Gastrointestinal toxicity among patients taking selective COX-2 inhibitors or conventional NSAIDs, alone or combined with proton pump inhibitors: a case-control study.

PubMed

Bakhriansyah, Mohammad; Souverein, Patrick C; de Boer, Anthonius; Klungel, Olaf H

2017-10-01

To assess the risk of gastrointestinal perforation, ulcers, or bleeding (PUB) associated with the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) with proton pump inhibitors (PPIs) and selective COX-2 inhibitors, with or without PPIs compared with conventional NSAIDs. A case-control study was performed within conventional NSAIDs and/or selective COX-2 inhibitors users identified from the Dutch PHARMO Record Linkage System in the period 1998-2012. Cases were patients aged ≥18 years with a first hospital admission for PUB. For each case, up to four controls were matched for age and sex at the date a case was hospitalized (index date). Logistic regression analysis was used to calculate odds ratios (ORs). At the index date, 2634 cases and 5074 controls were current users of conventional NSAIDs or selective COX-2 inhibitors. Compared with conventional NSAIDs, selective COX-2 inhibitors with PPIs had the lowest risk of PUB (adjusted OR 0.51, 95% confidence interval [CI]: 0.35-0.73) followed by selective COX-2 inhibitors (adjusted OR 0.66, 95%CI: 0.48-0.89) and conventional NSAIDs with PPIs (adjusted OR 0.79, 95%CI: 0.68-0.92). Compared with conventional NSAIDs, the risk of PUB was lower for those aged ≥75 years taking conventional NSAIDs with PPIs compared with younger patients (adjusted interaction OR 0.79, 95%CI: 0.64-0.99). However, those aged ≥75 years taking selective COX-2 inhibitors, the risk was higher compared with younger patients (adjusted interaction OR 1.22, 95%CI: 1.01-1.47). Selective COX-2 inhibitors with PPIs, selective COX-2 inhibitors, and conventional NSAIDs with PPIs were associated with lower risks of PUB compared with conventional NSAIDs. These effects were modified by age. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Association of Proton Pump Inhibitors Usage with Risk of Pneumonia in Dementia Patients.

PubMed

Ho, Sai-Wai; Teng, Ying-Hock; Yang, Shun-Fa; Yeh, Han-Wei; Wang, Yu-Hsun; Chou, Ming-Chih; Yeh, Chao-Bin

2017-07-01

To determine the association between usages of proton pump inhibitors (PPIs) and subsequent risk of pneumonia in dementia patients. Retrospective cohort study. Taiwanese National Health Insurance Research Database. The study cohort consisted of 786 dementia patients with new PPI usage and 786 matched dementia patients without PPI usage. The study endpoint was defined as the occurrence of pneumonia. The Cox proportional hazard model was used to estimate the pneumonia risk. Defined daily dose methodology was applied to evaluate the cumulative and dose-response relationships of PPI. Incidence of pneumonia was higher among patients with PPI usage (adjusted hazard ratio (HR) = 1.89; 95% CI = 1.51-2.37). Cox model analysis also demonstrated that age (adjusted HR = 1.05; 95% CI = 1.03-1.06), male gender (adjusted HR = 1.57; 95% CI = 1.25-1.98), underlying cerebrovascular disease (adjusted HR = 1.30; 95% CI = 1.04-1.62), chronic pulmonary disease (adjusted HR = 1.39; 95% CI = 1.09-1.76), congestive heart failure (adjusted HR = 1.54; 95% CI = 1.11-2.13), diabetes mellitus (adjusted HR = 1.54; 95% CI = 1.22-1.95), and usage of antipsychotics (adjusted HR = 1.29; 95% CI = 1.03-1.61) were independent risk factors for pneumonia. However, usage of cholinesterase inhibitors and histamine receptor-2 antagonists were shown to decrease pneumonia risk. PPI usage in dementia patients is associated with an 89% increased risk of pneumonia. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Quality Reporting of Multivariable Regression Models in Observational Studies: Review of a Representative Sample of Articles Published in Biomedical Journals.

PubMed

Real, Jordi; Forné, Carles; Roso-Llorach, Albert; Martínez-Sánchez, Jose M

2016-05-01

Controlling for confounders is a crucial step in analytical observational studies, and multivariable models are widely used as statistical adjustment techniques. However, the validation of the assumptions of the multivariable regression models (MRMs) should be made clear in scientific reporting. The objective of this study is to review the quality of statistical reporting of the most commonly used MRMs (logistic, linear, and Cox regression) that were applied in analytical observational studies published between 2003 and 2014 by journals indexed in MEDLINE.Review of a representative sample of articles indexed in MEDLINE (n = 428) with observational design and use of MRMs (logistic, linear, and Cox regression). We assessed the quality of reporting about: model assumptions and goodness-of-fit, interactions, sensitivity analysis, crude and adjusted effect estimate, and specification of more than 1 adjusted model.The tests of underlying assumptions or goodness-of-fit of the MRMs used were described in 26.2% (95% CI: 22.0-30.3) of the articles and 18.5% (95% CI: 14.8-22.1) reported the interaction analysis. Reporting of all items assessed was higher in articles published in journals with a higher impact factor.A low percentage of articles indexed in MEDLINE that used multivariable techniques provided information demonstrating rigorous application of the model selected as an adjustment method. Given the importance of these methods to the final results and conclusions of observational studies, greater rigor is required in reporting the use of MRMs in the scientific literature.

Flexible modeling improves assessment of prognostic value of C-reactive protein in advanced non-small cell lung cancer

PubMed Central

Gagnon, B; Abrahamowicz, M; Xiao, Y; Beauchamp, M-E; MacDonald, N; Kasymjanova, G; Kreisman, H; Small, D

2010-01-01

Background: C-reactive protein (CRP) is gaining credibility as a prognostic factor in different cancers. Cox's proportional hazard (PH) model is usually used to assess prognostic factors. However, this model imposes a priori assumptions, which are rarely tested, that (1) the hazard ratio associated with each prognostic factor remains constant across the follow-up (PH assumption) and (2) the relationship between a continuous predictor and the logarithm of the mortality hazard is linear (linearity assumption). Methods: We tested these two assumptions of the Cox's PH model for CRP, using a flexible statistical model, while adjusting for other known prognostic factors, in a cohort of 269 patients newly diagnosed with non-small cell lung cancer (NSCLC). Results: In the Cox's PH model, high CRP increased the risk of death (HR=1.11 per each doubling of CRP value, 95% CI: 1.03–1.20, P=0.008). However, both the PH assumption (P=0.033) and the linearity assumption (P=0.015) were rejected for CRP, measured at the initiation of chemotherapy, which kept its prognostic value for approximately 18 months. Conclusion: Our analysis shows that flexible modeling provides new insights regarding the value of CRP as a prognostic factor in NSCLC and that Cox's PH model underestimates early risks associated with high CRP. PMID:20234363

Sequential cohort design applying propensity score matching to analyze the comparative effectiveness of atorvastatin and simvastatin in preventing cardiovascular events.

PubMed

Helin-Salmivaara, Arja; Lavikainen, Piia; Aarnio, Emma; Huupponen, Risto; Korhonen, Maarit Jaana

2014-01-01

Sequential cohort design (SCD) applying matching for propensity scores (PS) in accrual periods has been proposed to mitigate bias caused by channeling when calendar time is a proxy for strong confounders. We studied the channeling of patients according to atorvastatin and simvastatin initiation in Finland, starting from the market introduction of atorvastatin in 1998, and explored the SCD PS approach to analyzing the comparative effectiveness of atorvastatin versus simvastatin in the prevention of cardiovascular events (CVE). Initiators of atorvastatin or simvastatin use in the 45-75-year age range in 1998-2006 were characterized by their propensity of receiving atorvastatin over simvastatin, as estimated for 17 six-month periods. Atorvastatin (10 mg) and simvastatin (20 mg) initiators were matched 1∶1 on the PS, as estimated for the whole cohort and within each period. Cox regression models were fitted conventionally, and also for the PS matched cohort and the periodically PS matched cohort, to estimate the hazard ratios (HR) for CVEs. Atorvastatin (10 mg) was associated with a 11%-12% lower incidence of CVE in comparison with simvastatin (20 mg). The HR estimates were the same for a conventional Cox model (0.88, 95% confidence interval 0.85-0.91), for the analysis in which the PS was used to match across all periods and the Cox model was adjusted for strong confounders (0.89, 0.85-0.92), and for the analysis in which PS matching was applied within sequential periods (0.88, 0.84-0.92). The HR from a traditional PS matched analysis was 0.80 (0.77-0.83). The SCD PS approach produced effect estimates similar to those obtained in matching for PS within the whole cohort and adjusting the outcome model for strong confounders, but at the cost of efficiency. A traditional PS matched analysis without further adjustment in the outcome model produced estimates further away from unity.

COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis

PubMed Central

2014-01-01

Background Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas. Methods The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n = 92), ampullary cancer (AC, n = 62) and distal bile duct cancer (DBC, n = 76). COX-2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed. Results COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p = 0.043 in PC, p = 0.011 in AC, p = 0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p = 0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p = 0.002). COX-2 and LNR independently predicted good prognosis in a multivariate model. Conclusions COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis. PMID:24950702

Long-term allopurinol use decreases the risk of prostate cancer in patients with gout: a population-based study.

PubMed

Shih, H-J; Kao, M-C; Tsai, P-S; Fan, Y-C; Huang, C-J

2017-09-01

Clinical observations indicated an increased risk of developing prostate cancer in gout patients. Chronic inflammation is postulated to be one crucial mechanism for prostate carcinogenesis. Allopurinol, a widely used antigout agent, possesses potent anti-inflammation capacity. We elucidated whether allopurinol decreases the risk of prostate cancer in gout patients. We analyzed data retrieved from Taiwan National Health Insurance Database between January 2000 and December 2012. Patients diagnosed with gout during the study period with no history of prostate cancer and who had never used allopurinol were selected. Four allopurinol use cohorts (that is, allopurinol use (>365 days), allopurinol use (181-365 days), allopurinol use (91-180 days) and allopurinol use (31-90 days)) and one cohort without using allopurinol (that is, allopurinol use (No)) were included. The study end point was the diagnosis of new-onset prostate cancer. Multivariable Cox proportional hazards regression and propensity score-adjusted Cox regression models were used to estimate the association between the risk of prostate cancer and allopurinol treatment in gout patients after adjusting for potential confounders. A total of 25 770 gout patients (aged between 40 and 100 years) were included. Multivariable Cox regression analyses revealed that the risk of developing prostate cancer in the allopurinol use (>365 days) cohort was significantly lower than the allopurinol use (No) cohort (adjusted hazard ratio (HR)=0.64, 95% confidence interval (CI)=0.45-0.9, P=0.011). After propensity score adjustment, the trend remained the same (adjusted HR=0.66, 95% CI=0.46-0.93, P=0.019). Long-term (more than 1 year) allopurinol use may associate with a decreased risk of prostate cancer in gout patients.

Toward the understanding of the molecular basis for the inhibition of COX-1 and COX-2 by phenolic compounds present in Uruguayan propolis and grape pomace.

PubMed

Paulino, Margot; Alvareda, Elena; Iribarne, Federico; Miranda, Pablo; Espinosa, Victoria; Aguilera, Sara; Pardo, Helena

2016-12-01

Propolis and grape pomace have significant amounts of phenols which can take part in anti-inflammatory mechanisms. As the cyclooxygenases 1 and 2 (COX-1 and COX-2) are involved in said mechanisms, the possibility for a selective inhibition of COX-2 was analyzed in vitro and in silico. Propolis and grape pomace from Uruguayan species were collected, extracted in hydroalcoholic mixture and analyzed. Based on phenols previously identified, and taking as reference the crystallographic structures of COX-1 and COX-2 in complex with the commercial drug Celecoxib, a molecular docking procedure was devised to adjust 123 phenolic molecular models at the enzyme-binding sites. The most important results of this work are that the extracts have an overall inhibition activity very similar in COX-1 and COX-2, i.e. they do not possess selective inhibition activity for COX-2. Nevertheless, 10 compounds of the phenolic database turned out to be more selective and 94 phenols resulted with similar selectivity than Celecoxib, an outcome that accounts for the overall experimental inhibition measures. Binding site environment observations showed increased polarity in COX-2 as compared with COX-1, suggesting that polarity is the key for selectivity. Accordingly, the screening of molecular contacts pointed to the residues: Arg106, Gln178, Leu338, Ser339, Tyr341, Tyr371, Arg499, Ala502, Val509, and Ser516, which would explain, at the atomic level, the anti-inflammatory effect of the phenolic compounds. Among them, Gln178 and Arg499 appear to be essential for the selective inhibition of COX-2.

COX-2/EGFR expression and survival among women with adenocarcinoma of the lung

PubMed Central

Van Dyke, Alison L.; Cote, Michele L.; Prysak, Geoffrey M.; Claeys, Gina B.; Wenzlaff, Angie S.; Murphy, Valerie C.; Lonardo, Fulvio; Schwartz, Ann G.

2008-01-01

Previous studies suggest that cyclooxygenase-2 (COX-2) expression may predict survival among patients with non-small cell lung cancer. COX-2 may interact with epidermal growth factor receptor (EGFR), suggesting that combined COX-2/EGFR expression may provide predictive value. The extent to which their independent or combined expression is associated with prognosis in women with adenocarcinoma of the lung is unknown. In the present study, we examined relationships between COX-2 expression (n = 238), EGFR expression (n = 158) and dual COX-2/EGFR expression (n = 157) and survival among women with adenocarcinoma of the lung. Overall survival was estimated by constructing Cox proportional hazards models adjusting for other significant variables and stratifying by stage at diagnosis and race. Clinical or demographic parameters were not associated with either COX-2 or EGFR expression. Patients with COX-2-positive tumors tended to have poorer prognosis than did patients with COX-2-negative tumors [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.01–2.78]. African-Americans with COX-2-positive tumors had a statistically non-significant higher risk of death than African-Americans with COX-2-negative tumors (HR 5.58, 95% CI 0.64–48.37). No association between COX-2 expression and survival was observed among Caucasians (HR 1.29, 95% CI 0.72–2.30). EGFR expression was associated with a 44% reduction in the risk of death (HR 0.56, 95% CI 0.32–0.98). COX-2−/EGFR+ tumor expression, but not COX-2+/EGFR+ tumor expression, was associated with survival when compared with other combined expression results. In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung. PMID:18453539

Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients.

PubMed

Markkula, Andrea; Simonsson, Maria; Rosendahl, Ann H; Gaber, Alexander; Ingvar, Christian; Rose, Carsten; Jernström, Helena

2014-10-15

The COX2 rs5277 (306G>C) polymorphism has been associated with inflammation-associated cancers. In breast cancer, tumor COX-2 expression has been associated with increased estrogen levels in estrogen receptor (ER)-positive and activated Akt-pathway in ER-negative tumors. Our study investigated the impact of COX2 genotypes on early breast cancer events and treatment response in relation to tumor ER status and body constitution. In Sweden, between 2002 and 2008, 634 primary breast cancer patients, aged 25-99 years, were included. Disease-free survival was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained preoperatively. Clinical data, patient- and tumor-characteristics were obtained from questionnaires, patients' charts, population registries and pathology reports. Minor allele(C) frequency was 16.1%. Genotype was not linked to COX-2 tumor expression. Median follow-up was 5.1 years. G/G genotype was not associated with early events in patients with ER-positive tumors, adjusted HR 0.77 (0.46-1.29), but conferred an over 4-fold increased risk in patients with ER-negative tumors, adjusted HR 4.41 (1.21-16.02)(p(interaction) = 0.015). Chemotherapy-treated G/G-carriers with a breast volume ≥ 850 ml had an increased risk of early events irrespective of ER status, adjusted HR 8.99 (1.14-70.89). Endocrine-treated C-allele carriers with ER-positive tumors and a breast volume ≥ 850 ml had increased risk of early events, adjusted HR 2.30 (1.12-4.75). COX2 genotype, body constitution and ER status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may identify patients in need of more personalized treatment. © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

Survival analysis of cervical cancer using stratified Cox regression

NASA Astrophysics Data System (ADS)

Purnami, S. W.; Inayati, K. D.; Sari, N. W. Wulan; Chosuvivatwong, V.; Sriplung, H.

2016-04-01

Cervical cancer is one of the mostly widely cancer cause of the women death in the world including Indonesia. Most cervical cancer patients come to the hospital already in an advanced stadium. As a result, the treatment of cervical cancer becomes more difficult and even can increase the death's risk. One of parameter that can be used to assess successfully of treatment is the probability of survival. This study raises the issue of cervical cancer survival patients at Dr. Soetomo Hospital using stratified Cox regression based on six factors such as age, stadium, treatment initiation, companion disease, complication, and anemia. Stratified Cox model is used because there is one independent variable that does not satisfy the proportional hazards assumption that is stadium. The results of the stratified Cox model show that the complication variable is significant factor which influent survival probability of cervical cancer patient. The obtained hazard ratio is 7.35. It means that cervical cancer patient who has complication is at risk of dying 7.35 times greater than patient who did not has complication. While the adjusted survival curves showed that stadium IV had the lowest probability of survival.

Polymorphism in COX-2 modifies the inverse association between Helicobacter pylori seropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study

PubMed Central

2009-01-01

Background Overexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC). One functional SNP, COX-2 -1195G/A, has been reported to mediate susceptibility of ESCC in Chinese populations. In our previous study, the presence of Helicobacter pylori (H. pylori) was found to play a protective role in development of ESCC. The interaction of COX-2 and H. pylori in gastric cancer was well investigated. However, literature on their interaction in ESCC risk is scarce. The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), H. pylori infection and the risk of developing ESCC. Methods One hundred and eighty patients with ESCC and 194 controls were enrolled in this study. Personal data regarding related risk factors, including alcohol consumption, smoking habits and betel quid chewing, were collected via questionnaire. Genotypes of the COX-2 -1195 polymorphism were determined by PCR-based restriction fragment length polymorphism. H. pylori seropositivity was defined by immunochromatographic screening test. Data was analyzed by chi-squared tests and polytomous logistics regression. Results In analysis adjusting for the covariates and confounders, H. pylori seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 – 0.9). COX-2 -1195 AA homozygous was associated with an increased risk of contracting ESCC in comparison with the non-AA group, especially among patients with H. pylori seronegative (adjusted OR ratio: 2.9, 95% CI: 1.2 – 7.3). The effect was strengthened among patients with lower third ESCC (adjusted OR ratio: 6.9, 95% CI 2.1 – 22.5). Besides, H. pylori seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 – 0.9), and the effect was observed to be enhanced for the lower third ESCC patients (AOR ratio: 0.09, 95% CI: 0.02 – 0.47, p for multiplicative interaction 0.008) Conclusion H. pylori seropositivity is inversely associated with the risk of ESCC in Taiwan, and COX-2 -1195 polymorphism plays a role in modifying the influence between H. pylori and ESCC, especially in lower third esophagus. PMID:19463183

Polymorphism in COX-2 modifies the inverse association between Helicobacter pylori seropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study.

PubMed

Hu, Huang-Ming; Kuo, Chao-Hung; Lee, Chien-Hung; Wu, I-Chen; Lee, Ka-Wo; Lee, Jang-Ming; Goan, Yih-Gang; Chou, Shah-Hwa; Kao, Ein-Long; Wu, Ming-Tsang; Wu, Deng-Chyang

2009-05-23

Overexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC). One functional SNP, COX-2 -1195G/A, has been reported to mediate susceptibility of ESCC in Chinese populations. In our previous study, the presence of Helicobacter pylori (H. pylori) was found to play a protective role in development of ESCC. The interaction of COX-2 and H. pylori in gastric cancer was well investigated. However, literature on their interaction in ESCC risk is scarce. The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), H. pylori infection and the risk of developing ESCC. One hundred and eighty patients with ESCC and 194 controls were enrolled in this study. Personal data regarding related risk factors, including alcohol consumption, smoking habits and betel quid chewing, were collected via questionnaire. Genotypes of the COX-2 -1195 polymorphism were determined by PCR-based restriction fragment length polymorphism. H. pylori seropositivity was defined by immunochromatographic screening test. Data was analyzed by chi-squared tests and polytomous logistics regression. In analysis adjusting for the covariates and confounders, H. pylori seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 - 0.9). COX-2 -1195 AA homozygous was associated with an increased risk of contracting ESCC in comparison with the non-AA group, especially among patients with H. pylori seronegative (adjusted OR ratio: 2.9, 95% CI: 1.2 - 7.3). The effect was strengthened among patients with lower third ESCC (adjusted OR ratio: 6.9, 95% CI 2.1 - 22.5). Besides, H. pylori seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 - 0.9), and the effect was observed to be enhanced for the lower third ESCC patients (AOR ratio: 0.09, 95% CI: 0.02 - 0.47, p for multiplicative interaction 0.008) H. pylori seropositivity is inversely associated with the risk of ESCC in Taiwan, and COX-2 -1195 polymorphism plays a role in modifying the influence between H. pylori and ESCC, especially in lower third esophagus.

Antipsychotics and mortality: adjusting for mortality risk scores to address confounding by terminal illness.

PubMed

Park, Yoonyoung; Franklin, Jessica M; Schneeweiss, Sebastian; Levin, Raisa; Crystal, Stephen; Gerhard, Tobias; Huybrechts, Krista F

2015-03-01

To determine whether adjustment for prognostic indices specifically developed for nursing home (NH) populations affect the magnitude of previously observed associations between mortality and conventional and atypical antipsychotics. Cohort study. A merged data set of Medicaid, Medicare, Minimum Data Set (MDS), Online Survey Certification and Reporting system, and National Death Index for 2001 to 2005. Dual-eligible individuals aged 65 and older who initiated antipsychotic treatment in a NH (N=75,445). Three mortality risk scores (Mortality Risk Index Score, Revised MDS Mortality Risk Index, Advanced Dementia Prognostic Tool) were derived for each participant using baseline MDS data, and their performance was assessed using c-statistics and goodness-of-fit tests. The effect of adjusting for these indices in addition to propensity scores (PSs) on the association between antipsychotic medication and mortality was evaluated using Cox models with and without adjustment for risk scores. Each risk score showed moderate discrimination for 6-month mortality, with c-statistics ranging from 0.61 to 0.63. There was no evidence of lack of fit. Imbalances in risk scores between conventional and atypical antipsychotic users, suggesting potential confounding, were much lower within PS deciles than the imbalances in the full cohort. Accounting for each score in the Cox model did not change the relative risk estimates: 2.24 with PS-only adjustment versus 2.20, 2.20, and 2.22 after further adjustment for the three risk scores. Although causality cannot be proven based on nonrandomized studies, this study adds to the body of evidence rejecting explanations other than causality for the greater mortality risk associated with conventional antipsychotics than with atypical antipsychotics. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

The occurrence of Simpson's paradox if site-level effect was ignored in the TREAT Asia HIV Observational Database.

PubMed

Jiamsakul, Awachana; Kerr, Stephen J; Chandrasekaran, Ezhilarasi; Huelgas, Aizobelle; Taecharoenkul, Sineenart; Teeraananchai, Sirinya; Wan, Gang; Ly, Penh Sun; Kiertiburanakul, Sasisopin; Law, Matthew

2016-08-01

In multisite human immunodeficiency virus (HIV) observational cohorts, clustering of observations often occurs within sites. Ignoring clustering may lead to "Simpson's paradox" (SP) where the trend observed in the aggregated data is reversed when the groups are separated. This study aimed to investigate the SP in an Asian HIV cohort and the effects of site-level adjustment through various Cox regression models. Survival time from combination antiretroviral therapy (cART) initiation was analyzed using four Cox models: (1) no site adjustment; (2) site as a fixed effect; (3) stratification through site; and (4) shared frailty on site. A total of 6,454 patients were included from 23 sites in Asia. SP was evident in the year of cART initiation variable. Model (1) shows the hazard ratio (HR) for years 2010-2014 was higher than the HR for 2006-2009, compared to 2003-2005 (HR = 0.68 vs. 0.61). Models (2)-(4) consistently implied greater improvement in survival for those who initiated in 2010-2014 than 2006-2009 contrasting findings from model (1). The effects of other significant covariates on survival were similar across four models. Ignoring site can lead to SP causing reversal of treatment effects. Greater emphasis should be made to include site in survival models when possible. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of Statistical Approaches Dealing with Time-dependent Confounding in Drug Effectiveness Studies

PubMed Central

Karim, Mohammad Ehsanul; Petkau, John; Gustafson, Paul; Platt, Robert W.; Tremlett, Helen

2017-01-01

In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models (MSCMs) are frequently used to deal with such confounding. To avoid some of the problems of fitting MSCM, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as MSCM in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995 – 2008). PMID:27659168

Methodological comparison of marginal structural model, time-varying Cox regression, and propensity score methods: the example of antidepressant use and the risk of hip fracture.

PubMed

Ali, M Sanni; Groenwold, Rolf H H; Belitser, Svetlana V; Souverein, Patrick C; Martín, Elisa; Gatto, Nicolle M; Huerta, Consuelo; Gardarsdottir, Helga; Roes, Kit C B; Hoes, Arno W; de Boer, Antonius; Klungel, Olaf H

2016-03-01

Observational studies including time-varying treatments are prone to confounding. We compared time-varying Cox regression analysis, propensity score (PS) methods, and marginal structural models (MSMs) in a study of antidepressant [selective serotonin reuptake inhibitors (SSRIs)] use and the risk of hip fracture. A cohort of patients with a first prescription for antidepressants (SSRI or tricyclic antidepressants) was extracted from the Dutch Mondriaan and Spanish Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) general practice databases for the period 2001-2009. The net (total) effect of SSRI versus no SSRI on the risk of hip fracture was estimated using time-varying Cox regression, stratification and covariate adjustment using the PS, and MSM. In MSM, censoring was accounted for by inverse probability of censoring weights. The crude hazard ratio (HR) of SSRI use versus no SSRI use on hip fracture was 1.75 (95%CI: 1.12, 2.72) in Mondriaan and 2.09 (1.89, 2.32) in BIFAP. After confounding adjustment using time-varying Cox regression, stratification, and covariate adjustment using the PS, HRs increased in Mondriaan [2.59 (1.63, 4.12), 2.64 (1.63, 4.25), and 2.82 (1.63, 4.25), respectively] and decreased in BIFAP [1.56 (1.40, 1.73), 1.54 (1.39, 1.71), and 1.61 (1.45, 1.78), respectively]. MSMs with stabilized weights yielded HR 2.15 (1.30, 3.55) in Mondriaan and 1.63 (1.28, 2.07) in BIFAP when accounting for censoring and 2.13 (1.32, 3.45) in Mondriaan and 1.66 (1.30, 2.12) in BIFAP without accounting for censoring. In this empirical study, differences between the different methods to control for time-dependent confounding were small. The observed differences in treatment effect estimates between the databases are likely attributable to different confounding information in the datasets, illustrating that adequate information on (time-varying) confounding is crucial to prevent bias. Copyright © 2016 John Wiley & Sons, Ltd.

Illness Perceptions and Mortality in Patients With Gout: A Prospective Observational Study.

PubMed

Serlachius, Anna; Gamble, Greg; House, Meaghan; Vincent, Zoe L; Knight, Julie; Horne, Anne; Taylor, William J; Petrie, Keith J; Dalbeth, Nicola

2017-09-01

To examine whether illness perceptions independently predict mortality in early-onset gout. Between December 2006 and January 2014, a total of 295 participants with early-onset gout (<10 years) were recruited in Auckland and Wellington, New Zealand. The participants were followed up until February 2015, and mortality information was collected. Participants with complete data were included in the current study (n = 242). Cox proportional hazards models were used to examine the association between illness perceptions and mortality risk, after adjustment for covariates associated with disease severity and mortality in gout. In a Cox proportional hazards model adjusted for predictors of disease severity and mortality in gout (number of tophi, serum urate level, and frequency of flares), consequence beliefs, identity beliefs, concern beliefs, and emotional response to gout were associated with all-cause mortality (hazard ratios [HRs] 1.29, 1.15, 1.18, and 1.19, respectively; P < 0.05 for all). In the fully saturated model, the association between consequence beliefs and mortality remained robust after additional adjustment for ethnicity, disease duration, diuretic use, serum creatinine, and pain score (HR 1.18 [95% confidence interval 1.02-1.37]; P = 0.029). Negative beliefs about the impact of gout and severity of symptoms, as well as concerns about gout and the emotional response to gout, were independently associated with all-cause mortality. Illness perceptions are important and potentially modifiable risk factors to target in future interventions. © 2016, American College of Rheumatology.

Comparing initial diagnostic excision biopsy of cutaneous malignant melanoma in primary versus secondary care: A study of Irish National data.

PubMed

Doherty, Sarah M; Jackman, Louise M; Kirwan, John F; Dunne, Deirdre; O'Connor, Kieran G; Rouse, John M

2016-12-01

The incidence of melanoma is rising worldwide. Current Irish guidelines from the National Cancer Control Programme state suspicious pigmented lesions should not be removed in primary care. There are conflicting guidelines and research advising who should remove possible melanomas. To determine whether initial diagnostic excision biopsy of cutaneous malignant melanoma in primary versus secondary care leads to poorer survival. Analysis of data comprising 7116 cases of cutaneous malignant melanoma from the National Cancer Registry Ireland between January 2002 and December 2011. Single predictor variables were examined by the chi-square or Mann-Whitney U test. The effects of single predictor variables on survival were examined by Cox proportionate hazards modelling and a multivariate Cox model of survival based on excision in a non-hospital setting versus hospital setting was derived with adjusted and unadjusted hazard ratios. Over a 10-year period 8.5% of melanomas in Ireland were removed in a non-hospital setting. When comparing melanoma death between the hospital and non-hospital groups, the adjusted hazard ratio was 1.56 (95%CI: 1.08-2.26); (P = .02), indicating a non-inferior outcome for the melanoma cases initially treated in the non-hospital group, after adjustment for significant covariates. This study suggests that initial excision biopsy carried out in general practice does not lead to a poorer outcome. [Box: see text].

Greater Collagen‐Induced Platelet Aggregation Following Cyclooxygenase 1 Inhibition Predicts Incident Acute Coronary Syndromes

PubMed Central

Becker, Diane M.; Yanek, Lisa R.; Faraday, Nauder; Vaidya, Dhananjay; Mathias, Rasika; Kral, Brian G.; Becker, Lewis C.

2014-01-01

Abstract Greater ex vivo platelet aggregation to agonists may identify individuals at risk of acute coronary syndromes (ACS). However, increased aggregation to a specific agonist may be masked by inherent variability in other activation pathways. In this study, we inhibited the cyclooxygenase‐1 (COX1) pathway with 2‐week aspirin therapy and measured residual aggregation to collagen and ADP to determine whether increased aggregation in a non‐COX1 pathway is associated with incident ACS. We assessed ex vivo whole blood platelet aggregation in 1,699 healthy individuals with a family history of early‐onset coronary artery disease followed for 6±1.2 years. Incident ACS events were observed in 22 subjects. Baseline aggregation was not associated with ACS. After COX1 pathway inhibition, collagen‐induced aggregation was significantly greater in participants with ACS compared with those without (29.0 vs. 23.6 ohms, p < 0.001). In Cox proportional hazards models, this association remained significant after adjusting for traditional cardiovascular risk factors (HR = 1.10, 95%CI = 1.06–1.15; p < 0.001). In contrast, ADP‐induced aggregation after COX1 inhibition was not associated with ACS. After COX1 pathway inhibition, subjects with greater collagen‐induced platelet aggregation demonstrated a significant excess risk of incident ACS. These data suggest that platelet activation related to collagen may play an important role in the risk of ACS. PMID:25066685

Comparing a marginal structural model with a Cox proportional hazard model to estimate the effect of time-dependent drug use in observational studies: statin use for primary prevention of cardiovascular disease as an example from the Rotterdam Study.

PubMed

de Keyser, Catherine E; Leening, Maarten J G; Romio, Silvana A; Jukema, J Wouter; Hofman, Albert; Ikram, M Arfan; Franco, Oscar H; Stijnen, Theo; Stricker, Bruno H

2014-11-01

When studying the causal effect of drug use in observational data, marginal structural modeling (MSM) can be used to adjust for time-dependent confounders that are affected by previous treatment. The objective of this study was to compare traditional Cox proportional hazard models (with and without time-dependent covariates) with MSM to study causal effects of time-dependent drug use. The example of primary prevention of cardiovascular disease (CVD) with statins was examined using up to 17.7 years of follow-up from 4,654 participants of the observational prospective population-based Rotterdam Study. In the MSM model, the weight was based on measurements of established cardiovascular risk factors and co-morbidity. In general, we could not demonstrate important differences in results from the Cox models and MSM. Results from analysis on duration of statin use suggested that substantial residual confounding by indication was not accounted for during the period shortly after statin initiation. In conclusion, although on theoretical grounds MSM is an elegant technique, lack of data on the precise time-dependent confounders, such as indication of treatment or other considerations of the prescribing physician jeopardizes the calculation of valid weights. Confounding remains a hurdle in observational effectiveness research on preventive drugs with a multitude of prescription determinants.

Nondestructive Evaluation (NDE) Technology Initiatives (NTIP). Delivery Order 0039: Statistical Comparison of Competing Material Models

DTIC Science & Technology

2003-01-01

adapted from Kass and Rafferty (1995) and Congdon (2001). Page 10 of 57 density adjusted for resin content, z, since resin contributes to the density...c.f.: Congdon , 2001). How to Download the WinBUGS Software Package BUGS was originally a statistical research project at the Medical Research...Likelihood Estimation,” July 2002, working paper to be published. 18) Congdon , Peter, Bayesian Statistical Modeling, Wiley, 2001 19) Cox, D. R. and

Lung cancer incidence and survival among HIV-infected and uninfected women and men.

PubMed

Hessol, Nancy A; Martínez-Maza, Otoniel; Levine, Alexandra M; Morris, Alison; Margolick, Joseph B; Cohen, Mardge H; Jacobson, Lisa P; Seaberg, Eric C

2015-06-19

To determine the lung cancer incidence and survival time among HIV-infected and uninfected women and men. Two longitudinal studies of HIV infection in the United States. Data from 2549 women in the Women's Interagency HIV Study (WIHS) and 4274 men in the Multicenter AIDS Cohort Study (MACS), all with a history of cigarette smoking, were analyzed. Lung cancer incidence rates and incidence rate ratios were calculated using Poisson regression analyses. Survival time was assessed using Kaplan-Meier and Cox proportional-hazard analyses. Thirty-seven women and 23 men developed lung cancer (46 HIV-infected and 14 HIV-uninfected) during study follow-up. In multivariable analyses, the factors that were found to be independently associated with a higher lung cancer incidence rate ratios were older age, less education, 10 or more pack-years of smoking, and a prior diagnosis of AIDS pneumonia (vs. HIV-uninfected women). In an adjusted Cox model that allowed different hazard functions for each cohort, a history of injection drug use was associated with shorter survival, and a lung cancer diagnosis after 2001 was associated with longer survival. In an adjusted Cox model restricted to HIV-infected participants, nadir CD4 lymphocyte cell count less than 200 was associated with shorter survival time. Our data suggest that pulmonary damage and inflammation associated with HIV infection may be causative for the increased risk of lung cancer. Encouraging and assisting younger HIV-infected smokers to quit and to sustain cessation of smoking is imperative to reduce the lung cancer burden in this population.

The effect of delayed graft function on graft and patient survival in kidney transplantation: an approach using competing events analysis.

PubMed

Fonseca, Isabel; Teixeira, Laetitia; Malheiro, Jorge; Martins, La Salete; Dias, Leonídio; Castro Henriques, António; Mendonça, Denisa

2015-06-01

In kidney transplantation, the impact of delayed graft function (DGF) on long-term graft and patient survival is controversial. We examined the impact of DGF on graft and recipient survival by accounting for the possibility that death with graft function may act as a competing risk for allograft failure. We used data from 1281 adult primary deceased-donor kidney recipients whose allografts functioned at least 1 year. The probability of graft loss occurrence is overestimated using the complement of Kaplan-Meier estimates (1-KM). Both the cause-specific Cox proportional hazard regression model (standard Cox) and the subdistribution hazard regression model proposed by Fine and Gray showed that DGF was associated with shorter time to graft failure (csHR = 2.0, P = 0.002; sHR = 1.57, P = 0.009), independent of acute rejection (AR) and after adjusting for traditional factors associated with graft failure. Regarding patient survival, DGF was a predictor of patient death using the cause-specific Cox model (csHR = 1.57, P = 0.029) but not using the subdistribution model. The probability of graft loss from competing end points should not be reported with the 1-KM. Application of a regression model for subdistribution hazard showed that, independent of AR, DGF has a detrimental effect on long-term graft survival, but not on patient survival. © 2015 Steunstichting ESOT.

Resting Heart Rate as Predictor for Left Ventricular Dysfunction and Heart Failure: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

Opdahl, Anders; Venkatesh, Bharath Ambale; Fernandes, Veronica R. S.; Wu, Colin O.; Nasir, Khurram; Choi, Eui-Young; Almeida, Andre L. C.; Rosen, Boaz; Carvalho, Benilton; Edvardsen, Thor; Bluemke, David A.; Lima, Joao A. C.

2014-01-01

OBJECTIVE To investigate the relationship between baseline resting heart rate and incidence of heart failure (HF) and global and regional left ventricular (LV) dysfunction. BACKGROUND The association of resting heart rate to HF and LV function is not well described in an asymptomatic multi-ethnic population. METHODS Participants in the Multi-Ethnic Study of Atherosclerosis had resting heart rate measured at inclusion. Incident HF was registered (n=176) during follow-up (median 7 years) in those who underwent cardiac MRI (n=5000). Changes in ejection fraction (ΔEF) and peak circumferential strain (Δεcc) were measured as markers of developing global and regional LV dysfunction in 1056 participants imaged at baseline and 5 years later. Time to HF (Cox model) and Δεcc and ΔEF (multiple linear regression models) were adjusted for demographics, traditional cardiovascular risk factors, calcium score, LV end-diastolic volume and mass in addition to resting heart rate. RESULTS Cox analysis demonstrated that for 1 bpm increase in resting heart rate there was a 4% greater adjusted relative risk for incident HF (Hazard Ratio: 1.04 (1.02, 1.06 (95% CI); P<0.001). Adjusted multiple regression models demonstrated that resting heart rate was positively associated with deteriorating εcc and decrease in EF, even in analyses when all coronary heart disease events were excluded from the model. CONCLUSION Elevated resting heart rate is associated with increased risk for incident HF in asymptomatic participants in MESA. Higher heart rate is related to development of regional and global LV dysfunction independent of subclinical atherosclerosis and coronary heart disease. PMID:24412444

Reduction of Racial Disparities in Prostate Cancer

DTIC Science & Technology

2007-12-01

anti-inflammatory medication, COX-2 inhibitors, aspirin, anti-TNF medications), and other medications of interest (testosterone, finasteride , alpha...compared to control-patients (mean 123) P=0.01. There were 14 (7%) control-patients who had Finasteride use, with an average of 398.6 doses per...individual. None of the prosate cancer patients had prior finasteride use. In a multiple logistic regression model (Table 2), after adjustment for the

Added prognostic value of CT characteristics and IASLC/ATS/ERS histologic subtype in surgically resected lung adenocarcinomas.

PubMed

Suh, Young Joo; Lee, Hyun-Ju; Kim, Young Tae; Kang, Chang Hyun; Park, In Kyu; Jeon, Yoon Kyung; Chung, Doo Hyun

2018-06-01

Our study investigates the added value of computed tomography (CT) characteristics, histologic subtype classification of the International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS), and genetic mutation for predicting postoperative prognoses of patients who received curative surgical resections for lung adenocarcinoma. We retrospectively enrolled 988 patients who underwent curative resection for invasive lung adenocarcinoma between October 2007 and December 2013. Cox's proportional hazard model was used to explore the risk of recurrence-free survival, based on the combination of conventional prognostic factors, CT characteristics, IASLC/ATS/ERS histologic subtype, and epidermal growth factor receptor (EGFR) mutations. Incremental prognostic values of CT characteristics, histologic subtype, and EGFR mutations over conventional risk factors were measured by C-statistics. During median follow-up period of 44.7 months (25th to 75th percentile 24.6-59.7 months), postoperative recurrence occurred in 248 patients (25.1%). In univariate Cox proportion hazard model, female sex, tumor size and stage, CT characteristics, and predominant histologic subtype were associated with tumor recurrence (P < 0.05). In multivariate Cox regression model adjusted for tumor size and stage, both CT characteristics and histologic subtype were independent tumor recurrence predictors (P < 0.05). Cox proportion hazard models combining CT characteristics or histologic subtype with size and tumor stage showed higher C-indices (0.763 and 0.767, respectively) than size and stage-only models (C-index 0.759, P > 0.05). CT characteristics and histologic subtype have relatively limited added prognostic values over tumor size and stage in surgically resected lung adenocarcinomas. Copyright © 2018 Elsevier B.V. All rights reserved.

Automated Box-Cox Transformations for Improved Visual Encoding.

PubMed

Maciejewski, Ross; Pattath, Avin; Ko, Sungahn; Hafen, Ryan; Cleveland, William S; Ebert, David S

2013-01-01

The concept of preconditioning data (utilizing a power transformation as an initial step) for analysis and visualization is well established within the statistical community and is employed as part of statistical modeling and analysis. Such transformations condition the data to various inherent assumptions of statistical inference procedures, as well as making the data more symmetric and easier to visualize and interpret. In this paper, we explore the use of the Box-Cox family of power transformations to semiautomatically adjust visual parameters. We focus on time-series scaling, axis transformations, and color binning for choropleth maps. We illustrate the usage of this transformation through various examples, and discuss the value and some issues in semiautomatically using these transformations for more effective data visualization.

A method for analyzing clustered interval-censored data based on Cox's model.

PubMed

Kor, Chew-Teng; Cheng, Kuang-Fu; Chen, Yi-Hau

2013-02-28

Methods for analyzing interval-censored data are well established. Unfortunately, these methods are inappropriate for the studies with correlated data. In this paper, we focus on developing a method for analyzing clustered interval-censored data. Our method is based on Cox's proportional hazard model with piecewise-constant baseline hazard function. The correlation structure of the data can be modeled by using Clayton's copula or independence model with proper adjustment in the covariance estimation. We establish estimating equations for the regression parameters and baseline hazards (and a parameter in copula) simultaneously. Simulation results confirm that the point estimators follow a multivariate normal distribution, and our proposed variance estimations are reliable. In particular, we found that the approach with independence model worked well even when the true correlation model was derived from Clayton's copula. We applied our method to a family-based cohort study of pandemic H1N1 influenza in Taiwan during 2009-2010. Using the proposed method, we investigate the impact of vaccination and family contacts on the incidence of pH1N1 influenza. Copyright © 2012 John Wiley & Sons, Ltd.

Drugs to Treat Systemic Lupus Erythematosus: Relationship between Current Use and Cardiovascular Risk Factors

PubMed Central

Rho, Young Hee; Oeser, Annette; Chung, Cecilia P; Morrow, Jason D; Stein, C Michael

2008-01-01

Objectives Cardiovascular risk is increased in patients with systemic lupus erythematosus (SLE). Drugs used to treat SLE can modify traditional cardiovascular risk factors. We examined the effect of selected drugs used in the treatment of SLE on cardiovascular risk factors. Methods We compared systolic and diastolic blood pressure, serum lipid concentrations, glucose, homocysteine, and urinary F2-isoprostane concentrations in 99 patients with lupus who were either current users or non-users of systemic corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective NSAIDs, azathioprine, and methotrexate. Multivariable adjustment was done with linear regression modeling using sex, age and disease activity (SLEDAI) as controlling variables. Results Serum triglyceride concentrations were higher (135.1 ± 61.4 vs. 95.3 ± 47.5 mg/dL, adjusted P = 0.003) in patients receiving corticosteroids. Homocysteine concentrations were marginally higher in patients receiving methotrexate (adjusted P = 0.08). Current use of either NSAIDs or COX-2 inhibitors was not associated with increased cardiovascular risk factors. Current hydroxychloroquine use was not associated with significant alterations in lipid profiles. Conclusions In a non-random sample of patients with SLE, current corticosteroid use was associated with increased triglyceride concentrations, but other drugs had little effect on traditional cardiovascular risk factors. PMID:20157365

Using instrumental variables to estimate a Cox's proportional hazards regression subject to additive confounding

PubMed Central

Tosteson, Tor D.; Morden, Nancy E.; Stukel, Therese A.; O'Malley, A. James

2014-01-01

The estimation of treatment effects is one of the primary goals of statistics in medicine. Estimation based on observational studies is subject to confounding. Statistical methods for controlling bias due to confounding include regression adjustment, propensity scores and inverse probability weighted estimators. These methods require that all confounders are recorded in the data. The method of instrumental variables (IVs) can eliminate bias in observational studies even in the absence of information on confounders. We propose a method for integrating IVs within the framework of Cox's proportional hazards model and demonstrate the conditions under which it recovers the causal effect of treatment. The methodology is based on the approximate orthogonality of an instrument with unobserved confounders among those at risk. We derive an estimator as the solution to an estimating equation that resembles the score equation of the partial likelihood in much the same way as the traditional IV estimator resembles the normal equations. To justify this IV estimator for a Cox model we perform simulations to evaluate its operating characteristics. Finally, we apply the estimator to an observational study of the effect of coronary catheterization on survival. PMID:25506259

Using instrumental variables to estimate a Cox's proportional hazards regression subject to additive confounding.

