fecal IgE concentrations did not change in either group during the study. Although allergen-specific IgE was detected in the feces of both groups, significant interassay variability made interpretation of the results difficult. The authors concluded that these Maltese x beagle dogs satisfied the currently recognized clinical criteria for the diagnosis of canine food hypersensitivity. Furthermore, the clinical and serologic responses seen in these dogs in response to oral allergen provocation suggest that this may be a useful model for the study of spontaneous food hypersensitivity.

The Nature and Variability of Automated Practice Alerts Derived from Electronic Health Records in a U.S. Nationwide Critical Care Research Network.

PubMed

Benthin, Cody; Pannu, Sonal; Khan, Akram; Gong, Michelle

2016-10-01

The nature, variability, and extent of early warning clinical practice alerts derived from automated query of electronic health records (e-alerts) currently used in acute care settings for clinical care or research is unknown. To describe e-alerts in current use in acute care settings at medical centers participating in a nationwide critical care research network. We surveyed investigators at 38 institutions involved in the National Institutes of Health-funded Clinical Trials Network for the Prevention and Early Treatment of Acute Lung Injury (PETAL) for quantitative and qualitative analysis. Thirty sites completed the survey (79% response rate). All sites used electronic health record systems. Epic Systems was used at 56% of sites; the others used alternate commercially available vendors or homegrown systems. Respondents at 57% of sites represented in this survey used e-alerts. All but 1 of these 17 sites used an e-alert for early detection of sepsis-related syndromes, and 35% used an e-alert for pneumonia. E-alerts were triggered by abnormal laboratory values (37%), vital signs (37%), or radiology reports (15%) and were used about equally for clinical decision support and research. Only 59% of sites with e-alerts have evaluated them either for accuracy or for validity. A majority of the research network sites participating in this survey use e-alerts for early notification of potential threats to hospitalized patients; however, there was significant variability in the nature of e-alerts between institutions. Use of one common electronic health record vendor at more than half of the participating sites suggests that it may be possible to standardize e-alerts across multiple sites in research networks, particularly among sites using the same medical record platform.

Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder.

PubMed

Ermer, James C; Adeyi, Ben A; Pucci, Michael L

2010-12-01

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmotic-release formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile. The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.

Control conditions for footwear insole and orthotic research.

PubMed

Lewinson, Ryan T; Worobets, Jay T; Stefanyshyn, Darren J

2016-07-01

Footwear insoles/orthotics alter variables associated with musculoskeletal injury; however, their clinical effectiveness is inconclusive. One explanation for this is the possibility that control conditions may actually produce biomechanical changes that induce clinical responses. The purpose of this study was to compare insole/orthotic control conditions to identify if variables at the ground, ankle and knee that are associated with injury are altered relative to what participants would normally experience in their own shoes. Gait analysis was performed on 15 participants during walking and running while wearing (1) their own shoes, (2) #1 with a 3mm flat insole, (3) a standardized shoe, and (4) #3 with a 3mm flat insole, where external knee adduction moments, external knee adduction angular impulses, internal ankle inversion moments, and vertical ground reaction force loading rates were determined. Conditions 2-4 were expressed as percent changes relative to condition 1, and tests of proportions assessed if there were a significant number of individuals experiencing a biomechanically relevant change for each variable. Repeated-measures ANOVAs were used to identify group differences between conditions. The majority of movement-footwear-variable combinations contained a proportion of individuals experiencing biomechanically relevant changes compared to condition 1 that was significantly greater than the expected proportion of 20%. No systematic differences were found between conditions. This suggests that conditions 2-4 may alter biomechanics relative to baseline for many participants, but not in a consistent way across participants. It is recommended that participant's own footwear be used as control conditions in future trials where biomechanics are primary variables of interest. Copyright © 2016 Elsevier B.V. All rights reserved.

MADRS symptom subtypes in ECT-treated depressed patients: relationship to response and subsequent ECT.

PubMed

Spashett, Renee; Fernie, Gordon; Reid, Ian C; Cameron, Isobel M

2014-09-01

This study aimed to explore the relationship of Montgomery-Åsberg Depression Rating Scale (MADRS) symptom subtypes with response to electroconvulsive therapy (ECT) and subsequent ECT treatment within 12 months. A consecutive sample of 414 patients with depression receiving ECT in the North East of Scotland was assessed by retrospective chart review. Response rate was defined as greater than or equal to 50% decrease in pretreatment total MADRS score or a posttreatment total MADRS less than or equal to 10. Principal component analyses were conducted on a sample with psychotic features (n = 124) and a sample without psychotic features (n = 290). Scores on extracted factor subscales, clinical and demographic characteristics were assessed for association with response and subsequent ECT treatment within 12 months. Where more than 1 variable was associated with response or subsequent ECT, logistic regression analysis was applied. MADRS symptom subtypes formed 3 separate factors in both samples. Logistic regression revealed older age and high "Despondency" subscale score predicted response in the nonpsychotic group. Older age alone predicted response in the group with psychotic features. Nonpsychotic patients subsequently re-treated with ECT were older than those not prescribed subsequent ECT. No association of variables emerged with subsequent ECT treatment in the group with psychotic features. Being of older age and the presence of psychotic features predicted response. Presence of psychotic features alone predicted subsequent retreatment. Subscale scores of the MADRS are of limited use in predicting which patients with depression will respond to ECT, with the exception of "Despondency" subscale scores in patients without psychotic features.

A Machine Learning Approach to Identifying Placebo Responders in Late-Life Depression Trials.

PubMed

Zilcha-Mano, Sigal; Roose, Steven P; Brown, Patrick J; Rutherford, Bret R

2018-01-11

Despite efforts to identify characteristics associated with medication-placebo differences in antidepressant trials, few consistent findings have emerged to guide participant selection in drug development settings and differential therapeutics in clinical practice. Limitations in the methodologies used, particularly searching for a single moderator while treating all other variables as noise, may partially explain the failure to generate consistent results. The present study tested whether interactions between pretreatment patient characteristics, rather than a single-variable solution, may better predict who is most likely to benefit from placebo versus medication. Data were analyzed from 174 patients aged 75 years and older with unipolar depression who were randomly assigned to citalopram or placebo. Model-based recursive partitioning analysis was conducted to identify the most robust significant moderators of placebo versus citalopram response. The greatest signal detection between medication and placebo in favor of medication was among patients with fewer years of education (≤12) who suffered from a longer duration of depression since their first episode (>3.47 years) (B = 2.53, t(32) = 3.01, p = 0.004). Compared with medication, placebo had the greatest response for those who were more educated (>12 years), to the point where placebo almost outperformed medication (B = -0.57, t(96) = -1.90, p = 0.06). Machine learning approaches capable of evaluating the contributions of multiple predictor variables may be a promising methodology for identifying placebo versus medication responders. Duration of depression and education should be considered in the efforts to modulate placebo magnitude in drug development settings and in clinical practice. Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.