PubMed

MacKenzie, Todd A; Tosteson, Tor D; Morden, Nancy E; Stukel, Therese A; O'Malley, A James

2014-06-01

The estimation of treatment effects is one of the primary goals of statistics in medicine. Estimation based on observational studies is subject to confounding. Statistical methods for controlling bias due to confounding include regression adjustment, propensity scores and inverse probability weighted estimators. These methods require that all confounders are recorded in the data. The method of instrumental variables (IVs) can eliminate bias in observational studies even in the absence of information on confounders. We propose a method for integrating IVs within the framework of Cox's proportional hazards model and demonstrate the conditions under which it recovers the causal effect of treatment. The methodology is based on the approximate orthogonality of an instrument with unobserved confounders among those at risk. We derive an estimator as the solution to an estimating equation that resembles the score equation of the partial likelihood in much the same way as the traditional IV estimator resembles the normal equations. To justify this IV estimator for a Cox model we perform simulations to evaluate its operating characteristics. Finally, we apply the estimator to an observational study of the effect of coronary catheterization on survival.

Stress Hyperglycemia and Prognosis of Minor Ischemic Stroke and Transient Ischemic Attack: The CHANCE Study (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events).

PubMed

Pan, Yuesong; Cai, Xueli; Jing, Jing; Meng, Xia; Li, Hao; Wang, Yongjun; Zhao, Xingquan; Liu, Liping; Wang, David; Johnston, S Claiborne; Wei, Tiemin; Wang, Yilong

2017-11-01

We aimed to determine the association between stress hyperglycemia and risk of new stroke in patients with a minor ischemic stroke or transient ischemic attack. A subgroup of 3026 consecutive patients from 73 prespecified sites of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) were analyzed. Stress hyperglycemia was measured by glucose/glycated albumin (GA) ratio. Glucose/GA ratio was calculated by fasting plasma glucose divided by GA and categorized into 4 even groups according to the quartiles. The primary outcome was a new stroke (ischemic or hemorrhagic) at 90 days. We assessed the association between glucose/GA ratio and risk of stroke by multivariable Cox regression models adjusted for potential covariates. Among 3026 patients included, a total of 299 (9.9%) new stroke occurred at 3 months. Compared with patients with the lowest quartile, patients with the highest quartile of glucose/GA ratio was associated with an increased risk of stroke at 3 months after adjusted for potential covariates (12.0% versus 9.2%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.06-2.01). Similar results were observed after further adjusted for fasting plasma glucose. We also observed that higher level of glucose/GA ratio was associated with an increased risk of stroke with a threshold of 0.29 using a Cox regression model with restricted cubic spline. Stress hyperglycemia, measured by glucose/GA ratio, was associated with an increased risk of stroke in patients with a minor ischemic stroke or transient ischemic attack. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589. © 2017 American Heart Association, Inc.

Is Genetic Background Important in Lung Cancer Survival?

PubMed Central

Lindström, Linda S.; Hall, Per; Hartman, Mikael; Wiklund, Fredrik; Czene, Kamila

2009-01-01

Background In lung cancer, a patient's survival is poor with a wide variation in survival within the stage of disease. The aim of this study was to investigate the familial concordance in lung cancer survival by means of analyses of pairs with different degrees of familial relationships. Methods Our population-based Swedish family database included three million families and over 58 100 lung cancer patients. We modelled the proband (parent, sibling, spouse) survival utilizing a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. Subsequently, the survival in proband's relative (child, sibling, spouse) was analysed with a Cox model. Findings By use of Cox modelling with 5 years follow-up, we noted a decreased hazard ratio for death in children with good parental survival (Hazard Ratio [HR] = 0.71, 95% CI = 0.51 to 0.99), compared to those with poor parental survival. Also for siblings, a very strong protective effect was seen (HR = 0.14, 95% CI = 0.030 to 0.65). Finally, in spouses no correlation in survival was found. Interpretation Our findings suggest that genetic factors are important in lung cancer survival. In a clinical setting, information on prognosis in a relative may be vital in foreseeing the survival in an individual newly diagnosed with lung cancer. Future molecular studies enhancing the understanding of the underlying mechanisms and pathways are needed. PMID:19478952

Is tree loss associated with cardiovascular-disease risk in the Women's Health Initiative? A natural experiment

Treesearch

Geoffrey H. Donovan; Yvonne L. Michael; Demetrios Gatziolis; Jeffrey P. Prestemon; Eric A. Whitsel

2015-01-01

Data from the Women's Health Initiative were used to quantify the relationship between the loss of trees to an invasive forest pest—the emerald ash borer—and cardiovascular disease. We estimated semi- parametric Cox proportional hazards model of time to cardiovascular disease, adjusting for confounders. We defined the incidence of cardiovascular disease as acute...

The Covariance Adjustment Approaches for Combining Incomparable Cox Regressions Caused by Unbalanced Covariates Adjustment: A Multivariate Meta-Analysis Study.

PubMed

Dehesh, Tania; Zare, Najaf; Ayatollahi, Seyyed Mohammad Taghi

2015-01-01

Univariate meta-analysis (UM) procedure, as a technique that provides a single overall result, has become increasingly popular. Neglecting the existence of other concomitant covariates in the models leads to loss of treatment efficiency. Our aim was proposing four new approximation approaches for the covariance matrix of the coefficients, which is not readily available for the multivariate generalized least square (MGLS) method as a multivariate meta-analysis approach. We evaluated the efficiency of four new approaches including zero correlation (ZC), common correlation (CC), estimated correlation (EC), and multivariate multilevel correlation (MMC) on the estimation bias, mean square error (MSE), and 95% probability coverage of the confidence interval (CI) in the synthesis of Cox proportional hazard models coefficients in a simulation study. Comparing the results of the simulation study on the MSE, bias, and CI of the estimated coefficients indicated that MMC approach was the most accurate procedure compared to EC, CC, and ZC procedures. The precision ranking of the four approaches according to all above settings was MMC ≥ EC ≥ CC ≥ ZC. This study highlights advantages of MGLS meta-analysis on UM approach. The results suggested the use of MMC procedure to overcome the lack of information for having a complete covariance matrix of the coefficients.

Low-dose aspirin, non-steroidal anti-inflammatory drugs, selective COX-2 inhibitors and breast cancer recurrence

PubMed Central

Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P; Lash, Timothy L; Christiansen, Peer; Ejlertsen, Bent; Sørensen, Henrik T

2017-01-01

Background Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors may improve outcomes in breast cancer patients. We investigated the association of aspirin, NSAIDs, and use of selective COX-2 inhibitors with breast cancer recurrence. Methods We identified incident stage I–III Danish breast cancer patients in the Danish Breast Cancer Cooperative Group registry, who were diagnosed during 1996–2008. Prescriptions for aspirin (>99% low-dose aspirin), NSAIDs, and selective COX-2 inhibitors were ascertained from the National Prescription Registry (NPR). Follow-up began on the date of breast cancer primary surgery and continued until the first of recurrence, death, emigration, or 01/01/2013. We used Cox regression models to compute hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) associating prescriptions with recurrence, adjusting for confounders. Results We identified 34,188 breast cancer patients with 233,130 person-years of follow-up. Median follow-up was 7.1 years; 5,325 patients developed recurrent disease. Use of aspirin, NSAIDs, or selective COX-2 inhibitors was not associated with the rate of recurrence (HRadjusted aspirin=1.0, 95% CI=0.90, 1.1; NSAIDs=0.99, 95% CI=0.92, 1.1; selective COX-2 inhibitors=1.1, 95% CI=0.98, 1.2), relative to non-use. Pre-diagnostic use of the exposure drugs was associated with reduced recurrence rates (HRaspirin=0.92, 95%CI=0.82, 1.0; HRNSAIDs=0.86, 95%CI=0.81, 0.91; HRsCOX-2inhibitors=0.88, 95%CI=0.83, 0.95). Conclusions This prospective cohort study suggests that post-diagnostic prescriptions for aspirin, NSAIDs, and selective COX-2 inhibitors have little or no association with the rate of breast cancer recurrence. Pre-diagnostic use of the drugs was, however, associated with a reduced rate of breast cancer recurrence. PMID:27007644

Comparative risk of cerebrovascular adverse events in community-dwelling older adults using risperidone, olanzapine and quetiapine: a multiple propensity score-adjusted retrospective cohort study.

PubMed

Chatterjee, Satabdi; Chen, Hua; Johnson, Michael L; Aparasu, Rajender R

2012-10-01

Atypical antipsychotic agents have been associated with cerebrovascular adverse events, particularly in elderly dementia patients. However, limited evidence exists regarding comparative cerebrovascular profiles of individual atypical agents, particularly in community settings. The objective of this study was to evaluate the risk of cerebrovascular events associated with use of risperidone, olanzapine and quetiapine in community-dwelling older adults in the US. A propensity score-adjusted retrospective cohort design involving the IMS LifeLink™ Health Plan Claims Database was used for the study. The study population included all older adults (aged ≥50 years) who initiated risperidone, olanzapine or quetiapine anytime during 1 July 2000 to 30 June 2008. Patients were followed until hospitalization or an emergency room visit for a cerebrovascular event, or the end of the study period, whichever occurred earlier. The Cox proportional hazard regression model with time-varying covariates was used to evaluate the risk of cerebrovascular events during the follow-up period, using olanzapine as the reference. The covariates adjusted for in the final model included multiple propensity scores and exposure to other medications that could be associated with the risk of cerebrovascular events. A total of 2,458 cerebrovascular events were identified in the study cohort: 1,081 (21.38%) for risperidone users, 816 (18.75%) for olanzapine users and 561 (21.05%) for quetiapine users. After adjusting for propensity scores and other covariates, the Cox proportional hazard model revealed that use of quetiapine [hazard ratio (HR) 0.88; 95% CI 0.78, 0.99] but not risperidone (HR 1.05; 95% CI 0.95, 1.16) was associated with a decrease in the risk of cerebrovascular adverse events compared with olanzapine. The study suggested that quetiapine use may be associated with a moderately lower risk of cerebrovascular events than olanzapine in older adults. Prescribers should closely monitor the patients treated with atypical agents for the incidence of cerebrovascular adverse events.

Racial differences in tumor stage and survival for colorectal cancer in an insured population.

PubMed

Doubeni, Chyke A; Field, Terry S; Buist, Diana S M; Korner, Eli J; Bigelow, Carol; Lamerato, Lois; Herrinton, Lisa; Quinn, Virginia P; Hart, Gene; Hornbrook, Mark C; Gurwitz, Jerry H; Wagner, Edward H

2007-02-01

Despite declining death rates from colorectal cancer (CRC), racial disparities have continued to increase. In this study, the authors examined disparities in a racially diverse group of insured patients. This study was conducted among patients who were diagnosed with CRC from 1993 to 1998, when they were enrolled in integrated healthcare systems. Patients were identified from tumor registries and were linked to information in administrative databases. The sample was restricted to non-Hispanic whites (n = 10,585), non-Hispanic blacks (n = 1479), Hispanics (n = 985), and Asians/Pacific Islanders (n = 909). Differences in tumor stage and survival were analyzed by using polytomous and Cox regression models, respectively. In multivariable regression analyses, blacks were more likely than whites to have distant or unstaged tumors. In Cox models that were adjusted for nonmutable factors, blacks had a higher risk of death from CRC (hazard ratio [HR], 1.17; 95% confidence interval [95% CI], 1.06-1.30). Hispanics had a risk of death similar to whites (HR, 1.04; 95% CI, 0.92-1.18), whereas Asians/Pacific Islanders had a lower risk of death from CRC (HR, 0.89; 95% CI, 0.78-1.02). Adjustment for tumor stage decreased the HR to 1.11 for blacks, and the addition of receipt of surgical therapy to the model decreased the HR further to 1.06. The HR among Hispanics and Asians/Pacific Islanders was stable to adjustment for tumor stage and surgical therapy. The relation between race and survival from CRC was complex and appeared to be related to differences in tumor stage and therapy received, even in insured populations. Targeted interventions to improve the use of effective screening and treatment among vulnerable populations may be needed to eliminate disparities in CRC. (c) 2007 American Cancer Society.

Population-based cohort study investigating the correlation of diabetes mellitus with pleural empyema in adults in Taiwan.

PubMed

Lai, Shih-Wei; Lin, Cheng-Li; Liao, Kuan-Fu

2017-09-01

We assessed the association between diabetes mellitus and the risk of pleural empyema in Taiwan.A population-based retrospective cohort study was conducted using the database of the Taiwan National Health Insurance Program. There were 28,802 subjects aged 20 to 84 years who were newly diagnosed with diabetes mellitus from 2000 to 2010 as the diabetes group and 114,916 randomly selected subjects without diabetes mellitus as the non-diabetes group. The diabetes group and the non-diabetes group were matched by sex, age, comorbidities, and the year of index date. The incidence of pleural empyema at the end of 2011 was estimated. A multivariable Cox proportional hazards regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) for pleural empyema associated with diabetes mellitus.The overall incidence of pleural empyema was 1.65-fold higher in the diabetes group than that in the non-diabetes group (1.58 vs 0.96 per 10,000 person-years, 95% CI 1.57-1.72). After adjusting for confounders, a multivariable Cox proportional hazards regression model revealed that the adjusted HR of pleural empyema was 1.71 in subjects with diabetes mellitus (95% CI 1.16-2.51), compared with those without diabetes mellitus. In further analysis, even in the absence of any comorbidity, the adjusted HR was 1.99 for subjects with diabetes mellitus alone (95% CI 1.18-3.38).Diabetic patients confer a 1.71-fold increased hazard of developing pleural empyema. Even in the absence of any comorbidity, the risk remains existent.

Prescriptions for cyclooxygenase-2 inhibitors and other nonsteroidal anti-inflammatory agents in a medicaid managed care population: African Americans versus Caucasians.

PubMed

Shaya, Fadia T; Blume, Steven

2005-01-01

To determine whether race is a predictor of a patient's likelihood of being prescribed selective cyclooxygenase-2 inhibitors (COX-2s) versus other nonsteroidal anti-inflammatory agents (NSAIDs) in Medicaid managed care plans (MCO). All medical and prescription claims for Medicaid MCO enrollees receiving at least one prescription for a COX-2 or NSAID between January 2000 and June 2002 were retrieved. Selected for study were adults claiming at least one COX-2 prescription or NSAID prescription with a minimum 30 days of supply after June 2000; having 60 total days of supply or more over the study period was also required for study inclusion. The probability of being prescribed a COX-2 was estimated as a logistic function of patient age, gender, race, city/suburban/rural residence, and history of rheumatoid arthritis, osteoarthritis, chronic back pain, acute pains, gastrointestinal problems, use of anticoagulants or corticosteroids, and comorbidities. Of the 16,868 enrollees meeting the selection criteria, 4,005 (24%) were prescribed a COX-2 and 12,863 another NSAID. Half of those studied were African American, three-quarters were female, and a third were 50-64 years old. After adjusting for confounders, odds of a COX-2 prescription were a third less for African Americans and other races compared to Caucasians (OR, 0.67; 95% confidence intervals, 0.62-0.73). Patient race is a significant predictor of COX-2 prescriptions in the Medicaid population, even after adjusting for other demographic and clinical variables. Cost to the patient was not a factor, as the patient copayment was 1 US dollar for any prescription.

Preadmission use of nonaspirin nonsteroidal anti-inflammatory drugs and 30-day stroke mortality.

PubMed

Schmidt, Morten; Hováth-Puhó, Erzsébet; Christiansen, Christian Fynbo; Petersen, Karin L; Bøtker, Hans Erik; Sørensen, Henrik Toft

2014-11-25

To examine whether preadmission use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) influenced 30-day stroke mortality. We conducted a nationwide population-based cohort study. Using medical databases, we identified all first-time stroke hospitalizations in Denmark between 2004 and 2012 (n = 100,043) and subsequent mortality. We categorized NSAID use as current (prescription redemption within 60 days before hospital admission), former, and nonuse. Current use was further classified as new or long-term use. Cox regression was used to compute hazard ratios (HRs) of death within 30 days, controlling for potential confounding through multivariable adjustment and propensity score matching. The adjusted HR of death for ischemic stroke was 1.19 (95% confidence interval [CI]: 1.02-1.38) for current users of selective cyclooxygenase (COX)-2 inhibitors compared with nonusers, driven by the effect among new users (1.42, 95% CI: 1.14-1.77). Comparing the different COX-2 inhibitors, the HR was driven by new use of older traditional COX-2 inhibitors (1.42, 95% CI: 1.14-1.78) among which it was 1.53 (95% CI: 1.02-2.28) for etodolac and 1.28 (95% CI: 0.98-1.68) for diclofenac. The propensity score-matched analysis supported the association between older COX-2 inhibitors and ischemic stroke mortality. There was no association for former users. Mortality from intracerebral hemorrhage was not associated with use of nonselective NSAIDs or COX-2 inhibitors. Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke. Use of nonselective NSAIDs at time of admission was not associated with mortality from ischemic stroke or intracerebral hemorrhage. © 2014 American Academy of Neurology.

Estimating restricted mean treatment effects with stacked survival models

PubMed Central

Wey, Andrew; Vock, David M.; Connett, John; Rudser, Kyle

2016-01-01

The difference in restricted mean survival times between two groups is a clinically relevant summary measure. With observational data, there may be imbalances in confounding variables between the two groups. One approach to account for such imbalances is estimating a covariate-adjusted restricted mean difference by modeling the covariate-adjusted survival distribution, and then marginalizing over the covariate distribution. Since the estimator for the restricted mean difference is defined by the estimator for the covariate-adjusted survival distribution, it is natural to expect that a better estimator of the covariate-adjusted survival distribution is associated with a better estimator of the restricted mean difference. We therefore propose estimating restricted mean differences with stacked survival models. Stacked survival models estimate a weighted average of several survival models by minimizing predicted error. By including a range of parametric, semi-parametric, and non-parametric models, stacked survival models can robustly estimate a covariate-adjusted survival distribution and, therefore, the restricted mean treatment effect in a wide range of scenarios. We demonstrate through a simulation study that better performance of the covariate-adjusted survival distribution often leads to better mean-squared error of the restricted mean difference although there are notable exceptions. In addition, we demonstrate that the proposed estimator can perform nearly as well as Cox regression when the proportional hazards assumption is satisfied and significantly better when proportional hazards is violated. Finally, the proposed estimator is illustrated with data from the United Network for Organ Sharing to evaluate post-lung transplant survival between large and small-volume centers. PMID:26934835

Box–Cox Transformation and Random Regression Models for Fecal egg Count Data

PubMed Central

da Silva, Marcos Vinícius Gualberto Barbosa; Van Tassell, Curtis P.; Sonstegard, Tad S.; Cobuci, Jaime Araujo; Gasbarre, Louis C.

2012-01-01

Accurate genetic evaluation of livestock is based on appropriate modeling of phenotypic measurements. In ruminants, fecal egg count (FEC) is commonly used to measure resistance to nematodes. FEC values are not normally distributed and logarithmic transformations have been used in an effort to achieve normality before analysis. However, the transformed data are often still not normally distributed, especially when data are extremely skewed. A series of repeated FEC measurements may provide information about the population dynamics of a group or individual. A total of 6375 FEC measures were obtained for 410 animals between 1992 and 2003 from the Beltsville Agricultural Research Center Angus herd. Original data were transformed using an extension of the Box–Cox transformation to approach normality and to estimate (co)variance components. We also proposed using random regression models (RRM) for genetic and non-genetic studies of FEC. Phenotypes were analyzed using RRM and restricted maximum likelihood. Within the different orders of Legendre polynomials used, those with more parameters (order 4) adjusted FEC data best. Results indicated that the transformation of FEC data utilizing the Box–Cox transformation family was effective in reducing the skewness and kurtosis, and dramatically increased estimates of heritability, and measurements of FEC obtained in the period between 12 and 26 weeks in a 26-week experimental challenge period are genetically correlated. PMID:22303406

Box-Cox Transformation and Random Regression Models for Fecal egg Count Data.

PubMed

da Silva, Marcos Vinícius Gualberto Barbosa; Van Tassell, Curtis P; Sonstegard, Tad S; Cobuci, Jaime Araujo; Gasbarre, Louis C

2011-01-01

Accurate genetic evaluation of livestock is based on appropriate modeling of phenotypic measurements. In ruminants, fecal egg count (FEC) is commonly used to measure resistance to nematodes. FEC values are not normally distributed and logarithmic transformations have been used in an effort to achieve normality before analysis. However, the transformed data are often still not normally distributed, especially when data are extremely skewed. A series of repeated FEC measurements may provide information about the population dynamics of a group or individual. A total of 6375 FEC measures were obtained for 410 animals between 1992 and 2003 from the Beltsville Agricultural Research Center Angus herd. Original data were transformed using an extension of the Box-Cox transformation to approach normality and to estimate (co)variance components. We also proposed using random regression models (RRM) for genetic and non-genetic studies of FEC. Phenotypes were analyzed using RRM and restricted maximum likelihood. Within the different orders of Legendre polynomials used, those with more parameters (order 4) adjusted FEC data best. Results indicated that the transformation of FEC data utilizing the Box-Cox transformation family was effective in reducing the skewness and kurtosis, and dramatically increased estimates of heritability, and measurements of FEC obtained in the period between 12 and 26 weeks in a 26-week experimental challenge period are genetically correlated.

Self-Regulation and Executive Functioning as Related to Survival in Motor Neuron Disease: Preliminary Findings.

PubMed

Garcia-Willingham, Natasha E; Roach, Abbey R; Kasarskis, Edward J; Segerstrom, Suzanne C

2018-05-16

Disease progression varies widely among patients with motor neuron disease (MND). Patients with MND and coexisting dementia have shorter survival. However, implications of mild cognitive and behavioral difficulties are unclear. The present study examined the relative contribution of executive functioning and self-regulation difficulties on survival over a 6-year period among patients with MND, who scored largely within normal limits on cognitive and behavioral indices. Patients with MND (N=37, age=59.97±11.57, 46% female) completed the Wisconsin Card Sorting Task (WCST) as an executive functioning perseveration index. The Behavior Rating Inventory of Executive Functions (BRIEF-A) was used as a behavioral measure of self-regulation in two subdomains self-regulatory behavior (Behavioral Regulation) and self-regulatory problem-solving (Metacognition). Cox proportional hazard regression analyses were used. In total, 23 patients died during follow-up. In Cox proportional hazard regressions adjusted for a priori covariates, each 10-point T-score increment in patient-reported BRIEF-A self-regulatory behavior and problem-solving difficulties increased mortality risk by 94% and103%, respectively (adjusted HR=1.94, 95% CI [1.07, 3.52]; adjusted HR=2.03, 95% CI [1.19, 3.48]). In sensitivity analyses, patient-reported self-regulatory problem-solving remained significant independent of disease severity and a priori covariates (adjusted HR=1.68, 95% CI [1.01, 2.78], though the predictive value of self-regulatory behavior was attenuated in adjusted models (HR=1.67, 95% CI [0.85, 3.27). Caregiver-reported BRIEF-A ratings of patients and WCST perseverative errors did not significantly predict survival. Preliminary evidence suggests patient-reported self-regulatory problem-solving difficulties indicate poorer prognosis in MND. Further research is needed to uncover mechanisms that negatively affect patient survival.

Intra-individual reaction time variability and all-cause mortality over 17 years: a community-based cohort study.

PubMed

Batterham, Philip J; Bunce, David; Mackinnon, Andrew J; Christensen, Helen

2014-01-01

very few studies have examined the association between intra-individual reaction time variability and subsequent mortality. Furthermore, the ability of simple measures of variability to predict mortality has not been compared with more complex measures. a prospective cohort study of 896 community-based Australian adults aged 70+ were interviewed up to four times from 1990 to 2002, with vital status assessed until June 2007. From this cohort, 770-790 participants were included in Cox proportional hazards regression models of survival. Vital status and time in study were used to conduct survival analyses. The mean reaction time and three measures of intra-individual reaction time variability were calculated separately across 20 trials of simple and choice reaction time tasks. Models were adjusted for a range of demographic, physical health and mental health measures. greater intra-individual simple reaction time variability, as assessed by the raw standard deviation (raw SD), coefficient of variation (CV) or the intra-individual standard deviation (ISD), was strongly associated with an increased hazard of all-cause mortality in adjusted Cox regression models. The mean reaction time had no significant association with mortality. intra-individual variability in simple reaction time appears to have a robust association with mortality over 17 years. Health professionals such as neuropsychologists may benefit in their detection of neuropathology by supplementing neuropsychiatric testing with the straightforward process of testing simple reaction time and calculating raw SD or CV.

Association of educational attainment with chronic disease and mortality: the Kidney Early Evaluation Program (KEEP).

PubMed

Choi, Andy I; Weekley, Cristin C; Chen, Shu-Cheng; Li, Suying; Tamura, Manjula Kurella; Norris, Keith C; Shlipak, Michael G

2011-08-01

Recent reports have suggested a close relationship between education and health, including mortality, in the United States. Observational cohort. We studied 61,457 participants enrolled in a national health screening initiative, the National Kidney Foundation's Kidney Early Evaluation Program (KEEP). Self-reported educational attainment. Chronic diseases (hypertension, diabetes, cardiovascular disease, reduced kidney function, and albuminuria) and mortality. We evaluated cross-sectional associations between self-reported educational attainment with the chronic diseases listed using logistic regression models adjusted for demographics, access to care, behaviors, and comorbid conditions. The association of educational attainment with survival was determined using multivariable Cox proportional hazards regression. Higher educational attainment was associated with a lower prevalence of each of the chronic conditions listed. In multivariable models, compared with persons not completing high school, college graduates had a lower risk of each chronic condition, ranging from 11% lower odds of decreased kidney function to 37% lower odds of cardiovascular disease. During a mean follow-up of 3.9 (median, 3.7) years, 2,384 (4%) deaths occurred. In the fully adjusted Cox model, those who had completed college had 24% lower mortality compared with participants who had completed at least some high school. Lack of income data does not allow us to disentangle the independent effects of education from income. In this diverse contemporary cohort, higher educational attainment was associated independently with a lower prevalence of chronic diseases and short-term mortality in all age and race/ethnicity groups. Published by Elsevier Inc.

Public injury prevention system in the Italian manufacturing sector: What types of inspection are more effective?

PubMed

Farina, Elena; Bena, Antonella; Fedeli, Ugo; Mastrangelo, Giuseppe; Veronese, Michela; Agnesi, Roberto

2016-04-01

Literature suggests that more research is needed to clarify the effect of workplace inspections by governmental officers on injury rates. This paper aims to compare comprehensive and partial inspections in Italian manufacturing companies. Survival analysis was applied to the period free from injuries following inspection by means of the Kaplan-Meier method and of Cox models. Kaplan-Meier curves show that, compared to companies with a partial inspection, companies which had a comprehensive inspection had a higher survival through the entire period. Adjusting for confounders, the Cox model confirms a significant preventive effect of comprehensive inspection for companies with 10-30 employees, but not for those with >30 employees. The results suggest that the effect on injuries is greater if all aspects of safety are addressed during the inspection instead of focusing on a single aspect. These findings are interesting because they can help in planning effective prevention activities. © 2016 Wiley Periodicals, Inc.

Racial differences in risks for first cardiovascular events and noncardiovascular death: the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis.

PubMed

Feinstein, Matthew; Ning, Hongyan; Kang, Joseph; Bertoni, Alain; Carnethon, Mercedes; Lloyd-Jones, Donald M

2012-07-03

No studies have compared first cardiovascular disease (CVD) events and non-CVD death between races in a competing risks framework, which examines risks for numerous events simultaneously. We used competing Cox models to estimate hazards for first CVD events and non-CVD death within and between races in 3 multicenter, National Heart, Lung, and Blood Institute-sponsored cohorts. Of 14 569 Atherosclerosis Risk in Communities (ARIC) study participants aged 45 to 64 years with mean follow-up of 10.5 years, 11.6% had CVD and 5.0% had non-CVD death as first events; among 4237 Cardiovascular Health Study (CHS) study participants aged 65 to 84 years and followed for 8.5 years, these figures were 43.2% and 15.7%, respectively. Middle-aged blacks were significantly more likely than whites to experience any CVD as a first event; this disparity disappeared by older adulthood and after adjustment for CVD risk factors. The pattern of results was similar for Multi-Ethnic Study of Atherosclerosis (MESA) participants. Traditional Cox and competing risks models yielded different results for coronary heart disease risk. Black men appeared somewhat more likely than white men to experience coronary heart disease with use of a standard Cox model (hazard ratio 1.06; 95% CI 0.90, 1.26), whereas they appeared less likely than white men to have a first coronary heart disease event with use of a competing risks model (hazard ratio, 0.77; 95% CI, 0.60, 1.00). CVD affects blacks at an earlier age than whites; this may be attributable in part to elevated CVD risk factor levels among blacks. Racial disparities in first CVD incidence disappear by older adulthood. Competing risks analyses may yield somewhat different results than traditional Cox models and provide a complementary approach to examining risks for first CVD events.

Association of Periodontitis and Subsequent Depression: A Nationwide Population-Based Study.

PubMed

Hsu, Chih-Chao; Hsu, Yi-Chao; Chen, Hsuan-Ju; Lin, Che-Chen; Chang, Kuang-Hsi; Lee, Chang-Yin; Chong, Lee-Won; Kao, Chia-Hung

2015-12-01

Periodontitis is a systemic and chronic inflammatory disease associated with multiple physical conditions. Distress and depression are other problems affecting the progression of periodontitis. However, the causal relationship between depression and periodontitis has not been adequately investigated. This aim of this study was to determine the association between periodontitis and the subsequent development of depression.We identified 12,708 patients with newly diagnosed periodontitis from 2000 to 2005 and 50,832 frequency-matched individuals without periodontitis. Both groups were followed until diagnosed with depression, withdrawal from the National Health Insurance program, or the end of 2011. The association between periodontitis and depressio was analyzed using Cox proportional hazard regression models.The incidence density rate of depression was higher in the periodontitis group than in the nonperiodontitis group, with an adjusted hazard ratio of 1.73 (95% confidence interval 1.58-1.89) when adjusting for sex, age, and comorbidity. Cox models revealed that periodontitis was an independent risk factor for depression in patients, except for comorbidities of diabetes mellitus (DM), alcohol abuse, and cancer.Periodontitis may increase the risk of subsequent depression and was suggested an independent risk factor regardless of sex, age, and most comorbidities. However, DM, alcohol abuse, and cancer may prevent the development of subsequent depression because of DM treatment, the paradoxical effect of alcohol, and emotional distress to cancer, respectively. Prospective studies on the relationship between periodontitis and depression are warranted.

Association of Periodontitis and Subsequent Depression

PubMed Central

Hsu, Chih-Chao; Hsu, Yi-Chao; Chen, Hsuan-Ju; Lin, Che-Chen; Chang, Kuang-Hsi; Lee, Chang-Yin; Chong, Lee-Won; Kao, Chia-Hung

2015-01-01

Abstract Periodontitis is a systemic and chronic inflammatory disease associated with multiple physical conditions. Distress and depression are other problems affecting the progression of periodontitis. However, the causal relationship between depression and periodontitis has not been adequately investigated. This aim of this study was to determine the association between periodontitis and the subsequent development of depression. We identified 12,708 patients with newly diagnosed periodontitis from 2000 to 2005 and 50,832 frequency-matched individuals without periodontitis. Both groups were followed until diagnosed with depression, withdrawal from the National Health Insurance program, or the end of 2011. The association between periodontitis and depressio was analyzed using Cox proportional hazard regression models. The incidence density rate of depression was higher in the periodontitis group than in the nonperiodontitis group, with an adjusted hazard ratio of 1.73 (95% confidence interval 1.58–1.89) when adjusting for sex, age, and comorbidity. Cox models revealed that periodontitis was an independent risk factor for depression in patients, except for comorbidities of diabetes mellitus (DM), alcohol abuse, and cancer. Periodontitis may increase the risk of subsequent depression and was suggested an independent risk factor regardless of sex, age, and most comorbidities. However, DM, alcohol abuse, and cancer may prevent the development of subsequent depression because of DM treatment, the paradoxical effect of alcohol, and emotional distress to cancer, respectively. Prospective studies on the relationship between periodontitis and depression are warranted. PMID:26705230

Low-level Environmental Metals and Metalloids and Incident Pregnancy Loss

PubMed Central

Buck Louis, Germaine M.; Smarr, Melissa M.; Sundaram, Rajeshwari; Steuerwald, Amy J.; Sapra, Katherine J.; Lu, Zhaohui; Parsons, Patrick J.

2017-01-01

Environmental exposure to metals and metalloids is associated with pregnancy loss in some but not all studies. We assessed arsenic, cadmium, mercury, and lead concentrations in 501 couples upon trying for pregnancy and followed them throughout pregnancy to estimate the risk of incident pregnancy loss. Using Cox proportional hazard models, we estimated hazard ratios (HR) and 95% confidence intervals (CIs) for pregnancy loss after covariate adjustment for each partner modeled individually then we jointly modeled both partners’ concentrations. Incidence of pregnancy loss was 28%. In individual partner models, the highest adjusted HRs were observed for female and male blood cadmium (HR=1.08; CI 0.81, 1.44; HR=1.09; 95% CI 0.84, 1.41, respectively). In couple based models, neither partner’s blood cadmium concentrations were associated with loss (HR=1.01; 95% CI 0.75, 1.37; HR=0.92; CI 0.68, 1.25, respectively). We observed no evidence of a significant relation between metal(loids) at environmentally relevant concentrations and pregnancy loss. PMID:28163209

Low-level environmental metals and metalloids and incident pregnancy loss.

PubMed

Buck Louis, Germaine M; Smarr, Melissa M; Sundaram, Rajeshwari; Steuerwald, Amy J; Sapra, Katherine J; Lu, Zhaohui; Parsons, Patrick J

2017-04-01

Environmental exposure to metals and metalloids is associated with pregnancy loss in some but not all studies. We assessed arsenic, cadmium, mercury, and lead concentrations in 501 couples upon trying for pregnancy and followed them throughout pregnancy to estimate the risk of incident pregnancy loss. Using Cox proportional hazard models, we estimated hazard ratios (HR) and 95% confidence intervals (CIs) for pregnancy loss after covariate adjustment for each partner modeled individually then we jointly modeled both partners' concentrations. Incidence of pregnancy loss was 28%. In individual partner models, the highest adjusted HRs were observed for female and male blood cadmium (HR=1.08; CI 0.81, 1.44; HR=1.09; 95% CI 0.84, 1.41, respectively). In couple based models, neither partner's blood cadmium concentrations were associated with loss (HR=1.01; 95% CI 0.75, 1.37; HR=0.92; CI 0.68, 1.25, respectively). We observed no evidence of a significant relation between metal(loids) at these environmentally relevant concentrations and pregnancy loss. Published by Elsevier Inc.

Association of Protein Translation and Extracellular Matrix Gene Sets with Breast Cancer Metastasis: Findings Uncovered on Analysis of Multiple Publicly Available Datasets Using Individual Patient Data Approach.

PubMed

Chowdhury, Nilotpal; Sapru, Shantanu

2015-01-01

Microarray analysis has revolutionized the role of genomic prognostication in breast cancer. However, most studies are single series studies, and suffer from methodological problems. We sought to use a meta-analytic approach in combining multiple publicly available datasets, while correcting for batch effects, to reach a more robust oncogenomic analysis. The aim of the present study was to find gene sets associated with distant metastasis free survival (DMFS) in systemically untreated, node-negative breast cancer patients, from publicly available genomic microarray datasets. Four microarray series (having 742 patients) were selected after a systematic search and combined. Cox regression for each gene was done for the combined dataset (univariate, as well as multivariate - adjusted for expression of Cell cycle related genes) and for the 4 major molecular subtypes. The centre and microarray batch effects were adjusted by including them as random effects variables. The Cox regression coefficients for each analysis were then ranked and subjected to a Gene Set Enrichment Analysis (GSEA). Gene sets representing protein translation were independently negatively associated with metastasis in the Luminal A and Luminal B subtypes, but positively associated with metastasis in Basal tumors. Proteinaceous extracellular matrix (ECM) gene set expression was positively associated with metastasis, after adjustment for expression of cell cycle related genes on the combined dataset. Finally, the positive association of the proliferation-related genes with metastases was confirmed. To the best of our knowledge, the results depicting mixed prognostic significance of protein translation in breast cancer subtypes are being reported for the first time. We attribute this to our study combining multiple series and performing a more robust meta-analytic Cox regression modeling on the combined dataset, thus discovering 'hidden' associations. This methodology seems to yield new and interesting results and may be used as a tool to guide new research.

Association of Protein Translation and Extracellular Matrix Gene Sets with Breast Cancer Metastasis: Findings Uncovered on Analysis of Multiple Publicly Available Datasets Using Individual Patient Data Approach

PubMed Central

Chowdhury, Nilotpal; Sapru, Shantanu

2015-01-01

Introduction Microarray analysis has revolutionized the role of genomic prognostication in breast cancer. However, most studies are single series studies, and suffer from methodological problems. We sought to use a meta-analytic approach in combining multiple publicly available datasets, while correcting for batch effects, to reach a more robust oncogenomic analysis. Aim The aim of the present study was to find gene sets associated with distant metastasis free survival (DMFS) in systemically untreated, node-negative breast cancer patients, from publicly available genomic microarray datasets. Methods Four microarray series (having 742 patients) were selected after a systematic search and combined. Cox regression for each gene was done for the combined dataset (univariate, as well as multivariate – adjusted for expression of Cell cycle related genes) and for the 4 major molecular subtypes. The centre and microarray batch effects were adjusted by including them as random effects variables. The Cox regression coefficients for each analysis were then ranked and subjected to a Gene Set Enrichment Analysis (GSEA). Results Gene sets representing protein translation were independently negatively associated with metastasis in the Luminal A and Luminal B subtypes, but positively associated with metastasis in Basal tumors. Proteinaceous extracellular matrix (ECM) gene set expression was positively associated with metastasis, after adjustment for expression of cell cycle related genes on the combined dataset. Finally, the positive association of the proliferation-related genes with metastases was confirmed. Conclusion To the best of our knowledge, the results depicting mixed prognostic significance of protein translation in breast cancer subtypes are being reported for the first time. We attribute this to our study combining multiple series and performing a more robust meta-analytic Cox regression modeling on the combined dataset, thus discovering 'hidden' associations. This methodology seems to yield new and interesting results and may be used as a tool to guide new research. PMID:26080057

Adiponectin and Mortality in Smokers and Non-Smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

PubMed

Delgado, Graciela E; Siekmeier, Rüdiger; März, Winfried; Kleber, Marcus E

2016-01-01

Cardiovascular diseases (CVD) are an important cause of morbidity and mortality worldwide. A decreased concentration of adiponectin has been reported in smokers. The aim of this study was to analyze the effect of cigarette smoking on the concentration of adiponectin and potassium in active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study, and the use of these two markers for risk prediction. Smoking status was assessed by a questionnaire and measurement of plasma cotinine concentration. The serum concentration of adiponectin was measured by ELISA. Adiponectin was binned into tertiles separately for AS and NS and the Cox regression was used to assess the effect on mortality. There were 777 AS and 1178 NS among the LURIC patients. Within 10 years (median) of follow-up 221 AS and 302 NS died. In unadjusted analyses, AS had lower concentrations of adiponectin. However, after adjustment for age and gender there was no significant difference in adiponectin concentration between AS and NS. In the Cox regression model adjusted for age and gender, adiponectin was significantly associated with mortality in AS, but not in NS, with hazard ratio (95 % CI) of 1.60 (1.14-2.24) comparing the third with first tertile. In a model further adjusted for the risk factors, such as diabetes mellitus, hypertension, coronary artery disease, body mass index, LDL-cholesterol and HDL-cholesterol, adiponectin was significantly associated with mortality with hazard ratio of 1.83 (1.28-2.62) and 1.56 (1.15-2.11) for AS and NS, respectively. We conclude that increased adiponectin is a strong and independent predictor of mortality in both AS and NS. The determination of adiponectin concentration could be used to identify individuals at increased mortality risk.

Herpes zoster correlates with increased risk of Parkinson's disease in older people

PubMed Central

Lai, Shih-Wei; Lin, Chih-Hsueh; Lin, Hsien-Feng; Lin, Cheng-Li; Lin, Cheng-Chieh; Liao, Kuan-Fu

2017-01-01

Abstract Little is known on the relationship between herpes zoster and Parkinson's disease in older people. This study aimed to explore whether herpes zoster could be associated with Parkinson's disease in older people in Taiwan. We conducted a retrospective cohort study using the claim data of the Taiwan National Health Insurance Program. There were 10,296 subjects aged 65 years and older with newly diagnosed herpes zoster as the herpes zoster group and 39,405 randomly selected subjects aged 65 years and older without a diagnosis of herpes zoster as the nonherpes zoster group from 1998 to 2010. Both groups were followed up until subjects received a diagnosis of Parkinson's disease. This follow-up design would explore whether subjects with herpes zoster were at an increased risk of Parkinson's disease. Relative risks were estimated by adjusted hazard ratio (HR) and 95% confidence interval (CI) using the multivariable Cox proportional hazards regression model. The incidence of Parkinson's disease was higher in the herpes zoster group than that in the nonherpes zoster group (4.86 vs 4.00 per 1000 person-years, 95% CI 1.14, 1.29). After adjustment for confounding factors, the multivariable Cox proportional hazards regression model revealed that the adjusted HR of Parkinson's disease was 1.17 for the herpes zoster group (95% CI 1.10, 1.25), compared with the nonherpes zoster group. Older people with herpes zoster confer a slightly increased hazard of developing Parkinson's disease when compared to those without herpes zoster. We think that herpes zoster correlates with increased risk of Parkinson's disease in older people. When older people with herpes zoster seek help, clinicians should pay more attention to the development of the cardinal symptoms of Parkinson's disease. PMID:28207515

Unfavorable effects of history of volume overload and late referral to a nephrologist on mortality in patients initiating dialysis: a multicenter prospective cohort study in Japan.

PubMed

Okazaki, Masaki; Inaguma, Daijo; Imaizumi, Takahiro; Kada, Akiko; Yaomura, Takaaki; Tsuboi, Naotake; Maruyama, Shoichi

2018-03-14

Patients with late referral and positive history of volume overload may have a poor prognosis after initiating dialysis due to insufficient and/or inadequate management of complications of renal failure and the lack of better dialysis preparation. Little is known about the influence of the relationship between history of volume overload and late referral on prognosis. We analyzed 1475 patients who had initiated dialysis for the first time from October 2011 to September 2013. late referral was defined as referral to a nephrologist < 3 months before dialysis initiation. The major outcomes were all-cause death and deaths due to cardiovascular diseases (CVD). The impact of late referral and history of volume overload on all-cause mortality was assessed by Cox proportional hazards models. Among 1475 patients, the mean patient age was 67.5 years. During the median follow-up of 2.2 years, 260 deaths occurred; 99 were due to CVD. Cox proportional hazards models demonstrated that late referral (adjusted hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.00-1.82) and history of volume overload (adjusted HR, 1.39; 95% CI, 1.06-1.81) were risk factors for all-cause mortality. Furthermore, late referral coexisting was associated with a history of volume overload increased mortality (adjusted HR, 2.10; 95% CI, 1.39-3.16 versus absence of late referral without history of volume overload) after adjusting for age, sex, diabetes, atherosclerotic disease, and laboratory values. Both late referral and history of volume overload were associated with increased risks of all-cause mortality. University Hospital Medical Information Network (UMIN000007096). Registered 18 January 2012, retrospectively registered. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000008349 .

Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria.

PubMed

Currie, Gemma E; von Scholten, Bernt Johan; Mary, Sheon; Flores Guerrero, Jose-Luis; Lindhardt, Morten; Reinhard, Henrik; Jacobsen, Peter K; Mullen, William; Parving, Hans-Henrik; Mischak, Harald; Rossing, Peter; Delles, Christian

2018-04-06

The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown. Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan-Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years. CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (β = 0.402, p < 0.001) and eGFR (β = - 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model. A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers.

Role of Body Mass Index and Gestational Weight Gain in Breastfeeding Outcomes

PubMed Central

Schaefer, Eric W.; Beiler, Jessica S.; Paul, Ian M.

2012-01-01

Abstract Objective This study determined whether high maternal prepregnancy body mass index (BMI) and/or excess gestational weight gain (GWG) is associated with reduced breastfeeding duration and earlier formula supplementation. Study Design A prospective longitudinal cohort of postpartum women (n=718), who were a subset of a larger randomized trial, was followed for 6 months postdelivery. We evaluated the relationship between BMI or BMI/GWG groups and timing of breastfeeding cessation and introduction of formula using Kaplan–Meier curves and log-rank tests. Then, we used multivariable Cox proportional hazards models to evaluate the relationship between BMI and BMI/GWG on these breastfeeding outcomes after controlling for potential confounding variables. Results The expected relationships between high BMI and high BMI/GWG and poor breastfeeding outcomes were observed in Kaplan–Meier curves. However, after adjusting for relevant maternal and infant covariates in the Cox models, the differences became nonsignificant. Prepregnancy BMI category was not statistically associated with breastfeeding duration (p=0.06) or timing of formula introduction (p=0.15). Similarly, BMI and GWG in combination were not associated with duration (p=0.33) or timing of formula introduction (p=0.18). Mothers' intended breastfeeding duration and rating of the importance of breastfeeding remained the only significant modifiable predictors of breastfeeding outcomes in the final models. Conclusions Maternal BMI and GWG were not significantly associated with breastfeeding outcomes after adjusting for confounding variables. Mothers' plans for breastfeeding duration and the importance mothers assign to breastfeeding remain the optimal intervention points for lengthening breastfeeding duration and reducing formula supplementation. PMID:23215909

Association of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery.

PubMed

Swords, Douglas S; Zhang, Chong; Presson, Angela P; Firpo, Matthew A; Mulvihill, Sean J; Scaife, Courtney L

2018-04-01

Time-to-surgery from cancer diagnosis has increased in the United States. We aimed to determine the association between time-to-surgery and oncologic outcomes in patients with resectable pancreatic ductal adenocarcinoma undergoing upfront surgery. The 2004-2012 National Cancer Database was reviewed for patients undergoing curative-intent surgery without neoadjuvant therapy for clinical stage I-II pancreatic ductal adenocarcinoma. A multivariable Cox model with restricted cubic splines was used to define time-to-surgery as short (1-14 days), medium (15-42), and long (43-120). Overall survival was examined using Cox shared frailty models. Secondary outcomes were examined using mixed-effects logistic regression models. Of 16,763 patients, time-to-surgery was short in 34.4%, medium in 51.6%, and long in 14.0%. More short time-to-surgery patients were young, privately insured, healthy, and treated at low-volume hospitals. Adjusted hazards of mortality were lower for medium (hazard ratio 0.94, 95% confidence interval, .90, 0.97) and long time-to-surgery (hazard ratio 0.91, 95% confidence interval, 0.86, 0.96) than short. There were no differences in adjusted odds of node positivity, clinical to pathologic upstaging, being unresectable or stage IV at exploration, and positive margins. Medium time-to-surgery patients had higher adjusted odds (odds ratio 1.11, 95% confidence interval, 1.03, 1.20) of receiving an adequate lymphadenectomy than short. Ninety-day mortality was lower in medium (odds ratio 0.75, 95% confidence interval, 0.65, 0.85) and long time-to-surgery (odds ratio 0.72, 95% confidence interval, 0.60, 0.88) than short. In this observational analysis, short time-to-surgery was associated with slightly shorter OS and higher perioperative mortality. These results may suggest that delays for medical optimization and referral to high volume surgeons are safe. Published by Elsevier Inc.

The Association between Triglyceride/High-Density Lipoprotein Cholesterol Ratio and All-Cause Mortality in Acute Coronary Syndrome after Coronary Revascularization

PubMed Central

Wan, Ke; Zhao, Jianxun; Huang, Hao; Zhang, Qing; Chen, Xi; Zeng, Zhi; Zhang, Li; Chen, Yucheng

2015-01-01

Aims High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are cardiovascular risk factors. A positive correlation between elevated TG/HDL-C ratio and all-cause mortality and cardiovascular events exists in women. However, utility of TG to HDL-C ratio for prediction is unknown among acute coronary syndrome (ACS). Methods Fasting lipid profiles, detailed demographic data, and clinical data were obtained at baseline from 416 patients with ACS after coronary revascularization. Subjects were stratified into three levels of TG/HDL-C. We constructed multivariate Cox-proportional hazard models for all-cause mortality over a median follow-up of 3 years using log TG to HDL-C ratio as a predictor variable and analyzing traditional cardiovascular risk factors. We constructed a logistic regression model for major adverse cardiovascular events (MACEs) to prove that the TG/HDL-C ratio is a risk factor. Results The subject’s mean age was 64 ± 11 years; 54.5% were hypertensive, 21.8% diabetic, and 61.0% current or prior smokers. TG/HDL-C ratio ranged from 0.27 to 14.33. During the follow-up period, there were 43 deaths. In multivariate Cox models after adjusting for age, smoking, hypertension, diabetes, and severity of angiographic coronary disease, patients in the highest tertile of ACS had a 5.32-fold increased risk of mortality compared with the lowest tertile. After adjusting for conventional coronary heart disease risk factors by the logistic regression model, the TG/HDL-C ratio was associated with MACEs. Conclusion The TG to HDL-C ratio is a powerful independent predictor of all-cause mortality and is a risk factor of cardiovascular events. PMID:25880982

Modeled Urea Distribution Volume and Mortality in the HEMO Study

PubMed Central

Greene, Tom; Depner, Thomas A.; Levin, Nathan W.; Chertow, Glenn M.

2011-01-01

Summary Background and objectives In the Hemodialysis (HEMO) Study, observed small decreases in achieved equilibrated Kt/Vurea were noncausally associated with markedly increased mortality. Here we examine the association of mortality with modeled volume (Vm), the denominator of equilibrated Kt/Vurea. Design, setting, participants, & measurements Parameters derived from modeled urea kinetics (including Vm) and blood pressure (BP) were obtained monthly in 1846 patients. Case mix–adjusted time-dependent Cox regressions were used to relate the relative mortality hazard at each time point to Vm and to the change in Vm over the preceding 6 months. Mixed effects models were used to relate Vm to changes in intradialytic systolic BP and to other factors at each follow-up visit. Results Mortality was associated with Vm and change in Vm over the preceding 6 months. The association between change in Vm and mortality was independent of vascular access complications. In contrast, mortality was inversely associated with V calculated from anthropometric measurements (Vant). In case mix–adjusted analysis using Vm as a time-dependent covariate, the association of mortality with Vm strengthened after statistical adjustment for Vant. After adjustment for Vant, higher Vm was associated with slightly smaller reductions in intradialytic systolic BP and with risk factors for mortality including recent hospitalization and reductions in serum albumin concentration and body weight. Conclusions An increase in Vm is a marker for illness and mortality risk in hemodialysis patients. PMID:21511841

Surveillance for Hepatocellular Carcinoma Reduces Mortality: an Inverse Probability of Treatment Weighted Analysis.

PubMed

Chaiteerakij, Roongruedee; Chattieng, Piyanat; Choi, Jonggi; Pinchareon, Nutcha; Thanapirom, Kessirin; Geratikornsupuk, Nopavut

Evidence supporting benefit of hepatocellular carcinoma (HCC) surveillance in reducing mortality is not well-established. The effect of HCC surveillance in reducing mortality was assessed by an inverse probability of treatment weighting (IPTW)-based analysis controlled for inherent bias and confounders in observational studies. This retrospective cohort study was conducted on 446 patients diagnosed with HCC between 2007 and 2013 at a major referral center. Surveillance was defined as having at least 1 ultrasound test within a year before HCC diagnosis. Primary outcome was survival estimated using the Kaplan-Meier method with lead-time bias adjustment and compared using the log-rank test. Hazard ratio (HR) and 95% confidence interval (CI) were computed using conventional Cox and weighted Cox proportional hazards analysis with IPTW adjustment. Of the 446 patients, 103 (23.1%) were diagnosed with HCC through surveillance. The surveillance group had more patients with the Barcelona-Clinic Liver Cancer stage A (80.6% vs. 33.8%, P < 0.0001), more patients eligible for potentially curative treatment (73.8% vs. 44.9%, P < 0.0001), and longer median survival (49.6 vs. 15.9 months, P < 0.0001). By conventional multivariate Cox analysis, HR (95% CI) of surveillance was 0.63 (0.45-0.87), P = 0.005. The estimated effect of surveillance remained similar in the IPTW-adjusted Cox analysis (HR: 0.57; 95% CI: 0.43-0.76, P < 0.001). HCC surveillance by ultrasound is associated with a 37% reduction in mortality. Even though surveillance is recommended in all guidelines, but in practice, it is underutilized. Interventions are needed to increase surveillance rate for improving HCC outcome.

Survival in Alzheimer disease

PubMed Central

Helzner, E P.; Scarmeas, N; Cosentino, S; Tang, M X.; Schupf, N; Stern, Y

2008-01-01

Objective: To describe factors associated with survival in Alzheimer disease (AD) in a multiethnic, population-based longitudinal study. Methods: AD cases were identified in the Washington Heights Inwood Columbia Aging Project, a longitudinal, community-based study of cognitive aging in Northern Manhattan. The sample comprised 323 participants who were initially dementia-free but developed AD during study follow-up (incident cases). Participants were followed for an average of 4.1 (up to 12.6) years. Possible factors associated with shorter lifespan were assessed using Cox proportional hazards models with attained age as the time to event (time from birth to death or last follow-up). In subanalyses, median postdiagnosis survival durations were estimated using postdiagnosis study follow-up as the timescale. Results: The mortality rate was 10.7 per 100 person-years. Mortality rates were higher among those diagnosed at older ages, and among Hispanics compared to non-Hispanic whites. The median lifespan of the entire sample was 92.2 years (95% CI: 90.3, 94.1). In a multivariable-adjusted Cox model, history of diabetes and history of hypertension were independently associated with a shorter lifespan. No differences in lifespan were seen by race/ethnicity after multivariable adjustment. The median postdiagnosis survival duration was 3.7 years among non-Hispanic whites, 4.8 years among African Americans, and 7.6 years among Hispanics. Conclusion: Factors influencing survival in Alzheimer disease include race/ethnicity and comorbid diabetes and hypertension. GLOSSARY AD = Alzheimer disease; NDI = National Death Index; WHICAP = Washington Heights Inwood Columbia Aging Project. PMID:18981370

Ethnicity matching and outcomes after kidney transplantation in the United Kingdom.

PubMed

Pisavadia, Bhavini; Arshad, Adam; Chappelow, Imogen; Nightingale, Peter; Anderson, Benjamin; Nath, Jay; Sharif, Adnan

2018-01-01

Kidneys from non-white donors have inferior outcomes, but it is unclear if ethnicity matching between donors and recipients achieves better post kidney transplant outcomes. We undertook a retrospective, population cohort study utilising UK Transplant Registry data. The cohort comprised adult, kidney-alone, transplant recipients receiving their first kidney transplant between 2003-2015, with data censored at 1st October 2016. We included 27,970 recipients stratified into white (n = 23,215), black (n = 1,679) and south Asian (n = 3,076) ethnicity, with median post-transplant follow-up of 1,676 days (IQR 716-2,869 days). Unadjusted and adjusted Cox regression survival analyses were performed to investigate ethnicity effect on risk for graft loss and mortality. In unadjusted analyses, matched ethnicity between donors-recipients resulted in better outcomes for delayed graft function, one-year creatinine, graft and patient survival but these differed by ethnicity matches. Compared to white-to-white transplants, risk for death-censored graft loss was higher in black-to-black and similar among Asian-to-Asian transplants, but mortality risk was lower for both black-to-black and Asian-to-Asian transplants. In Cox regression models, compared to white donors, we observed higher risk for graft loss with both south Asian (HR 1.38, 95%CI 1.12-1.70, p = 0.003) and black (HR 1.66, 95%CI 1.30-2.11, p<0.001) donated kidneys independent of recipient ethnicity. We observed no mortality difference with south Asian donated kidneys but increased mortality with black donated kidneys (HR 1.68, 95%CI 1.21-2.35, p = 0.002). Matching ethnicities made no significant difference in any Cox regression model. Similar results were observed after stratifying our analysis by living and deceased-donor kidney transplantation. Our data confirm inferior outcomes associated with non-white kidney donors for kidney transplant recipients of any ethnicity in a risk-adjusted model for the United Kingdom population. However, contrary to non-renal transplant literature, we did not identify any survival benefits associated with donor-recipient ethnicity matching.

Drugs Used in the Treatment of Rheumatoid Arthritis: Relationship between Current Use and Cardiovascular Risk Factors

PubMed Central

Rho, Young Hee; Oeser, Annette; Chung, Cecilia P; Milne, Ginger L; Stein, C Michael

2009-01-01

Objectives Drugs used for the treatment of rheumatoid arthritis (RA) have the potential to affect cardiovascular risk factors. There is concern that corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors could affect cardiovascular risk adversely, while drugs such as the antimalarial, hydroxychloroquine, may have beneficial effects. However, there is limited information about cardiovascular risk factors in patients with RA receiving different drugs. Methods We measured cardiovascular risk factors including systolic and diastolic blood pressure, serum HDL and LDL cholesterol, glucose and homocysteine concentrations and urinary F2-isoprostane excretion in 169 patients with RA. Risk factors were compared according to current use of corticosteroids, methotrexate, antimalarials, NSAIDs, COX-2 inhibitors, leflunomide and TNF-α blockers. Comparisons were adjusted for age, sex, race, disease activity (DAS28 score), current hypertension, diabetes, smoking status and statin use. Results No cardiovascular risk factor differed significantly among current users and non-users of NSAIDs, COX-2 inhibitors, methotrexate and TNF-α blockers. Serum HDL cholesterol concentrations were significantly higher in patients currently receiving corticosteroids (42.2 ± 10.5 vs. 50.2 ± 15.3 mg/dL, adjusted P < 0.001). Diastolic blood pressure (75.9 ± 11.2 vs. 72.0 ± 9.1 mm Hg, adjusted P = 0.02), serum LDL cholesterol (115.6 ± 34.7 vs. 103.7 ± 27.8 mg/dL, adjusted P = 0.03) and triglyceride concentrations (157.7 ± 202.6 vs. 105.5 ± 50.5 mg/dL, adjusted P = 0.03) were significantly lower in patients taking antimalarial drugs. Plasma glucose was significantly lower in current lefunomide users (93.0 ± 19.2 vs. 83.6 ± 13.4 mg/dL, adjusted P = 0.006). Conclusions In a cross-sectional setting drugs used to treat RA did not have major adverse effects on cardiovascular risk factors and use of antimalarials was associated with beneficial lipid profiles. PMID:19684849

Early Pancreatic Ductal Adenocarcinoma Survival Is Dependent on Size: Positive Implications for Future Targeted Screening.

PubMed

Hur, Chin; Tramontano, Angela C; Dowling, Emily C; Brooks, Gabriel A; Jeon, Alvin; Brugge, William R; Gazelle, G Scott; Kong, Chung Yin; Pandharipande, Pari V

2016-08-01

Pancreatic ductal adenocarcinoma (PDAC) has not experienced a meaningful mortality improvement for the past few decades. Successful screening is difficult to accomplish because most PDACs present late in their natural history, and current interventions have not provided significant benefit. Our goal was to identify determinants of survival for early PDAC to help inform future screening strategies. Early PDACs from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program database (2000-2010) were analyzed. We stratified by size and included carcinomas in situ (Tis). Overall cancer-specific survival was calculated. A Cox proportional hazards model was developed and the significance of key covariates for survival prediction was evaluated. A Kaplan-Meier plot demonstrated significant differences in survival by size at diagnosis; these survival benefits persisted after adjustment for key covariates in the Cox proportional hazards analysis. In addition, relatively weaker predictors of worse survival included older age, male sex, black race, nodal involvement, tumor location within the head of the pancreas, and no surgery or radiotherapy. For early PDAC, we found tumor size to be the strongest predictor of survival, even after adjustment for other patient characteristics. Our findings suggest that early PDAC detection can have clinical benefit, which has positive implications for future screening strategies.

Improved Horvitz-Thompson Estimation of Model Parameters from Two-phase Stratified Samples: Applications in Epidemiology

PubMed Central

Breslow, Norman E.; Lumley, Thomas; Ballantyne, Christie M; Chambless, Lloyd E.; Kulich, Michal

2009-01-01

The case-cohort study involves two-phase sampling: simple random sampling from an infinite super-population at phase one and stratified random sampling from a finite cohort at phase two. Standard analyses of case-cohort data involve solution of inverse probability weighted (IPW) estimating equations, with weights determined by the known phase two sampling fractions. The variance of parameter estimates in (semi)parametric models, including the Cox model, is the sum of two terms: (i) the model based variance of the usual estimates that would be calculated if full data were available for the entire cohort; and (ii) the design based variance from IPW estimation of the unknown cohort total of the efficient influence function (IF) contributions. This second variance component may be reduced by adjusting the sampling weights, either by calibration to known cohort totals of auxiliary variables correlated with the IF contributions or by their estimation using these same auxiliary variables. Both adjustment methods are implemented in the R survey package. We derive the limit laws of coefficients estimated using adjusted weights. The asymptotic results suggest practical methods for construction of auxiliary variables that are evaluated by simulation of case-cohort samples from the National Wilms Tumor Study and by log-linear modeling of case-cohort data from the Atherosclerosis Risk in Communities Study. Although not semiparametric efficient, estimators based on adjusted weights may come close to achieving full efficiency within the class of augmented IPW estimators. PMID:20174455

Magnesium intake, plasma C-peptide, and colorectal cancer incidence in US women: a 28-year follow-up study

PubMed Central

Zhang, X; Giovannucci, E L; Wu, K; Smith-Warner, S A; Fuchs, C S; Pollak, M; Willett, W C; Ma, J

2012-01-01

Background: Laboratory studies suggest a possible role of magnesium intake in colorectal carcinogenesis but epidemiological evidence is inconclusive. Method: We tested magnesium–colorectal cancer hypothesis in the Nurses' Health Study, in which 85 924 women free of cancer in 1980 were followed until June 2008. Cox proportional hazards regression models were used to estimate multivariable relative risks (MV RRs, 95% confidence intervals). Results: In the age-adjusted model, magnesium intake was significantly inversely associated with colorectal cancer risk; the RRs from lowest to highest decile of total magnesium intake were 1.0 (ref), 0.93, 0.81, 0.72, 0.74, 0.77, 0.72, 0.75, 0.80, and 0.67 (Ptrend<0.001). However, in the MV model adjusted for known dietary and non-dietary risk factors for colorectal cancer, the association was significantly attenuated; the MV RRs were 1.0 (ref), 0.96, 0.85, 0.78, 0.82, 0.86, 0.84, 0.91, 1.02, and 0.93 (Ptrend=0.77). Similarly, magnesium intakes were significantly inversely associated with concentrations of plasma C-peptide in age-adjusted model (Ptrend=0.002) but not in multivariate-adjusted model (Ptrend=0.61). Results did not differ by subsite or modified by calcium intakes or body mass index. Conclusion: These prospective results do not support an independent association of magnesium intake with either colorectal cancer risk or plasma C-peptide levels in women. PMID:22415230

Survival in Adult Lung Transplant Recipients Receiving Pediatric Versus Adult Donor Allografts.

PubMed

Hayes, Don; Whitson, Bryan A; Ghadiali, Samir N; Lloyd, Eric A; Tobias, Joseph D; Mansour, Heidi M; Black, Sylvester M

2015-10-01

Recent evidence showed that pediatric donor lungs increased rates of allograft failure in adult lung transplant recipients; however, the influence on survival is unclear. The United Network for Organ Sharing (UNOS) database was queried from 2005 to 2013 for adult lung transplant recipients (≥18 years) to assess survival differences among donor age categories (<18 years, 18 to 29 years, 30 to 59 years, ≥60 years). Of 12,297 adult lung transplants, 12,209 were used for univariate Cox models and Kaplan-Meier (KM) analysis and 11,602 for multivariate Cox models. A total of 1,187 adult recipients received pediatric donor lungs compared with 11,110 receiving adult donor organs. Univariate and multivariate Cox models found no difference in survival between donor ages 0 to 17 and donor ages 18 to 29, whereas donor ages 60 and older were significantly associated with increased mortality hazard, relative to the modal category of donor ages 30 to 59 (adjusted hazard ratio = 1.381; 95% confidence interval = 1.188% to 1.606%; p < 0.001). Interactions between recipient and donor age range found that the oldest donor age range was negatively associated with survival among middle-aged (30 to 59) and older (≥60) lung transplant recipients. Pediatric donor lung allografts were not negatively associated with survival in adult lung transplant recipients; however, the oldest donor age range was associated with increased mortality hazard for adult lung transplant recipients. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Cox proportional hazards model of myopic regression for laser in situ keratomileusis flap creation with a femtosecond laser and with a mechanical microkeratome.

PubMed

Lin, Meng-Yin; Chang, David C K; Hsu, Wen-Ming; Wang, I-Jong

2012-06-01

To compare predictive factors for postoperative myopic regression between laser in situ keratomileusis (LASIK) with a femtosecond laser and LASIK with a mechanical microkeratome. Nobel Eye Clinic, Taipei, Taiwan. Retrospective comparative study. Refractive outcomes were recorded 1 day, 1 week, and 1, 3, 6, 9, and 12 months after LASIK. A Cox proportional hazards model was used to evaluate the impact of the 2 flap-creating methods and other covariates on postoperative myopic regression. The femtosecond group comprised 409 eyes and the mechanical microkeratome group, 377 eyes. For both methods, significant predictors for myopic regression after LASIK included preoperative manifest spherical equivalent (P=.0001) and central corneal thickness (P=.027). Laser in situ keratomileusis with a mechanical microkeratome had a higher probability of postoperative myopic regression than LASIK with a femtosecond laser (P=.0002). After adjusting for other covariates in the Cox proportional hazards model, the cumulative risk for myopic regression with a mechanical microkeratome was higher than with a femtosecond laser 12 months postoperatively (P=.0002). With the definition of myopic regression as a myopic shift of 0.50 diopter (D) or more and residual myopia of -0.50 D or less, the risk estimate based on the mean covariates in all eyes in the femtosecond group and mechanical microkeratome group at 12 months was 43.6% and 66.9%, respectively. Laser in situ keratomileusis with a mechanical microkeratome had a higher risk for myopic regression than LASIK with a femtosecond laser through 12 months postoperatively. Copyright © 2012. Published by Elsevier Inc.

Increased risk of incident stroke associated with the cyclooxygenase 2 (COX-2) G-765C polymorphism in African-Americans: the Atherosclerosis Risk in Communities Study.

PubMed

Kohsaka, Shun; Volcik, Kelly A; Folsom, Aaron R; Wu, Kenneth K; Ballantyne, Christie M; Willerson, James T; Boerwinkle, Eric

2008-02-01

A hallmark feature of atherosclerosis is inflammation mediated by prostaglandins (PGs) catalyzed by the enzyme cyclooxygenase (COX). The present study explored whether the COX-2 G-765C polymorphism contributes to increased incidence of coronary heart disease (CHD) or stroke in the large prospective Atherosclerosis Risk in Communities (ARIC) Study. Incidences of CHD and stroke were identified through annual follow-up and hospital and death certificate surveillance. The study included 1488 incident CHD and 527 stroke events after an average of 14 years of follow-up. The frequency of the -765C variant allele was markedly different between African-Americans and whites, therefore all analyses were performed separately by race. Due to the small number of persons with the -765CC genotype, heterozygous and homozygous variant genotypes were combined for this analysis. The COX-2 G-765C polymorphism was not a significant predictor of CHD in either racial group, but it was a significant predictor of incident stroke in African-Americans. After adjustment for age and gender, the hazard rate ratio for developing stroke for the CG+CC genotypes relative to the GG genotype was 1.34 (95% confidence interval [CI] 1.03-1.74, P=0.03) in African-Americans. This result was essentially unchanged when established predictors such as smoking, diabetes and hypertension were added to the model (HRR 1.34, 95%CI 1.03-1.76, P=0.03). We have found the COX-2 G-765C polymorphism to be a risk factor for incident stroke in African-Americans. This study provides additional evidence for utilizing inflammation-related genetic polymorphisms for identifying individuals at increased risk for stroke.

The importance of extent of choroid plexus cauterization in addition to endoscopic third ventriculostomy for infantile hydrocephalus: a retrospective North American observational study using propensity score-adjusted analysis.

PubMed

Fallah, Aria; Weil, Alexander G; Juraschka, Kyle; Ibrahim, George M; Wang, Anthony C; Crevier, Louis; Tseng, Chi-Hong; Kulkarni, Abhaya V; Ragheb, John; Bhatia, Sanjiv

2017-12-01

OBJECTIVE Combined endoscopic third ventriculostomy (ETC) and choroid plexus cauterization (CPC)-ETV/CPC- is being investigated to increase the rate of shunt independence in infants with hydrocephalus. The degree of CPC necessary to achieve improved rates of shunt independence is currently unknown. METHODS Using data from a single-center, retrospective, observational cohort study involving patients who underwent ETV/CPC for treatment of infantile hydrocephalus, comparative statistical analyses were performed to detect a difference in need for subsequent CSF diversion procedure in patients undergoing partial CPC (describes unilateral CPC or bilateral CPC that only extended from the foramen of Monro [FM] to the atrium on one side) or subtotal CPC (describes CPC extending from the FM to the posterior temporal horn bilaterally) using a rigid neuroendoscope. Propensity scores for extent of CPC were calculated using age and etiology. Propensity scores were used to perform 1) case-matching comparisons and 2) Cox multivariable regression, adjusting for propensity score in the unmatched cohort. Cox multivariable regression adjusting for age and etiology, but not propensity score was also performed as a third statistical technique. RESULTS Eighty-four patients who underwent ETV/CPC had sufficient data to be included in the analysis. Subtotal CPC was performed in 58 patients (69%) and partial CPC in 26 (31%). The ETV/CPC success rates at 6 and 12 months, respectively, were 49% and 41% for patients undergoing subtotal CPC and 35% and 31% for those undergoing partial CPC. Cox multivariate regression in a 48-patient cohort case-matched by propensity score demonstrated no added effect of increased extent of CPC on ETV/CPC survival (HR 0.868, 95% CI 0.422-1.789, p = 0.702). Cox multivariate regression including all patients, with adjustment for propensity score, demonstrated no effect of extent of CPC on ETV/CPC survival (HR 0.845, 95% CI 0.462-1.548, p = 0.586). Cox multivariate regression including all patients, with adjustment for age and etiology, but not propensity score, demonstrated no effect of extent of CPC on ETV/CPC survival (HR 0.908, 95% CI 0.495-1.664, p = 0.755). CONCLUSIONS Using multiple comparative statistical analyses, no difference in need for subsequent CSF diversion procedure was detected between patients in this cohort who underwent partial versus subtotal CPC. Further investigation regarding whether there is truly no difference between partial versus subtotal extent of CPC in larger patient populations and whether further gain in CPC success can be achieved with complete CPC is warranted.

Association Between Obstetric Mode of Delivery and Autism Spectrum Disorder: A Population-Based Sibling Design Study.

PubMed

Curran, Eileen A; Dalman, Christina; Kearney, Patricia M; Kenny, Louise C; Cryan, John F; Dinan, Timothy G; Khashan, Ali S

2015-09-01

Because the rates of cesarean section (CS) are increasing worldwide, it is becoming increasingly important to understand the long-term effects that mode of delivery may have on child development. To investigate the association between obstetric mode of delivery and autism spectrum disorder (ASD). Perinatal factors and ASD diagnoses based on the International Classification of Diseases, Ninth Revision (ICD-9),and the International Statistical Classification of Diseases, 10th Revision (ICD-10),were identified from the Swedish Medical Birth Register and the Swedish National Patient Register. We conducted stratified Cox proportional hazards regression analysis to examine the effect of mode of delivery on ASD. We then used conditional logistic regression to perform a sibling design study, which consisted of sibling pairs discordant on ASD status. Analyses were adjusted for year of birth (ie, partially adjusted) and then fully adjusted for various perinatal and sociodemographic factors. The population-based cohort study consisted of all singleton live births in Sweden from January 1, 1982, through December 31, 2010. Children were followed up until first diagnosis of ASD, death, migration, or December 31, 2011 (end of study period), whichever came first. The full cohort consisted of 2,697,315 children and 28,290 cases of ASD. Sibling control analysis consisted of 13,411 sibling pairs. Obstetric mode of delivery defined as unassisted vaginal delivery (VD), assisted VD, elective CS, and emergency CS (defined by before or after onset of labor). The ASD status as defined using codes from the ICD-9 (code 299) and ICD-10 (code F84). In adjusted Cox proportional hazards regression analysis, elective CS (hazard ratio, 1.21; 95% CI, 1.15-1.27) and emergency CS (hazard ratio, 1.15; 95% CI, 1.10-1.20) were associated with ASD when compared with unassisted VD. In the sibling control analysis, elective CS was not associated with ASD in partially (odds ratio [OR], 0.97; 95% CI, 0.85-1.11) or fully adjusted (OR, 0.89; 95% CI, 0.76-1.04) models. Emergency CS was significantly associated with ASD in partially adjusted analysis (OR, 1.20; 95% CI, 1.06-1.36), but this effect disappeared in the fully adjusted model (OR, 0.97; 95% CI, 0.85-1.11). This study confirms previous findings that children born by CS are approximately 20% more likely to be diagnosed as having ASD. However, the association did not persist when using sibling controls, implying that this association is due to familial confounding by genetic and/or environmental factors.

The impact of high serum bicarbonate levels on mortality in hemodialysis patients.

PubMed

Chang, Kyung Yoon; Kim, Hyung Wook; Kim, Woo Jeong; Kim, Yong Kyun; Kim, Su-Hyun; Song, Ho Chul; Kim, Young Ok; Jin, Dong Chan; Choi, Euy Jin; Yang, Chul Woo; Kim, Yong-Lim; Kim, Nam-Ho; Kang, Shin-Wook; Kim, Yon-Su; Kim, Young Soo

2017-01-01

The optimal serum bicarbonate level is controversial for patients who are undergoing hemodialysis (HD). In this study, we analyzed the impact of serum bicarbonate levels on mortality among HD patients. Prevalent HD patients were selected from the Clinical Research Center registry for End Stage Renal Disease cohort in Korea. Patients were categorized into quartiles according to their total carbon dioxide (tCO 2 ) levels: quartile 1, a tCO 2 of < 19.4 mEq/L; quartile 2, a tCO 2 of 19.4 to 21.5 mEq/L; quartile 3, a tCO 2 of 21.6 to 23.9 mEq/L; and quartile 4, a tCO 2 of ≥ 24 mEq/L. Cox regression analysis was used to calculate the adjusted hazard ratio (HR) and confidence interval (CI) for mortality. We included 1,159 prevalent HD patients, with a median follow-up period of 37 months. Kaplan-Meier analysis revealed that the all-cause mortality was significantly higher in patients from quartile 4, compared to those from the other quartiles ( p = 0.009, log-rank test). The multivariate Cox proportional hazard model revealed that patients from quartile 4 had significantly higher risk of mortality than those from quartile 1, 2 and 3, after adjusting for the clinical variables in model 1 (HR, 1.99; 95% CI, 1.15 to 3.45; p = 0.01) and model 2 (HR, 1.82; 95% CI, 1.03 to 3.22; p = 0.04). Our data indicate that high serum bicarbonate levels (a tCO2 of ≥ 24 mEq/L) were associated with increased mortality among prevalent HD patients. Further effort might be necessary in finding the cause and correcting metabolic alkalosis in the chronic HD patients with high serum bicarbonate levels.

Chronic Stenotrophomonas maltophilia infection and mortality or lung transplantation in cystic fibrosis patients.

PubMed

Waters, Valerie; Atenafu, Eshetu G; Lu, Annie; Yau, Yvonne; Tullis, Elizabeth; Ratjen, Felix

2013-09-01

Chronic Stenotrophomonas maltophilia infection is an independent risk factor for severe pulmonary exacerbations in cystic fibrosis (CF) patients. The goal of this study was to determine the effect of chronic S. maltophilia infection on mortality and the need for lung transplantation in a longitudinal study of children and adults with CF. This was a cohort study of CF patients from the Hospital for Sick Children and St Michael's Hospital (Toronto, Canada) from 1997 to 2008. A Cox Regression model was used to estimate the hazard ratio (HR) to time of death or lung transplantation adjusting for age, gender, genotype, pancreatic status, CF related diabetes (CFRD), forced expiratory volume in 1 s (FEV1), body mass index, number of pulmonary exacerbations, Pseudomonas aeruginosa, Burkholderia cepacia complex, Aspergillus and chronic S. maltophilia infection. A total of 687 patients were followed over the 12 year study period; 95 patients underwent a lung transplantation (of which 26 died) and an additional 49 patients died (total 144 events). In a Cox Regression model adjusting for baseline FEV1, baseline infection with B. cepacia complex (HR 1.72, 95% CI 1.09-2.71) and baseline chronic S. maltophilia infection (HR 2.80, 95% CI 1.65-4.76) were significantly associated with death or lung transplant. However, in a time-varying model, infection with B. cepacia complex and chronic S. maltophilia infection were no longer significant. Baseline chronic S. maltophilia infection is associated with an almost three-fold increased risk of death or lung transplant in CF patients. It is still unclear, however, whether chronic S. maltophilia infection is simply a marker of severity of disease and ultimate mortality or whether it is causally related to disease progression. Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Renin-angiotensin II-aldosterone system blockers and time to renal replacement therapy in children with CKD.

PubMed

Abraham, Alison G; Betoko, Aisha; Fadrowski, Jeffrey J; Pierce, Christopher; Furth, Susan L; Warady, Bradley A; Muñoz, Alvaro

2017-04-01

Clinical care decisions to treat chronic kidney disease (CKD) in a growing child must often be made without the benefit of evidence from clinical trials. We used observational data from the Chronic Kidney Disease in Children cohort to estimate the effectiveness of renin-angiotensin II-aldosterone system blockade (RAAS) to delay renal replacement therapy (RRT) in children with CKD. A total of 851 participants (median age: 11 years, median glomerular filtration rate [GFR]: 52 ml/min/1.73 m 2 , median urine protein to creatinine ratio: 0.35 mg/mg) were included. RAAS use was reported at annual study visits. Both Cox proportional hazards models with time-varying RAAS exposure and Cox marginal structural models (MSM) were used to evaluate the effect of RAAS use on time to RRT. Analyses were adjusted or weighted to control for age, male sex, glomerular diagnosis, GFR, nephrotic range proteinuria, anemia, elevated blood pressure, acidosis, elevated phosphate and elevated potassium. There were 217 RRT events over a 4.1-year median follow-up. At baseline, 472 children (55 %) were prevalent RAAS users, who were more likely to be older, have a glomerular etiology, have higher urine protein, be anemic, have elevated serum phosphate and potassium, take more medications, but less likely to have elevated blood pressure, compared with non-users. RAAS use was found to reduce the risk of RRT by 21 % (hazard ratio: 0.79) to 37 % (hazard ratio: 0.63) from standard regression adjustment and MSM models, respectively. These results support inferences from adult studies of a substantial benefit of RAAS use in pediatric CKD patients.

Statin Treatment and Clinical Outcomes of Heart Failure Among Africans: An Inverse Probability Treatment Weighted Analysis.

PubMed

Bonsu, Kwadwo Osei; Owusu, Isaac Kofi; Buabeng, Kwame Ohene; Reidpath, Daniel D; Kadirvelu, Amudha

2017-04-01

Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF. This was a retrospective longitudinal study of HF patients aged ≥18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3±14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse-probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use. Among Africans with HF, statin treatment was associated with significant reduction in mortality. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Calorie intake and patient outcomes in severe acute kidney injury: findings from The Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study trial

PubMed Central

2014-01-01

Introduction Current practice in the delivery of caloric intake (DCI) in patients with severe acute kidney injury (AKI) receiving renal replacement therapy (RRT) is unknown. We aimed to describe calorie administration in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study and to assess the association between DCI and clinical outcomes. Methods We performed a secondary analysis in 1456 patients from the RENAL trial. We measured the dose and evolution of DCI during treatment and analyzed its association with major clinical outcomes using multivariable logistic regression, Cox proportional hazards models, and time adjusted models. Results Overall, mean DCI during treatment in ICU was low at only 10.9 ± 9 Kcal/kg/day for non-survivors and 11 ± 9 Kcal/kg/day for survivors. Among patients with a lower DCI (below the median) 334 of 729 (45.8%) had died at 90-days after randomization compared with 316 of 727 (43.3%) patients with a higher DCI (above the median) (P = 0.34). On multivariable logistic regression analysis, mean DCI carried an odds ratio of 0.95 (95% confidence interval (CI): 0.91-1.00; P = 0.06) per 100 Kcal increase for 90-day mortality. DCI was not associated with significant differences in renal replacement (RRT) free days, mechanical ventilation free days, ICU free days and hospital free days. These findings remained essentially unaltered after time adjusted analysis and Cox proportional hazards modeling. Conclusions In the RENAL study, mean DCI was low. Within the limits of such low caloric intake, greater DCI was not associated with improved clinical outcomes. Trial registration ClinicalTrials.gov number, NCT00221013 PMID:24629036

Relation of Pericardial Fat, Intrathoracic Fat, and Abdominal Visceral Fat with Incident Atrial Fibrillation (From the Framingham Heart Study)

PubMed Central

Lee, Jane J.; Yin, Xiaoyan; Hoffmann, Udo; Fox, Caroline S.; Benjamin, Emelia J.

2016-01-01

Obesity is associated with increased risk of developing atrial fibrillation (AF). Different fat depots may have differential associations with cardiac pathology. We examined the longitudinal associations between pericardial, intrathoracic, and visceral fat with incident AF. We studied Framingham Heart Study Offspring and Third Generation Cohorts who participated in the multi-detector computed tomography sub-study examination 1. We constructed multivariable-adjusted Cox proportional hazard models for risk of incident AF. Body mass index (BMI) was included in the multivariable-adjusted model as a secondary adjustment. We included 2,135 participants (53.3% women; mean age 58.8 years). During a median follow-up of 9.7 years, we identified 162 cases of incident AF. Across the increasing tertiles of pericardial fat volume, age- and sex-adjusted incident AF rate per 1000 person-years of follow-up were 8.4, 7.5, and 10.2. Based on an age- and sex-adjusted model, greater pericardial fat [hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.03-1.34] and intrathoracic fat (HR 1.24, 95% CI 1.06-1.45) were associated with increased risk of incident AF. The HRs (95% CI) for incident AF were 1.13 (0.99-1.30) for pericardial fat, 1.19 (1.01-1.40) for intrathoracic fat, and 1.09 (0.93-1.28) for abdominal visceral fat after multivariable adjustment. After additional adjustment of BMI, none of the associations remained significant (all p>0.05). Our findings suggest that cardiac ectopic fat depots may share common risk factors with AF, which may have led to a lack of independence in the association between pericardial fat with incident AF. PMID:27666172

Gradient adjustment method for better discriminating correlating and non-correlating regions of physiological signals: application to the partitioning of impaired and intact zones of cerebral autoregulation.

PubMed

Addison, Paul S; Antunes, André; Montgomery, Dean; Borg, Ulf R

2017-08-01

Cerebral blood flow (CBF) is regulated over a range of systemic blood pressures by the cerebral autoregulation (CA) control mechanism. This range lies within the lower and upper limits of autoregulation (LLA, ULA), beyond which blood pressure drives CBF, and CA function is considered impaired. A standard method to determine autoregulation limits noninvasively using NIRS technology is via the COx measure: a moving correlation index between mean arterial pressure and regional oxygen saturation. In the intact region, there should be no correlation between these variables whereas in the impaired region, the correlation index should approximate unity. In practice, however, the data may be noisy and/or the intact region may often exhibit a slightly positive relationship. This positive relationship may render traditional autoregulation limit calculations difficult to perform, resulting in the need for manual interpretation of the data using arbitrary thresholds. Further, the underlying mathematics of the technique are asymmetric in terms of the results produced for impaired and intact regions and are, in fact, not computable for the ideal case within the intact region. In this work, we propose a novel gradient adjustment method (GACOx) to enhance the differences in COx values observed in the intact and impaired regions. Results from a porcine model (N = 8) are used to demonstrate that GACOx is successful in determining LLA values where traditional methods fail. It is shown that the derived GACOx indices exhibit a mean difference between the intact/impaired regions of 1.54 ± 0.26 (mean ± SD), compared to 0.14 ± 0.10 for the traditional COx method. The GACOx effectively polarizes the COx data in order to better differentiate the intact and impaired zones and, in doing so, makes the determination of the LLA and ULA points a simpler and more consistent task. The method lends itself to the automation of the robust determination of autoregulation zone limits.

The age and other factors in the evaluation of compliance with nasal continuous positive airway pressure for obstructive sleep apnea syndrome. A Cox's proportional hazard analysis.

PubMed

Pelletier-Fleury, N; Rakotonanahary, D; Fleury, B

2001-05-01

Objective: To elucidate the predictive role of age and other pre-treatment, putative confounding factors on compliance with nasal continuous positive airway pressure (nCPAP) therapy.Patients and methods: This study was designed as a prospective cohort study in the setting of a sleep laboratory in a teaching hospital at Saint Antoine, Paris. One hundred and sixty-three patients referred to the sleep laboratory with complaints of snoring and excessive daytime sleepiness for whom nCPAP had been prescribed for obstructive sleep apnea syndrome (OSAS; defined as an apnea-hypopnea index (AHI) of >15/h of sleep during a polysomnographic recording) were followed for a median period of 887 days. The main outcome measure was the risk ratio for elderly patients associated with nCPAP compliance.Results: Four patients, who remained under treatment, died before the end of the study, and 50 patients stopped their nCPAP therapy for reasons other than death (insomnia, equipment too noisy, etc.). When compliance curves were compared by univariate analysis (log-rank test), the oldest group (57/163 patients, >60 years old) was significantly less compliant with nCPAP than the youngest (P=0.01). However, in the Cox's proportional hazards model, age did not exert any independent effect on compliance with nCPAP after controlling for confounding factors (adjusted relative risk, 1.09, 0.5-2; P=0.70). On the other hand, female sex (adjusted relative risk, 2.8, 1.4-5.4; P=0.002), a body mass index (BMI) of /=12 cmH(2)O (adjusted relative risk, 2.3, 1.2-4.4; P=0.011) were predictive factors for non-compliance.Conclusion: This study suggests that there is no independent effect of age on compliance with nCPAP therapy.

Multi-omics facilitated variable selection in Cox-regression model for cancer prognosis prediction.

PubMed

Liu, Cong; Wang, Xujun; Genchev, Georgi Z; Lu, Hui

2017-07-15

New developments in high-throughput genomic technologies have enabled the measurement of diverse types of omics biomarkers in a cost-efficient and clinically-feasible manner. Developing computational methods and tools for analysis and translation of such genomic data into clinically-relevant information is an ongoing and active area of investigation. For example, several studies have utilized an unsupervised learning framework to cluster patients by integrating omics data. Despite such recent advances, predicting cancer prognosis using integrated omics biomarkers remains a challenge. There is also a shortage of computational tools for predicting cancer prognosis by using supervised learning methods. The current standard approach is to fit a Cox regression model by concatenating the different types of omics data in a linear manner, while penalty could be added for feature selection. A more powerful approach, however, would be to incorporate data by considering relationships among omics datatypes. Here we developed two methods: a SKI-Cox method and a wLASSO-Cox method to incorporate the association among different types of omics data. Both methods fit the Cox proportional hazards model and predict a risk score based on mRNA expression profiles. SKI-Cox borrows the information generated by these additional types of omics data to guide variable selection, while wLASSO-Cox incorporates this information as a penalty factor during model fitting. We show that SKI-Cox and wLASSO-Cox models select more true variables than a LASSO-Cox model in simulation studies. We assess the performance of SKI-Cox and wLASSO-Cox using TCGA glioblastoma multiforme and lung adenocarcinoma data. In each case, mRNA expression, methylation, and copy number variation data are integrated to predict the overall survival time of cancer patients. Our methods achieve better performance in predicting patients' survival in glioblastoma and lung adenocarcinoma. Copyright © 2017. Published by Elsevier Inc.

Statistical Methodology for the Analysis of Repeated Duration Data in Behavioral Studies.

PubMed

Letué, Frédérique; Martinez, Marie-José; Samson, Adeline; Vilain, Anne; Vilain, Coriandre

2018-03-15

Repeated duration data are frequently used in behavioral studies. Classical linear or log-linear mixed models are often inadequate to analyze such data, because they usually consist of nonnegative and skew-distributed variables. Therefore, we recommend use of a statistical methodology specific to duration data. We propose a methodology based on Cox mixed models and written under the R language. This semiparametric model is indeed flexible enough to fit duration data. To compare log-linear and Cox mixed models in terms of goodness-of-fit on real data sets, we also provide a procedure based on simulations and quantile-quantile plots. We present two examples from a data set of speech and gesture interactions, which illustrate the limitations of linear and log-linear mixed models, as compared to Cox models. The linear models are not validated on our data, whereas Cox models are. Moreover, in the second example, the Cox model exhibits a significant effect that the linear model does not. We provide methods to select the best-fitting models for repeated duration data and to compare statistical methodologies. In this study, we show that Cox models are best suited to the analysis of our data set.

A new semi-supervised learning model combined with Cox and SP-AFT models in cancer survival analysis.

PubMed

Chai, Hua; Li, Zi-Na; Meng, De-Yu; Xia, Liang-Yong; Liang, Yong

2017-10-12

Gene selection is an attractive and important task in cancer survival analysis. Most existing supervised learning methods can only use the labeled biological data, while the censored data (weakly labeled data) far more than the labeled data are ignored in model building. Trying to utilize such information in the censored data, a semi-supervised learning framework (Cox-AFT model) combined with Cox proportional hazard (Cox) and accelerated failure time (AFT) model was used in cancer research, which has better performance than the single Cox or AFT model. This method, however, is easily affected by noise. To alleviate this problem, in this paper we combine the Cox-AFT model with self-paced learning (SPL) method to more effectively employ the information in the censored data in a self-learning way. SPL is a kind of reliable and stable learning mechanism, which is recently proposed for simulating the human learning process to help the AFT model automatically identify and include samples of high confidence into training, minimizing interference from high noise. Utilizing the SPL method produces two direct advantages: (1) The utilization of censored data is further promoted; (2) the noise delivered to the model is greatly decreased. The experimental results demonstrate the effectiveness of the proposed model compared to the traditional Cox-AFT model.

Comparison between alcohol- and hepatitis C virus-related hepatocellular carcinoma: clinical presentation, treatment and outcome.

PubMed

Bucci, L; Garuti, F; Camelli, V; Lenzi, B; Farinati, F; Giannini, E G; Ciccarese, F; Piscaglia, F; Rapaccini, G L; Di Marco, M; Caturelli, E; Zoli, M; Borzio, F; Sacco, R; Maida, M; Felder, M; Morisco, F; Gasbarrini, A; Gemini, S; Foschi, F G; Missale, G; Masotto, A; Affronti, A; Bernardi, M; Trevisani, F

2016-02-01

Hepatitis C virus (HCV) and alcohol abuse are the main risk factors for hepatocellular carcinoma (HCC) in Western countries. To investigate the role of alcoholic aetiology on clinical presentation, treatment and outcome of HCC as well as on each Barcelona Clinic Liver Cancer (BCLC) stage, as compared to HCV-related HCCs. A total of 1642 HCV and 573 alcoholic patients from the Italian Liver Cancer (ITA.LI.CA) database, diagnosed with HCC between January 2000 and December 2012 were compared for age, gender, type of diagnosis, tumour burden, portal vein thrombosis (PVT), oesophageal varices, liver function tests, alpha-fetoprotein, BCLC, treatment and survival. Aetiology was tested as predictor of survival in multivariate Cox regression models and according to HCC stages. Cirrhosis was present in 96% of cases in both groups. Alcoholic patients were younger, more likely male, with HCC diagnosed outside surveillance, in intermediate/terminal BCLC stage and had worse liver function. After adjustment for the lead-time, median (95% CI) overall survival (OS) was 27.4 months (21.5-33.2) in alcoholic and 33.6 months (30.7-36.5) in HCV patients (P = 0.021). The prognostic role of aetiology disappeared when survival was assessed in each BCLC stage and in the Cox regression multivariate models. Alcoholic aetiology affects survival of HCC patients through its negative effects on secondary prevention and cancer presentation but not through a greater cancer aggressiveness or worse treatment result. In fact, survival adjusted for confounding factors was similar in alcoholic and HCV patients. © 2015 John Wiley & Sons Ltd.

Incompletely treated malignancies of the major salivary gland: Toward evidence-based care.

PubMed

Tam, Samantha; Sandulache, Vlad C; Metwalli, Kareem A; Rock, Crosby D; Eraj, Salman A; Sheu, Tommy; El-Naggar, Adel K; Fuller, Clifton D; Weber, Randal S; Lai, Stephen Y

2018-05-07

Unexpected malignancy is common in major salivary gland tumors due to variability of workup, creating challenging treatment decisions. The purpose of this study was to define treatment-related outcomes for patients with incompletely treated major salivary gland tumors. A retrospective cohort study was completed of patients with incompletely treated major salivary gland tumors. Tumor burden at presentation was established and treatment categorized. The Cox Proportional Hazards model was used to determine predictors of survival and failure. Of the 440 included patients, patients with gross residual or metastatic disease had a worse overall survival (OS; P < .001). Presentation status was an independent predictor of OS on multivariate analysis (gross residual disease adjusted hazard ratio [HR adjusted ] 2.55; 95% confidence interval [CI] 1.20-5.30; metastatic disease HR adjusted 9.53; 95% CI 3.04-27.06). Failure to achieve gross total resection during initial surgery resulted in worse OS. Adequate preoperative planning is required for initial surgical management to optimize tumor control and survival. © 2018 Wiley Periodicals, Inc.

External adjustment sensitivity analysis for unmeasured confounding: an application to coronary stent outcomes, Pennsylvania 2004-2008.

PubMed

Huesch, Marco D

2013-06-01

Assessing the real-world comparative effectiveness of common interventions is challenged by unmeasured confounding. To determine whether the mortality benefit shown for drug-eluting stents (DES) over bare metal stents (BMS) in observational studies persists after controls for/tests for confounding. Retrospective observational study involving 38,019 patients, 65 years or older admitted for an index percutaneous coronary intervention receiving DES or BMS in Pennsylvania in 2004-2005 followed up for death through 3 years. Analysis was at the patient level. Mortality was analyzed with Cox proportional hazards models allowing for stratification by disease severity or DES use propensity, accounting for clustering of patients. Instrumental variables analysis used lagged physician stent usage to proxy for the focal stent type decision. A method originating in work by Cornfield and others in 1954 and popularized by Greenland in 1996 was used to assess robustness to confounding. DES was associated with a significantly lower adjusted risk of death at 3 years in Cox and in instrumented analyses. An implausibly strong hypothetical unobserved confounder would be required to fully explain these results. Confounding by indication can bias observational studies. No strong evidence of such selection biases was found in the reduced risk of death among elderly patients receiving DES instead of BMS in a Pennsylvanian state-wide population. © Health Research and Educational Trust.

Association between local inflammation and breast tissue age-related lobular involution among premenopausal and postmenopausal breast cancer patients

PubMed Central

Hanna, Mirette; Dumas, Isabelle; Orain, Michèle; Jacob, Simon; Têtu, Bernard; Sanschagrin, François; Bureau, Alexandre; Poirier, Brigitte; Diorio, Caroline

2017-01-01

Increased levels of pro-inflammatory markers and decreased levels of anti-inflammatory markers in the breast tissue can result in local inflammation. We aimed to investigate whether local inflammation in the breast tissue is associated with age-related lobular involution, a process inversely related to breast cancer risk. Levels of eleven pro- and anti-inflammatory markers were assessed by immunohistochemistry in normal breast tissue obtained from 164 pre- and postmenopausal breast cancer patients. Involution status of the breast (degree of lobular involution and the predominant lobule type) was microscopically assessed in normal breast tissue on hematoxylin-eosin stained mastectomy slides. Multivariate generalized linear models were used to assess the associations. In age-adjusted analyses, higher levels of pro-inflammatory markers IL-6, TNF-α, CRP, COX-2, leptin, SAA1 and IL-8; and anti-inflammatory marker IL-10, were inversely associated with the prevalence of complete lobular involution (all P≤0.04). Higher levels of the pro-inflammatory marker COX-2 were also associated with lower prevalence of predominant type 1/no type 3 lobules in the breast, an indicator of complete involution, in age-adjusted analysis (P = 0.017). Higher tissue levels of inflammatory markers, mainly the pro-inflammatory ones, are associated with less involuted breasts and may consequently be associated with an increased risk of developing breast cancer. PMID:28846716

Risk of Stroke Among Survivors of the September 11, 2001 World Trade Center Disaster.

PubMed

Yu, Shengchao; Alper, Howard E; Nguyen, Angela-Maithy; Brackbill, Robert M

2018-05-30

The aim of this study was to investigate the association between 9/11-related posttraumatic stress disorder (PTSD), dust cloud exposure, and subsequent development of stroke among 42,527 enrollees in the World Trade Center (WTC) Health Registry. Using four waves of longitudinal data from the WTC Health Registry surveys, we employed Cox proportional hazards regression models to assess the associations. Incidence of stroke was higher among those with PTSD or intense dust cloud exposure than those without, and it was even higher for those who had experienced both. In fully adjusted models, participants with PTSD had an increased risk of developing stroke [adjusted hazards ratio (AHR) 1.69, 95% confidence interval (95% CI) 1.42 to 2.02], as did those with intense dust exposure (AHR 1.29, 95% CI 1.09 to 1.53). We found that individuals with 9/11-related PTSD and/or intense dust exposure may have an increased risk of developing stroke.

Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer.

PubMed

Hao, Yanni; Lin, Peggy L; Xie, Jipan; Li, Nanxin; Koo, Valerie; Ohashi, Erika; Wu, Eric Q; Rogerio, Jaqueline

2015-08-01

Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI). Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics. 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

Acupuncture Therapy and Incidence of Depression After Stroke.

PubMed

Lu, Chung-Yen; Huang, Hsin-Chia; Chang, Hen-Hong; Yang, Tsung-Hsien; Chang, Chee-Jen; Chang, Su-Wei; Chen, Pei-Chun

2017-06-01

We investigated whether use of acupuncture within a 3-month poststroke period after hospital discharge is associated with reduced risk of depression. This cohort study included 16 046 patients aged ≥18 years with an initial hospitalization for stroke during 2000 and 2012 in the claims database of a universal health insurance program. Patients who had received acupuncture therapies within 3 months of discharge were defined as acupuncture users (n=1714). All patients were followed up for incidence of depression until the end of 2013. We assessed the association between use of acupuncture and incidence of depression using Cox proportional hazards models in all subjects and in propensity score-matched samples consisting of 1714 pairs of users and nonusers. During the follow-up period, the incidence of depression per 1000 person-years was 11.1 and 9.7 in users and nonusers, respectively. Neither multivariable-adjusted Cox models (hazard ratio, 1.04; 95% confidence interval, 0.84-1.29) nor the propensity score-matching model (hazard ratio, 1.06; 95% confidence interval, 0.79-1.42) revealed an association between use of acupuncture and incidence of depression. In patients admitted to hospital for stroke, acupuncture therapy within 3 months after discharge was not associated with subsequent incidence of depression. © 2017 American Heart Association, Inc.

Modified CLIP with objective liver reserve assessment retains prognosis prediction for patients with advanced hepatocellular carcinoma.

PubMed

Shao, Yu-Yun; Liu, Tsung-Hao; Lee, Ying-Hui; Hsu, Chih-Hung; Cheng, Ann-Lii

2016-07-01

The Cancer of the Liver Italian Program (CLIP) score is a commonly used staging system for hepatocellular carcinoma (HCC) helpful with predicting prognosis of advanced HCC. CLIP uses the Child-Turcotte-Pugh (CTP) score to evaluate liver reserve. A new scoring system, the albumin-bilirubin (ALBI) grade, has been proposed as they objectively evaluate liver reserve. We examined whether the modification of CLIP with ALBI retained its prognosis prediction for patients with advanced HCC. We included patients who received first-line antiangiogenic therapy for advanced HCC. Liver reserve was assessed using CTP and ALBI scores, which were then incorporated into CLIP and ALBI-CLIP, respectively. To assess their efficacies of prognostic prediction, the Cox's proportional hazard model and concordance indexes were used. A total of 142 patients were included; 137 of them were classified CTP A and 5 patients CTP B. Patients could be divided into four or five groups with different prognosis according to CLIP and ALBI-CLIP, respectively. Higher R(2) (0.249 vs 0.216) and lower Akaike information criterion (995.0 vs 1001.1) were observed for ALBI-CLIP than for CLIP in the Cox's model predicting overall survival. ALBI-CLIP remained an independent predictor for overall survival when CLIP and ALBI-CLIP were simultaneously incorporated in Cox's models allowing variable selection with adjustment for hepatitis etiology, treatment, and performance status. The concordance index was also higher for ALBI-CLIP than for CLIP (0.724 vs 0.703). Modification of CLIP scoring with ALBI, which objectively assesses liver reserve, retains and might have improved prognosis prediction for advanced HCC. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Cardiorespiratory fitness and components of the metabolic syndrome in sedentary men.

PubMed

Riou, Marie-Eve; Pigeon, Etienne; St-Onge, Josée; Tremblay, Angelo; Marette, André; Weisnagel, John; Joanisse, Denis R

2009-01-01

To investigate the relationships between fitness and components of the metabolic syndrome in sedentary men. 39 subjects (34-53 years) were evaluated for fitness (VO(2max)) and anthropometric, metabolic, and skeletal muscle phenotypes. VO(2max) was assessed on a bicycle ergometer whereas other variables were obtained from an oral glucose tolerance test (OGTT), hydrostatic weighing, and a muscle biopsy. Pearson and partial correlations adjusted for fat mass (FM), waist circumference (WC), muscle enzyme activities (citrate synthase (CS), cytochrome c oxidase (COX)), and capillary density were used to investigate the independent relationships be tween variables. Negative correlations between VO(2max) and WC as well as blood pressure and OGTT test were observed. When adjusted for FM, correlations remained between VO(2max) and WC (r = -0.46, p < 0.01) and systolic blood pressure (r = -0.35, p < 0.05). When adjusted for WC and CS activity, all correlations were lost except for high-sensitivity C-reactive protein (hs-CRP) (r = -0.34, p < 0.05) which remained when adjusted for CS activity. Adjustment for COX activity failed to remove correlations with hs-CRP (r = -0.36, p < 0.05), age (r = 0.34, p < 0.05), WC (r = -0.35, p < 0.05), and blood pressure. Negative correlations persisted when fitness was adjusted for the mean number of capillaries. The effects of fitness on components of the metabolic syndrome in sedentary men are explained by abdominal obesity and muscle phenotypes.

Statins use and risk of new-onset diabetes in hypertensive patients: a population-based retrospective cohort study in Yinzhou district, Ningbo city, People's Republic of China.

PubMed

Li, Hailong; Lin, Hongbo; Zhao, Houyu; Xu, Yang; Cheng, Yinchu; Shen, Peng; Zhan, Siyan

2018-01-01

Reports have suggested that statin use is associated with an increased incidence of type 2 diabetes mellitus (T2DM). Guidelines suggested that statins should be prescribed in hypertensive patients for primary prevention. However, there were very few studies on the risk of T2DM associated with statin use among patients with hypertension in mainland People's Republic of China. To determine the association between statin use and new-onset diabetes mellitus among patients with hypertension in mainland People's Republic of China. We performed a retrospective cohort study of hypertensive patients using the Yinzhou regional health care database from January 1, 2010, to August 31, 2016. Patients aged 30-90 years old without T2DM were eligible for inclusion. We identified new statin initiators and nonusers by using prescription records of inpatients and outpatients. Multivariate Cox model and propensity score methods were used to adjust potential confounders, including age, sex, body mass index, comorbidities, lifestyle characteristics, and baseline antihypertensive drug use. The risk of incident T2DM among statin initiators compared to nonusers was estimated by the Cox proportional hazards model. Propensity scores for statin use were then developed using logistic regression, statin initiators were matched 1:1 with nonusers according to propensity scores with the nearest neighbor matching method within 0.2 caliper width, and Cox regression was again conducted. Among 67,993 patients (21,551 statin initiators; 46,442 nonusers), the unadjusted incidence rate of incident T2DM was higher in statin initiators than nonusers (25.68 versus 14.19 events/1,000 person-years; adjusted hazard ratio: 1.55; 95% confidence interval: 1.44-1.66). After propensity score 1:1 matching (19,818 statin initiators; 19,818 nonusers), baseline characteristics between 2 groups were balanced except that the nonusers group was 0.53 years older on average ( P <0.001). Then statin use was still associated with a significant increased risk for T2DM in the matched cohort (adjusted hazard ratio: 1.54; 95% confidence interval: 1.41-1.67). Subgroup analyses also demonstrated similar findings. Our study indicated an association between statin use and an increased risk of new-onset diabetes mellitus. It provides better understanding of statin and new-onset diabetes mellitus association among hypertensive patients in real-word setting. As an observational study, our findings were prone to unmeasured confounding and bias.

Analyzing Student Learning Outcomes: Usefulness of Logistic and Cox Regression Models. IR Applications, Volume 5

ERIC Educational Resources Information Center

Chen, Chau-Kuang

2005-01-01

Logistic and Cox regression methods are practical tools used to model the relationships between certain student learning outcomes and their relevant explanatory variables. The logistic regression model fits an S-shaped curve into a binary outcome with data points of zero and one. The Cox regression model allows investigators to study the duration…

Myocardial Injury in Patients With Sepsis and Its Association With Long-Term Outcome.

PubMed

Frencken, Jos F; Donker, Dirk W; Spitoni, Cristian; Koster-Brouwer, Marlies E; Soliman, Ivo W; Ong, David S Y; Horn, Janneke; van der Poll, Tom; van Klei, Wilton A; Bonten, Marc J M; Cremer, Olaf L

2018-02-01

Sepsis is frequently complicated by the release of cardiac troponin, but the clinical significance of this myocardial injury remains unclear. We studied the associations between troponin release during sepsis and 1-year outcomes. We enrolled consecutive patients with sepsis in 2 Dutch intensive care units between 2011 and 2013. Subjects with a clinically apparent cause of troponin release were excluded. High-sensitivity cardiac troponin I (hs-cTnI) concentration in plasma was measured daily during the first 4 intensive care unit days, and multivariable Cox regression analysis was used to model its association with 1-year mortality while adjusting for confounding. In addition, we studied cardiovascular morbidity occurring during the first year after hospital discharge. Among 1258 patients presenting with sepsis, 1124 (89%) were eligible for study inclusion. Hs-cTnI concentrations were elevated in 673 (60%) subjects on day 1, and 755 (67%) ever had elevated levels in the first 4 days. Cox regression analysis revealed that high hs-cTnI concentrations were associated with increased death rates during the first 14 days (adjusted hazard ratio, 1.72; 95% confidence interval, 1.14-2.59 and hazard ratio, 1.70; 95% confidence interval, 1.10-2.62 for hs-cTnI concentrations of 100-500 and >500 ng/L, respectively) but not thereafter. Furthermore, elevated hs-cTnI levels were associated with the development of cardiovascular disease among 200 hospital survivors who were analyzed for this end point (adjusted subdistribution hazard ratio, 1.25; 95% confidence interval, 1.04-1.50). Myocardial injury occurs in the majority of patients with sepsis and is independently associated with early-but not late-mortality, as well as postdischarge cardiovascular morbidity. © 2018 American Heart Association, Inc.

SURVIVAL DISPARITIES BY MEDICAID STATUS: AN ANALYSIS OF EIGHT CANCERS

PubMed Central

Koroukian, Siran M.; Bakaki, Paul M.; Raghavan, Derek

2011-01-01

Study Objective To compare survival and 5-year mortality, by Medicaid status, in adults diagnosed with 8 select cancers. Methods Linking records from the Ohio Cancer Incidence Surveillance System (OCISS) with Ohio Medicaid enrollment data, we identified Medicaid and non-Medicaid patients aged 15–54 years and diagnosed with the following incident cancers in the years 1996–2002: cancer of the testis; Hodgkin’s and non-Hodgkin’s lymphoma; early-stage melanoma, colon, lung, and bladder cancer; or pediatric malignancies (n=12,703). Medicaid beneficiaries were identified in the pre-diagnosis group if they were enrolled in Medicaid at least 3 months before cancer diagnosis, and in the peri/post-diagnosis group if they enrolled in Medicaid upon or after being diagnosed with cancer. We also linked the OCISS with death certificates and data from the U.S. Census. Using Cox and logistic regression analysis, we examined the association between Medicaid status and each of survival and 5-year mortality, respectively, after adjusting for patient covariates. Results Nearly 11% of the study population were Medicaid beneficiaries. Of those, 45% were identified in the peri/post-diagnosis group. Consistent with higher mortality, findings from the Cox regression model indicated that compared to non-Medicaid, patients in the Medicaid pre-diagnosis and peri/post-diagnosis groups experienced unfavorable survival outcomes (adjusted hazard ratio (AHR): 1.52, 95% confidence interval (1.27, 1.82), and 2.01 (1.70, 2.38), respectively). Conclusions Medicaid status was associated with unfavorable survival, even after adjusting for confounders. Impact The findings reflect the vulnerability of Medicaid beneficiaries and possible inadequacies in the process of care. PMID:22213271

Comparing of Cox model and parametric models in analysis of effective factors on event time of neuropathy in patients with type 2 diabetes.

PubMed

Kargarian-Marvasti, Sadegh; Rimaz, Shahnaz; Abolghasemi, Jamileh; Heydari, Iraj

2017-01-01

Cox proportional hazard model is the most common method for analyzing the effects of several variables on survival time. However, under certain circumstances, parametric models give more precise estimates to analyze survival data than Cox. The purpose of this study was to investigate the comparative performance of Cox and parametric models in a survival analysis of factors affecting the event time of neuropathy in patients with type 2 diabetes. This study included 371 patients with type 2 diabetes without neuropathy who were registered at Fereydunshahr diabetes clinic. Subjects were followed up for the development of neuropathy between 2006 to March 2016. To investigate the factors influencing the event time of neuropathy, significant variables in univariate model ( P < 0.20) were entered into the multivariate Cox and parametric models ( P < 0.05). In addition, Akaike information criterion (AIC) and area under ROC curves were used to evaluate the relative goodness of fitted model and the efficiency of each procedure, respectively. Statistical computing was performed using R software version 3.2.3 (UNIX platforms, Windows and MacOS). Using Kaplan-Meier, survival time of neuropathy was computed 76.6 ± 5 months after initial diagnosis of diabetes. After multivariate analysis of Cox and parametric models, ethnicity, high-density lipoprotein and family history of diabetes were identified as predictors of event time of neuropathy ( P < 0.05). According to AIC, "log-normal" model with the lowest Akaike's was the best-fitted model among Cox and parametric models. According to the results of comparison of survival receiver operating characteristics curves, log-normal model was considered as the most efficient and fitted model.

Age of first arrest varies by gambling status in a cohort of young adults

PubMed Central

Martins, Silvia S.; Lee, Grace P.; Santaella, Julian; Liu, Weiwei; Ialongo, Nicholas S.; Storr, Carla L.

2015-01-01

Background and objectives To describe the association between social and problem gambling and first criminal arrest by age 23 in a cohort of urban, mainly African-American youth. Methods: Data for this study was derived from several annual interviews being completed on a community sample of 617 participants during late adolescence until age 23. Information on gambling status, engagement in deviant behaviors, illegal drug use, and arrest history were collected through yearly interviews. Analysis was carried out using Nelson-Aalen cumulative hazard models and simple and adjusted Cox proportional hazards models. Results More problem gamblers had been arrested before age 23 than social gamblers and non-gamblers, i.e. 65% of problem gamblers were arrested before age 23, compared to 38% of social gamblers and 24% non-gamblers. Social gambling was only significantly associated with the hazard of first arrest by age 23 in the unadjusted model (HR: 1.6, p<.001), but not after adjustment for covariates (HR: 1.1, p=0.47). Problem gambling was significantly associated with the hazard of first arrest by age 23 years in the unadjusted (HR: 3.6,p<.001) and adjusted models (HR:1.6, p=0.05). Conclusions and Scientific Significance Problem gambling was significantly associated with earlier age of being arrested. Dilution effects after adjustment for several deviant behaviors and illegal drug use by age 17 suggest that youth exposed to certain common factors may result in engagement in multiple risky behaviors, including problem gambling. Studies are needed to investigate the developmental pathways that lead to these combined behaviors among youth. PMID:24628694

Associations of coronary artery calcified plaque density with mortality in type 2 diabetes: the Diabetes Heart Study.

PubMed

Raffield, Laura M; Cox, Amanda J; Criqui, Michael H; Hsu, Fang-Chi; Terry, James G; Xu, Jianzhao; Freedman, Barry I; Carr, J Jeffrey; Bowden, Donald W

2018-05-11

Coronary artery calcified plaque (CAC) is strongly predictive of cardiovascular disease (CVD) events and mortality, both in general populations and individuals with type 2 diabetes at high risk for CVD. CAC is typically reported as an Agatston score, which is weighted for increased plaque density. However, the role of CAC density in CVD risk prediction, independently and with CAC volume, remains unclear. We examined the role of CAC density in individuals with type 2 diabetes from the family-based Diabetes Heart Study and the African American-Diabetes Heart Study. CAC density was calculated as mass divided by volume, and associations with incident all-cause and CVD mortality [median follow-up 10.2 years European Americans (n = 902, n = 286 deceased), 5.2 years African Americans (n = 552, n = 93 deceased)] were examined using Cox proportional hazards models, independently and in models adjusted for CAC volume. In European Americans, CAC density, like Agatston score and volume, was consistently associated with increased risk of all-cause and CVD mortality (p ≤ 0.002) in models adjusted for age, sex, statin use, total cholesterol, HDL, systolic blood pressure, high blood pressure medication use, and current smoking. However, these associations were no longer significant when models were additionally adjusted for CAC volume. CAC density was not significantly associated with mortality, either alone or adjusted for CAC volume, in African Americans. CAC density is not associated with mortality independent from CAC volume in European Americans and African Americans with type 2 diabetes.

Thrombosis Is Reduced by Inhibition of COX-1, but Unaffected by Inhibition of COX-2, in an Acute Model of Platelet Activation in the Mouse

PubMed Central

Armstrong, Paul C.; Kirkby, Nicholas S.; Zain, Zetty N.; Emerson, Michael; Mitchell, Jane A.; Warner, Timothy D.

2011-01-01

Background Clinical use of selective inhibitors of cyclooxygenase (COX)-2 appears associated with increased risk of thrombotic events. This is often hypothesised to reflect reduction in anti-thrombotic prostanoids, notably PGI2, formed by COX-2 present within endothelial cells. However, whether COX-2 is actually expressed to any significant extent within endothelial cells is controversial. Here we have tested the effects of acute inhibition of COX on platelet reactivity using a functional in vivo approach in mice. Methodology/Principal Findings A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin (7 days orally as control) diclofenac (1 mg.kg−1, i.v.) and parecoxib (0.5 mg.kg−1, i.v.) on thrombus formation induced by collagen or the thromboxane (TX) A2-mimetic, U46619. The COX inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo. Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin. Diclofenac inhibited COX-1 and COX-2 ex vivo and reduced thrombus formation in response to collagen, but not U46619. Parecoxib inhibited only COX-2 and had no effect upon thrombus formation caused by either agonist. Conclusions/Significance Inhibition of COX-1 by diclofenac or aspirin reduced thrombus formation induced by collagen, which is partly dependent upon platelet-derived TXA2, but not that induced by U46619, which is independent of platelet TXA2. These results are consistent with the model demonstrating the effects of COX-1 inhibition in platelets, but provide no support for the hypothesis that acute inhibition of COX-2 in the circulation increases thrombosis. PMID:21629780

Introduction to the use of regression models in epidemiology.

PubMed

Bender, Ralf

2009-01-01

Regression modeling is one of the most important statistical techniques used in analytical epidemiology. By means of regression models the effect of one or several explanatory variables (e.g., exposures, subject characteristics, risk factors) on a response variable such as mortality or cancer can be investigated. From multiple regression models, adjusted effect estimates can be obtained that take the effect of potential confounders into account. Regression methods can be applied in all epidemiologic study designs so that they represent a universal tool for data analysis in epidemiology. Different kinds of regression models have been developed in dependence on the measurement scale of the response variable and the study design. The most important methods are linear regression for continuous outcomes, logistic regression for binary outcomes, Cox regression for time-to-event data, and Poisson regression for frequencies and rates. This chapter provides a nontechnical introduction to these regression models with illustrating examples from cancer research.

Confounding by dietary patterns of the inverse association between alcohol consumption and type 2 diabetes risk.

PubMed

Imamura, Fumiaki; Lichtenstein, Alice H; Dallal, Gerard E; Meigs, James B; Jacques, Paul F

2009-07-01

The ability to interpret epidemiologic observations is limited because of potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as standard risk factors and selected nutrients, the authors modeled the longitudinal association between alcohol consumption and 7-year risk of type 2 diabetes mellitus in 2,879 healthy adults enrolled in the Framingham Offspring Study (1991-2001) by Cox proportional hazard models. After adjustment for standard risk factors, consumers of > or =9.0 drinks/week had a significantly lower risk of type 2 diabetes mellitus compared with abstainers (hazard ratio = 0.47, 95% confidence interval (CI): 0.27, 0.81). Adjustment for selected nutrients had little effect on the hazard ratio, whereas adjustment for dietary pattern variables by factor analysis significantly shifted the hazard ratio away from null (hazard ratio = 0.33, 95% CI: 0.17, 0.64) by 40.0% (95% CI: 16.8, 57.0; P = 0.002). Dietary pattern variables by partial least squares showed similar results. Therefore, the observed inverse association, consistent with past studies, was confounded by dietary patterns, and this confounding was not captured by individual nutrient adjustment. The data suggest that alcohol intake, not dietary patterns associated with alcohol intake, is responsible for the observed inverse association with type 2 diabetes mellitus risk.

Many multicenter trials had few events per center, requiring analysis via random-effects models or GEEs.

PubMed

Kahan, Brennan C; Harhay, Michael O

2015-12-01

Adjustment for center in multicenter trials is recommended when there are between-center differences or when randomization has been stratified by center. However, common methods of analysis (such as fixed-effects, Mantel-Haenszel, or stratified Cox models) often require a large number of patients or events per center to perform well. We reviewed 206 multicenter randomized trials published in four general medical journals to assess the average number of patients and events per center and determine whether appropriate methods of analysis were used in trials with few patients or events per center. The median number of events per center/treatment arm combination for trials using a binary or survival outcome was 3 (interquartile range, 1-10). Sixteen percent of trials had less than 1 event per center/treatment combination, 50% fewer than 3, and 63% fewer than 5. Of the trials which adjusted for center using a method of analysis which requires a large number of events per center, 6% had less than 1 event per center-treatment combination, 25% fewer than 3, and 50% fewer than 5. Methods of analysis that allow for few events per center, such as random-effects models or generalized estimating equations (GEEs), were rarely used. Many multicenter trials contain few events per center. Adjustment for center using random-effects models or GEE with model-based (non-robust) standard errors may be beneficial in these scenarios. Copyright © 2015 Elsevier Inc. All rights reserved.

High morale is associated with increased survival in the very old.

PubMed

Niklasson, Johan; Hörnsten, Carl; Conradsson, Mia; Nyqvist, Fredrica; Olofsson, Birgitta; Lövheim, Hugo; Gustafson, Yngve

2015-07-01

high morale is defined as future-oriented optimism. Previous research suggests that a high morale independently predicts increased survival among old people, though very old people have not been specifically studied. to investigate whether high morale is associated with increased survival among very old people. the Umeå 85+/GErontological Regional DAtabase-study (GERDA) recruited participants aged 85 years and older in northern Sweden and western Finland during 2000-02 and 2005-07, of whom 646 were included in this study. demographic, functional- and health-related data were collected in this population-based study through structured interviews and assessments carried out during home visits and from reviews of medical records. The 17-item Philadelphia Geriatric Center Morale Scale (PGCMS) was used to assess morale. the 5-year survival rate was 31.9% for participants with low morale, 39.4% for moderate and 55.6% for those with high morale. In an unadjusted Cox model, the relative risk (RR) of mortality was higher among participants with low morale (RR = 1.86, P < 0.001) and moderate morale (RR = 1.59, P < 0.001) compared with participants with high morale. Similar results were found after adjustment for age and gender. In a Cox model adjusted for several demographic, health- and function-related confounders, including age and gender, mortality was higher among participants with low morale (RR = 1.36, P = 0.032) than those with high morale. There was a similar but non-significant pattern towards increased mortality in participants with moderate morale (RR = 1.21, P value = 0.136). high morale is independently associated with increased survival among very old people. © The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cortical superficial siderosis and first-ever cerebral hemorrhage in cerebral amyloid angiopathy

PubMed Central

Boulouis, Gregoire; Xiong, Li; Jessel, Michel J.; Roongpiboonsopit, Duangnapa; Ayres, Alison; Schwab, Kristin M.; Rosand, Jonathan; Gurol, M. Edip; Greenberg, Steven M.; Viswanathan, Anand

2017-01-01

Objective: To investigate whether cortical superficial siderosis (cSS) is associated with increased risk of future first-ever symptomatic lobar intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA) presenting with neurologic symptoms and without ICH. Methods: Consecutive patients meeting modified Boston criteria for probable CAA in the absence of ICH from a single-center cohort were analyzed. cSS and other small vessel disease MRI markers were assessed according to recent consensus recommendations. Patients were followed prospectively for future incident symptomatic lobar ICH. Prespecified Cox proportional hazard models were used to investigate cSS and first-ever lobar ICH risk adjusting for potential confounders. Results: The cohort included 236 patients with probable CAA without lobar ICH at baseline. cSS prevalence was 34%. During a median follow-up of 3.26 years (interquartile range 1.42–5.50 years), 27 of 236 patients (11.4%) experienced a first-ever symptomatic lobar ICH. cSS was a predictor of time until first ICH (p = 0.0007, log-rank test). The risk of symptomatic ICH at 5 years of follow-up was 19% (95% confidence interval [CI] 11%–32%) for patients with cSS at baseline vs 6% (95% CI 3%–12%) for patients without cSS. In multivariable Cox regression models, cSS presence was the only independent predictor of increased symptomatic ICH risk during follow-up (HR 4.04; 95% CI 1.73–9.44, p = 0.001), after adjusting for age, lobar cerebral microbleeds burden, and white matter hyperintensities. Conclusions: cSS is consistently associated with an increased risk of future lobar ICH in CAA with potentially important clinical implications for patient care decisions such as antithrombotic use. PMID:28356458

Risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy.

PubMed

Kesselring, Anouk M; Wit, Ferdinand W; Sabin, Caroline A; Lundgren, Jens D; Gill, M John; Gatell, Jose M; Rauch, Andri; Montaner, Julio S; de Wolf, Frank; Reiss, Peter; Mocroft, Amanda

2009-08-24

This collaboration of seven observational clinical cohorts investigated risk factors for treatment-limiting toxicities in both antiretroviral-naive and experienced patients starting nevirapine-based combination antiretroviral therapy (NVPc). Patients starting NVPc after 1 January 1998 were included. CD4 cell count at starting NVPc was classified as high (>400/microl/>250/microl for men/women, respectively) or low. Cox models were used to investigate risk factors for discontinuations due to hypersensitivity reactions (HSR, n = 6547) and discontinuation of NVPc due to treatment-limiting toxicities and/or patient/physician choice (TOXPC, n = 10,186). Patients were classified according to prior antiretroviral treatment experience and CD4 cell count/viral load at start NVPc. Models were stratified by cohort and adjusted for age, sex, nadir CD4 cell count, calendar year of starting NVPc and mode of transmission. Median time from starting NVPc to TOXPC and HSR were 162 days [interquartile range (IQR) 31-737] and 30 days (IQR 17-60), respectively. In adjusted Cox analyses, compared to naive patients with a low CD4 cell count, treatment-experienced patients with high CD4 cell count and viral load more than 400 had a significantly increased risk for HSR [hazard ratio 1.45, confidence interval (CI) 1.03-2.03] and TOXPC within 18 weeks (hazard ratio 1.34, CI 1.08-1.67). In contrast, treatment-experienced patients with high CD4 cell count and viral load less than 400 had no increased risk for HSR 1.10 (0.82-1.46) or TOXPC within 18 weeks (hazard ratio 0.94, CI 0.78-1.13). Our results suggest it may be relatively well tolerated to initiate NVPc in antiretroviral-experienced patients with high CD4 cell counts provided there is no detectable viremia.

A prognostic scoring system for arm exercise stress testing.

PubMed

Xie, Yan; Xian, Hong; Chandiramani, Pooja; Bainter, Emily; Wan, Leping; Martin, Wade H

2016-01-01

Arm exercise stress testing may be an equivalent or better predictor of mortality outcome than pharmacological stress imaging for the ≥50% for patients unable to perform leg exercise. Thus, our objective was to develop an arm exercise ECG stress test scoring system, analogous to the Duke Treadmill Score, for predicting outcome in these individuals. In this retrospective observational cohort study, arm exercise ECG stress tests were performed in 443 consecutive veterans aged 64.1 (11.1) years. (mean (SD)) between 1997 and 2002. From multivariate Cox models, arm exercise scores were developed for prediction of 5-year and 12-year all-cause and cardiovascular mortality and 5-year cardiovascular mortality or myocardial infarction (MI). Arm exercise capacity in resting metabolic equivalents (METs), 1 min heart rate recovery (HRR) and ST segment depression ≥1 mm were the stress test variables independently associated with all-cause and cardiovascular mortality by step-wise Cox analysis (all p<0.01). A score based on the relation HRR (bpm)+7.3×METs-10.5×ST depression (0=no; 1=yes) prognosticated 5-year cardiovascular mortality with a C-statistic of 0.81 before and 0.88 after adjustment for significant demographic and clinical covariates. Arm exercise scores for the other outcome end points yielded C-statistic values of 0.77-0.79 before and 0.82-0.86 after adjustment for significant covariates versus 0.64-0.72 for best fit pharmacological myocardial perfusion imaging models in a cohort of 1730 veterans who were evaluated over the same time period. Arm exercise scores, analogous to the Duke Treadmill Score, have good power for prediction of mortality or MI in patients who cannot perform leg exercise.

Relationship between quantitative GRB7 RNA expression and recurrence after adjuvant anthracycline chemotherapy in triple-negative breast cancer.

PubMed

Sparano, Joseph A; Goldstein, Lori J; Childs, Barrett H; Shak, Steven; Brassard, Diana; Badve, Sunil; Baehner, Frederick L; Bugarini, Roberto; Rowley, Steve; Perez, Edith A; Shulman, Lawrence N; Martino, Silvana; Davidson, Nancy E; Kenny, Paraic A; Sledge, George W; Gray, Robert

2011-11-15

To conduct an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy. RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative reverse transcriptase PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests. Growth factor receptor bound protein 7 (GRB7) was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn's adjusted P value = 0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR = 2.31; P = 0.04 using the median as the split). The 5-year recurrence rates were 10.5% [95% confidence intervals (CI), 7.8-14.1] in the low and 20.4% (95% CI, 16.5-25.0) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy. GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered.

Relationship Between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple Negative Breast Cancer

PubMed Central

Sparano, Joseph A.; Goldstein, Lori J.; Childs, Barrett H.; Shak, Steven; Brassard, Diana; Badve, Sunil; Baehner, Frederick L.; Bugarini, Roberto; Rowley, Steve; Perez, Edith; Shulman, Lawrence N.; Martino, Silvana; Davidson, Nancy E.; Kenny, Paraic A.; Sledge, George W.; Gray, Robert

2012-01-01

Purpose To perform an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy. Experimental design RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative RT-PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests. Results GRB7 was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn’s adjusted p value=0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR 2.31, p=0.04 using the median as the split). The 5-year recurrence rates were 10.5% (95% confidence intervals [CI] 7.8%, 14.1%) in the low and 20.4% (95% CI 16.5%, 25.0%) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy. Conclusions GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered. PMID:21933890

Skin autofluorescence and all-cause mortality in stage 3 CKD.

PubMed

Fraser, Simon D S; Roderick, Paul J; McIntyre, Natasha J; Harris, Scott; McIntyre, Christopher W; Fluck, Richard J; Taal, Maarten W

2014-08-07

Novel markers may help to improve risk prediction in CKD. One potential candidate is tissue advanced glycation end product accumulation, a marker of cumulative metabolic stress, which can be assessed by a simple noninvasive measurement of skin autofluorescence. Skin autofluorescence correlates with higher risk of cardiovascular events and mortality in people with diabetes or people requiring RRT, but its role in earlier CKD has not been studied. A prospective cohort of 1741 people with CKD stage 3 was recruited from primary care between August 2008 and March 2010. Participants underwent medical history, clinical assessment, blood and urine sampling for biochemistry, and measurement of skin autofluorescence. Kaplan-Meier plots and multivariate Cox proportional hazards models were used to investigate associations between skin autofluorescence (categorical in quartiles) and all-cause mortality. In total, 1707 participants had skin autofluorescence measured; 170 (10%) participants died after a median of 3.6 years of follow-up. The most common cause of death was cardiovascular disease (41%). Higher skin autofluorescence was associated significantly with poorer survival (all-cause mortality, P<0.001) on Kaplan-Meier analysis. Univariate and age/sex-adjusted Cox proportional hazards models showed that the highest quartile of skin autofluorescence was associated with all-cause mortality (hazard ratio, 2.64; 95% confidence interval, 1.71 to 4.08; P<0.001 and hazard ratio, 1.84; 95% confidence interval, 1.18 to 2.86; P=0.003, respectively, compared with the lowest quartile). This association was not maintained after additional adjustment to include cardiovascular disease, diabetes, smoking, body mass index, eGFR, albuminuria, and hemoglobin. Skin autofluorescence was not independently associated with all-cause mortality in this study. Additional research is needed to clarify whether it has a role in risk prediction in CKD. Copyright © 2014 by the American Society of Nephrology.

Smoking, body weight, physical exercise, and risk of lower limb total joint replacement in a population-based cohort of men.

PubMed

Mnatzaganian, George; Ryan, Philip; Norman, Paul E; Davidson, David C; Hiller, Janet E

2011-08-01

To assess the associations of smoking, body weight, and physical activity with risk of undergoing total joint replacement (TJR) in a population-based cohort of men. A cohort study of 11,388 men that integrated clinical data with hospital morbidity data and mortality records was undertaken. The risk of undergoing TJR was modeled on baseline weight, height, comorbidity, socioeconomic status, years of smoking, and exercise in 3 separate age groups, using Cox proportional hazards regressions and competing risk regressions (CRRs). Dose-response relationships between weight and risk of TJR and between smoking and risk of TJR were observed. Being overweight independently increased the risk of TJR, while smoking lowered the risk. The decreased risk among smokers was demonstrated in both Cox and CRR models and became apparent after 23 years of exposure. Men who were in the highest quartile (≥48 years of smoking) were 42-51% less likely to undergo TJR than men who had never smoked. Tests for trend in the log hazard ratios (HRs) across both smoking and weight quantiles yielded significant P values. Vigorous exercise increased the hazard of TJR; however, the association reached statistical significance only in the 70-74-year-old age group (adjusted HR 1.64 [95% confidence interval 1.19-2.24]). Adjusting for Deyo-Charlson Index or Elixhauser's comorbidity measures did not eliminate these associations. Our findings indicate that being overweight and reporting vigorous physical activity increase the risk of TJR. This study is the first to demonstrate a strong inverse dose-response relationship between duration of smoking and risk of TJR. More research is needed to better understand the role of smoking in the pathogenesis of osteoarthritis. Copyright © 2011 by the American College of Rheumatology.

Recovery free of heart failure after acute coronary syndrome and coronary revascularization.

PubMed

Falkenham, Alec; Saraswat, Manoj K; Wong, Chloe; Gawdat, Kareem; Myers, Tanya; Begum, Jahanara; Buth, Karen J; Haidl, Ian; Marshall, Jean; Légaré, Jean-Francois

2018-02-01

Previous studies have examined risk factors for the development of heart failure (HF) subsequent to acute coronary syndrome (ACS). Our study seeks to clarify the clinical variables that best characterize patients who remain free from HF after coronary artery bypass grafting (CABG) surgery for ACS to determine novel biological factors favouring freedom from HF in prospective translational studies. Nova Scotia residents (1995-2012) undergoing CABG within 3 weeks of ACS were included. The primary outcome was freedom from readmission to hospital due to HF. Descriptive statistics were generated, and a Cox proportional hazards model assessed outcome with adjustment for clinical characteristics. Of 11 936 Nova Scotians who underwent isolated CABG, 3264 (27%) had a recent ACS and were included. Deaths occurred in 210 (6%) of subjects prior to discharge. A total of 3054 patients were included in the long-term analysis. During follow-up, HF necessitating readmission occurred in 688 (21%) subjects with a hazard ratio of 12% at 2 years. The adjusted Cox model demonstrated significantly better freedom from HF for younger, male subjects without metabolic syndrome and no history of chronic obstructive pulmonary disease, renal insufficiency, atrial fibrillation, or HF. Our findings have outlined important clinical variables that predict freedom from HF. Furthermore, we have shown that 12% of patients undergoing CABG after ACS develop HF (2 years). Our findings support our next phase in which we plan to prospectively collect blood and tissue specimens from ACS patients undergoing CABG in order to determine novel biological mechanism(s) that favour resolution of post-ACS inflammation. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Treatment Patterns and Differences in Survival of Non-Small Cell Lung Cancer Patients Between Academic and Non-Academic Hospitals in the Netherlands.

PubMed

van der Linden, Naomi; Bongers, Mathilda L; Coupé, Veerle M H; Smit, Egbert F; Groen, Harry J M; Welling, Alle; Schramel, Franz M N H; Uyl-de Groot, Carin A

2017-09-01

The aims of this study are to analyze differences in survival between academic and non-academic hospitals and to provide insight into treatment patterns for non-small cell lung cancer (NSCLC). Results show the state of NSCLC survival and care in the Netherlands. The Netherlands Cancer Registry provided data on NSCLC survival for all Dutch hospitals. We used the Kaplan-Meier estimate to calculate median survival time by hospital type and a Cox proportional hazards model to estimate the relative risk of mortality (expressed as hazard ratios) for patients diagnosed in academic versus non-academic hospitals, with adjustment for age, gender, and tumor histology, and stratifying for disease stage. Data on treatment patterns in Dutch hospitals was obtained from 4 hospitals (2 academic, 2 non-academic). A random sample of patients diagnosed with NSCLC from January 2009 until January 2011 was identified through hospital databases. Data was obtained on patient characteristics, tumor characteristics, and treatments. The Cox proportional hazards model shows a significantly decreased hazard ratio of mortality for patients diagnosed in academic hospitals, as opposed to patients diagnosed in non-academic hospitals. This is specifically true for primary radiotherapy patients and patients who receive systemic treatment for non-metastasized NSCLC. Patients diagnosed in academic hospitals have better median overall survival than patients diagnosed in non-academic hospitals, especially for patients treated with radiotherapy, systemic treatment, or combinations. This difference may be caused by residual confounding since the estimates were not adjusted for performance status. A wide variety of surgical, radiotherapeutic, and systemic treatments is prescribed. Copyright © 2015 Elsevier Inc. All rights reserved.

Neuropsychiatric Symptoms and Alzheimer's Disease Biomarkers Predict Driving Decline: Brief Report.

PubMed

Babulal, Ganesh M; Stout, Sarah H; Head, Denise; Holtzman, David M; Fagan, Anne M; Morris, John C; Roe, Catherine M

2017-01-01

We examined whether neuropsychiatric symptoms (NPS) interact with cerebrospinal fluid (CSF) biomarkers (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, and ptau181/Aβ42) of Alzheimer's disease pathology to predict driving decline among cognitively-normal older adults (N = 116) aged ≥65. Cox proportional hazards models examined time to receiving a rating of marginal or fail on the driving test. Age, education, and gender were adjusted in the models. Participants with more abnormal CSF (Aβ42, tau/Aβ42, ptau181/Aβ42) and NPS were faster to receive a marginal/fail on the road test compared to those without NPS. NPS interact with abnormal CSF biomarkers to impact driving performance among cognitively-normal older adults.

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.

Association of dipeptidyl peptidase 4 inhibitors with risk of metastases in patients with type 2 diabetes and breast, prostate or digestive system cancer.

PubMed

Rathmann, Wolfgang; Kostev, Karel

2017-04-01

Experimental and animal studies have supported the hypothesis that dipeptidyl peptidase-4 inhibitors (DPP-4i) may accelerate tumor metastasis. The aim was to analyze the relationships between DPP-4i therapy with risk of metastases in type 2 diabetes patients with breast, prostate and digestive organ cancers. Type 2 diabetes patients with first diagnoses of breast, prostate or digestive organ cancer were selected in general and internal medicine practices (Disease Analyzer Germany: 01/2008-12/2014). Propensity score matching between DPP-4i users and non-users was carried out for age, sex, diabetes duration, and metformin use. Time-dependent Cox regression models were used to estimate hazard ratios (HR) for metastases further adjusting for HbA1c, body mass index, comorbidity and co-therapy with glucose-lowering drugs (3-4years follow-up). 668 patients with newly diagnosed breast cancer, 906 with prostate cancer and 908 with digestive organ cancer were analyzed. In Cox regression, use of DPP-4i was not associated with an increased risk of metastases in patients with breast (adjusted HR, 95%CI: 1.00, 0.49-2.02), prostate (0.98, 0.54-1.77) or digestive organ cancers (0.97, 0.57-1.66). This first observational study in patients with type 2 diabetes and breast, prostate or digestive organ cancer found no increased risk of metastases in DPP-4i users. Copyright © 2017 Elsevier Inc. All rights reserved.

Association between participation in outdoor play and sport at 10 years old with physical activity in adulthood.

PubMed

Smith, Lee; Gardner, Benjamin; Aggio, Daniel; Hamer, Mark

2015-05-01

This study aimed to investigate whether active outdoor play and/or sports at age 10 is associated with sport/physical activity at 32 year follow-up using a birth cohort study. Data were from the 1970 British Cohort Study, a longitudinal observational study. The present paper included data from the age 10 years and age 42 years surveys. At age 10 the participant's mother provided information regarding how often their child played sports, and played outside on streets, parks or playgrounds. At age 42 participants reported frequency of participation in physical activities and sports. Associations between participation in sport/active outdoor play at age 10 years and adult sport/physical activity were investigated using adjusted (gender, fathers socio-occupational class, child's BMI, father's BMI, self-rated health at age 42, assessment of own weight at age 42, participant's education) Cox regression. Final adjusted Cox regression models showed that participants (n=6458) who often participated in sports at age 10 were significantly more likely to participate in sport/physical activity at age 42 (RR 1.10; 95% CI 1.01 to 1.19). Active outdoor play at age 10 was not associated with participation in sport/physical activity at age 42 (RR 0.99; 95% CI 0.91 to 1.07). Childhood activity interventions might best achieve lasting change by promoting engagement in sport rather than active outdoor play. Copyright © 2015. Published by Elsevier Inc.

The effect of low-dose aspirin on the decreased risk of development of dyspepsia and gastrointestinal ulcers associated to cyclooxygenase-2 selective inhibitors.

PubMed

Benito-Garcia, Elizabeth; Michaud, Kaleb; Wolfe, Frederick

2007-08-01

To evaluate the risk of gastrointestinal (GI) symptoms and ulcers associated to the use of low-dose aspirin (ASA) among patients with rheumatoid arthritis (RA) and osteoarthritis (OA) treated with cyclooxygenase-2 (COX-2) drugs, to clarify the controversy in the literature. Using a longitudinal databank, a prospective study using Cox proportional hazards models was performed in patients receiving COX-2 therapy for RA or OA to examine the effect of ASA on GI events. In 4 separate analyses patients reported dyspeptic symptoms and GI ulcers at semiannual intervals for up to 3 years. Ulcers were validated by review of medical records. Among 4240 patients taking COX-2-specific inhibitors, with no ulcer at study start, the age- and sex-adjusted hazard ratios for the effect of ASA on the development of epigastric pain, heartburn, nausea, and ulcers, without these previous events, were 1.11 (95% CI 0.97-1.29), 1.00 (95% CI 0.88-1.15), 1.32 (95% CI 1.13-1.54), and 1.27 (95% CI 0.78-2.05). The use of a propensity score to account for the risk of ASA prescription showed an even lower effect of ASA among all GI variables. This risk occurs within the setting of no prior GI symptoms or GI events, and independently of the use of proton pump inhibitors, other GI drugs, other nonsteroidal antiinflammatory drugs, prednisone, or methotrexate. In actual practice, the use of low-dose ASA has a small effect on the risk of developing dyspeptic symptoms in a group of patients with rheumatic disease.

Dialysate Sodium Concentration and the Association with Interdialytic Weight Gain, Hospitalization, and Mortality

PubMed Central

Hecking, Manfred; Karaboyas, Angelo; Saran, Rajiv; Sen, Ananda; Inaba, Masaaki; Rayner, Hugh; Hörl, Walter H.; Pisoni, Ronald L.; Robinson, Bruce M.; Sunder-Plassmann, Gere; Port, Friedrich K.

2012-01-01

Summary Background and objectives Recommendations to decrease the dialysate sodium (DNa) prescription demand analyses of patient outcomes. We analyzed morbidity and mortality at various levels of DNa, simultaneously accounting for interdialytic weight gain (IDWG) and for the mortality risk associated with lower predialysis serum sodium (SNa) levels. Design, setting, participants, & measurements We used multiply-adjusted linear mixed models to evaluate the magnitude of IDWG and Cox proportional hazards models to assess hospitalizations and deaths in 29,593 patients from the Dialysis Outcomes and Practice Patterns Study with baseline DNa and SNa as predictors, categorized according to lowest to highest levels. Results IDWG increased with higher DNa across all SNa categories, by 0.17% of body weight per 2 mEq/L higher DNa; however, higher DNa was not associated with higher mortality in a fully adjusted model (also adjusted for SNa; hazard ratio [HR]=0.98 per 2 mEq/L higher DNa, 95% confidence interval [CI] 0.95–1.02). Instead, higher DNa was associated with lower hospitalization risk (HR=0.97 per 2 mEq/L higher DNa, 95% CI 0.95–1.00, P=0.04). Additional adjustments for IDWG did not change these results. In sensitivity analyses restricted to study facilities, in which 90%–100% of patients have the same DNa (56%), the adjusted HR for mortality was 0.88 per 2 mEq/L higher DNa (95% CI 0.83–0.94). These analyses represented a pseudo-randomized experiment in which the association between DNa and mortality is unlikely to have been confounded by indication. Conclusions In the absence of randomized prospective studies, the benefit of reducing IDWG by decreasing DNa prescriptions should be carefully weighed against an increased risk for adverse outcomes. PMID:22052942

Reproductive Factors and Incidence of Heart Failure Hospitalization in the Women’s Health Initiative

PubMed Central

Hall, Philip S.; Nah, Gregory; Howard, Barbara V.; Lewis, Cora E.; Allison, Matthew A.; Sarto, Gloria E.; Waring, Molly E.; Jacobson, Lisette T.; Manson, JoAnn E.; Klein, Liviu; Parikh, Nisha I.

2017-01-01

BACKGROUND Reproductive factors reflective of endogenous sex hormone exposure might have an effect on cardiac remodeling and the development of heart failure (HF). OBJECTIVES This study examined the association between key reproductive factors and the incidence of HF. METHODS Women from a cohort of the Women’s Health Initiative were systematically evaluated for the incidence of HF hospitalization from study enrollment through 2014. Reproductive factors (number of live births, age at first pregnancy, and total reproductive duration [time from menarche to menopause]) were self-reported at study baseline in 1993 to 1998. We employed Cox proportional hazards regression analysis in age- and multivariable-adjusted models. RESULTS Among 28,516 women, with an average age of 62.7 ± 7.1 years at baseline, 1,494 (5.2%) had an adjudicated incident HF hospitalization during an average follow-up of 13.1 years. After adjusting for covariates, total reproductive duration in years was inversely associated with incident HF: hazard ratios (HRs) of 0.99 per year (95% confidence interval [CI]: 0.98 to 0.99 per year) and 0.95 per 5 years (95% CI: 0.91 to 0.99 per 5 years). Conversely, early age at first pregnancy and nulliparity were significantly associated with incident HF in age-adjusted models, but not after multivariable adjustment. Notably, nulliparity was associated with incident HF with preserved ejection fraction in the fully adjusted model (HR: 2.75; 95% CI: 1.16 to 6.52). CONCLUSIONS In postmenopausal women, shorter total reproductive duration was associated with higher risk of incident HF, and nulliparity was associated with higher risk for incident HF with preserved ejection fraction. Whether exposure to endogenous sex hormones underlies this relationship should be investigated in future studies. PMID:28521890

Inference of median difference based on the Box-Cox model in randomized clinical trials.

PubMed

Maruo, K; Isogawa, N; Gosho, M

2015-05-10

In randomized clinical trials, many medical and biological measurements are not normally distributed and are often skewed. The Box-Cox transformation is a powerful procedure for comparing two treatment groups for skewed continuous variables in terms of a statistical test. However, it is difficult to directly estimate and interpret the location difference between the two groups on the original scale of the measurement. We propose a helpful method that infers the difference of the treatment effect on the original scale in a more easily interpretable form. We also provide statistical analysis packages that consistently include an estimate of the treatment effect, covariance adjustments, standard errors, and statistical hypothesis tests. The simulation study that focuses on randomized parallel group clinical trials with two treatment groups indicates that the performance of the proposed method is equivalent to or better than that of the existing non-parametric approaches in terms of the type-I error rate and power. We illustrate our method with cluster of differentiation 4 data in an acquired immune deficiency syndrome clinical trial. Copyright © 2015 John Wiley & Sons, Ltd.

Long QT syndrome in African-Americans.

PubMed

Fugate, Thomas; Moss, Arthur J; Jons, Christian; McNitt, Scott; Mullally, Jamie; Ouellet, Gregory; Goldenberg, Ilan; Zareba, Wojciech; Robinson, Jennifer L

2010-01-01

We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients. The study involved 41 African-Americans and 3456 Caucasians with a QTc > or = 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS-related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation. The QTc was 29 ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that beta-blockers were equally effective in reducing cardiac events in the two racial groups. The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from beta-blocker therapy in the two racial groups.

Microarray analysis of gene expression in the cyclooxygenase knockout mice - a connection to autism spectrum disorder.

PubMed

Rai-Bhogal, Ravneet; Ahmad, Eizaaz; Li, Hongyan; Crawford, Dorota A

2018-03-01

The cellular and molecular events that take place during brain development play an important role in governing function of the mature brain. Lipid-signalling molecules such as prostaglandin E 2 (PGE 2 ) play an important role in healthy brain development. Abnormalities along the COX-PGE 2 signalling pathway due to genetic or environmental causes have been linked to autism spectrum disorder (ASD). This study aims to evaluate the effect of altered COX-PGE 2 signalling on development and function of the prenatal brain using male mice lacking cyclooxygenase-1 and cyclooxygenase-2 (COX-1 -/- and COX-2 -/- ) as potential model systems of ASD. Microarray analysis was used to determine global changes in gene expression during embryonic days 16 (E16) and 19 (E19). Gene Ontology: Biological Process (GO:BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were implemented to identify affected developmental genes and cellular processes. We found that in both knockouts the brain at E16 had nearly twice as many differentially expressed genes, and affected biological pathways containing various ASD-associated genes important in neuronal function. Interestingly, using GeneMANIA and Cytoscape we also show that the ASD-risk genes identified in both COX-1 -/- and COX-2 -/- models belong to protein-interaction networks important for brain development despite of different cellular localization of these enzymes. Lastly, we identified eight genes that belong to the Wnt signalling pathways exclusively in the COX-2 -/- mice at E16. The level of PKA-phosphorylated β-catenin (S552), a major activator of the Wnt pathway, was increased in this model, suggesting crosstalk between the COX-2-PGE 2 and Wnt pathways during early brain development. Overall, these results provide further molecular insight into the contribution of the COX-PGE 2 pathways to ASD and demonstrate that COX-1 -/- and COX-2 -/- animals might be suitable new model systems for studying the disorders. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates.

PubMed

McCann, Nicole C; Lynch, Terrie J; Kim, Soon Ok; Duffy, Diane M

2013-12-01

Cyclooxygenase-2 (COX-2) inhibitors reduce prostaglandin synthesis and disrupt essential reproductive processes. Ultrasound studies in women demonstrated that oral COX-2 inhibitors can delay or prevent follicle collapse associated with ovulation. The goal of this study was to determine if oral administration of a COX-2 inhibitor can inhibit reproductive function with sufficient efficacy to prevent pregnancy in primates. The COX-2 inhibitor meloxicam (or vehicle) was administered orally to proven fertile female cynomolgus macaques using one emergency contraceptive model and three monthly contraceptive models. In the emergency contraceptive model, females were bred with a proven fertile male once 2±1 days before ovulation, returned to the females' home cage, and then received 5 days of meloxicam treatment. In the monthly contraceptive models, females were co-caged for breeding with a proven fertile male for a total of 5 days beginning 2±1 days before ovulation. Animals received meloxicam treatment (1) cycle days 5-22, or (2) every day, or (3) each day of the 5-day breeding period. Female were then assessed for pregnancy. The pregnancy rate with meloxicam administration using the emergency contraception model was 6.5%, significantly lower than the pregnancy rate of 33.3% when vehicle without meloxicam was administered. Pregnancy rates with the three monthly contraceptive models (75%-100%) were not consistent with preventing pregnancy. Oral COX-2 inhibitor administration can prevent pregnancy after a single instance of breeding in primates. While meloxicam may be ineffective for regular contraception, pharmacological inhibition of COX-2 may be an effective method of emergency contraception for women. COX-2 inhibitors can interfere with ovulation, but the contraceptive efficacy of drugs of this class has not been directly tested. This study, conducted in nonhuman primates, is the first to suggest that a COX-2 inhibitor may be effective as an emergency contraceptive. © 2013.

Inhalants as intermediate drugs between legal and illegal drugs among middle and high school students.

PubMed

Sanchez, Zila M; Ribeiro, Luciana A; Moura, Yone G; Noto, Ana R; Martins, Silvia S

2013-01-01

The aims of this study are to: (1) describe the prevalence and sociodemographic characteristics of inhalant use among middle and high school students in Brazil, and (2) test the hypothesis of inhalants being intermediate drugs between legal and illegal drug use. A representative sample of 5226 students from private schools in São Paulo, Brazil, was selected to answer a self-report questionnaire. Weighted data was analyzed through Cox proportional hazards models. In the overall sample, inhalants seems to be an intermediate drug, since prior inhalant initiation was associated with first marijuana use, adjusted for previous alcohol and tobacco initiation.

Immortal time bias in observational studies of time-to-event outcomes.

PubMed

Jones, Mark; Fowler, Robert

2016-12-01

The purpose of the study is to show, through simulation and example, the magnitude and direction of immortal time bias when an inappropriate analysis is used. We compare 4 methods of analysis for observational studies of time-to-event outcomes: logistic regression, standard Cox model, landmark analysis, and time-dependent Cox model using an example data set of patients critically ill with influenza and a simulation study. For the example data set, logistic regression, standard Cox model, and landmark analysis all showed some evidence that treatment with oseltamivir provides protection from mortality in patients critically ill with influenza. However, when the time-dependent nature of treatment exposure is taken account of using a time-dependent Cox model, there is no longer evidence of a protective effect of treatment. The simulation study showed that, under various scenarios, the time-dependent Cox model consistently provides unbiased treatment effect estimates, whereas standard Cox model leads to bias in favor of treatment. Logistic regression and landmark analysis may also lead to bias. To minimize the risk of immortal time bias in observational studies of survival outcomes, we strongly suggest time-dependent exposures be included as time-dependent variables in hazard-based analyses. Copyright © 2016 Elsevier Inc. All rights reserved.

Taxation categories for long-term care insurance premiums and mortality among elderly Japanese: a cohort study.

PubMed

Fujino, Yoshihisa; Tanaka, Ryuichi; Kubo, Tatsuhiko; Matsuda, Shinya

2013-01-01

This cohort study examined the association between taxation categories of long-term care insurance premiums and survival among elderly Japanese. A total of 3000 participants aged 60 years or older were randomly recruited in Y City, Japan in 2002, of whom 2964 provided complete information for analysis. Information on income level, mobility status, medical status, and vital status of each participant was collected annually from 2002 to 2006. Follow-up surveys on survival were conducted until August 2007. Hazard ratios (HRs) were estimated by a Cox model, using taxation categories at baseline. In these analyses, age-adjusted and age- and mobility-adjusted models were used. A significantly higher mortality risk was seen only in the lowest taxation category among men: as compared with men in the second highest taxation category, the HR in the lowest category was 2.53 (95% CI, 1.26-5.08, P = 0.009). This significant association between taxation category and mortality was lost after adjustment for mobility. There was no other difference in mortality among taxation categories in men or women. The present findings only partly supported our hypothesis that taxation category is a good indicator of socioeconomic status in examining health inequalities among elderly Japanese.

Cognitive decline and survival in Alzheimer's disease according to education level.

PubMed

Bruandet, A; Richard, F; Bombois, S; Maurage, C A; Masse, I; Amouyel, P; Pasquier, F

2008-01-01

We tested the hypothesis that a higher education level is associated with faster cognitive decline and lower survival in a cohort of 670 Alzheimer's disease patients, followed for 3.5 years at the Lille-Bailleul memory centre. The patients were categorized in 3 groups according to educational levels: low (12 years). Cognitive function was measured with the Mini Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (DRS). Survival was analyzed with a Cox model. Analyses were adjusted for age, sex, cholinesterase inhibitor treatment, diabetes, hypertension, visible vascular lesions on MRI, baseline DRS and MMSE. The adjusted mixed random model showed that MMSE declined faster for patients with high and intermediate educational levels compared with those with a low educational level (p < 0.0001). The mean annually adjusted DRS decline was highest for the groups with the most education (p = 0.05). The mortality risk was not higher in the better-educated groups (high vs. low: RR = 0.84; 95% CI = 0.35-1.99, intermediate vs. low: RR = 0.82; 95% CI = 0.41-1.63). In our cohort, highly educated patients had a faster cognitive decline than less educated patients but similar mortality rates. Our findings support the cognitive reserve hypothesis. (c) 2007 S. Karger AG, Basel.

Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: Secondary analysis of the Acute Renal Failure Trial Network Study

PubMed Central

Afshinnia, Farsad; Belanger, Karen; Palevsky, Paul M.; Young, Eric W.

2014-01-01

Background Hypocalcemia is very common in critically ill patients. While the effect of ionized calcium (iCa) on outcome is not well understood, manipulation of iCa in critically ill patients is a common practice. We analyzed all-cause mortality and several secondary outcomes in patients with acute kidney injury (AKI) by categories of serum iCa among participants in the Acute Renal Failure Trial Network (ATN) Study. Methods This is a post hoc secondary analysis of the ATN Study which was not preplanned in the original trial. Risk of mortality and renal recovery by categories of iCa were compared using multiple fixed and adjusted time-varying Cox regression models. Multiple linear regression models were used to explore the impact of baseline iCa on days free from ICU and hospital. Results A total of 685 patients were included in the analysis. Mean age was 60 (SD=15) years. There were 502 male patients (73.3%). Sixty-day all-cause mortality was 57.0%, 54.8%, and 54.4%, in patients with an iCa <1, 1–1.14, and ≥1.15 mmol/L, respectively (P=0.87). Mean of days free from ICU or hospital in all patients and the 28-day renal recovery in survivors to day 28 were not significantly different by categories of iCa. The hazard for death in a fully adjusted time-varying Cox regression survival model was 1.7 (95% CI: 1.3–2.4) comparing iCa <1 to iCa ≥1.15 mmol/L. No outcome was different for levels of iCa >1 mmol/L. Conclusion Severe hypocalcemia with iCa <1 mmol/L independently predicted mortality in patients with AKI needing renal replacement therapy. PMID:23992422

Cisplatin and Etoposide Versus Carboplatin and Paclitaxel With Concurrent Radiotherapy for Stage III Non–Small-Cell Lung Cancer: An Analysis of Veterans Health Administration Data

PubMed Central

Santana-Davila, Rafael; Devisetty, Kiran; Szabo, Aniko; Sparapani, Rodney; Arce-Lara, Carlos; Gore, Elizabeth M.; Moran, Amy; Williams, Christina D.; Kelley, Michael J.; Whittle, Jeffrey

2015-01-01

Purpose The optimal chemotherapy regimen to use with radiotherapy in stage III non–small-cell lung cancer is unknown. Here, we compare the outcome of patents treated within the Veterans Health Administration with either etoposide-cisplatin (EP) or carboplatin-paclitaxel (CP). Methods We identified patients treated with EP and CP with concurrent radiotherapy from 2001 to 2010. Survival rates were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods and an instrumental variables analysis. Comorbidities and treatment complications were identified through administrative data. Results A total of 1,842 patients were included; EP was used in 27% (n = 499). Treatment with EP was not associated with a survival advantage in a Cox proportional hazards model (hazard ratio [HR], 0.97; 95% CI, 0.85 to 1.10), a propensity score matched cohort (HR, 1.07; 95% CI, 0.91 to 1.24), or a propensity score adjusted model (HR, 0.97; 95% CI, 0.85 to 1.10). In an instrumental variables analysis, there was no survival advantage for patients treated in centers where EP was used more than 50% of the time as compared with centers where EP was used in less than 10% of the patients (HR, 1.07; 95% CI, 0.90 to 1.26). Patients treated with EP, compared with patients treated with CP, had more hospitalizations (2.4 v 1.7 hospitalizations, respectively; P < .001), outpatient visits (17.6 v 12.6 visits, respectively; P < .001), infectious complications (47.3% v 39.4%, respectively; P = .0022), acute kidney disease/dehydration (30.5% v 21.2%, respectively; P < .001), and mucositis/esophagitis (18.6% v 14.4%, respectively; P = .0246). Conclusion After accounting for prognostic variables, patients treated with EP versus CP had similar overall survival, but EP was associated with increased morbidity. PMID:25422491

Prostate Cancer Radiation Therapy and Risk of Thromboembolic Events

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

Bosco, Cecilia, E-mail: Cecilia.t.bosco@kcl.ac.uk; Garmo, Hans; Regional Cancer Centre, Uppsala, Akademiska Sjukhuset, Uppsala

Purpose: To investigate the risk of thromboembolic disease (TED) after radiation therapy (RT) with curative intent for prostate cancer (PCa). Patients and Methods: We identified all men who received RT as curative treatment (n=9410) and grouped according to external beam RT (EBRT) or brachytherapy (BT). By comparing with an age- and county-matched comparison cohort of PCa-free men (n=46,826), we investigated risk of TED after RT using Cox proportional hazard regression models. The model was adjusted for tumor characteristics, demographics, comorbidities, PCa treatments, and known risk factors of TED, such as recent surgery and disease progression. Results: Between 2006 and 2013, 6232more » men with PCa received EBRT, and 3178 underwent BT. A statistically significant association was found between EBRT and BT and risk of pulmonary embolism in the crude analysis. However, upon adjusting for known TED risk factors these associations disappeared. No significant associations were found between BT or EBRT and deep venous thrombosis. Conclusion: Curative RT for prostate cancer using contemporary methodologies was not associated with an increased risk of TED.« less

Chronic obstructive pulmonary disease mortality in railroad workers.

PubMed

Hart, J E; Laden, F; Eisen, E A; Smith, T J; Garshick, E

2009-04-01

There is little information describing the risk of non-malignant respiratory disease and occupational exposure to diesel exhaust. US railroad workers have been exposed to diesel exhaust since diesel locomotives were introduced after World War II. In a retrospective cohort study we examined the association of chronic obstructive pulmonary disease (COPD) mortality with years of work in diesel-exposed jobs. To examine the possible confounding effects of smoking, multiple imputation was used to model smoking history. A Cox proportional hazards model was used to estimate an incidence rate ratio, adjusted for age, calendar year, and length of follow-up after leaving work (to reduce bias due to a healthy worker survivor effect). Workers in jobs with diesel exhaust exposure had an increased risk of COPD mortality relative to those in unexposed jobs. Workers hired after the introduction of diesel locomotives had a 2.5% increase in COPD mortality risk for each additional year of work in a diesel-exposed job. This risk was only slightly attenuated after adjustment for imputed smoking history. These results support an association between occupational exposure to diesel exhaust and COPD mortality.

Cyclooxygenase-2 expression in non-metastatic triple-negative breast cancer patients.

PubMed

Mosalpuria, Kailash; Hall, Carolyn; Krishnamurthy, Savitri; Lodhi, Ashutosh; Hallman, D Michael; Baraniuk, Mary S; Bhattacharyya, Anirban; Lucci, Anthony

2014-09-01

Triple-negative breast cancer (TNBC) is characterised by lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)2/neu gene amplification. TNBC patients typically present at a younger age, with a larger average tumor size, higher grade and higher rates of lymph node positivity compared to patients with ER/PR-positive tumors. Cyclooxygenase (COX)-2 regulates the production of prostaglandins and is overexpressed in a variety of solid tumors. In breast cancer, the overexpression of COX-2 is associated with indicators of poor prognosis, such as lymph node metastasis, poor differentiation and large tumor size. Since both TNBC status and COX-2 overexpression are known poor prognostic markers in primary breast cancer, we hypothesized that the COX-2 protein is overexpressed in the primary tumors of TNBC patients. The purpose of this study was to determine whether there exists an association between TNBC status and COX-2 protein overexpression in primary breast cancer. We prospectively evaluated COX-2 expression levels in primary tumor samples obtained from 125 patients with stage I-III breast cancer treated between February, 2005 and October, 2007. Information on clinicopathological factors was obtained from a prospective database. Baseline tumor characteristics and patient demographics were compared between TNBC and non-TNBC patients using the Chi-square and Fisher's exact tests. In total, 60.8% of the patients were classified as having ER-positive tumors, 51.2% were PR-positive, 14.4% had HER-2/neu amplification and 28.0% were classified as TNBC. COX-2 overexpression was found in 33.0% of the patients. TNBC was associated with COX-2 overexpression (P=0.009), PR expression (P=0.048) and high tumor grade (P=0.001). After adjusting for age, menopausal status, body mass index (BMI), lymph node status and neoadjuvant chemotherapy (NACT), TNBC was an independent predictor of COX-2 overexpression (P=0.01). In conclusion, the association between TNBC and COX-2 overexpression in operable breast cancer supports further investigation into COX-2-targeted therapy for patients with TNBC.

Birth by Caesarean Section and the Risk of Adult Psychosis: A Population-Based Cohort Study

PubMed Central

O’Neill, Sinéad M.; Curran, Eileen A.; Dalman, Christina; Kenny, Louise C.; Kearney, Patricia M.; Clarke, Gerard; Cryan, John F.; Dinan, Timothy G.; Khashan, Ali S.

2016-01-01

Despite the biological plausibility of an association between obstetric mode of delivery and psychosis in later life, studies to date have been inconclusive. We assessed the association between mode of delivery and later onset of psychosis in the offspring. A population-based cohort including data from the Swedish National Registers was used. All singleton live births between 1982 and 1995 were identified (n = 1 345 210) and followed-up to diagnosis at age 16 or later. Mode of delivery was categorized as: unassisted vaginal delivery (VD), assisted VD, elective Caesarean section (CS) (before onset of labor), and emergency CS (after onset of labor). Outcomes included any psychosis; nonaffective psychoses (including schizophrenia only) and affective psychoses (including bipolar disorder only and depression with psychosis only). Cox regression analysis was used reporting partially and fully adjusted hazard ratios (HR) with 95% confidence intervals (CI). Sibling-matched Cox regression was performed to adjust for familial confounding factors. In the fully adjusted analyses, elective CS was significantly associated with any psychosis (HR 1.13, 95% CI 1.03, 1.24). Similar findings were found for nonaffective psychoses (HR 1.13, 95% CI 0.99, 1.29) and affective psychoses (HR 1.17, 95% CI 1.05, 1.31) (χ2 for heterogeneity P = .69). In the sibling-matched Cox regression, this association disappeared (HR 1.03, 95% CI 0.78, 1.37). No association was found between assisted VD or emergency CS and psychosis. This study found that elective CS is associated with an increase in offspring psychosis. However, the association did not persist in the sibling-matched analysis, implying the association is likely due to familial confounding by unmeasured factors such as genetics or environment. PMID:26615187

Exposure to traffic noise and air pollution and risk for febrile seizure: a cohort study.

PubMed

Hjortebjerg, Dorrit; Nybo Andersen, Anne-Marie; Ketzel, Matthias; Raaschou-Nielsen, Ole; Sørensen, Mette

2018-03-25

Objectives Exposure to traffic noise and air pollution is suspected to increase susceptibility to viral infections - the main triggering factor for febrile seizures. No studies have examined these two exposures in relation to febrile seizures. We aimed to investigate whether exposure to road traffic noise and air pollution are associated with risk of febrile seizures in childhood. Methods From our study base of 51 465 singletons from a national birth cohort, we identified 2175 cases with febrile seizures using a nationwide registry. Residential address history from conception to six years of age were found in national registers, and road traffic noise (L den ) and air pollution (NO 2 ) were modeled for all addresses. Analyses were done using Cox proportional hazard model with adjustment for potential confounders, including mutual exposure adjustment. Results An interquartile range (IQR) increase in childhood exposure to road traffic noise and air pollution was associated with an 11% [incidence rate ratio (IRR) 1.11, 95% confidence interval (CI) 1.04-1.19) and 5% (IRR 1.05, 95% CI 1.02-1.07) higher risk for febrile seizures, respectively, after adjustment for potential confounders. Weaker tendencies were seen for pregnancy exposure. In models with mutual exposure adjustment, the estimates were slightly lower, with IRR of 1.08 (95% CI 1.00-1.16) and 1.03 (95% CI 0.99-1.06) per IQR increase in childhood exposure to road traffic noise and air pollution, respectively. Conclusions This study suggests that residential exposure to road traffic noise and air pollution is associated with higher risk for febrile seizures.

Adherence to oral anticoagulants in patients with atrial fibrillation-a population-based retrospective cohort study linking health information systems in the Valencia region, Spain: a study protocol.

PubMed

Sanfélix-Gimeno, G; Rodríguez-Bernal, C L; Hurtado, I; Baixáuli-Pérez, C; Librero, J; Peiró, S

2015-10-19

Adherence to oral anticoagulation (OAC) treatment, vitamin K antagonists or new oral anticoagulants, is an essential element for effectiveness. Information on adherence to OAC in atrial fibrillation (AF) and the impact of adherence on clinical outcomes using real-world data barely exists. We aim to describe the patterns of adherence to OAC over time in patients with AF, estimate the associated factors and their impact on clinical events, and assess the same issues with conventional measures of primary and secondary adherence-proportion of days covered (PDC) and persistence-in routine clinical practice. This is a population-based retrospective cohort study including all patients with AF treated with OAC from 2010 to date in Valencia, Spain; data will be obtained from diverse electronic records of the Valencia Health Agency. adherence trajectories. (1) primary non-adherence; (2) secondary adherence: (a) PDC, (b) persistence. Clinical outcomes: hospitalisation for haemorrhagic or thromboembolic events and death during follow-up. (1) description of baseline characteristics, adherence patterns (trajectory models or latent class growth analysis models) and conventional adherence measures; (2) logistic or Cox multivariate regression models, to assess the associations between adherence measures and the covariates, and logistic multinomial regression models, to identify characteristics associated with each trajectory; (3) Cox proportional hazard models, to assess the relationship between adherence and clinical outcomes, with propensity score adjustment applied to further control for potential confounders; (4) to estimate the importance of different healthcare levels in the variations of adherence, logistic or Cox multilevel regression models. This study has been approved by the corresponding Clinical Research Ethics Committee. We plan to disseminate the project's findings through peer-reviewed publications and presentations at relevant health conferences. Policy reports will also be prepared in order to promote the translation of our findings into policy and clinical practice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Cyclooxygenase metabolites mediate glomerular monocyte chemoattractant protein-1 formation and monocyte recruitment in experimental glomerulonephritis.

PubMed

Schneider, A; Harendza, S; Zahner, G; Jocks, T; Wenzel, U; Wolf, G; Thaiss, F; Helmchen, U; Stahl, R A

1999-02-01

Monocyte chemoattractant protein-1 (MCP-1) has been shown to play a significant role in the recruitment of monocytes/macrophages in experimental glomerulonephritis. Whereas a number of inflammatory mediators have been characterized that are involved in the expression of MCP-1 in renal disease, little is known about repressors of chemokine formation in vivo. We hypothesized that cyclooxygenase (COX) products influence the formation of MCP-1 and affect inflammatory cell recruitment in glomerulonephritis. The effect of COX inhibitors was evaluated in the antithymocyte antibody model and an anti-glomerular basement membrane model of glomerulonephritis. Rats were treated with the COX-1/COX-2 inhibitor indomethacin and the selective COX-2 inhibitors meloxicam and SC 58125. Animals were studied at 1 hour, 24 hours, and 5 days after induction of the disease. Indomethacin, to a lesser degree the selective COX-2 inhibitors, enhanced glomerular MCP-1 and RANTES mRNA levels. Indomethacin enhanced glomerular monocyte chemoattractant activity an the infiltration of monocytes/macrophages at 24 hours and 5 days. Our studies demonstrate that COX products may serve as endogenous repressors of MCP-1 formation in experimental glomerulonephritis. The data suggest that COX-1 and COX-2 products mediate these effects differently because the selective COX-2 inhibitors had less influence on chemokine expression.

Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study.

PubMed

Banerjee, Chirantan; Moon, Yeseon P; Paik, Myunghee C; Rundek, Tatjana; Mora-McLaughlin, Consuelo; Vieira, Julio R; Sacco, Ralph L; Elkind, Mitchell S V

2012-05-01

Diabetes increases stroke risk, but whether diabetes status immediately before stroke improves prediction and whether duration is important are less clear. We hypothesized that diabetes duration independently predicts ischemic stroke. Among 3298 stroke-free participants in the Northern Manhattan Study, baseline diabetes and age at diagnosis were determined. Incident diabetes was assessed annually (median, 9 years). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI for incident ischemic stroke using baseline diabetes, diabetes as a time-dependent covariate, and duration of diabetes as a time-varying covariate; models were adjusted for demographic and cardiovascular risk factors. Mean age was 69 ± 10 years (52% Hispanic, 21% white, and 24% black); 22% had diabetes at baseline and 10% had development of diabetes. There were 244 ischemic strokes, and both baseline diabetes (HR, 2.5; 95% CI, 1.9-3.3) and diabetes considered as a time-dependent covariate (HR, 2.4; 95% CI, 1.8-3.2) were similarly associated with stroke risk. Duration of diabetes was associated with ischemic stroke (adjusted HR, 1.03 per year with diabetes; 95% CI, 1.02-1.04). Compared to nondiabetic participants, those with diabetes for 0 to 5 years (adjusted HR, 1.7; 95% CI, 1.1-2.7), 5 to 10 years (adjusted HR, 1.8; 95% CI, 1.1-3.0), and ≥ 10 years (adjusted HR, 3.2; 95% CI, 2.4-4.5) were at increased risk. Duration of diabetes is independently associated with ischemic stroke risk adjusting for risk factors. The risk increases 3% each year, and triples with diabetes ≥ 10 years.

Antidepressant use and mortality in very old people.

PubMed

Boström, Gustaf; Hörnsten, Carl; Brännström, Jon; Conradsson, Mia; Nordström, Peter; Allard, Per; Gustafson, Yngve; Littbrand, Håkan

2016-07-01

Antidepressant treatment may increase the risk of death. The association between antidepressants and mortality has been evaluated in community-dwelling older people, but not in representative samples of very old people, among whom dementia, multimorbidity, and disability are common. Umeå 85+/GERDA study participants (n = 992) aged 85, 90, and ≥95 years were followed for up to five years. Cox proportional hazard regression models were used to analyze mortality risk associated with baseline antidepressant treatment, adjusted for potential confounders. Mean age was 89 years; 27% of participants had dementia, 20% had stroke histories, 29% had heart failure, and 16% used antidepressants. In age- and sex-adjusted analyses, antidepressant use was associated with a 76% increased mortality risk (hazard ratio [HR] = 1.76; 95% confidence interval [CI], 1.41-2.19). Adding adjustment for Geriatric Depression Scale score, HR was 1.62 (95% CI, 1.29-2.03). The association was not significant when adjusting for additional confounding factors (HR = 1.08; 95% CI, 0.85-1.38). Interaction analyses in the fully adjusted model revealed a significant interaction between sex and antidepressant use (HR: 1.76; 95% CI, 1.05-2.94). Among male and female antidepressant users, the HRs for death were 0.76 (95% CI, 0.47-1.24) and 1.28 (95% CI, 0.97-1.70), respectively. Among very old people, baseline antidepressant treatment does not seem to be independently associated with increased mortality risk. However, the risk may be different in men and women. This difference and the potential risk of initial treatment require further investigation in future cohort studies of very old people.

Paternal age at childbirth and eating disorders in offspring.

PubMed

Javaras, K N; Rickert, M E; Thornton, L M; Peat, C M; Baker, J H; Birgegård, A; Norring, C; Landén, M; Almqvist, C; Larsson, H; Lichtenstein, P; Bulik, C M; D'Onofrio, B M

2017-02-01

Advanced paternal age at childbirth is associated with psychiatric disorders in offspring, including schizophrenia, bipolar disorder and autism. However, few studies have investigated paternal age's relationship with eating disorders in offspring. In a large, population-based cohort, we examined the association between paternal age and offspring eating disorders, and whether that association remains after adjustment for potential confounders (e.g. parental education level) that may be related to late/early selection into fatherhood and to eating disorder incidence. Data for 2 276 809 individuals born in Sweden 1979-2001 were extracted from Swedish population and healthcare registers. The authors used Cox proportional hazards models to examine the effect of paternal age on the first incidence of healthcare-recorded anorexia nervosa (AN) and all eating disorders (AED) occurring 1987-2009. Models were adjusted for sex, birth order, maternal age at childbirth, and maternal and paternal covariates including country of birth, highest education level, and lifetime psychiatric and criminal history. Even after adjustment for covariates including maternal age, advanced paternal age was associated with increased risk, and younger paternal age with decreased risk, of AN and AED. For example, the fully adjusted hazard ratio for the 45+ years (v. the 25-29 years) paternal age category was 1.32 [95% confidence interval (CI) 1.14-1.53] for AN and 1.26 (95% CI 1.13-1.40) for AED. In this large, population-based cohort, paternal age at childbirth was positively associated with eating disorders in offspring, even after adjustment for potential confounders. Future research should further explore potential explanations for the association, including de novo mutations in the paternal germline.

An artificial neural network improves prediction of observed survival in patients with laryngeal squamous carcinoma.

PubMed

Jones, Andrew S; Taktak, Azzam G F; Helliwell, Timothy R; Fenton, John E; Birchall, Martin A; Husband, David J; Fisher, Anthony C

2006-06-01

The accepted method of modelling and predicting failure/survival, Cox's proportional hazards model, is theoretically inferior to neural network derived models for analysing highly complex systems with large datasets. A blinded comparison of the neural network versus the Cox's model in predicting survival utilising data from 873 treated patients with laryngeal cancer. These were divided randomly and equally into a training set and a study set and Cox's and neural network models applied in turn. Data were then divided into seven sets of binary covariates and the analysis repeated. Overall survival was not significantly different on Kaplan-Meier plot, or with either test model. Although the network produced qualitatively similar results to Cox's model it was significantly more sensitive to differences in survival curves for age and N stage. We propose that neural networks are capable of prediction in systems involving complex interactions between variables and non-linearity.

Malnutrition risk predicts recovery of full oral intake among older adult stroke patients undergoing enteral nutrition: Secondary analysis of a multicentre survey (the APPLE study).

PubMed

Nishioka, Shinta; Okamoto, Takatsugu; Takayama, Masako; Urushihara, Maki; Watanabe, Misuzu; Kiriya, Yumiko; Shintani, Keiko; Nakagomi, Hiromi; Kageyama, Noriko

2017-08-01

Whether malnutrition risk correlates with recovery of swallowing function of convalescent stroke patients is unknown. This study was conducted to clarify whether malnutrition risks predict achievement of full oral intake in convalescent stroke patients undergoing enteral nutrition. We conducted a secondary analysis of 466 convalescent stroke patients, aged 65 years or over, who were undergoing enteral nutrition. Patients were extracted from the "Algorithm for Post-stroke Patients to improve oral intake Level; APPLE" study database compiled at the Kaifukuki (convalescent) rehabilitation wards. Malnutrition risk was determined by the Geriatric Nutritional Risk Index as follows: severe (<82), moderate (82 to <92), mild (92 to <98), and no malnutrition risks (≥98). Swallowing function was assessed by Fujishima's swallowing grade (FSG) on admission and discharge. The primary outcome was achievement of full oral intake, indicated by FSG ≥ 7. Binary logistic regression analysis was performed to identify predictive factors, including malnutrition risk, for achieving full oral intake. Estimated hazard risk was computed by Cox's hazard model. Of the 466 individuals, 264 were ultimately included in this study. Participants with severe malnutrition risk showed a significantly lower proportion of achievement of full oral intake than lower severity groups (P = 0.001). After adjusting for potential confounders, binary logistic regression analysis showed that patients with severe malnutrition risk were less likely to achieve full oral intake (adjusted odds ratio: 0.232, 95% confidence interval [95% CI]: 0.047-1.141). Cox's proportional hazard model revealed that severe malnutrition risk was an independent predictor of full oral intake (adjusted hazard ratio: 0.374, 95% CI: 0.166-0.842). Compared to patients who did not achieve full oral intake, patients who achieved full oral intake had significantly higher energy intake, but there was no difference in protein intake and weight change. Severe malnutrition risk independently predicts the achievement of full oral intake in convalescent stroke patients undergoing enteral nutrition. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

COX-1 Inhibitors: Beyond Structure Toward Therapy.

PubMed

Vitale, Paola; Panella, Andrea; Scilimati, Antonio; Perrone, Maria Grazia

2016-07-01

Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed. © 2016 Wiley Periodicals, Inc.

Properties of added variable plots in Cox's regression model.

PubMed

Lindkvist, M

2000-03-01

The added variable plot is useful for examining the effect of a covariate in regression models. The plot provides information regarding the inclusion of a covariate, and is useful in identifying influential observations on the parameter estimates. Hall et al. (1996) proposed a plot for Cox's proportional hazards model derived by regarding the Cox model as a generalized linear model. This paper proves and discusses properties of this plot. These properties make the plot a valuable tool in model evaluation. Quantities considered include parameter estimates, residuals, leverage, case influence measures and correspondence to previously proposed residuals and diagnostics.

Cancer survival analysis using semi-supervised learning method based on Cox and AFT models with L1/2 regularization.

PubMed

Liang, Yong; Chai, Hua; Liu, Xiao-Ying; Xu, Zong-Ben; Zhang, Hai; Leung, Kwong-Sak

2016-03-01

One of the most important objectives of the clinical cancer research is to diagnose cancer more accurately based on the patients' gene expression profiles. Both Cox proportional hazards model (Cox) and accelerated failure time model (AFT) have been widely adopted to the high risk and low risk classification or survival time prediction for the patients' clinical treatment. Nevertheless, two main dilemmas limit the accuracy of these prediction methods. One is that the small sample size and censored data remain a bottleneck for training robust and accurate Cox classification model. In addition to that, similar phenotype tumours and prognoses are actually completely different diseases at the genotype and molecular level. Thus, the utility of the AFT model for the survival time prediction is limited when such biological differences of the diseases have not been previously identified. To try to overcome these two main dilemmas, we proposed a novel semi-supervised learning method based on the Cox and AFT models to accurately predict the treatment risk and the survival time of the patients. Moreover, we adopted the efficient L1/2 regularization approach in the semi-supervised learning method to select the relevant genes, which are significantly associated with the disease. The results of the simulation experiments show that the semi-supervised learning model can significant improve the predictive performance of Cox and AFT models in survival analysis. The proposed procedures have been successfully applied to four real microarray gene expression and artificial evaluation datasets. The advantages of our proposed semi-supervised learning method include: 1) significantly increase the available training samples from censored data; 2) high capability for identifying the survival risk classes of patient in Cox model; 3) high predictive accuracy for patients' survival time in AFT model; 4) strong capability of the relevant biomarker selection. Consequently, our proposed semi-supervised learning model is one more appropriate tool for survival analysis in clinical cancer research.

Pioglitazone does not affect the risk of ovarian cancer: analysis of a nationwide reimbursement database in Taiwan.

PubMed

Tseng, Chin-Hsiao

2013-10-01

The association between pioglitazone and ovarian cancer has not been studied. The reimbursement databases of all Taiwanese patients with a diagnosis of diabetes and under oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2006 and a total of 546,632 female patients with type 2 diabetes were followed up for ovarian cancer incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of pioglitazone exposure [using cutoffs of the Kaiser Permanente Northern California study and tertile cutoffs derived from the databases] were calculated and the hazard ratios were estimated by Cox regression in unadjusted, age-adjusted and fully adjusted models. There were 30,783 ever-users and 515,849 never-users, with respective numbers of incident ovarian cancer of 49 (0.16%) and 946 (0.18%), and respective incidence of 43.08 and 51.47 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) in unadjusted, age-adjusted and fully adjusted models were 0.822 (0.616-1.095), 0.823 (0.617-1.097) and 0.968 (0.718-1.305), respectively. In the dose-response analyses, none of the categories showed a significant hazard ratio, and all P-trends were >0.05 without statistical significance. This study does not support a positive or negative association between pioglitazone use and ovarian cancer in female patients with type 2 diabetes. © 2013.

Scoring and staging systems using cox linear regression modeling and recursive partitioning.

PubMed

Lee, J W; Um, S H; Lee, J B; Mun, J; Cho, H

2006-01-01

Scoring and staging systems are used to determine the order and class of data according to predictors. Systems used for medical data, such as the Child-Turcotte-Pugh scoring and staging systems for ordering and classifying patients with liver disease, are often derived strictly from physicians' experience and intuition. We construct objective and data-based scoring/staging systems using statistical methods. We consider Cox linear regression modeling and recursive partitioning techniques for censored survival data. In particular, to obtain a target number of stages we propose cross-validation and amalgamation algorithms. We also propose an algorithm for constructing scoring and staging systems by integrating local Cox linear regression models into recursive partitioning, so that we can retain the merits of both methods such as superior predictive accuracy, ease of use, and detection of interactions between predictors. The staging system construction algorithms are compared by cross-validation evaluation of real data. The data-based cross-validation comparison shows that Cox linear regression modeling is somewhat better than recursive partitioning when there are only continuous predictors, while recursive partitioning is better when there are significant categorical predictors. The proposed local Cox linear recursive partitioning has better predictive accuracy than Cox linear modeling and simple recursive partitioning. This study indicates that integrating local linear modeling into recursive partitioning can significantly improve prediction accuracy in constructing scoring and staging systems.

Applying Additive Hazards Models for Analyzing Survival in Patients with Colorectal Cancer in Fars Province, Southern Iran

PubMed

Madadizadeh, Farzan; Ghanbarnejad, Amin; Ghavami, Vahid; Zare Bandamiri, Mohammad; Mohammadianpanah, Mohammad

2017-04-01

Introduction: Colorectal cancer (CRC) is a commonly fatal cancer that ranks as third worldwide and third and the fifth in Iranian women and men, respectively. There are several methods for analyzing time to event data. Additive hazards regression models take priority over the popular Cox proportional hazards model if the absolute hazard (risk) change instead of hazard ratio is of primary concern, or a proportionality assumption is not made. Methods: This study used data gathered from medical records of 561 colorectal cancer patients who were admitted to Namazi Hospital, Shiraz, Iran, during 2005 to 2010 and followed until December 2015. The nonparametric Aalen’s additive hazards model, semiparametric Lin and Ying’s additive hazards model and Cox proportional hazards model were applied for data analysis. The proportionality assumption for the Cox model was evaluated with a test based on the Schoenfeld residuals and for test goodness of fit in additive models, Cox-Snell residual plots were used. Analyses were performed with SAS 9.2 and R3.2 software. Results: The median follow-up time was 49 months. The five-year survival rate and the mean survival time after cancer diagnosis were 59.6% and 68.1±1.4 months, respectively. Multivariate analyses using Lin and Ying’s additive model and the Cox proportional model indicated that the age of diagnosis, site of tumor, stage, and proportion of positive lymph nodes, lymphovascular invasion and type of treatment were factors affecting survival of the CRC patients. Conclusion: Additive models are suitable alternatives to the Cox proportionality model if there is interest in evaluation of absolute hazard change, or no proportionality assumption is made. Creative Commons Attribution License

Quantification of Treatment Effect Modification on Both an Additive and Multiplicative Scale

PubMed Central

Girerd, Nicolas; Rabilloud, Muriel; Pibarot, Philippe; Mathieu, Patrick; Roy, Pascal

2016-01-01

Background In both observational and randomized studies, associations with overall survival are by and large assessed on a multiplicative scale using the Cox model. However, clinicians and clinical researchers have an ardent interest in assessing absolute benefit associated with treatments. In older patients, some studies have reported lower relative treatment effect, which might translate into similar or even greater absolute treatment effect given their high baseline hazard for clinical events. Methods The effect of treatment and the effect modification of treatment were respectively assessed using a multiplicative and an additive hazard model in an analysis adjusted for propensity score in the context of coronary surgery. Results The multiplicative model yielded a lower relative hazard reduction with bilateral internal thoracic artery grafting in older patients (Hazard ratio for interaction/year = 1.03, 95%CI: 1.00 to 1.06, p = 0.05) whereas the additive model reported a similar absolute hazard reduction with increasing age (Delta for interaction/year = 0.10, 95%CI: -0.27 to 0.46, p = 0.61). The number needed to treat derived from the propensity score-adjusted multiplicative model was remarkably similar at the end of the follow-up in patients aged < = 60 and in patients >70. Conclusions The present example demonstrates that a lower treatment effect in older patients on a relative scale can conversely translate into a similar treatment effect on an additive scale due to large baseline hazard differences. Importantly, absolute risk reduction, either crude or adjusted, can be calculated from multiplicative survival models. We advocate for a wider use of the absolute scale, especially using additive hazard models, to assess treatment effect and treatment effect modification. PMID:27045168

Accounting for individual differences and timing of events: estimating the effect of treatment on criminal convictions in heroin users.

PubMed

Røislien, Jo; Clausen, Thomas; Gran, Jon Michael; Bukten, Anne

2014-05-17

The reduction of crime is an important outcome of opioid maintenance treatment (OMT). Criminal intensity and treatment regimes vary among OMT patients, but this is rarely adjusted for in statistical analyses, which tend to focus on cohort incidence rates and rate ratios. The purpose of this work was to estimate the relationship between treatment and criminal convictions among OMT patients, adjusting for individual covariate information and timing of events, fitting time-to-event regression models of increasing complexity. National criminal records were cross linked with treatment data on 3221 patients starting OMT in Norway 1997-2003. In addition to calculating cohort incidence rates, criminal convictions was modelled as a recurrent event dependent variable, and treatment a time-dependent covariate, in Cox proportional hazards, Aalen's additive hazards, and semi-parametric additive hazards regression models. Both fixed and dynamic covariates were included. During OMT, the number of days with criminal convictions for the cohort as a whole was 61% lower than when not in treatment. OMT was associated with reduced number of days with criminal convictions in all time-to-event regression models, but the hazard ratio (95% CI) was strongly attenuated when adjusting for covariates; from 0.40 (0.35, 0.45) in a univariate model to 0.79 (0.72, 0.87) in a fully adjusted model. The hazard was lower for females and decreasing with older age, while increasing with high numbers of criminal convictions prior to application to OMT (all p < 0.001). The strongest predictors were level of criminal activity prior to entering into OMT, and having a recent criminal conviction (both p < 0.001). The effect of several predictors was significantly time-varying with their effects diminishing over time. Analyzing complex observational data regarding to fixed factors only overlooks important temporal information, and naïve cohort level incidence rates might result in biased estimates of the effect of interventions. Applying time-to-event regression models, properly adjusting for individual covariate information and timing of various events, allows for more precise and reliable effect estimates, as well as painting a more nuanced picture that can aid health care professionals and policy makers.

Selecting risk factors: a comparison of discriminant analysis, logistic regression and Cox's regression model using data from the Tromsø Heart Study.

PubMed

Brenn, T; Arnesen, E

1985-01-01

For comparative evaluation, discriminant analysis, logistic regression and Cox's model were used to select risk factors for total and coronary deaths among 6595 men aged 20-49 followed for 9 years. Groups with mortality between 5 and 93 per 1000 were considered. Discriminant analysis selected variable sets only marginally different from the logistic and Cox methods which always selected the same sets. A time-saving option, offered for both the logistic and Cox selection, showed no advantage compared with discriminant analysis. Analysing more than 3800 subjects, the logistic and Cox methods consumed, respectively, 80 and 10 times more computer time than discriminant analysis. When including the same set of variables in non-stepwise analyses, all methods estimated coefficients that in most cases were almost identical. In conclusion, discriminant analysis is advocated for preliminary or stepwise analysis, otherwise Cox's method should be used.

Modeling the safety impacts of driving hours and rest breaks on truck drivers considering time-dependent covariates.

PubMed

Chen, Chen; Xie, Yuanchang

2014-12-01

Driving hours and rest breaks are closely related to driver fatigue, which is a major contributor to truck crashes. This study investigates the effects of driving hours and rest breaks on commercial truck driver safety. A discrete-time logistic regression model is used to evaluate the crash odds ratios of driving hours and rest breaks. Driving time is divided into 11 one hour intervals. These intervals and rest breaks are modeled as dummy variables. In addition, a Cox proportional hazards regression model with time-dependent covariates is used to assess the transient effects of rest breaks, which consists of a fixed effect and a variable effect. Data collected from two national truckload carriers in 2009 and 2010 are used. The discrete-time logistic regression result indicates that only the crash odds ratio of the 11th driving hour is statistically significant. Taking one, two, and three rest breaks can reduce drivers' crash odds by 68%, 83%, and 85%, respectively, compared to drivers who did not take any rest breaks. The Cox regression result shows clear transient effects for rest breaks. It also suggests that drivers may need some time to adjust themselves to normal driving tasks after a rest break. Overall, the third rest break's safety benefit is very limited based on the results of both models. The findings of this research can help policy makers better understand the impact of driving time and rest breaks and develop more effective rules to improve commercial truck safety. Copyright © 2014 National Safety Council and Elsevier Ltd. All rights reserved.

Cyclooxygenase-2 regulated by the nuclear factor-κB pathway plays an important role in endometrial breakdown in a female mouse menstrual-like model.

PubMed

Xu, Xiangbo; Chen, Xihua; Li, Yunfeng; Cao, Huizi; Shi, Cuige; Guan, Shuo; Zhang, Shucheng; He, Bin; Wang, Jiedong

2013-08-01

The role of prostaglandins (PGs) in menstruation has long been proposed. Although evidence from studies on human and nonhuman primates supports the involvement of PGs in menstruation, whether PGs play an obligatory role in the process remains unclear. Although cyclooxygenase (COX) inhibitors have been used in the treatment of irregular uterine bleeding, the mechanism involved has not been elucidated. In this study, we used a recently established mouse menstrual-like model for investigating the role of COX in endometrial breakdown and its regulation. Administration of the nonspecific COX inhibitor indomethacin and the COX-2 selective inhibitor DuP-697 led to inhibition of the menstrual-like process. Furthermore, immunostaining analysis showed that the nuclear factor (NF)κB proteins P50, P65, and COX-2 colocalized in the outer decidual stroma at 12 to 16 hours after progesterone withdrawal. Chromatin immunoprecipitation analysis showed that NFκB binding to the Cox-2 promoter increased at 12 hours after progesterone withdrawal in vivo, and real-time PCR analysis showed that the NFκB inhibitors pyrrolidine dithiocarbamate and MG-132 inhibited Cox-2 mRNA expression in vivo and in vitro, respectively. Furthermore, COX-2 and NFκB inhibitors similarly reduced endometrial breakdown, suggesting that NFκB/COX-2-derived PGs play a critical role in this process. In addition, the CD45(+) leukocyte numbers were sharply reduced following indomethacin (COX-1 and COX-2 inhibitor), DuP-697 (COX-2 inhibitor), and pyrrolidine dithiocarbamate (NFκB inhibitor) treatment. Collectively, these data indicate that NFκB/COX-2-induced PGs regulate leukocyte influx, leading to endometrial breakdown.

Resistance to hypertension mediated by intercalated cells of the collecting duct

PubMed Central

Chen, Daian; Herrera, Marcela; Sparks, Matthew A.; Gurley, Susan B.

2017-01-01

The renal collecting duct (CD), as the terminal segment of the nephron, is responsible for the final adjustments to the amount of sodium excreted in urine. While angiotensin II modulates reabsorptive functions of the CD, the contribution of these actions to physiological homeostasis is not clear. To examine this question, we generated mice with cell-specific deletion of AT1A receptors from the CD. Elimination of AT1A receptors from both principal and intercalated cells (CDKO mice) had no effect on blood pressures at baseline or during successive feeding of low- or high-salt diets. In contrast, the severity of hypertension caused by chronic infusion of angiotensin II was paradoxically exaggerated in CDKO mice compared with controls. In wild-type mice, angiotensin II induced robust expression of cyclooxygenase-2 (COX-2) in renal medulla, primarily localized to intercalated cells. Upregulation of COX-2 was diminished in CDKO mice, resulting in reduced generation of vasodilator prostanoids. This impaired expression of COX-2 has physiological consequences, since administration of a specific COX-2 inhibitor to CDKO and control mice during angiotensin II infusion equalized their blood pressures. Stimulation of COX-2 was also triggered by exposure of isolated preparations of medullary CDs to angiotensin II. Deletion of AT1A receptors from principal cells alone did not affect angiotensin II–dependent COX2 stimulation, implicating intercalated cells as the main source of COX2 in this setting. These findings suggest a novel paracrine role for the intercalated cell to attenuate the severity of hypertension. Strategies for preserving or augmenting this pathway may have value for improving the management of hypertension. PMID:28405625

Coastal Storm Surge Analysis: Storm Forcing. Report 3. Intermediate Submission No. 1.3

DTIC Science & Technology

2013-07-01

No. 1.3 C oa st al a n d H yd ra u lic s La b or at or y Peter Vickery, Dhiraj Wadhera, Andrew Cox, Vince Cardone , Jeffrey Hanson, and Brian...Andrew Cox and Vince Cardone Oceanweather, Inc 5 River Road, Suite 1 Cos Cob, CT 06807 Jeffrey L. Hanson Field Research Facility US Army Engineer...Zou Modeling Mesh Modeling Mesh Modeling Mesh Elizabeth City State University Jinchun Yuan Web/GIS Oceanweather Vince Cardone Andrew Cox Wind

Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

PubMed

Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard; Heyman, Mats; Wesenberg, Finn; Kristinsson, Jon; Vettenranta, Kim; Schrøeder, Henrik; Weinshilboum, Richard; Jensen, Katrine Lykke; Grell, Kathrine; Rosthoej, Susanne

2016-12-01

6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10 9 /l. After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10 9 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10 9 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r s  = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model. This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy. © 2016 Wiley Periodicals, Inc.

WebDISCO: a web service for distributed cox model learning without patient-level data sharing.

PubMed

Lu, Chia-Lun; Wang, Shuang; Ji, Zhanglong; Wu, Yuan; Xiong, Li; Jiang, Xiaoqian; Ohno-Machado, Lucila

2015-11-01

The Cox proportional hazards model is a widely used method for analyzing survival data. To achieve sufficient statistical power in a survival analysis, it usually requires a large amount of data. Data sharing across institutions could be a potential workaround for providing this added power. The authors develop a web service for distributed Cox model learning (WebDISCO), which focuses on the proof-of-concept and algorithm development for federated survival analysis. The sensitive patient-level data can be processed locally and only the less-sensitive intermediate statistics are exchanged to build a global Cox model. Mathematical derivation shows that the proposed distributed algorithm is identical to the centralized Cox model. The authors evaluated the proposed framework at the University of California, San Diego (UCSD), Emory, and Duke. The experimental results show that both distributed and centralized models result in near-identical model coefficients with differences in the range [Formula: see text] to [Formula: see text]. The results confirm the mathematical derivation and show that the implementation of the distributed model can achieve the same results as the centralized implementation. The proposed method serves as a proof of concept, in which a publicly available dataset was used to evaluate the performance. The authors do not intend to suggest that this method can resolve policy and engineering issues related to the federated use of institutional data, but they should serve as evidence of the technical feasibility of the proposed approach.Conclusions WebDISCO (Web-based Distributed Cox Regression Model; https://webdisco.ucsd-dbmi.org:8443/cox/) provides a proof-of-concept web service that implements a distributed algorithm to conduct distributed survival analysis without sharing patient level data. © 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.

Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis.

PubMed

Hull, M L; Prentice, A; Wang, D Y; Butt, R P; Phillips, S C; Smith, S K; Charnock-Jones, D S

2005-02-01

Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. The hypothesized biological properties of COX-2 inhibition did not influence lesion number or size in the nude mouse model of endometriosis.

EuroQol (EQ-5D) measure of quality of life predicts mortality, emergency department utilization, and hospital discharge rates in HIV-infected adults under care.

PubMed

Mathews, William C; May, Susanne

2007-01-25

Health-related quality of life (HR-QOL) is a relevant and quantifiable outcome of care. We implemented HR-QOL assessment at all primary care visits at UCSD Owen Clinic using EQ-5D. The study aim was to estimate the prognostic value of EQ-5D for survival, hospitalization, and emergency department (ED) utilization after controlling for CD4 and HIV plasma viral load (pVL). We conducted a retrospective analysis of HIV clinic based cohort (1996-2000). The EQ-5D includes single item measures of: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each item is coded using 3-levels (1 = no problems; 2 = some problems; 3 = severe problems). The instrument includes a global rating of current health using a visual analog scale (VAS) ranging from 0 (worst imaginable) to 100 (best imaginable). An additional single item measure of health change (better, much the same, worse) was included. A predicted VAS (pVAS) was estimated by regressing the 5 EQ-5D health states on VAS using reference cell coding of health states and random effects linear models. Survival models were fit using Cox modelling. Hospitalization and ED rate models were estimated using population-averaged Poisson models. 965 patients met eligibility criteria. 12% were female; 42% were non-white. Median time-at-risk was 1.2 years. Median CD4 was 233. Median log10(pVL) was 4.6. 47 deaths occurred. In two Cox models controlling for CD4 and pVL, the adjusted hazard ratios (aHR) for VAS and pVAS as time-varying covariates were 0.73 (95% CI: 0.63-0.83) and 0.66 (95% CI: 0.56-0.77) respectively, for every 10 point increase in (p)VAS rating. In Poisson regression models predicting ED visit rates and hospital discharge rates controlling for current CD4 and pVL, each of the EQ-5D health dimensions, VAS, and health change items were significantly (p < 0.05) associated with the outcomes. For ED visit rates, the adjusted incidence rate ratios (aIRR) were 0.86 (0.83-0.89) and 0.79 (0.75-0.82) for VAS and pVAS, respectively. For hospital discharge rates, the aIRR's were 0.85 (0.82-0.88) and 0.79 (0.75-0.82) for VAS and pVAS, respectively. EQ-5D is a brief and prognostically useful predictor of mortality, hospitalization, and ED utilization among adults under care for HIV infection, even after adjusting for CD4 and HIV plasma viral load.

Left ventricular energy model predicts adverse events in women with suspected myocardial ischemia: results from the NHLBI-sponsored women’s ischemia syndrome evaluation (WISE) study

PubMed Central

Weinberg, Nicole; Pohost, Gerald M.; Bairey Merz, C. Noel; Shaw, Leslee J.; Sopko, George; Fuisz, Anthon; Rogers, William J.; Walsh, Edward G.; Johnson, B. Delia; Sharaf, Barry L.; Pepine, Carl J.; Mankad, Sunil; Reis, Steven E.; Rayarao, Geetha; Vido, Diane A.; Bittner, Vera; Tauxe, Lindsey; Olson, Marian B.; Kelsey, Sheryl F.; Biederman, Robert WW

2013-01-01

Objectives To assess the prognostic value of a left ventricular energy-model in women with suspected myocardial ischemia. Background The prognostic value of internal energy utilization (IEU) of the left ventricle in women with suspected myocardial ischemia is unknown. Methods Women [n=227, mean age 59±12 years (range, 31-86 years)], with symptoms of myocardial ischemia, underwent myocardial perfusion imaging (MPI) assessment for regional perfusion defects along with measurement of ventricular volumes separately by gated Single Photon Emission Computed Tomography (SPECT) (n=207) and magnetic resonance imaging (MRI) (n=203). During follow-up (40±17 months), time to first major adverse cardiovascular event (MACE, death, myocardial infarction or hospitalization for congestive heart failure) was analyzed using MRI and gated SPECT variables. Results Adverse events occurred in 31 (14%). Multivariable Cox models were formed for each modality: IEU and wall thickness by MRI (Chi-squared 34, P<0.005) and IEU and systolic blood pressure by gated SEPCT (Chi-squared 34, P<0.005). The models remained predictive after adjustment for age, disease history and Framingham risk score. For each Cox model, patients were categorized as high-risk if the model hazard was positive and not high-risk otherwise. Kaplan-Meier analysis of time to MACE was performed for high-risk vs. not high-risk for MR (log rank 25.3, P<0.001) and gated SEPCT (log rank 18.2, P<0.001) models. Conclusions Among women with suspected myocardial ischemia a high internal energy utilization has higher prognostic value than either a low EF or the presence of a myocardial perfusion defect assessed using two independent modalities of MR or gated SPECT. PMID:24015377

Lack of Impact of Race Alone on Cervical Cancer Survival in Brazil

PubMed

Nogueira Rodrigues, Angelica; Melo, Andreia Cristina de; Alves, Flavia Vieira Guerra; Vilaca, Mariana do Nascimento; Silva, Laisa Gabrielle; Goncalves, Cristiane Alves; Fabrini, Juliana Chaves; Carneiro, Anderson Thiago Vieira; Thuler, Luiz Claudio Santos

2018-05-26

Objective: To analyze differences in survival between black and non-black women diagnosed with cervical cancer and treated at the National Cancer Institute in Brazil. Methods: This retrospective cohort study was conducted using medical records of patients who were treated for cervical cancer between 2006 and 2009 at the Brazilian National Cancer Institute - Rio de Janeiro - Brazil. The clinical and epidemiological characteristics of black and non-black patients were compared using the chi-square test. Survival functions over five years were calculated using the Kaplan-Meier estimator and compared using the log-rank test. Associations between race and mortality risk were analyzed using the Cox proportional hazards model. P-values <0.05 were considered statistically significant. Results: The study included 1,482 women, of whom 188 (12.7%) were black, 1,209 (81.6%) were non-black and 85 (5.7%) were of unspecified race. The age at diagnosis of the patients ranged from 19 to 84 years (mean 50.1 years; SD±13.2). Hemoglobin <12 g/dL at the time of diagnosis (p=0.008) and absence of surgery as primary treatment (p = 0.005) were more frequent among black women. Cox analysis adjusted for these two factors showed no statistically significant difference in the mortality risk associated with cervical cancer among black and non-black women (HR=1.1 95% CI 0.9-1.5; p=0.27). Conclusion: After adjusting for hemoglobin levels and surgery, race alone was not shown to be a prognostic factor for patients with cervical cancer. Creative Commons Attribution License

Anthropometric factors and cutaneous melanoma: Prospective data from the population-based Janus Cohort.

PubMed

Stenehjem, Jo S; Veierød, Marit B; Nilsen, Lill Tove; Ghiasvand, Reza; Johnsen, Bjørn; Grimsrud, Tom K; Babigumira, Ronnie; Rees, Judith R; Robsahm, Trude E

2018-02-15

The aim of the present study was to prospectively examine risk of cutaneous melanoma (CM) according to measured anthropometric factors, adjusted for exposure to ultraviolet radiation (UVR), in a large population-based cohort in Norway. The Janus Cohort, including 292,851 Norwegians recruited 1972-2003, was linked to the Cancer Registry of Norway and followed for CM through 2014. Cox regression was used to estimate hazard ratios (HRs) of CM with 95% confidence intervals (CIs). Restricted cubic splines were incorporated into the Cox models to assess possible non-linear relationships. All analyses were adjusted for attained age, indicators of UVR exposure, education, and smoking status. During a mean follow-up of 27 years, 3,000 incident CM cases were identified. In men, CM risk was positively associated with body mass index, body surface area (BSA), height and weight (all p trends  < 0.001), and the exposure-response curves indicated an exponential increase in risk for all anthropometric factors. Weight loss of more than 2 kg in men was associated with a 53% lower risk (HR 0.47, 95% CI: 0.39, 0.57). In women, CM risk increased with increasing BSA (p trend  = 0.002) and height (p trend  < 0.001). The shape of the height-CM risk curve indicated an exponential increase. Our study suggests that large body size, in general, is a CM risk factor in men, and is the first to report that weight loss may reduce the risk of CM among men. © 2017 UICC.

Periodontal Disease Associated with Higher Risk of Dementia: Population-Based Cohort Study in Taiwan.

PubMed

Lee, Ya-Ling; Hu, Hsiao-Yun; Huang, Li-Ying; Chou, Pesus; Chu, Dachen

2017-09-01

To determine the magnitude and temporal aspect of the effect of poor dental health and periodontal disease (PD) on dementia. Retrospective cohort study SETTING: Taiwan National Health Insurance Research Database. Individuals with newly diagnosed PD (N = 182,747) MEASUREMENTS: Participants were followed from January 1, 2000, to December 31, 2010. Participants were assigned to dental prophylaxis, intensive periodontal treatment, tooth extraction, or no treatment, according to International Classification of Diseases codes and PD treatment codes. The incidence rate of dementia of the groups was compared. The association between PD and dementia was analyzed using Cox regression, with adjustments for age, sex, monthly income, residential urbanicity, and comorbidities. The incidence of dementia was significantly higher in the group with PD that did not receive treatment (0.76% per year) and in the group that had teeth extracted (0.57% per year) than in the group that underwent intensive PD treatment (0.35% per year) and the group that received dental prophylaxis (0.39% per year) (P < .001). After adjusting for confounders, the Cox proportional hazards model revealed a higher risk of dementia in the group with PD who did not undergo treatment (hazard ratio (HR) = 1.14, 95% confidence interval (CI) = 1.04-1.24) and the group that had teeth extracted (HR = 1.10, 95% CI = 1.04-1.16) than in the group that received dental prophylaxis. Subjects who had more severe PD or did not receive periodontal treatment were at greater risk of developing dementia. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Centre characteristics associated with the risk of peritonitis in peritoneal dialysis: a hierarchical modelling approach based on the data of the French Language Peritoneal Dialysis Registry.

PubMed

Béchade, Clémence; Guillouët, Sonia; Verger, Christian; Ficheux, Maxence; Lanot, Antoine; Lobbedez, Thierry

2017-06-01

This study investigated the centre effect on the risk of peritonitis in peritoneal dialysis (PD) patients. This was a retrospective cohort study based on data from the French Language Peritoneal Dialysis Registry. We analysed 5017 incident patients starting PD between January 2008 and December 2012 in 127 PD centres. The end of the observation period was 1 January 2014. The event of interest was the first peritonitis episode. The analysis was performed with a multilevel Cox model and a Fine and Gray model. Among the 5017 patients, 3190 peritonitis episodes occurred in 1796 patients. There was significant heterogeneity between centres (variance of the random effect: 0.11). The variance of the centre effect was reduced by 9% after adjusting for patient characteristics and by 35% after adjusting on centre covariate. In the multivariate analysis with a multilevel Cox model, centre with a nurse specialized in PD or centre providing home visits before dialysis initiation decreased the centre effect on peritonitis. Patients treated in centres with a nurse specialized in PD or in centres providing home visits before dialysis initiation had a lower risk of peritonitis [cause-specific hazard ratio (cs-HR): 0.75 (95% confidence interval, CI, 0.67-0.83) and cs-HR: 0.87 (95% CI 0.76-0.97), respectively]. The data show that neither centre type nor centre volume influenced peritonitis risk. In the competing risk analysis, centre with a nurse specialized in PD and centre with home visits had a protective effect on peritonitis [sub-distribution HR (sd-HR): 0.77 (95% CI 0.70-0.85) and sd-HR: 0.85 (95% CI 0.77-0.94), respectively]. There is a significant centre effect on the risk of peritonitis that can be decreased by home visits before dialysis initiation and by the presence of a nurse specialized in PD. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

A global goodness-of-fit statistic for Cox regression models.

PubMed

Parzen, M; Lipsitz, S R

1999-06-01

In this paper, a global goodness-of-fit test statistic for a Cox regression model, which has an approximate chi-squared distribution when the model has been correctly specified, is proposed. Our goodness-of-fit statistic is global and has power to detect if interactions or higher order powers of covariates in the model are needed. The proposed statistic is similar to the Hosmer and Lemeshow (1980, Communications in Statistics A10, 1043-1069) goodness-of-fit statistic for binary data as well as Schoenfeld's (1980, Biometrika 67, 145-153) statistic for the Cox model. The methods are illustrated using data from a Mayo Clinic trial in primary billiary cirrhosis of the liver (Fleming and Harrington, 1991, Counting Processes and Survival Analysis), in which the outcome is the time until liver transplantation or death. The are 17 possible covariates. Two Cox proportional hazards models are fit to the data, and the proposed goodness-of-fit statistic is applied to the fitted models.

Lifetime comorbidities between phobic disorders and major depression in Japan: results from the World Mental Health Japan 2002-2004 Survey.

PubMed

Tsuchiya, Masao; Kawakami, Norito; Ono, Yutaka; Nakane, Yoshibumi; Nakamura, Yosikazu; Tachimori, Hisateru; Iwata, Noboru; Uda, Hidenori; Nakane, Hideyuki; Watanabe, Makoto; Naganuma, Yoichi; Furukawa, Toshiaki A; Hata, Yukihiro; Kobayashi, Masayo; Miyake, Yuko; Takeshima, Tadashi; Kikkawa, Takehiko; Kessler, Ronald C

2009-01-01

Although often considered of minor significance in themselves, evidence exists that early-onset phobic disorders might be predictors of later more serious disorders, such as major depressive disorder (MDD). The purpose of this study is to investigate the association of phobic disorders with the onset of MDD in the community in Japan. Data from the World Mental Health Japan 2002-2004 Survey were analyzed. A total of 2,436 community residents aged 20 and older were interviewed using the WHO Composite International Diagnostic Interview 3.0 (response rate, 58.4%). A Cox proportional hazard model was used to predict the onset of MDD as a function of prior history of DSM-IV specific phobia, agoraphobia, or social phobia, adjusting for gender, birth-cohort, other anxiety disorders, education, and marital status at survey. Social phobia was strongly associated with the subsequent onset of MDD (hazard ratio [HR]=4.1 [95% CI: 2.0-8.7]) after adjusting for sex, birth cohort, and the number of other anxiety disorders. The association between agoraphobia or specific phobia and MDD was not statistically significant after adjusting for these variables. Social phobia is a powerful predictor of the subsequent first onset of MDD in Japan. Although this finding argues against a simple neurobiological model and in favor of a model in which the cultural meanings of phobia play a part in promoting MDD, an elucidation of causal pathways will require more fine-grained comparative research.

Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor

PubMed Central

Mahdi, Chanif; Nurdiana, Nurdiana; Kikuchi, Takheshi; Fatchiyah, Fatchiyah

2014-01-01

To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX), the three-dimensional (3D) structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent) of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117) was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2. PMID:25484897

Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules.

PubMed

Altorki, Nasser K; Yip, Rowena; Hanaoka, Takaomi; Bauer, Thomas; Aye, Ralph; Kohman, Leslie; Sheppard, Barry; Thurer, Richard; Andaz, Shahriyour; Smith, Michael; Mayfield, William; Grannis, Fred; Korst, Robert; Pass, Harvey; Straznicka, Michaela; Flores, Raja; Henschke, Claudia I

2014-02-01

A single randomized trial established lobectomy as the standard of care for the surgical treatment of early-stage non-small cell lung cancer. Recent advances in imaging/staging modalities and detection of smaller tumors have once again rekindled interest in sublobar resection for early-stage disease. The objective of this study was to compare lung cancer survival in patients with non-small cell lung cancer with a diameter of 30 mm or less with clinical stage 1 disease who underwent lobectomy or sublobar resection. We identified 347 patients diagnosed with lung cancer who underwent lobectomy (n = 294) or sublobar resection (n = 53) for non-small cell lung cancer manifesting as a solid nodule in the International Early Lung Cancer Action Program from 1993 to 2011. Differences in the distribution of the presurgical covariates between sublobar resection and lobectomy were assessed using unadjusted P values determined by logistic regression analysis. Propensity scoring was performed using the same covariates. Differences in the distribution of the same covariates between sublobar resection and lobectomy were assessed using adjusted P values determined by logistic regression analysis with adjustment for the propensity scores. Lung cancer-specific survival was determined by the Kaplan-Meier method. Cox survival regression analysis was used to compare sublobar resection with lobectomy, adjusted for the propensity scores, surgical, and pathology findings, when adjusted and stratified by propensity quintiles. Among 347 patients, 10-year Kaplan-Meier for 53 patients treated by sublobar resection compared with 294 patients treated by lobectomy was 85% (95% confidence interval, 80-91) versus 86% (confidence interval, 75-96) (P = .86). Cox survival analysis showed no significant difference between sublobar resection and lobectomy when adjusted for propensity scores or when using propensity quintiles (P = .62 and P = .79, respectively). For those with cancers 20 mm or less in diameter, the 10-year rates were 88% (95% confidence interval, 82-93) versus 84% (95% confidence interval, 73-96) (P = .45), and Cox survival analysis showed no significant difference between sublobar resection and lobectomy using either approach (P = .42 and P = .52, respectively). Sublobar resection and lobectomy have equivalent survival for patients with clinical stage IA non-small cell lung cancer in the context of computed tomography screening for lung cancer. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

COX-2 expression and function in the hyperalgesic response to paw inflammation in mice

PubMed Central

Jain, Naveen K.; Ishikawa, Tomo-o; Spigelman, Igor; Herschman, Harvey R.

2009-01-01

Peripheral inflammation and edema are often accompanied by primary and secondary hyperalgesia which are mediated by both peripheral and central mechanisms. The role of cyclooxygenase-2 (COX-2)-mediated prostanoid production in hyperalgesia is a topic of substantial current interest. We have established a murine foot-pad inflammation model in which both pharmacologic and genetic tools can be used to characterize the role of COX-2 in hyperalgesia. Zymosan, an extract from yeast, injected into the plantar surface of the hind paw induces an edema response and an increase in COX-2 expression in the hindpaw, spinal cord and brain. Zymosan-induced primary hyperalgesia, measured as a decrease in hindpaw withdrawal latency in response to a thermal stimulus, is long-lasting and is not inhibited by pre-treatment with the systemic COX-2 selective inhibitor, parecoxib (20 mg/kg). In contrast, the central component of hyperalgesia, measured as a reduction in tail flick latency in response to heat, is reduced by parecoxib. Zymosan-induced primary hyperalgesia in Cox-2−/− mice is similar to that of their Cox-2+/+ littermate controls. However, the central component of hyperalgesia is substantially reduced in Cox-2−/− versus Cox-2+/+ mice, and returns to baseline values much more rapidly. Thus pharmacological data suggest, and genetic experiments confirm, (i) that primary hyperalgesia in response to zymosan inflammation in the mouse paw is not mediated by COX-2 function and (ii) that COX-2 function plays a major role in the central component of hyperalgesia in this model of inflammation. PMID:18829279

Tramadol for noncancer pain and the risk of hyponatremia.

PubMed

Fournier, Jean-Pascal; Yin, Hui; Nessim, Sharon J; Montastruc, Jean-Louis; Azoulay, Laurent

2015-04-01

Case reports have signaled a possible association between tramadol, a weak opioid analgesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol is associated with an increased risk of hyponatremia, when compared with codeine. Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, a population-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998 through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol, compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highly restricted sub-cohort, which additionally excluded patients with any serum sodium level abnormality in the year before cohort entry. All models were adjusted for propensity score quintiles. The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95% CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model, the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the use of tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 3.54; 95% CI, 1.32-9.54). In this first population-based study, the use of tramadol was associated with an increased risk of hyponatremia requiring hospitalization. Copyright © 2015 Elsevier Inc. All rights reserved.

Antidepressant Medication Use and Its Association With Cardiovascular Disease and All-Cause Mortality in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

PubMed

Hansen, Richard A; Khodneva, Yulia; Glasser, Stephen P; Qian, Jingjing; Redmond, Nicole; Safford, Monika M

2016-04-01

Mixed evidence suggests that second-generation antidepressants may increase the risk of cardiovascular and cerebrovascular events. To assess whether antidepressant use is associated with acute coronary heart disease (CHD), stroke, cardiovascular disease (CVD) death, and all-cause mortality. Secondary analyses of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) longitudinal cohort study were conducted. Use of selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, bupropion, nefazodone, and trazodone was measured during the baseline (2003-2007) in-home visit. Outcomes of CHD, stroke, CVD death, and all-cause mortality were assessed every 6 months and adjudicated by medical record review. Cox proportional hazards time-to-event analysis followed patients until their first event on or before December 31, 2011, iteratively adjusting for covariates. Among 29 616 participants, 3458 (11.7%) used an antidepressant of interest. Intermediate models adjusting for everything but physical and mental health found an increased risk of acute CHD (hazard ratio [HR] = 1.21; 95% CI = 1.04-1.41), stroke (HR = 1.28; 95% CI = 1.02-1.60), CVD death (HR = 1.29; 95% CI = 1.09-1.53), and all-cause mortality (HR = 1.27; 95% CI = 1.15-1.41) for antidepressant users. Risk estimates trended in this direction for all outcomes in the fully adjusted model but only remained statistically associated with increased risk of all-cause mortality (HR = 1.12; 95% CI = 1.01-1.24). This risk was attenuated in sensitivity analyses censoring follow-up time at 2 years (HR = 1.37; 95% CI = 1.11-1.68). In fully adjusted models, antidepressant use was associated with a small increase in all-cause mortality. © The Author(s) 2016.

Association between anxiety and depression in patients with acute coronary syndromes due to financial crisis.

PubMed

Lampropoulos, Kostandinos; Kavvouras, Charalampos; Megalou, Aikaterini; Tsikouri, Pinelopi; Kafkala, Chrysanthi; Derka, Dimitra; Bonou, Maria; Barbetseas, John

2016-01-01

The effect of anxiety and depression on patients with acute coronary syndromes (ACS) warrants investigation, especially during periods of economic crisis. To investigate the relation between anxiety and depression in patients presenting with ACS due to financial crisis and to investigate whether these two entities could predict long-term cardiovascular mortality. Anxiety and depression symptoms were assessed in 350 patients (210 men) presenting with ACS, with 70 (20%) patients showing elevated scores (Hellenic Heart Failure Protocol). Over a mean follow-up of 48 months there were 36 (10%) cardiovascular deaths. Cox proportional hazards models adjusted for other prognostic factors (including age, sex, marital status, creatinine levels, left ventricular ejection fraction, heart failure, atrial fibrillation, previous hospitalisation, and baseline medications) showed that elevated anxiety and depression scores significantly predicted cardiovascular mortality (primary outcome) and all-cause mortality. Elevated anxiety and depression symptoms are related to cardiovascular mortality due probably to financial crisis, even after adjustment for other prognostic indicators in patients with ACS, who received optimised medical treatment.

[Smoking and student survival at Universidad Santiago de Cali, 2004-2007].

PubMed

Tafur-Calderón, Luis A; Millán-Estupiñan, Juan C; Zapata-Ossa, Helmer; Ordoñez-Arana, Gustavo A; Varela, Jesús M

2010-04-01

This article presents the results of monitoring students who enrolled at Universidad Santiago de Cali (USC) during the second half of 2004. Its purpose was to determine the influence of smoking, the academic programme and the cost of enrollment on student survival over a three-year period (2004-2007). The study involved a prospective cohort of 970 students who entered the university in 2004. Cox regression was used for survival analysis to determine the relationship between independent variables and university stay. The results of this model established associations between smoking and department with survival in the university, but discarded association with the cost of enrollment. The risk of university desertion was higher amongst students from the Health faculty adjusted for smoking (RR = 1.277 (1.121-1.455)). Similarly, the risk of desertion was higher in smokers adjusted by faculty (RR = 1.194 (1.026-1.390). It was found that habitual smokers had shorter university stay than nonsmokers. University stay was longer in students enrolled in academic programmes other than health.

Localized Scleroderma, Systemic Sclerosis and Cardiovascular Risk: A Danish Nationwide Cohort Study.

PubMed

Hesselvig, Jeanette Halskou; Kofoed, Kristian; Wu, Jashin J; Dreyer, Lene; Gislason, Gunnar; Ahlehoff, Ole

2018-03-13

Recent findings indicate that patients with systemic sclerosis have an increased risk of cardiovascular disease. To determine whether patients with systemic sclerosis or localized scleroderma are at increased risk of cardiovascular disease, a cohort study of the entire Danish population aged ≥ 18 and ≤ 100 years was conducted, followed from 1997 to 2011 by individual-level linkage of nationwide registries. Multivariable adjusted Cox regression models were used to estimate the hazard ratios (HRs) for a composite cardiovascular disease endpoint. A total of 697 patients with localized scleroderma and 1,962 patients with systemic sclerosis were identified and compared with 5,428,380 people in the reference population. In systemic sclerosis, the adjusted HR was 2.22 (95% confidence interval 1.99-2.48). No association was seen between patients with localized scleroderma and cardiovascular disease. In conclusion, systemic sclerosis is a significant cardiovascular disease risk factor, while patients with localized scleroderma are not at increased risk of cardiovascular disease.

Lung Quality and Utilization in Controlled Donation after Circulatory Determination of Death Donors within the United States

PubMed Central

Mooney, Joshua J; Hedlin, Haley; Mohabir, Paul K; Vazquez, Rodrigo; Nguyen, John; Ha, Richard; Chiu, Peter; Patel, Kapilkumar; Zamora, Martin R.; Weill, David; Nicolls, Mark R; Dhillon, Gundeep S

2016-01-01

While controlled donation after circulatory determination of death (cDCDD) donors could increase the supply of donor lungs within the United States, the yield of lungs from cDCDD donors remain low compared to donation after neurologic determination of death (DNDD) donors. To explore the reason for low lung yield from cDCDD donors, Scientific Registry of Transplant Recipient data were used to assess the impact of donor lung quality on cDCDD lung utilization by fitting a logistic regression model. The relationship between center volume and cDCDD use was assessed and distance between center and donor hospital was calculated by cDCDD status. Recipient survival was compared using a multivariable Cox regression model. Lung utilization was 2.1% for cDCDD donors and 21.4% for DNDD donors. Being a cDCDD donor decreased lung donation (adjusted OR 0.101, CI 0.085–0.120). A minority of centers have performed cDCDD transplant with higher volume centers generally performing more cDCDD transplants. There was no difference in center to donor distance or recipient survival (adjusted HR 1.03, CI 0.78–1.37) between cDCDD and DNDD transplants. cDCDD lungs are underutilized compared to DNDD lungs after adjusting for lung quality. Increasing transplant center expertise and commitment to cDCDD lung procurement is needed to improve utilization. PMID:26844673

Traffic air pollution and mortality from cardiovascular disease and all causes: a Danish cohort study.

PubMed

Raaschou-Nielsen, Ole; Andersen, Zorana Jovanovic; Jensen, Steen Solvang; Ketzel, Matthias; Sørensen, Mette; Hansen, Johnni; Loft, Steffen; Tjønneland, Anne; Overvad, Kim

2012-09-05

Traffic air pollution has been linked to cardiovascular mortality, which might be due to co-exposure to road traffic noise. Further, personal and lifestyle characteristics might modify any association. We followed up 52 061 participants in a Danish cohort for mortality in the nationwide Register of Causes of Death, from enrollment in 1993-1997 through 2009, and traced their residential addresses from 1971 onwards in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO₂) since 1971 as indicator of traffic air pollution and used Cox regression models to estimate mortality rate ratios (MRRs) with adjustment for potential confounders. Mean levels of NO₂ at the residence since 1971 were significantly associated with mortality from cardiovascular disease (MRR, 1.26; 95% confidence interval [CI], 1.06-1.51, per doubling of NO₂ concentration) and all causes (MRR, 1.13; 95% CI, 1.04-1.23, per doubling of NO₂ concentration) after adjustment for potential confounders. For participants who ate < 200 g of fruit and vegetables per day, the MRR was 1.45 (95% CI, 1.13-1.87) for mortality from cardiovascular disease and 1.25 (95% CI, 1.11-1.42) for mortality from all causes. Traffic air pollution is associated with mortality from cardiovascular diseases and all causes, after adjustment for traffic noise. The association was strongest for people with a low fruit and vegetable intake.

Neighborhood disadvantage and ischemic stroke: the Cardiovascular Health Study (CHS).

PubMed

Brown, Arleen F; Liang, Li-Jung; Vassar, Stefanie D; Stein-Merkin, Sharon; Longstreth, W T; Ovbiagele, Bruce; Yan, Tingjian; Escarce, José J

2011-12-01

Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status and incident ischemic stroke and examine potential mediators of these associations. We analyzed data from 3834 whites and 785 blacks enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages≥65 years from 4 US counties. The primary outcome was adjudicated incident ischemic stroke. Neighborhood socioeconomic status was measured using a composite of 6 census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed adjusted for sociodemographic, behavioral, and biological risk factors. Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared with the highest neighborhood socioeconomic status quartile (hazard ratio, 1.32; 95% CI, 1.01-1.72) with greater attenuation of the hazard ratio after adjustment for biological risk factors (hazard ratio, 1.16; 0.88-1.52) than for behavioral risk factors (hazard ratio, 1.30; 0.99-1.70). Among blacks, we found no significant associations between neighborhood socioeconomic status and ischemic stroke. Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among blacks. The relationship between neighborhood socioeconomic status and stroke among whites appears to be mediated more strongly by biological than behavioral risk factors.

Does stage of cancer, comorbidity or lifestyle factors explain educational differences in survival after endometrial cancer? A cohort study among Danish women diagnosed 2005-2009.

PubMed

Seidelin, Ulla Holten; Ibfelt, Else; Andersen, Ingelise; Steding-Jessen, Marianne; Høgdall, Claus; Kjær, Susanne Krüger; Dalton, Susanne Oksbjerg

2016-06-01

Several studies have documented an association between socioeconomic position and survival from gynaecological cancer, but the mechanisms are unclear. The aim of this study was to examine the association between level of education and survival after endometrial cancer among Danish women; and whether differences in stage at diagnosis and comorbidity contribute to the educational differences in survival. Women with endometrial cancer diagnosed between 2005 and 2009 were identified in the Danish Gynaecological Cancer Database, with information on clinical characteristics, surgery, body mass index (BMI) and smoking status. Information on highest attained education, cohabitation and comorbidity was obtained from nationwide administrative registries. Logistic regression models were used to determine the association between level of education and cancer stage and Cox proportional hazards model for analyses of overall survival. Of the 3638 patients identified during the study period, 787 had died by the end of 2011. The group of patients with short education had a higher odds ratio (OR) for advanced stage at diagnosis, but this was not statistically significant (adjusted OR 1.20; 95% CI 0.97-1.49). The age-adjusted hazard ratio (HR) for dying of patients with short education was 1.47 (CI 95% 1.17-1.80). Adjustment for cohabitation status, BMI, smoking and comorbidity did not change HRs, but further adjustment for cancer stage yielded a HR of 1.36 (1.11-1.67). Early detection in all educational groups might reduce social inequalities in survival, however, the unexplained increased risk for death after adjustment for prognostic factors, warrants increased attention to patients with short education in all age groups throughout treatment and rehabilitation.

Quantifying parameter uncertainty in stochastic models using the Box Cox transformation

NASA Astrophysics Data System (ADS)

Thyer, Mark; Kuczera, George; Wang, Q. J.

2002-08-01

The Box-Cox transformation is widely used to transform hydrological data to make it approximately Gaussian. Bayesian evaluation of parameter uncertainty in stochastic models using the Box-Cox transformation is hindered by the fact that there is no analytical solution for the posterior distribution. However, the Markov chain Monte Carlo method known as the Metropolis algorithm can be used to simulate the posterior distribution. This method properly accounts for the nonnegativity constraint implicit in the Box-Cox transformation. Nonetheless, a case study using the AR(1) model uncovered a practical problem with the implementation of the Metropolis algorithm. The use of a multivariate Gaussian jump distribution resulted in unacceptable convergence behaviour. This was rectified by developing suitable parameter transformations for the mean and variance of the AR(1) process to remove the strong nonlinear dependencies with the Box-Cox transformation parameter. Applying this methodology to the Sydney annual rainfall data and the Burdekin River annual runoff data illustrates the efficacy of these parameter transformations and demonstrate the value of quantifying parameter uncertainty.

External validation of a Cox prognostic model: principles and methods

PubMed Central

2013-01-01

Background A prognostic model should not enter clinical practice unless it has been demonstrated that it performs a useful role. External validation denotes evaluation of model performance in a sample independent of that used to develop the model. Unlike for logistic regression models, external validation of Cox models is sparsely treated in the literature. Successful validation of a model means achieving satisfactory discrimination and calibration (prediction accuracy) in the validation sample. Validating Cox models is not straightforward because event probabilities are estimated relative to an unspecified baseline function. Methods We describe statistical approaches to external validation of a published Cox model according to the level of published information, specifically (1) the prognostic index only, (2) the prognostic index together with Kaplan-Meier curves for risk groups, and (3) the first two plus the baseline survival curve (the estimated survival function at the mean prognostic index across the sample). The most challenging task, requiring level 3 information, is assessing calibration, for which we suggest a method of approximating the baseline survival function. Results We apply the methods to two comparable datasets in primary breast cancer, treating one as derivation and the other as validation sample. Results are presented for discrimination and calibration. We demonstrate plots of survival probabilities that can assist model evaluation. Conclusions Our validation methods are applicable to a wide range of prognostic studies and provide researchers with a toolkit for external validation of a published Cox model. PMID:23496923

Increased incidence of peptic ulcer disease in central serous chorioretinopathy patients: a population-based retrospective cohort study.

PubMed

Chen, San-Ni; Lian, Iebin; Chen, Yi-Chiao; Ho, Jau-Der

2015-02-01

To investigate peptic ulcer disease and other possible risk factors in patients with central serous chorioretinopathy (CSR) using a population-based database. In this population-based retrospective cohort study, longitudinal data from the Taiwan National Health Insurance Research Database were analyzed. The study cohort comprised 835 patients with CSR and the control cohort comprised 4175 patients without CSR from January 2000 to December 2009. Conditional logistic regression was applied to examine the association of peptic ulcer disease and other possible risk factors for CSR, and stratified Cox regression models were applied to examine whether patients with CSR have an increased chance of peptic ulcer disease and hypertension development. The identifiable risk factors for CSR included peptic ulcer disease (adjusted odd ratio: 1.39, P = 0.001) and higher monthly income (adjusted odd ratio: 1.30, P = 0.006). Patients with CSR also had a significantly higher chance of developing peptic ulcer disease after the diagnosis of CSR (adjusted odd ratio: 1.43, P = 0.009). Peptic ulcer disease and higher monthly income are independent risk factors for CSR. Whereas, patients with CSR also had increased risk for peptic ulcer development.

Experiments to Determine Whether Recursive Partitioning (CART) or an Artificial Neural Network Overcomes Theoretical Limitations of Cox Proportional Hazards Regression

NASA Technical Reports Server (NTRS)

Kattan, Michael W.; Hess, Kenneth R.; Kattan, Michael W.

1998-01-01

New computationally intensive tools for medical survival analyses include recursive partitioning (also called CART) and artificial neural networks. A challenge that remains is to better understand the behavior of these techniques in effort to know when they will be effective tools. Theoretically they may overcome limitations of the traditional multivariable survival technique, the Cox proportional hazards regression model. Experiments were designed to test whether the new tools would, in practice, overcome these limitations. Two datasets in which theory suggests CART and the neural network should outperform the Cox model were selected. The first was a published leukemia dataset manipulated to have a strong interaction that CART should detect. The second was a published cirrhosis dataset with pronounced nonlinear effects that a neural network should fit. Repeated sampling of 50 training and testing subsets was applied to each technique. The concordance index C was calculated as a measure of predictive accuracy by each technique on the testing dataset. In the interaction dataset, CART outperformed Cox (P less than 0.05) with a C improvement of 0.1 (95% Cl, 0.08 to 0.12). In the nonlinear dataset, the neural network outperformed the Cox model (P less than 0.05), but by a very slight amount (0.015). As predicted by theory, CART and the neural network were able to overcome limitations of the Cox model. Experiments like these are important to increase our understanding of when one of these new techniques will outperform the standard Cox model. Further research is necessary to predict which technique will do best a priori and to assess the magnitude of superiority.

Effect of Box-Cox transformation on power of Haseman-Elston and maximum-likelihood variance components tests to detect quantitative trait Loci.

PubMed

Etzel, C J; Shete, S; Beasley, T M; Fernandez, J R; Allison, D B; Amos, C I

2003-01-01

Non-normality of the phenotypic distribution can affect power to detect quantitative trait loci in sib pair studies. Previously, we observed that Winsorizing the sib pair phenotypes increased the power of quantitative trait locus (QTL) detection for both Haseman-Elston (HE) least-squares tests [Hum Hered 2002;53:59-67] and maximum likelihood-based variance components (MLVC) analysis [Behav Genet (in press)]. Winsorizing the phenotypes led to a slight increase in type 1 error in H-E tests and a slight decrease in type I error for MLVC analysis. Herein, we considered transforming the sib pair phenotypes using the Box-Cox family of transformations. Data were simulated for normal and non-normal (skewed and kurtic) distributions. Phenotypic values were replaced by Box-Cox transformed values. Twenty thousand replications were performed for three H-E tests of linkage and the likelihood ratio test (LRT), the Wald test and other robust versions based on the MLVC method. We calculated the relative nominal inflation rate as the ratio of observed empirical type 1 error divided by the set alpha level (5, 1 and 0.1% alpha levels). MLVC tests applied to non-normal data had inflated type I errors (rate ratio greater than 1.0), which were controlled best by Box-Cox transformation and to a lesser degree by Winsorizing. For example, for non-transformed, skewed phenotypes (derived from a chi2 distribution with 2 degrees of freedom), the rates of empirical type 1 error with respect to set alpha level=0.01 were 0.80, 4.35 and 7.33 for the original H-E test, LRT and Wald test, respectively. For the same alpha level=0.01, these rates were 1.12, 3.095 and 4.088 after Winsorizing and 0.723, 1.195 and 1.905 after Box-Cox transformation. Winsorizing reduced inflated error rates for the leptokurtic distribution (derived from a Laplace distribution with mean 0 and variance 8). Further, power (adjusted for empirical type 1 error) at the 0.01 alpha level ranged from 4.7 to 17.3% across all tests using the non-transformed, skewed phenotypes, from 7.5 to 20.1% after Winsorizing and from 12.6 to 33.2% after Box-Cox transformation. Likewise, power (adjusted for empirical type 1 error) using leptokurtic phenotypes at the 0.01 alpha level ranged from 4.4 to 12.5% across all tests with no transformation, from 7 to 19.2% after Winsorizing and from 4.5 to 13.8% after Box-Cox transformation. Thus the Box-Cox transformation apparently provided the best type 1 error control and maximal power among the procedures we considered for analyzing a non-normal, skewed distribution (chi2) while Winzorizing worked best for the non-normal, kurtic distribution (Laplace). We repeated the same simulations using a larger sample size (200 sib pairs) and found similar results. Copyright 2003 S. Karger AG, Basel

Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor.

PubMed

Rordorf, Christiane M; Choi, Les; Marshall, Paul; Mangold, James B

2005-01-01

Lumiracoxib (Prexige) is a selective cyclo-oxygenase (COX)-2 inhibitor developed for the treatment of osteoarthritis, rheumatoid arthritis and acute pain. Lumiracoxib possesses a carboxylic acid group that makes it weakly acidic (acid dissociation constant [pKa] 4.7), distinguishing it from other selective COX-2 inhibitors. Lumiracoxib has good oral bioavailability (74%). It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. Lumiracoxib has a short elimination half-life from plasma (mean 4 hours) and demonstrates dose-proportional plasma pharmacokinetics with no accumulation during multiple dosing. In patients with rheumatoid arthritis, peak lumiracoxib synovial fluid concentrations occur 3-4 hours later than in plasma and exceed plasma concentrations from 5 hours after dosing to the end of the 24-hour dosing interval. These data suggest that lumiracoxib may be associated with reduced systemic exposure, while still reaching sites where COX-2 inhibition is required for pain relief. Lumiracoxib is metabolised extensively prior to excretion, with only a small amount excreted unchanged in urine or faeces. Lumiracoxib and its metabolites are excreted via renal and faecal routes in approximately equal amounts. The major metabolic pathways identified involve oxidation of the 5-methyl group of lumiracoxib and/or hydroxylation of its dihaloaromatic ring. Major metabolites of lumiracoxib in plasma are the 5-carboxy, 4'-hydroxy and 4'-hydroxy-5-carboxy derivatives, of which only the 4'-hydroxy derivative is active and COX-2 selective. In vitro, the major oxidative pathways are catalysed primarily by cytochrome P450 (CYP) 2C9 with very minor contribution from CYP1A2 and CYP2C19. However, in patients genotyped as poor CYP2C9 metabolisers, exposure to lumiracoxib (area under the plasma concentration-time curve) is not significantly increased compared with control subjects, indicating no requirement for adjustment of lumiracoxib dose in these subjects. Lumiracoxib is selective for COX-2 compared with COX-1 in the human whole blood assay with a ratio of 515 : 1 in healthy subjects and in patients with osteoarthritis or rheumatoid arthritis. COX-2 selectivity was confirmed by a lack of inhibition of arachidonic acid and collagen-induced platelet aggregation. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen and a lack of effect on both small and large bowel permeability. Lumiracoxib does not exhibit any clinically meaningful interactions with a range of commonly used medications including aspirin (acetylsalicylic acid), fluconazole, an ethinylestradiol- and levonorgestrel-containing oral contraceptive, omeprazole, the antacid Maalox, methotrexate and warfarin (although, as in common practice, routine monitoring of coagulation is recommended when lumiracoxib is co-administered with warfarin). As such, dose adjustments are not required when co-administering these agents with lumiracoxib. In addition, moderate hepatic impairment and mild to moderate renal impairment do not appear to influence lumiracoxib exposure.

Prognostic significance of hemoglobin level in patients with congestive heart failure and normal ejection fraction.

PubMed

Varadarajan, Padmini; Gandhi, Siddharth; Sharma, Sanjay; Umakanthan, Branavan; Pai, Ramdas G

2006-10-01

Previous studies have shown low hemoglobin (Hb) to have an adverse effect on survival in patients with congestive heart failure (CHF) and reduced left ventricular (LV) ejection fraction (EF); but its effect on survival in patients with CHF and normal EF is not known. This study sought to determine whether low Hb has an effect on survival in patients with both CHF and normal EF. Detailed chart reviews were performed by medical residents on 2,246 patients (48% with normal EF) with a discharge diagnosis of CHF in a large tertiary care hospital from 1990 to 1999. The CHF diagnosis was validated using the Framingham criteria. Mortality data were obtained from the National Death Index. Survival analysis was performed using Kaplan-Meier and Cox regression models. By Kaplan-Meier analysis, low Hb (< 12 gm/dl) compared with normal hemoglobin was associated with a lower 5-year survival in patients with CHF and both normal (38 vs. 50%, p = 0.0008) and reduced (35 vs. 48%, p = 0.0009) EF. Using the Cox regression model, low Hb was an independent predictor of mortality after adjusting for age, gender, renal dysfunction, diabetes mellitus, hypertension, and EF in both groups of patients. Low Hb has an independent adverse effect on survival in patients with CHF and both normal and reduced EF in both groups of patients.

Parental Warmth and Risks of Substance Use in Children with Attention-Deficit/Hyperactivity Disorder: Findings from a 10–12 Year Longitudinal Investigation

PubMed Central

Tandon, Mini; Tillman, Rebecca; Spitznagel, Edward; Luby, Joan

2013-01-01

Objective The study examined factors in the risk trajectory for Substance Use Disorder (SUD) over a 10–12 year period in children with ADHD. Method N=145 children between the ages of 7 and 16 with ADHD and healthy controls were assessed every 2 years for 10–12 years as part of a larger, longitudinal investigation. Onset of substance use disorder was examined using Cox proportional hazards modeling, and included child and parent psychopathology, and parental warmth as well as other key factors. Results Low paternal warmth and maternal SUD were predictors of SUD in n=59 ADHD participants after adjusting for gender, child ODD, paternal SUD, maternal/paternal ADHD, maternal/paternal major depressive disorder (MDD), maternal/paternal anxiety, and low maternal warmth in the Cox model. Conclusions Longitudinal study findings suggest that in addition to the established risk of ADHD and maternal SUD in development of child SUD, low paternal warmth is also associated with onset of SUD. This was evident after controlling for pertinent parent and child psychopathology. These findings suggest that paternal warmth warrants further investigation as a key target for novel interventions to prevent SUD in children with ADHD. More focused investigations examining paternal parenting factors in addition to parent and child psychopathology in the risk trajectory from ADHD to SUD are now warranted. PMID:24955084

Keeping data continuous when analyzing the prognostic impact of a tumor marker: an example with cathepsin D in breast cancer.

PubMed

Bossard, N; Descotes, F; Bremond, A G; Bobin, Y; De Saint Hilaire, P; Golfier, F; Awada, A; Mathevet, P M; Berrerd, L; Barbier, Y; Estève, J

2003-11-01

The prognostic value of cathepsin D has been recently recognized, but as many quantitative tumor markers, its clinical use remains unclear partly because of methodological issues in defining cut-off values. Guidelines have been proposed for analyzing quantitative prognostic factors, underlining the need for keeping data continuous, instead of categorizing them. Flexible approaches, parametric and non-parametric, have been proposed in order to improve the knowledge of the functional form relating a continuous factor to the risk. We studied the prognostic value of cathepsin D in a retrospective hospital cohort of 771 patients with breast cancer, and focused our overall survival analysis, based on the Cox regression, on two flexible approaches: smoothing splines and fractional polynomials. We also determined a cut-off value from the maximum likelihood estimate of a threshold model. These different approaches complemented each other for (1) identifying the functional form relating cathepsin D to the risk, and obtaining a cut-off value and (2) optimizing the adjustment for complex covariate like age at diagnosis in the final multivariate Cox model. We found a significant increase in the death rate, reaching 70% with a doubling of the level of cathepsin D, after the threshold of 37.5 pmol mg(-1). The proper prognostic impact of this marker could be confirmed and a methodology providing appropriate ways to use markers in clinical practice was proposed.

Parental Warmth and Risks of Substance Use in Children with Attention-Deficit/Hyperactivity Disorder: Findings from a 10-12 Year Longitudinal Investigation.

PubMed

Tandon, Mini; Tillman, Rebecca; Spitznagel, Edward; Luby, Joan

2014-06-01

The study examined factors in the risk trajectory for Substance Use Disorder (SUD) over a 10-12 year period in children with ADHD. N=145 children between the ages of 7 and 16 with ADHD and healthy controls were assessed every 2 years for 10-12 years as part of a larger, longitudinal investigation. Onset of substance use disorder was examined using Cox proportional hazards modeling, and included child and parent psychopathology, and parental warmth as well as other key factors. Low paternal warmth and maternal SUD were predictors of SUD in n=59 ADHD participants after adjusting for gender, child ODD, paternal SUD, maternal/paternal ADHD, maternal/paternal major depressive disorder (MDD), maternal/paternal anxiety, and low maternal warmth in the Cox model. Longitudinal study findings suggest that in addition to the established risk of ADHD and maternal SUD in development of child SUD, low paternal warmth is also associated with onset of SUD. This was evident after controlling for pertinent parent and child psychopathology. These findings suggest that paternal warmth warrants further investigation as a key target for novel interventions to prevent SUD in children with ADHD. More focused investigations examining paternal parenting factors in addition to parent and child psychopathology in the risk trajectory from ADHD to SUD are now warranted.

Transgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice.

PubMed

Kim, Joohwee; Vaish, Vivek; Feng, Mingxiao; Field, Kevin; Chatzistamou, Ioulia; Shim, Minsub

2016-10-07

Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders.

Role of phosphorylated extracellular signal-regulated kinase, calcitonin gene-related peptide and cyclooxygenase-2 in experimental rat models of migraine

PubMed Central

DONG, XIAOMENG; HU, YAOZHI; JING, LONG; CHEN, JINBO

2015-01-01

Although migraine is a common neurological condition, the pathomechanism is not yet fully understood. Activation of the trigeminovascular system (TVS) has an important function in this disorder and neurogenic inflammation and central sensitization are important mechanisms underlying this condition. Nitroglycerin (NTG) infusion in rats closely mimics a universally accepted human model of migraine. Electrical stimulation of the trigeminal ganglion (ESTG) of rats can also activate TVS during a migraine attack. Numerous studies have revealed that phosphorylated extracellular signal-regulated kinase (p-ERK), calcitonin gene-related peptide (CGRP) and cyclooxygenase-2 (COX-2) are involved in pain and nociceptive pathways. However, few studies have examined whether p-ERK, CGRP and COX-2 are involved in neurogenic inflammation and central sensitization. In the present study, the expression of p-ERK, CGRP and COX-2 was detected in the dura mater, trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis in NTG-induced rats and ESTG models by immunohistochemistry. The three areas considered were crucial components of the TVS. The selective COX-2 inhibitor nimesulide was used in ESTG rats to examine the association between p-ERK, CGRP and COX-2. The results demonstrated that p-ERK, CGRP and COX-2 mediated neurogenic inflammation and central sensitization in migraine. In addition, the expression of p-ERK and CGRP was attenuated by the COX-2 inhibitor. PMID:25892078

Indomethacin treatment prior to pentylenetetrazole-induced seizures downregulates the expression of il1b and cox2 and decreases seizure-like behavior in zebrafish larvae.

PubMed

Barbalho, Patrícia Gonçalves; Lopes-Cendes, Iscia; Maurer-Morelli, Claudia Vianna

2016-03-09

It has been demonstrated that the zebrafish model of pentylenetetrazole (PTZ)-evoked seizures and the well-established rodent models of epilepsy are similar pertaining to behavior, electrographic features, and c-fos expression. Although this zebrafish model is suitable for studying seizures, to date, inflammatory response after seizures has not been investigated using this model. Because a relationship between epilepsy and inflammation has been established, in the present study we investigated the transcript levels of the proinflammatory cytokines interleukin-1 beta (il1b) and cyclooxygenase-2 (cox2a and cox2b) after PTZ-induced seizures in the brain of zebrafish 7 days post fertilization. Furthermore, we exposed the fish to the nonsteroidal anti-inflammatory drug indomethacin prior to PTZ, and we measured its effect on seizure latency, number of seizure behaviors, and mRNA expression of il1b, cox2b, and c-fos. We used quantitative real-time PCR to assess the mRNA expression of il1b, cox2a, cox2b, and c-fos, and visual inspection was used to monitor seizure latency and the number of seizure-like behaviors. We found a short-term upregulation of il1b, and we revealed that cox2b, but not cox2a, was induced after seizures. Indomethacin treatment prior to PTZ-induced seizures downregulated the mRNA expression of il1b, cox2b, and c-fos. Moreover, we observed that in larvae exposed to indomethacin, seizure latency increased and the number of seizure-like behaviors decreased. This is the first study showing that il1b and cox-2 transcripts are upregulated following PTZ-induced seizures in zebrafish. In addition, we demonstrated the anticonvulsant effect of indomethacin based on (1) the inhibition of PTZ-induced c-fos transcription, (2) increase in seizure latency, and (3) decrease in the number of seizure-like behaviors. Furthermore, anti-inflammatory effect of indomethacin is clearly demonstrated by the downregulation of the mRNA expression of il1b and cox2b. Our results are supported by previous evidences suggesting that zebrafish is a suitable alternative for studying inflammation, seizures, and the effect of anti-inflammatory compounds on seizure suppression.

Simulation program for estimating statistical power of Cox's proportional hazards model assuming no specific distribution for the survival time.

PubMed

Akazawa, K; Nakamura, T; Moriguchi, S; Shimada, M; Nose, Y

1991-07-01

Small sample properties of the maximum partial likelihood estimates for Cox's proportional hazards model depend on the sample size, the true values of regression coefficients, covariate structure, censoring pattern and possibly baseline hazard functions. Therefore, it would be difficult to construct a formula or table to calculate the exact power of a statistical test for the treatment effect in any specific clinical trial. The simulation program, written in SAS/IML, described in this paper uses Monte-Carlo methods to provide estimates of the exact power for Cox's proportional hazards model. For illustrative purposes, the program was applied to real data obtained from a clinical trial performed in Japan. Since the program does not assume any specific function for the baseline hazard, it is, in principle, applicable to any censored survival data as long as they follow Cox's proportional hazards model.

Effects of Transferring to the Rehabilitation Ward on Long-Term Mortality Rate of First-Time Stroke Survivors: A Population-Based Study.

PubMed

Chen, Chien-Min; Yang, Yao-Hsu; Chang, Chia-Hao; Chen, Pau-Chung

2017-12-01

To assess the long-term health outcomes of acute stroke survivors transferred to the rehabilitation ward. Long-term mortality rates of first-time stroke survivors during hospitalization were compared among the following sets of patients: patients transferred to the rehabilitation ward, patients receiving rehabilitation without being transferred to the rehabilitation ward, and patients receiving no rehabilitation. Retrospective cohort study. Patients (N = 11,419) with stroke from 2005 to 2008 were initially assessed for eligibility. After propensity score matching, 390 first-time stroke survivors were included. None. Cox proportional hazards regression model was used to assess differences in 5-year poststroke mortality rates. Based on adjusted hazard ratios (HRs), the patients receiving rehabilitation without being transferred to the rehabilitation ward (adjusted HR, 2.20; 95% confidence interval [CI], 1.36-3.57) and patients receiving no rehabilitation (adjusted HR, 4.00; 95% CI, 2.55-6.27) had significantly higher mortality risk than the patients transferred to the rehabilitation ward. Mortality rate of the stroke survivors was affected by age ≥65 years (compared with age <45y; adjusted HR, 3.62), being a man (adjusted HR, 1.49), having ischemic stroke (adjusted HR, 1.55), stroke severity (Stroke Severity Index [SSI] score≥20, compared with SSI score<10; adjusted HR, 2.68), and comorbidity (Charlson-Deyo Comorbidity Index [CCI] score≥3, compared with CCI score=0; adjusted HR, 4.23). First-time stroke survivors transferred to the rehabilitation ward had a 5-year mortality rate 2.2 times lower than those who received rehabilitation without transfer to the rehabilitation ward and 4 times lower than those who received no rehabilitation. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Low-level laser therapy (LLLT) reduces the COX-2 mRNA expression in both subplantar and total brain tissues in the model of peripheral inflammation induced by administration of carrageenan.

PubMed

Prianti, Antonio Carlos Guimarães; Silva, José Antonio; Dos Santos, Regiane Feliciano; Rosseti, Isabela Bueno; Costa, Maricilia Silva

2014-07-01

In the classical model of edema formation and hyperalgesia induced by carrageenan administration in rat paw, the increase in prostaglandin E2 (PGE2) production in the central nervous system (CNS) contributes to the severity of the inflammatory and pain responses. Prostaglandins are generated by the cyclooxygenase (COX). There are two distinct COX isoforms, COX-1 and COX-2. In inflammatory tissues, COX-2 is greatly expressed producing proinflammatory prostaglandins (PGs). Low-level laser therapy (LLLT) has been used in the treatment of inflammatory pathologies, reducing both pain and acute inflammatory process. Herein we studied the effect of LLLT on both COX-2 and COX-1 messenger RNA (mRNA) expression in either subplantar or brain tissues taken from rats treated with carrageenan. The experiment was designed as follows: A1 (saline), A2 (carrageenan-0.5 mg/paw), A3 (carrageenan-0.5 mg/paw + LLLT), A4 (carrageenan-1.0 mg/paw), and A5 (carrageenan-1.0 mg/paw + LLLT). Animals from the A3 and A5 groups were irradiated at 1 h after carrageenan administration, using a diode laser with an output power of 30 mW and a wavelength of 660 nm. The laser beam covered an area of 0.785 cm(2), resulting in an energy dosage of 7.5 J/cm(2). Both COX-2 and COX-1 mRNAs were measured by RT-PCR. Six hours after carrageenan administration, COX-2 mRNA expression was significantly increased both in the subplantar (2.2-4.1-fold) and total brain (8.65-13.79-fold) tissues. COX-1 mRNA expression was not changed. LLLT (7.5 J/cm(2)) reduced significantly the COX-2 mRNA expression both in the subplantar (~2.5-fold) and brain (4.84-9.67-fold) tissues. The results show that LLLT is able to reduce COX-2 mRNA expression. It is possible that the mechanism of LLLT decreasing hyperalgesia is also related to its effect in reducing the COX-2 expression in the CNS.

Association of Fitness With Incident Dyslipidemias Over 25 Years in the Coronary Artery Risk Development in Young Adults Study.

PubMed

Sarzynski, Mark A; Schuna, John M; Carnethon, Mercedes R; Jacobs, David R; Lewis, Cora E; Quesenberry, Charles P; Sidney, Stephen; Schreiner, Pamela J; Sternfeld, Barbara

2015-11-01

Few studies have examined the longitudinal associations of fitness or changes in fitness on the risk of developing dyslipidemias. This study examined the associations of (1) baseline fitness with 25-year dyslipidemia incidence and (2) 20-year fitness change on dyslipidemia development in middle age in the Coronary Artery Risk Development in Young Adults Study (CARDIA). Multivariable Cox proportional hazards regression models were used to test the association of baseline fitness (1985-1986) with dyslipidemia incidence over 25 years (2010-2011) in CARDIA (N=4,898). Modified Poisson regression models were used to examine the association of 20-year change in fitness with dyslipidemia incidence between Years 20 and 25 (n=2,487). Data were analyzed in June 2014 and February 2015. In adjusted models, the risk of incident low high-density lipoprotein cholesterol (HDL-C); high triglycerides; and high low-density lipoprotein cholesterol (LDL-C) was significantly lower, by 9%, 16%, and 14%, respectively, for each 2.0-minute increase in baseline treadmill endurance. After additional adjustment for baseline trait level, the associations remained significant for incident high triglycerides and high LDL-C in the total population and for incident high triglycerides in both men and women. In race-stratified models, these associations appeared to be limited to whites. In adjusted models, change in fitness did not predict 5-year incidence of dyslipidemias, whereas baseline fitness significantly predicted 5-year incidence of high triglycerides. Our findings demonstrate the importance of cardiorespiratory fitness in young adulthood as a risk factor for developing dyslipidemias, particularly high triglycerides, during the transition to middle age. Copyright © 2015 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Association of Fitness With Incident Dyslipidemias Over 25 Years in the Coronary Artery Risk Development in Young Adults Study

PubMed Central

Sarzynski, Mark A.; Schuna, John M.; Carnethon, Mercedes R.; Jacobs, David R.; Lewis, Cora E.; Quesenberry, Charles P.; Sidney, Stephen; Schreiner, Pamela J.; Sternfeld, Barbara

2015-01-01

Introduction Few studies have examined the longitudinal associations of fitness or changes in fitness on the risk of developing dyslipidemias. This study examined the associations of: (1) baseline fitness with 25-year dyslipidemia incidence; and (2) 20-year fitness change on dyslipidemia development in middle age in the Coronary Artery Risk Development in young Adults (CARDIA) study. Methods Multivariable Cox proportional hazards regression models were used to test the association of baseline fitness (1985–1986) with dyslipidemia incidence over 25 years (2010–2011) in CARDIA (N=4,898). Modified Poisson regression models were used to examine the association of 20-year change in fitness with dyslipidemia incidence between Years 20 and 25 (n=2,487). Data were analyzed in June 2014 and February 2015. Results In adjusted models, the risk of incident low high-density lipoprotein cholesterol (HDL-C), high triglycerides, and high low-density lipoprotein cholesterol (LDL-C) was significantly lower, by 9%, 16%, and 14%, respectively, for each 2.0-minute increase in baseline treadmill endurance. After additional adjustment for baseline trait level, the associations remained significant for incident high triglycerides and high LDL-C in the total population and for incident high triglycerides in both men and women. In race-stratified models, these associations appeared to be limited to whites. In adjusted models, change in fitness did not predict 5-year incidence of dyslipidemias, whereas baseline fitness significantly predicted 5-year incidence of high triglycerides. Conclusions Our findings demonstrate the importance of cardiorespiratory fitness in young adulthood as a risk factor for developing dyslipidemias, particularly high triglycerides, during the transition to middle age. PMID:26165197

Long-term exposure to residential railway and road traffic noise and risk for diabetes in a Danish cohort.

PubMed

Roswall, Nina; Raaschou-Nielsen, Ole; Jensen, Steen Solvang; Tjønneland, Anne; Sørensen, Mette

2018-01-01

Road traffic noise exposure has been found associated with diabetes incidence. Evidence for an association between railway noise exposure is less clear, as large studies with detailed railway noise modelling are lacking. To investigate the association between residential railway noise and diabetes incidence, and to repeat previous analyses on road traffic noise and diabetes with longer follow-up time. Among 50,534 middle-aged Danes enrolled into the Diet, Cancer and Health cohort from 1993 to 97, we identified 5062 cases of incident diabetes during a median follow-up of 15.5 years. Present and historical residential addresses from 1987 to 2012 were found in national registries, and railway and road traffic noise (L den ) were modelled for all addresses, using the Nordic prediction method. We used Cox proportional hazard models to investigate the association between residential traffic noise over 1 and 5 years before diagnosis, and diabetes incidence. Hazard ratios (HRs) were calculated as crude and adjusted for potential confounders. We found no association between railway noise exposure and diabetes incidence among the 9527 persons exposed, regardless of exposure time-window: HR 0.99 (0.94-1.04) per 10dB for 5-year exposure in fully adjusted models. There was no effect modification by sex, road traffic noise, and education. We confirmed the previously found association between road traffic noise exposure and diabetes including 6 additional years of follow-up: HR 1.08 (1.04-1.13) per 10dB for 5-year exposure in fully adjusted models. The study does not suggest an association between residential railway noise exposure and diabetes incidence, but supports the finding of a direct association with residential road traffic noise. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of dynamic treatment regimes via inverse probability weighting.

PubMed

Hernán, Miguel A; Lanoy, Emilie; Costagliola, Dominique; Robins, James M

2006-03-01

Appropriate analysis of observational data is our best chance to obtain answers to many questions that involve dynamic treatment regimes. This paper describes a simple method to compare dynamic treatment regimes by artificially censoring subjects and then using inverse probability weighting (IPW) to adjust for any selection bias introduced by the artificial censoring. The basic strategy can be summarized in four steps: 1) define two regimes of interest, 2) artificially censor individuals when they stop following one of the regimes of interest, 3) estimate inverse probability weights to adjust for the potential selection bias introduced by censoring in the previous step, 4) compare the survival of the uncensored individuals under each regime of interest by fitting an inverse probability weighted Cox proportional hazards model with the dichotomous regime indicator and the baseline confounders as covariates. In the absence of model misspecification, the method is valid provided data are available on all time-varying and baseline joint predictors of survival and regime discontinuation. We present an application of the method to compare the AIDS-free survival under two dynamic treatment regimes in a large prospective study of HIV-infected patients. The paper concludes by discussing the relative advantages and disadvantages of censoring/IPW versus g-estimation of nested structural models to compare dynamic regimes.

Carotid Atherosclerosis Progression and Risk of Cardiovascular Events in a Community in Taiwan.

PubMed

Chen, Pei-Chun; Jeng, Jiann-Shing; Hsu, Hsiu-Ching; Su, Ta-Chen; Chien, Kuo-Liong; Lee, Yuan-Teh

2016-05-12

The authors investigated the association between progression of carotid atherosclerosis and incidence of cardiovascular disease in a community cohort in Taiwan. Data has rarely been reported in Asian populations. Study subjects were 1,398 participants who underwent ultrasound measures of common carotid artery intima-media thickness (IMT) and extracranial carotid artery plaque score at both 1994-1995 and 1999-2000 surveys. Cox proportional hazards model was used to assess the risk of incident cardiovascular disease. During a median follow-up of 13 years (1999-2013), 71 strokes and 68 coronary events occurred. The 5-year individual IMT change was not associated with development of cardiovascular events in unadjusted and adjusted models. Among subjects without plaque in 1994-1995, we observed elevated risk associated with presence of new plaque (plaque score >0 in 1999-2000) in a dose-response manner in unadjusted and age- and sex- adjusted models. The associations attenuated and became statistically non-significant after controlling for cardiovascular risk factors (hazard ratio [95% confidence interval] for plaque score >2 vs. 0: stroke, 1.61 [0.79-3.27], coronary events, 1.13 [0.48-2.69]). This study suggested that carotid plaque formation measured by ultrasound is associated increased risk of developing cardiovascular disease, and cardiovascular risk factors explain the associations to a large extent.

Squamous cell carcinoma of the breast in the United States: incidence, demographics, tumor characteristics, and survival.

PubMed

Yadav, Siddhartha; Yadav, Dhiraj; Zakalik, Dana

2017-07-01

Squamous cell carcinoma of breast accounts for less than 0.1% of all breast cancers. The purpose of this study is to describe the epidemiology and survival of this rare malignancy. Data were extracted from the National Cancer Institute's Surveillance, Epidemiology and End Results Registry to identify women diagnosed with squamous cell carcinoma of breast between 1998 and 2013. SEER*Stat 8.3.1 was used to calculate age-adjusted incidence, age-wise distribution, and annual percentage change in incidence. Kaplan-Meier curves were plotted for survival analysis. Univariate and multivariate Cox proportional hazard regression model was used to determine predictors of survival. A total of 445 cases of squamous cell carcinoma of breast were diagnosed during the study period. The median age of diagnosis was 67 years. The overall age-adjusted incidence between 1998 and 2013 was 0.62 per 1,000,000 per year, and the incidence has been on a decline. Approximately half of the tumors were poorly differentiated. Stage II was the most common stage at presentation. Majority of the cases were negative for expression of estrogen and progesterone receptor. One-third of the cases underwent breast conservation surgery while more than half of the cases underwent mastectomy (unilateral or bilateral). Approximately one-third of cases received radiation treatment. The 1-year and 5-year cause-specific survival was 81.6 and 63.5%, respectively. Excluding patient with metastasis or unknown stage at presentation, in multivariate Cox proportional hazard model, older age at diagnosis and higher tumor stage (T3 or T4) or nodal stage at presentation were significant predictors of poor survival. Our study describes the unique characteristics of squamous cell carcinoma of breast and demonstrates that it is an aggressive tumor with a poor survival. Older age and higher tumor or nodal stages at presentation were independent predictors of poor survival for loco-regional stages.

Impact of residual kidney function on hemodialysis adequacy and patient survival.

PubMed

Wang, Mengjing; Obi, Yoshitsugu; Streja, Elani; Rhee, Connie M; Chen, Jing; Hao, Chuanming; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

2018-04-23

Both dialysis dose and residual kidney function (RKF) contribute to solute clearance and are associated with outcomes in hemodialysis patients. We hypothesized that the association between dialysis dose and mortality is attenuated with greater RKF. Among 32 251 incident hemodialysis patients in a large US dialysis organization (2007-11), we examined the interaction between single-pool Kt/V (spKt/V) and renal urea clearance (rCLurea) levels in survival analyses using multivariable Cox proportional hazards regression model. The median rCLurea and mean baseline spKt/V were 3.06 [interquartile range (IQR) 1.74-4.85] mL/min/1.73 m2 and 1.32 ± 0.28, respectively. A total of 7444 (23%) patients died during the median follow-up of 1.2 years (IQR 0.5-2.2 years) with an incidence of 15.4 deaths per 100 patient-years. The Cox model with adjustment for case-mix and laboratory variables showed that rCLurea modified the association between spKt/V and mortality (Pinteraction = 0.03); lower spKt/V was associated with higher mortality among patients with low rCLurea (i.e. <3  mL/min/1.73 m2) but not among those with higher rCLurea. The adjusted mortality hazard ratios (aHRs) and 95% confidence intervals of the low (<1.2) versus high (≥1.2) spKt/V were 1.40 (1.12-1.74), 1.21 (1.10-1.33), 1.06 (0.98-1.14), and 1.00 (0.93-1.08) for patients with rCLurea of 0.0, 1.0, 3.0 and 6.0 mL/min/1.73 m2, respectively. Incident hemodialysis patients with substantial RKF do not exhibit the expected better survival at higher hemodialysis doses. RKF levels should be taken into account when deciding on the dose of dialysis treatment among incident hemodialysis patients.

Prevalence and Evolution of Renal Impairment in People Living With HIV in Rural Tanzania.

PubMed

Mapesi, Herry; Kalinjuma, Aneth V; Ngerecha, Alphonce; Franzeck, Fabian; Hatz, Christoph; Tanner, Marcel; Mayr, Michael; Furrer, Hansjakob; Battegay, Manuel; Letang, Emilio; Weisser, Maja; Glass, Tracy R

2018-04-01

We assessed the prevalence, incidence, and predictors of renal impairment among people living with HIV (PLWHIV) in rural Tanzania. In a cohort of PLWHIV aged ≥15 years enrolled from January 2013 to June 2016, we assessed the association between renal impairment (estimated glomerural filtration rate < 90 mL/min/1.73 m 2 ) at enrollment and during follow-up with demographic and clinical characteristcis using logistic regression and Cox proportional hazards models. Of 1093 PLWHIV, 172 (15.7%) had renal impairment at enrollment. Of 921 patients with normal renal function at baseline, 117 (12.7%) developed renal impairment during a median follow-up (interquartile range) of 6.2 (0.4-14.7) months. The incidence of renal impairment was 110 cases per 1000 person-years (95% confidence interval [CI], 92-132). At enrollment, logistic regression identified older age (adjusted odds ratio [aOR], 1.79; 95% CI, 1.52-2.11), hypertension (aOR, 1.84; 95% CI, 1.08-3.15), CD4 count <200 cells/mm 3 (aOR, 1.80; 95% CI, 1.23-2.65), and World Health Organization (WHO) stage III/IV (aOR, 3.00; 95% CI, 1.96-4.58) as risk factors for renal impairment. Cox regression model confirmed older age (adjusted hazard ratio [aHR], 1.85; 95% CI, 1.56-2.20) and CD4 count <200 cells/mm 3 (aHR, 2.05; 95% CI, 1.36-3.09) to be associated with the development of renal impairment. Our study found a low prevalence of renal impairment among PLWHIV despite high usage of tenofovir and its association with age, hypertension, low CD4 count, and advanced WHO stage. These important and reassuring safety data stress the significance of noncommunicable disease surveillance in aging HIV populations in sub-Saharan Africa.

Delivery of a very low birth weight infant and increased maternal risk of cancer and death: a population study with 16 years of follow-up.

PubMed

Grisaru-Granovsky, Sorina; Gordon, Ethel Sherry; Haklai, Ziona; Schimmel, Michael S; Drukker, Lior; Samueloff, Arnon; Keinan-Boker, Lital

2015-11-01

Pregnancy complications represent sentinel events for women's future health. We investigated whether delivery of a very low birth weight (VLBW) infant is associated with increased maternal risk for future incidence of maternal cancer and death. This is a population-based cohort study of linked Israeli Ministry of Health datasets between 1995 and 2011. Women delivering a live singleton <1,500 g infant (VLBW group) were compared with women delivering a live singleton, 3,000-3,500 g (control). The first pregnancy eligible for entry into the study, the "index pregnancy," reflected exposure status for each participant. Primary outcomes were maternal cancer and death. Cancer diagnoses were further classified by primary site. Cox regression models adjusted for follow-up period and maternal characteristics at index pregnancy: Age at delivery, ethnicity, years of education, marital status, and previous cancer afforded calculation of hazard ratios (HR) and 95% confidence intervals (CI). During the study period, 982,091 mothers with 2,243,736 live births were identified; of these, 13,773 births were VLBW eligible for inclusion in the study and 448,743 births were controls. Groups differed significantly by average follow-up and all maternal characteristics evaluated. Overall rate of cancers and death was significantly increased for VLBW women compared to controls: 18.4 versus 15.7% and 7.3 versus 3.2%, both p < 0.0001. The Cox model adjusted for maternal characteristics showed significantly increased risk of cancer (all sites) in the VLBW women: HR 1.18 (95% CI 1.02-1.37) and for death: HR 2.13 (95% CI 1.68-2.71), and an increased combined risk of both outcomes: HR 1.4 (95% CI 1.23-1.59). The delivery of a VLBW newborn is an independent lifetime risk factor for subsequent maternal cancers and death. These women may benefit from targeted cancer screening and counseling.

Identifying an Inciting Antigen Is Associated With Improved Survival in Patients With Chronic Hypersensitivity Pneumonitis

PubMed Central

Swigris, Jeffrey J.; Forssén, Anna V.; Tourin, Olga; Solomon, Joshua J.; Huie, Tristan J.; Olson, Amy L.; Brown, Kevin K.

2013-01-01

Background: The cornerstone of hypersensitivity pneumonitis (HP) management is having patients avoid the inciting antigen (IA). Often, despite an exhaustive search, an IA cannot be found. The objective of this study was to examine whether identifying the IA impacts survival in patients with chronic HP. Methods: We used the Kaplan-Meier method to display, and the log-rank test to compare, survival curves of patients with well-characterized chronic HP stratified on identification of an IA exposure. A Cox proportional hazards (PH) model was used to identify independent predictors in time-to-death analysis. Results: Of 142 patients, 67 (47%) had an identified IA, and 75 (53%) had an unidentified IA. Compared with survivors, patients who died (n = 80, 56%) were older, more likely to have smoked, had lower total lung capacity % predicted and FVC % predicted, had higher severity of dyspnea, were more likely to have pulmonary fibrosis, and were less likely to have an identifiable IA. In a Cox PH model, the inability to identify an IA (hazard ratio [HR], 1.76; 95% CI, 1.01-3.07), older age (HR, 1.04; 95% CI, 1.01-1.07), the presences of pulmonary fibrosis (HR, 2.43; 95% CI, 1.36-4.35), a lower FVC% (HR, 1.36; 95% CI, 1.10-1.68), and a history of smoking (HR, 2.01; 95% C1, 1.15-3.50) were independent predictors of shorter survival. After adjusting for mean age, presence of fibrosis, mean FVC%, mean diffusing capacity of the lung for carbon monoxide (%), and history of smoking, survival was longer for patients with an identified IA exposure than those with an unidentified IA exposure (median, 8.75 years vs 4.88 years; P = .047). Conclusions: Among patients with chronic HP, when adjusting for a number of potentially influential predictors, including the presence of fibrosis, the inability to identify an IA was independently associated with shortened survival. PMID:23828161

Dipeptidyl Peptidase-4 Inhibitor Use is Associated with Decreased Risk of Fracture in Patients with Type 2 Diabetes: A Population-Based Cohort Study.

PubMed

Hou, Wen-Hsuan; Chang, Kai-Cheng; Li, Chung-Yi; Ou, Huang-Tz

2018-05-16

To investigate the putative link between dipeptidyl peptidase-4 inhibitor (DPP-4i) use and the risk of fracture in patients with type 2 diabetes. This propensity-score-matched population-based cohort study was performed between 2009 and 2013 on patients with type 2 diabetes who were stable metformin users. A total of 3,996 patients with type 2 diabetes used DPP-4i as a second-line antidiabetic drug. The same number of matched non-DPP-4i users were followed up until fracture occurrence, health insurance policy termination, or the end of 2013. The incidence rates of overall and cause-specific fractures were estimated based on the Poisson assumption. A multiple Cox proportional hazard model was used to estimate the covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) to determine the association between DPP-4i use and overall and cause-specific fractures stratified by age and sex. Over a maximum follow-up period of 5 years, 340 DPP-4i users and 419 non-DPP-4i users were newly diagnosed with fractures, yielding incidence rates of 28.03 and 32.04 per 1,000 people per year, respectively. The Cox proportional hazard model revealed that DPP-4i use significantly reduced the risk of all-cause fractures and upper extremity fractures, with adjusted HRs of 0.86 (95% CI: 0.74-0.99) and 0.75 (95% CI: 0.59-0.95), respectively. The aforementioned associations of DDP-4i use with fracture were sustained across sex and age stratifications. The results of this study supported the premise that DPP-4i usage is associated with a reduced risk of all-cause fractures and upper extremity fractures in patients with type 2 diabetes. This article is protected by copyright. All rights reserved.

Risk of Nonfatal Stroke in Type 2 Diabetes Mellitus Patients: A Retrospective Comparison Between Disease Management Programs and Standard Care

PubMed Central

Wiefarn, Stefan; Heumann, Christian; Rettelbach, Anja; Kostev, Karel

2017-01-01

Objective: The present retrospective study examines the influence of disease management programs on nonfatal stroke in type 2 diabetes mellitus (T2DM) patients in Germany. Methods: The evaluation is based on retrospective patient data from the Disease Analyzer (IMS Health). The analysis included 169 414 T2DM patients aged 40 years and older with an initial prescription of antihyperglycemic therapy between January 2004 and December 2014. A total of 86 713 patients participated in a disease management program (DMP) for T2DM and 82 701 patients received standard care. The main outcome measure of this study was nonfatal stroke. Kaplan-Meier curves of DMP and SC patients were compared using log rank test. The Cox proportional hazards model was used to provide an adjusted estimate of the DMP effect. Results: It is apparent from the baseline characteristics that the general health of patients receiving standard care was poorer than that of patients participating in a DMP. The baseline HbA1c value was 7.6% in the DMP group and 7.8% in the SC group. Furthermore, the SC group had a higher proportion of preexisting conditions, such as coronary heart disease (CHD), peripheral arterial occlusive disease (pAOD), and renal insufficiency. The proportion of patients who received insulin in first year therapy was higher in the SC group. Time to event analysis showed that DMP was associated with a delayed occurrence of stroke, because stroke occurred an average of 350 days later in DMP patients than in patients receiving SC (DMP: 1.216 days, RV: 866 days). The Cox model with covariable adjustment confirmed the significant association of DMPs with nonfatal stroke in patients with type 2 diabetes mellitus (HR 0.71; 95% CI: 0.69-0.74). Conclusion: The present study indicates that DMPs are positively associated with stroke. The possible reasons for this must be verified in further studies. PMID:28300432

Risk of Nonfatal Stroke in Type 2 Diabetes Mellitus Patients: A Retrospective Comparison Between Disease Management Programs and Standard Care.

PubMed

Wiefarn, Stefan; Heumann, Christian; Rettelbach, Anja; Kostev, Karel

2017-07-01

The present retrospective study examines the influence of disease management programs on nonfatal stroke in type 2 diabetes mellitus (T2DM) patients in Germany. The evaluation is based on retrospective patient data from the Disease Analyzer (IMS Health). The analysis included 169 414 T2DM patients aged 40 years and older with an initial prescription of antihyperglycemic therapy between January 2004 and December 2014. A total of 86 713 patients participated in a disease management program (DMP) for T2DM and 82 701 patients received standard care. The main outcome measure of this study was nonfatal stroke. Kaplan-Meier curves of DMP and SC patients were compared using log rank test. The Cox proportional hazards model was used to provide an adjusted estimate of the DMP effect. It is apparent from the baseline characteristics that the general health of patients receiving standard care was poorer than that of patients participating in a DMP. The baseline HbA1c value was 7.6% in the DMP group and 7.8% in the SC group. Furthermore, the SC group had a higher proportion of preexisting conditions, such as coronary heart disease (CHD), peripheral arterial occlusive disease (pAOD), and renal insufficiency. The proportion of patients who received insulin in first year therapy was higher in the SC group. Time to event analysis showed that DMP was associated with a delayed occurrence of stroke, because stroke occurred an average of 350 days later in DMP patients than in patients receiving SC (DMP: 1.216 days, RV: 866 days). The Cox model with covariable adjustment confirmed the significant association of DMPs with nonfatal stroke in patients with type 2 diabetes mellitus (HR 0.71; 95% CI: 0.69-0.74). The present study indicates that DMPs are positively associated with stroke. The possible reasons for this must be verified in further studies.

Utilization of Body Contouring Procedures Following Weight Loss Surgery: A Study of 37,806 Patients.

PubMed

Altieri, Maria S; Yang, Jie; Park, Jihye; Novikov, David; Kang, Lijuan; Spaniolas, Konstantinos; Bates, Andrew; Talamini, Mark; Pryor, Aurora

2017-11-01

Bariatric surgery has substantial health benefits; however, some patients desire body contouring (BC) procedures following rapid weight loss. There is a paucity of data regarding the true rate of BC following bariatric procedures. The purpose of our study is to examine the utilization of two common procedures, abdominoplasty, and panniculectomy, following bariatric surgery in New York State. The SPARCS longitudinal administrative database was used to identify bariatric procedures by using ICD-9 and CPT codes between 2004 and 2010. Procedures included sleeve gastrectomy, Roux-en-Y gastric bypass, and laparoscopic adjustable gastric banding. Using a unique patient identifier, we tracked those patients who subsequently underwent either abdominoplasty or panniculectomy with at least a 4-year follow-up (until 2014). Multivariable Cox proportional hazard model was used to evaluate predictors of follow-up BC surgery. 37,806 patients underwent bariatric surgery between 2004 and 2010. Only 5.58% (n = 2112) of these patients subsequently had a BC procedure, with 143 of them (6.8%) having ≥1 plastic surgery. The average time to plastic surgery after band, bypass, or sleeve was 1134.83 ± 671.09, 984.70 ± 570.53, and 903.02 ± 497.31 days, respectively (P < 0.0001). Following the multivariable Cox proportional hazard model, a female, SG patients, patients with Medicare or Medicaid, and patients in either <20 or >80%ile in yearly income were more likely to have plastic surgery after adjusting for age, race/ethnicity, comorbidities and complications (P values < 0.0001). This study shows that plastic surgery is completed by only 6% of patients following bariatric procedures. As insurance and income are associated with pursuing surgery, improved access may increase the number of patients who are able to undergo these reconstructive procedures.

Hypertension Control in Adults With Diabetes Mellitus and Recurrent Cardiovascular Events: Global Results From the Trial Evaluating Cardiovascular Outcomes With Sitagliptin.

PubMed

Navar, Ann Marie; Gallup, Dianne S; Lokhnygina, Yuliya; Green, Jennifer B; McGuire, Darren K; Armstrong, Paul W; Buse, John B; Engel, Samuel S; Lachin, John M; Standl, Eberhard; Van de Werf, Frans; Holman, Rury R; Peterson, Eric D

2017-11-01

Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan-Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP ≥140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ≈130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91-1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02-1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function. © 2017 American Heart Association, Inc.

Differences in Colorectal Cancer Outcomes by Race and Insurance.

PubMed

Tawk, Rima; Abner, Adrian; Ashford, Alicestine; Brown, Clyde Perry

2015-12-22

Colorectal cancer (CRC) is the second most common cancer among African American women and the third most common cancer for African American men. The mortality rate from CRC is highest among African Americans compared to any other racial or ethnic group. Much of the disparity in mortality is likely due to diagnosis at later stages of the disease, which could result from unequal access to screening. The purpose of this study is to determine the impact of race and insurance status on CRC outcomes among CRC patients. Data were drawn from the Surveillance, Epidemiology, and End Results database. Logistic regressions models were used to examine the odds of receiving treatment after adjusting for insurance, race, and other variables. Cox proportional hazard models were used to measure the risk of CRC death after adjusting for sociodemographic and tumor characteristics when associating race and insurance with CRC-related death. Blacks were diagnosed at more advanced stages of disease than whites and had an increased risk of death from both colon and rectal cancers. Lacking insurance was associated with an increase in CRC related-deaths. Findings from this study could help profile and target patients with the greatest disparities in CRC health outcomes.

Impact of Neighborhood Socioeconomic Conditions on the Risk of Stroke in Japan

PubMed Central

Honjo, Kaori; Iso, Hiroyasu; Nakaya, Tomoki; Hanibuchi, Tomoya; Ikeda, Ai; Inoue, Manami; Sawada, Norie; Tsugane, Shoichiro

2015-01-01

Background Neighborhood deprivation has been shown in many studies to be an influential factor in cardiovascular disease risk. However, no previous studies have examined the effect of neighborhood socioeconomic conditions on the risk of stroke in Asian countries. Methods This study investigated whether neighborhood deprivation was associated with the risk of stroke and stroke death using data from the Japan Public Health Center-based Prospective Study. We calculated the adjusted hazard ratios of stroke mortality (mean follow-up, 16.4 years) and stroke incidence (mean follow-up, 15.4 years) according to the area deprivation index (ADI) among 90 843 Japanese men and women aged 40–69 years. A Cox proportional-hazard regression model using a shared frailty model was applied. Results The adjusted hazard ratios of stroke incidence, in order of increasing deprivation with reference to the least deprived area, were 1.16 (95% CI, 1.04–1.29), 1.12 (95% CI, 1.00–1.26), 1.18 (95% CI, 1.02–1.35), and 1.19 (95% CI, 1.01–1.41), after adjustment for individual socioeconomic conditions. Behavioral and psychosocial factors attenuated the association, but the association remained significant. The associations were explained by adjusting for biological cardiovascular risk factors. No significant association with stroke mortality was identified. Conclusions Our results indicate that the neighborhood deprivation level influences stroke incidence in Japan, suggesting that area socioeconomic conditions could be a potential target for public health intervention to reduce the risk of stroke. PMID:25757802

Tobacco smoking and alcohol drinking at diagnosis of head and neck cancer and all-cause mortality: Results from head and neck 5000, a prospective observational cohort of people with head and neck cancer.

PubMed

Beynon, Rhona A; Lang, Samantha; Schimansky, Sarah; Penfold, Christopher M; Waylen, Andrea; Thomas, Steven J; Pawlita, Michael; Tim Waterboer; Martin, Richard M; May, Margaret; Ness, Andy R

2018-04-01

Tobacco smoking and alcohol consumption are well-established risk factors for head and neck cancer. The prognostic role of smoking and alcohol intake at diagnosis have been less well studied. We analysed 1,393 people prospectively enrolled into the Head and Neck 5000 study (oral cavity cancer, n=403; oropharyngeal cancer, n=660; laryngeal cancer, n=330) and followed up for a median of 3.5 years. The primary outcome was all-cause mortality. We used Cox proportional hazard models to derive minimally adjusted (age and gender) and fully adjusted (age, gender, ethnicity, stage, comorbidity, body mass index, HPV status, treatment, education, deprivation index, income, marital status, and either smoking or alcohol use) mortality hazard ratios (HR) for the effects of smoking status and alcohol intake at diagnosis. Models were stratified by cancer site, stage and HPV status. The fully-adjusted HR for current versus never-smokers was 1.7 overall (95% confidence interval [CI] 1.1, 2.6). In stratified analyses, associations of smoking with mortality were observed for oropharyngeal and laryngeal cancers (fully adjusted HRs for current smokers: 1.8 (95% CI=0.9, 3.40 and 2.3 (95% CI=0.8, 6.4)). We found no evidence that people who drank hazardous to harmful amounts of alcohol at diagnosis had a higher mortality risk compared to non-drinkers (HR=1.2 (95% CI=0.9, 1.6)). There was no strong evidence that HPV status or tumour stage modified the association of smoking with survival. Smoking status at the time of a head and neck cancer diagnosis influenced all-cause mortality in models adjusted for important prognostic factors. © 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Behavioural disorders in 6-year-old children and pyrethroid insecticide exposure: the PELAGIE mother-child cohort.

PubMed

Viel, Jean-François; Rouget, Florence; Warembourg, Charline; Monfort, Christine; Limon, Gwendolina; Cordier, Sylvaine; Chevrier, Cécile

2017-03-01

The potential impact of environmental exposure to pyrethroid insecticides on child neurodevelopment has only just started to receive attention despite their widespread use. We investigated the associations between prenatal and childhood exposure to pyrethroid insecticides and behavioural skills in 6-year-olds. The PELAGIE cohort enrolled 3421 pregnant women from Brittany, France between 2002 and 2006. 428 mothers were randomly selected for the study when their children turned 6, and 287 (67%) agreed to participate. Children's behaviour was assessed using the Strengths and Difficulties Questionnaire (SDQ). Three subscales (prosocial behaviour, internalising disorders and externalising disorders) were considered. Five pyrethroid metabolites were measured in maternal and child urine samples collected between 6 and 19 gestational weeks and at 6 years of age, respectively. Logistic regression and reverse-scale Cox regression models were used to estimate the associations between SDQ scores and urinary pyrethroid metabolite concentrations, adjusting for organophosphate metabolite concentrations and potential confounders. Increased prenatal cis -3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA) concentrations were associated with internalising difficulties (Cox p value=0.05). For childhood 3-phenoxybenzoic acid (PBA) concentrations, a positive association was observed with externalising difficulties (Cox p value=0.04) and high ORs were found for abnormal or borderline social behaviour (OR 2.93, 95% CI 1.27 to 6.78, and OR 1.91, 95% CI 0.80 to 4.57, for the intermediate and highest metabolite categories, respectively). High childhood trans -DCCA concentrations were associated with reduced externalising disorders (Cox p value=0.03). The present study suggests that exposure to certain pyrethroids, at environmental levels, may negatively affect neurobehavioral development by 6 years of age. 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/.

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.

Compensatory Hypertrophy Induced by Ventricular Cardiomyocyte Specific COX-2 Expression in Mice

PubMed Central

Streicher, John M.; Kamei, Kenichiro; Ishikawa, Tomo-o; Herschman, Harvey; Wang, Yibin

2010-01-01

Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases, due to the finding that highly specific COX-2 inhibitors (i.e. Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact heart remains to be determined. We report here the development of a transgenic mouse model, using a loxP-Cre approach, that displays robust COX-2 overexpression and subsequent prostaglandin synthesis specifically in ventricular myocytes. Histological, functional and molecular analyses showed that ventricular myocyte specific COX-2 overexpression led to cardiac hypertrophy and fetal gene marker activation, but with preserved cardiac function. Therefore, specific induction of COX-2 and prostaglandin in vivo is sufficient to induce compensated hypertrophy and molecular remodeling. PMID:20170663

COX-2 and Prostate Cancer Angiogenesis

DTIC Science & Technology

2001-03-01

the optimal dosing and timing of a COX-2 inhibitor (NS398) in an animal model of human prostate cancer, (2)and (3) the mechanisms underlying the...cancer tissues (14) and that a COX-2 inhibitor selectively induces apoptosis in a prostate cancer cell line (15). We also demonstrated that treatment of...human prostate tumor-bearing mice with a selective COX-2 inhibitor (NS-398) significantly reduces tumor size, microvessel density and levels of a

Targeting Estrogen-Induced COX-2 Activity in Lymphangioleiomyomatosis (LAM)

DTIC Science & Technology

2014-12-01

production was also increased in TSC2-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had...increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of...inhibit COX-2 pharmacologically, we treated TSC2-deficient cells with aspirin or NS398, and found that both agents reduced COX-2 protein levels and

Birth by Caesarean Section and the Risk of Adult Psychosis: A Population-Based Cohort Study.

PubMed

O'Neill, Sinéad M; Curran, Eileen A; Dalman, Christina; Kenny, Louise C; Kearney, Patricia M; Clarke, Gerard; Cryan, John F; Dinan, Timothy G; Khashan, Ali S

2016-05-01

Despite the biological plausibility of an association between obstetric mode of delivery and psychosis in later life, studies to date have been inconclusive. We assessed the association between mode of delivery and later onset of psychosis in the offspring. A population-based cohort including data from the Swedish National Registers was used. All singleton live births between 1982 and 1995 were identified (n= 1,345,210) and followed-up to diagnosis at age 16 or later. Mode of delivery was categorized as: unassisted vaginal delivery (VD), assisted VD, elective Caesarean section (CS) (before onset of labor), and emergency CS (after onset of labor). Outcomes included any psychosis; nonaffective psychoses (including schizophrenia only) and affective psychoses (including bipolar disorder only and depression with psychosis only). Cox regression analysis was used reporting partially and fully adjusted hazard ratios (HR) with 95% confidence intervals (CI). Sibling-matched Cox regression was performed to adjust for familial confounding factors. In the fully adjusted analyses, elective CS was significantly associated with any psychosis (HR 1.13, 95% CI 1.03, 1.24). Similar findings were found for nonaffective psychoses (HR 1.13, 95% CI 0.99, 1.29) and affective psychoses (HR 1.17, 95% CI 1.05, 1.31) (χ(2)for heterogeneityP= .69). In the sibling-matched Cox regression, this association disappeared (HR 1.03, 95% CI 0.78, 1.37). No association was found between assisted VD or emergency CS and psychosis. This study found that elective CS is associated with an increase in offspring psychosis. However, the association did not persist in the sibling-matched analysis, implying the association is likely due to familial confounding by unmeasured factors such as genetics or environment. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation.

PubMed

Burnett, B P; Jia, Q; Zhao, Y; Levy, R M

2007-09-01

A mixed extract containing two naturally occurring flavonoids, baicalin from Scutellaria baicalensis and catechin from Acacia catechu, was tested for cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibition via enzyme, cellular, and in vivo models. The 50% inhibitory concentration for inhibition of both ovine COX-1 and COX-2 peroxidase enzyme activities was 15 microg/mL, while the mixed extract showed a value for potato 5-LOX enzyme activity of 25 microg/mL. Prostaglandin E2 generation was inhibited by the mixed extract in human osteosarcoma cells expressing COX-2, while leukotriene production was inhibited in both human cell lines, immortalized THP-1 monocyte and HT-29 colorectal adenocarcinoma. In an arachidonic acid-induced mouse ear swelling model, the extract decreased edema in a dose-dependent manner. When arachidonic acid was injected directly into the intra-articular space of mouse ankle joints, the mixed extract abated the swelling and restored function in a rotary drum walking model. These results suggest that this natural, flavonoid mixture acts via "dual inhibition" of COX and LOX enzymes to reduce production of pro-inflammatory eicosanoids and attenuate edema in an in vivo model of inflammation.

Effect of a community intervention programme promoting social interactions on functional disability prevention for older adults: propensity score matching and instrumental variable analyses, JAGES Taketoyo study.

PubMed

Hikichi, Hiroyuki; Kondo, Naoki; Kondo, Katsunori; Aida, Jun; Takeda, Tokunori; Kawachi, Ichiro

2015-09-01

The efficacy of promoting social interactions to improve the health of older adults is not fully established due to residual confounding and selection bias. The government of Taketoyo town, Aichi Prefecture, Japan, developed a resident-centred community intervention programme called 'community salons', providing opportunities for social interactions among local older residents. To evaluate the impact of the programme, we conducted questionnaire surveys for all older residents of Taketoyo. We carried out a baseline survey in July 2006 (prior to the introduction of the programme) and assessed the onset of functional disability during March 2012. We analysed the data of 2421 older people. In addition to the standard Cox proportional hazard regression, we conducted Cox regression with propensity score matching (PSM) and an instrumental variable (IV) analysis, using the number of community salons within a radius of 350 m from the participant's home as an instrument. In the 5 years after the first salon was launched, the salon participants showed a 6.3% lower incidence of functional disability compared with non-participants. Even adjusting for sex, age, equivalent income, educational attainment, higher level activities of daily living and depression, the Cox adjusted HR for becoming disabled was 0.49 (95% CI 0.33 to 0.72). Similar results were observed using PSM (HR 0.52, 95% CI 0.33 to 0.83) and IV-Cox analysis (HR 0.50, 95% CI 0.34 to 0.74). A community health promotion programme focused on increasing social interactions among older adults may be effective in preventing the onset of disability. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Shoulder surgery in the beach chair position is associated with diminished cerebral autoregulation but no differences in postoperative cognition or brain injury biomarker levels compared with supine positioning: the anesthesia patient safety foundation beach chair study.

PubMed

Laflam, Andrew; Joshi, Brijen; Brady, Kenneth; Yenokyan, Gayane; Brown, Charles; Everett, Allen; Selnes, Ola; McFarland, Edward; Hogue, Charles W

2015-01-01

Although controversial, failing to consider the gravitational effects of head elevation on cerebral perfusion is speculated to increase susceptibility to rare, but devastating, neurologic complications after shoulder surgery in the beach chair position (BCP). We hypothesized that patients in the BCP have diminished cerebral blood flow autoregulation than those who undergo surgery in the lateral decubitus position (LDP). A secondary aim was to examine whether there is a relationship between patient positioning during surgery and postoperative cognition or serum brain injury biomarker levels. Patients undergoing shoulder surgery in the BCP (n = 109) or LDP (n = 109) had mean arterial blood pressure (MAP) and regional cerebral oxygen saturation (rScO2) monitored with near-infrared spectroscopy. A continuous, moving Pearson correlation coefficient was calculated between MAP and rScO2, generating the variable cerebral oximetry index (COx). When MAP is in the autoregulated range, COx approaches zero because there is no correlation between cerebral blood flow and arterial blood pressure. In contrast, when MAP is below the limit of autoregulation, COx is higher because there is a direct relationship between lower arterial blood pressure and lower cerebral blood flow. Thus, diminished autoregulation would be manifest as higher COx. Psychometric testing was performed before surgery and then 7 to 10 days and 4 to 6 weeks after surgery. A composite cognitive outcome was determined as the Z-score. Serum S100β, neuron-specific enolase, and glial fibrillary acidic protein were measured at baseline, after surgery, and on postoperative day 1. After adjusting for age and history of hypertension, COx (P = 0.035) was higher and rScO2 lower (P < 0.0001) in the BCP group than in the LDP group. After adjusting for baseline composite cognitive outcome, there was no difference in Z-score 7 to 10 days (P = 0.530) or 4 to 6 weeks (P = 0.202) after surgery between the BCP and the LDP groups. There was no difference in serum biomarker levels between the 2 position groups : Compared with patients in the LDP, patients undergoing shoulder surgery in the BCP are more likely to have higher COx indicating diminished cerebral autoregulation and lower rScO2. There were no differences in the composite cognitive outcome between the BCP and the LDP groups after surgery after accounting for baseline Z-score.

Generating a Multiphase Equation of State with Swarm Intelligence

NASA Astrophysics Data System (ADS)

Cox, Geoffrey

2017-06-01

Hydrocode calculations require knowledge of the variation of pressure of a material with density and temperature, which is given by the equation of state. An accurate model needs to account for discontinuities in energy, density and properties of a material across a phase boundary. When generating a multiphase equation of state the modeller attempts to balance the agreement between the available data for compression, expansion and phase boundary location. However, this can prove difficult because minor adjustments in the equation of state for a single phase can have a large impact on the overall phase diagram. Recently, Cox and Christie described a method for combining statistical-mechanics-based condensed matter physics models with a stochastic analysis technique called particle swarm optimisation. The models produced show good agreement with experiment over a wide range of pressure-temperature space. This talk details the general implementation of this technique, shows example results, and describes the types of analysis that can be performed with this method.

Comparative efficacy of oral meloxicam and phenylbutazone in 2 experimental pain models in the horse

PubMed Central

Banse, Heidi; Cribb, Alastair E.

2017-01-01

The efficacy of oral phenylbutazone [PBZ; 4.4 mg/kg body weight (BW), q12h], a non-selective non-steroidal anti-inflammatory drug (NSAID), and oral meloxicam (MXM; 0.6 mg/kg BW, q24h), a COX-2 selective NSAID, were evaluated in 2 experimental pain models in horses: the adjustable heart bar shoe (HBS) model, primarily representative of mechanical pain, and the lipopolysaccharide-induced synovitis (SYN) model, primarily representative of inflammatory pain. In the HBS model, PBZ reduced multiple indicators of pain compared with the placebo and MXM. Meloxicam did not reduce indicators of pain relative to the placebo. In the SYN model, MXM and PBZ reduced increases in carpal skin temperature compared to the placebo. Meloxicam reduced lameness scores and lameness-induced changes in head movement compared to the placebo and PBZ. Phenylbutazone reduced lameness-induced change in head movement compared to the placebo. Overall, PBZ was more effective than MXM at reducing pain in the HBS model, while MXM was more effective at reducing pain in the SYN model at the oral doses used. PMID:28216685

Unilateral robotic hybrid mini-maze: a novel experimental approach.

PubMed

Moslemi, Mohammad; Rawashdeh, Badi; Meyer, Mark; Nguyen, Duy; Poston, Robert; Gharagozloo, Farid

2016-03-01

A complete Cox maze IV procedure is difficult to accomplish using current endoscopic and minimally invasive techniques. These techniques are hampered by inability to adequately dissect the posterior structures of the heart and place all necessary lesions. We present a novel approach, using robotic technology, that achieves placement of all the lesions of the complete maze procedure. In three cadaveric human models, the technical feasibility of using robotic instruments through the right chest to dissect the posterior structures of the heart and place all Cox maze lesions was performed. The entire posterior aspect of the heart was dissected in the cadaveric model facilitating successful placement of all Cox maze IV lesions with robotic assistance through minimally invasive incisions. The robotic Cox maze IV procedure through the novel right thoracic approach is feasible. This obviates the need for sternotomy and avoids the associated morbidity of the conventional Cox-maze procedure. Copyright © 2015 John Wiley & Sons, Ltd.

In vitro enantioselective pharmacodynamics of Carprofen and Flunixin-meglumine in feedlot cattle.

PubMed

Miciletta, M; Cuniberti, B; Barbero, R; Re, G

2014-02-01

The activity of the anti-inflammatory agents Flunixin-meglumine (FLU), RS (±) Carprofen (CPF) and S (+) CPF on bovine cyclooxygenases (COXs) has been characterized in feedlot calves using an in vitro whole blood model. The drugs showed equivalent efficacy in their inhibitory activity on COXs, and the rank order of potency for both COX-1 and COX-2 inhibition was FLU > S (+) CPF > RS (±) CPF. Our results indicated that FLU is a nonselective inhibitor of bovine COXs, whereas RS (±) CPF and S (+) CPF exhibited different degrees of preferential inhibition of COX-2 isoenzyme. The rank order of IC50 COX-1: IC50 COX-2 potency ratios was in fact S (+) CPF (51.882) > RS (±) CPF (13.964) > FLU (0.606), and the calculated percentage inhibition of COX-1 corresponding to COX-2 inhibition values comprised between 80% and 95% was comprised between 57.697 and 79.865 for FLU, 33.373 and 51.319 for RS (±) CPF, and 0.230 and 4.622 for S (+) CPF, respectively. These findings are discussed in relation to the prediction of the clinical relevance of COX inhibition by the test drugs in cattle. © 2013 John Wiley & Sons Ltd.

Comparative cardiovascular safety of nonsteroidal anti-inflammatory drugs in patients with hypertension: a population-based cohort study.

PubMed

Dong, Yaa-Hui; Chang, Chia-Hsuin; Wu, Li-Chiu; Hwang, Jing-Shiang; Toh, Sengwee

2018-05-01

Previous studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with higher cardiovascular risks. However, few have been active comparison studies that directly assessed the potential differential cardiovascular risk between NSAID classes or across individual NSAIDs. We compared the risk of major cardiovascular events between cyclooxygenase 2 (COX-2)-selective and nonselective NSAIDs in patients with hypertension. We conducted a cohort study of patients with hypertension who initiated COX-2-selective or nonselective NSAIDs in a population-based Taiwanese database. The outcomes included hospitalization for the following major cardiovascular events: ischaemic stroke, acute myocardial infarction, congestive heart failure, transient ischaemic attack, unstable angina or coronary revascularization. We followed patients for up to 4 weeks, based on the as-treated principle. We used inverse probability weighting to control for baseline and time-varying covariates, and estimated the on-treatment hazard ratios (HRs) and 95% conservative confidence interval (CIs). We identified 2749 eligible COX-2-selective NSAID users and 52 880 eligible nonselective NSAID users. The HR of major cardiovascular events comparing COX-2-selective with nonselective NSAIDs after adjusting for baseline and time-varying covariates was 1.07 (95% CI 0.65, 1.74). We did not observe a differential risk when comparing celecoxib to diclofenac (HR 1.17; 95% CI 0.61, 2.25), ibuprofen (HR 1.36; 95% CI 0.58, 3.18) or naproxen (HR 0.75; 95% CI 0.23, 2.44). There was an increased risk with COX-2-selective NSAIDs, however, when comparing COX-2-selective NSAIDs with mefenamic acid (HR 2.11; 95% CI 1.09, 4.09). Our results provide important information about the comparative cardiovascular safety of NSAIDs in patients with hypertension. © 2018 The British Pharmacological Society.

A stratification approach using logit-based models for confounder adjustment in the study of continuous outcomes.

PubMed

Tan, Chuen Seng; Støer, Nathalie C; Chen, Ying; Andersson, Marielle; Ning, Yilin; Wee, Hwee-Lin; Khoo, Eric Yin Hao; Tai, E-Shyong; Kao, Shih Ling; Reilly, Marie

2017-01-01

The control of confounding is an area of extensive epidemiological research, especially in the field of causal inference for observational studies. Matched cohort and case-control study designs are commonly implemented to control for confounding effects without specifying the functional form of the relationship between the outcome and confounders. This paper extends the commonly used regression models in matched designs for binary and survival outcomes (i.e. conditional logistic and stratified Cox proportional hazards) to studies of continuous outcomes through a novel interpretation and application of logit-based regression models from the econometrics and marketing research literature. We compare the performance of the maximum likelihood estimators using simulated data and propose a heuristic argument for obtaining the residuals for model diagnostics. We illustrate our proposed approach with two real data applications. Our simulation studies demonstrate that our stratification approach is robust to model misspecification and that the distribution of the estimated residuals provides a useful diagnostic when the strata are of moderate size. In our applications to real data, we demonstrate that parity and menopausal status are associated with percent mammographic density, and that the mean level and variability of inpatient blood glucose readings vary between medical and surgical wards within a national tertiary hospital. Our work highlights how the same class of regression models, available in most statistical software, can be used to adjust for confounding in the study of binary, time-to-event and continuous outcomes.

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

PubMed

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

2010-01-01

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

Famine Exposure in the Young and the Risk of Type 2 Diabetes in Adulthood

PubMed Central

van Abeelen, Annet F.M.; Elias, Sjoerd G.; Bossuyt, Patrick M.M.; Grobbee, Diederick E.; van der Schouw, Yvonne T.; Roseboom, Tessa J.; Uiterwaal, Cuno S.P.M.

2012-01-01

The developmental origins hypothesis proposes that undernutrition during early development is associated with an increased type 2 diabetes risk in adulthood. We investigated the association between undernutrition during childhood and young adulthood and type 2 diabetes in adulthood. We studied 7,837 women from Prospect-EPIC (European Prospective Investigation Into Cancer and Nutrition) who were exposed to the 1944–1945 Dutch famine when they were between age 0 and 21 years. We used Cox proportional hazards regression models to explore the effect of famine on the risk of subsequent type 2 diabetes in adulthood. We adjusted for potential confounders, including age at famine exposure, smoking, and level of education. Self-reported famine exposure during childhood and young adulthood was associated with an increased type 2 diabetes risk in a dose-dependent manner. In those who reported moderate famine exposure, the age-adjusted type 2 diabetes hazard ratio (HR) was 1.36 (95% CI [1.09–1.70]); in those who reported severe famine exposure, the age-adjusted HR was 1.64 (1.26–2.14) relative to unexposed women. These effects did not change after adjustment for confounders. This study provides the first direct evidence, using individual famine exposure data, that a short period of moderate or severe undernutrition during postnatal development increases type 2 diabetes risk in adulthood. PMID:22648386

Cox Proportional Hazards Models for Modeling the Time to Onset of Decompression Sickness in Hypobaric Environments

NASA Technical Reports Server (NTRS)

Thompson, Laura A.; Chhikara, Raj S.; Conkin, Johnny

2003-01-01

In this paper we fit Cox proportional hazards models to a subset of data from the Hypobaric Decompression Sickness Databank. The data bank contains records on the time to decompression sickness (DCS) and venous gas emboli (VGE) for over 130,000 person-exposures to high altitude in chamber tests. The subset we use contains 1,321 records, with 87% censoring, and has the most recent experimental tests on DCS made available from Johnson Space Center. We build on previous analyses of this data set by considering more expanded models and more detailed model assessments specific to the Cox model. Our model - which is stratified on the quartiles of the final ambient pressure at altitude - includes the final ambient pressure at altitude as a nonlinear continuous predictor, the computed tissue partial pressure of nitrogen at altitude, and whether exercise was done at altitude. We conduct various assessments of our model, many of which are recently developed in the statistical literature, and conclude where the model needs improvement. We consider the addition of frailties to the stratified Cox model, but found that no significant gain was attained above a model that does not include frailties. Finally, we validate some of the models that we fit.

Drug-Eluting Stents versus Bare-Metal Stents in Taiwanese Patients with Acute Coronary Syndrome: An Outcome Report of a Multicenter Registry

PubMed Central

Lai, Chi-Cheng; Yip, Hon-Kan; Lin, Tsung-Hsien; Wu, Chiung-Jen; Lai, Wen-Ter; Liu, Chun-Peng; Chang, Shu-Chen; Mar, Guang-Yuan

2014-01-01

Background The study aims to compare cardiovascular outcomes of using bare-metal stents (BMS) and drug-eluting stents (DES) in patients with acute coronary syndrome (ACS) through analysis of the database from the Taiwan ACS registry. Large domestic studies comparing outcomes of interventional strategies using DES and BMS in a Taiwanese population with ACS are limited. Methods and Results Collected data regarding characteristics and cardiovascular outcomes from the registry database were compared between the BMS and DES groups. A Cox regression model was used in an unadjusted or adjusted manner for analysis. Baseline characteristics apparently varied between DES group (n = 650) and BMS group (n = 1672) such as ACS types, Killip’s classifications, or coronary blood flows. Compared with the BMS group, the DES group was associated with significantly lower cumulative incidence of all-cause mortality (3.4% vs. 5.8%, p = 0.008), target vessel revascularization (TVR) (5.2% vs. 7.4%, p = 0.035), or major adverse cardiac events (MACE) (10.2% vs. 15.6%, p < 0.001) at 1 year in a real-world setting. Cox regression analysis showed the BMS group referenced as the DES group had significantly higher risk-adjusted total mortality [hazard ratio (HR) = 1.85, p = 0.026], target vessel revascularization (TVR) (HR = 1.59, p = 0.035), and MACE (HR = 1.68, p = 0.001). Conclusions The data show use of DES over BMS provided advantages to patients with ACS in terms of lower 1-year mortality, TVR, and MACE. The study suggests implantation of DES compared with BMS in Taiwanese patients with ACS is safe and beneficial in the real-world setting. PMID:27122834

Is schizophrenia associated with an increased risk of chronic kidney disease? A nationwide matched-cohort study.

PubMed

Tzeng, Nian-Sheng; Hsu, Yung-Ho; Ho, Shinn-Ying; Kuo, Yu-Ching; Lee, Hua-Chin; Yin, Yun-Ju; Chen, Hong-An; Chen, Wen-Liang; Chu, William Cheng-Chung; Huang, Hui-Ling

2015-01-27

The impact of schizophrenia on vital diseases, such as chronic kidney disease (CKD), has not as yet been verified. This study aims to establish whether there is an association between schizophrenia and CKD. A nationwide matched cohort study. Taiwan's National Health Insurance Research Database. A total of 2338 patients with schizophrenia, and 7014 controls without schizophrenia (1:3), matched cohort for sex, age group, geography, urbanisation and monthly income, between 1 January 2003 and 31 December 2007, based on the International Classifications of Disease Ninth Edition (ICD-9), Clinical Modification codes. After making adjustments for confounding risk factors, a Cox proportional hazards model was used to compare the risk of developing CKD during a 3-year follow-up period from the index date. Of the 2338-subject case cohort, 163 (6.97%) developed a CKD, as did 365 (5.20%) of the 7014 control participants. Cox proportional hazards regression analysis revealed that patients with schizophrenia were more likely to develop CKD (HR=1.36, 95% CI 1.13 to 1.63; p<0.001). After adjusting for gender, age group, hypertension, diabetes mellitus, hyperlipidaemia, heart disease and non-steroid anti-inflammatory drugs (NSAIDs) usage, the HR for patients with schizophrenia was 1.25 (95% CI 1.04 to 1.50; p<0.05). Neither typical nor atypical antipsychotics was associated an increased risk of CKD in patients with schizophrenia. The findings from this population-based retrospective cohort study suggest that schizophrenia is associated with a 25% increase in the risk of developing CKD within only a 3-year follow-up period. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Inability to access addiction treatment predicts injection initiation among street-involved youth in a Canadian setting.

PubMed

DeBeck, Kora; Kerr, Thomas; Nolan, Seonaid; Dong, Huiru; Montaner, Julio; Wood, Evan

2016-01-06

Preventing injection drug use among vulnerable youth is critical for reducing serious drug-related harms. Addiction treatment is one evidence-based intervention to decrease problematic substance use; however, youth frequently report being unable to access treatment services and the impact of this on drug use trajectories remains largely unexplored. This study examines the relationship between being unable to access addiction treatment and injection initiation among street-involved youth. Data were derived from the At-Risk Youth Study (ARYS), a prospective cohort of street-involved youth aged 14-26 who use illicit drugs, from September 2005 to May 2014. An extended Cox model with time-dependent variables was used to identify factors independently associated with injection initiation. Among 462 participants who were injection naïve at baseline, 97 (21 %) initiated injection drug use over study follow-up and 129 (28 %) reported trying but being unable to access addiction treatment in the previous 6 months at some point during the study period. The most frequently reported reason for being unable to access treatment was being put on a wait list. In a multivariable Cox regression analysis, being unable to access addiction treatment remained independently associated with a more rapid rate of injection initiation (Adjusted Hazard Ratio =2.02; 95 % Confidence Interval: 1.12-3.62), after adjusting for potential confounders. Inability to access addiction treatment was common among our sample and associated with injection initiation. Findings highlight the need for easily accessible, evidence-based addiction treatment for high-risk youth as a means to prevent injection initiation and subsequent serious drug-related harms.

The relationship of age-adjusted Charlson comorbidity ındex and diurnal variation of blood pressure.

PubMed

Kalaycı, Belma; Erten, Yunus Turgay; Akgün, Tunahan; Karabag, Turgut; Kokturk, Furuzan

2018-03-05

Charlson Comorbidity index (CCI) is a scoring system to predict prognosis and mortality. It exhibits better utility when combined with age, age-adjusted Charlson Comorbidity Index (ACCI). The aim of this study was to evaluate the relationship between ACCI and diurnal variation of blood pressure parameters in hypertensive patients and normotensive patients. We enrolled 236 patients. All patients underwent a 24-h ambulatory blood pressure monitoring (ABPM) for evaluation of dipper or non-dipper pattern. We searched the correlation between ACCI and dipper or non-dipper pattern and other ABPM parameters. To further investigate the role of these parameters in predicting survival, a multivariate analysis using the Cox proportional hazard model was performed. 167 patients were in the hypertensive group (87 patients in non-dipper status) and 69 patients were in the normotensive group (41 patients in non-dipper status) of all study patients. We found a significant difference and negative correlation between AACI and 24-h diastolic blood pressure (DBP), awake DBP, awake mean blood pressure (MBP) and 24-h MBP and awake systolic blood pressure(SBP). Night decrease ratio of blood pressure had also a negative correlation with ACCI (p = 0.003, r = -0.233). However, we found a relationship with non-dipper pattern and ACCI in the hypertensive patients (p = 0.050). In multivariate Cox analysis sleep MBP was found related to mortality like ACCI (p = 0.023, HR = 1.086, %95 CI 1.012-1.165) Conclusion: ACCI was statistically significantly higher in non-dipper hypertensive patients than dipper hypertensive patients while ACCI had a negative correlation with blood pressure. Sleep MBP may predict mortality.

The effect of anti-rheumatic medications for coronary artery diseases risk in patients with rheumatoid arthritis might be changed over time: A nationwide population-based cohort study

PubMed Central

Lin, Lichi; Chen, Chyong-Mei; Chiou, Jeng-Yuan; Wang, Yu-Hsun; Wang, Paul Yung-Pou; Wei, James Cheng-Chung

2017-01-01

Objectives To determine whether anti-rheumatic drug usage is associated with risk of coronary artery diseases (CAD) in incident Rheumatoid Arthritis (RA) patients. Methods Data were obtained from the Taiwan National Health Insurance Research Database. The study cohort comprised 6260 patients who were newly diagnosed with RA between 2001–2010. The study endpoint was occurrence of CAD according to the ICD-9-CM codes. We used the WHO Defined Daily Dose (DDD) as a tool to assess the drugs exposure. The Cox proportional hazards regression model was used to estimate the hazard ratio (HR) of disease after controlling for demographic and other co-morbidities. When the proportionality assumption is violated, a spline curve of the Scaled Schoenfeld residuals is fitted to demonstrate the estimated effect on CAD over time for drug usage. Results Among RA patients, use of celecoxib, and etoricoxib was associated with significantly decreased incidence of CAD. The adjusted HR(95% CI) of CAD for low-dose celecoxib (DDD≦1) and high-dose user were 0.47(0.34, 0.65) and 0.37(0.24, 0.58) during the 4 year follow-up time; however, it became 0.98(0.70, 1.37) and1.29(0.85, 1.95). Adjusted HR(95% CI) of CAD for etoricoxib users remained 0.47(0.26, 0.84). Conclusions This study revealed association of decreased CAD risk in RA patients taking 2 different kinds of COX-2i in comparison with nonusers. The effect might be changed over time, after about 4 years. PMID:28658301

Intradermal and virosomal influenza vaccines for preventing influenza hospitalization in the elderly during the 2011-2012 influenza season: a comparative effectiveness study using the Valencia health care information system.

PubMed

Puig-Barberà, J; Natividad-Sancho, A; Calabuig-Pérez, J; Lluch-Rodrigo, J A; Pastor-Villalba, E; Martínez-Úbeda, S; Díez-Domingo, J

2014-09-22

The use of intradermal vaccination or virosomal vaccines could increase protection against influenza among the vulnerable population of older adults. Studies assessing the comparative effectiveness of these two influenza vaccine types in this age group are lacking. We conducted a retrospective cohort study to estimate the comparative effectiveness of intradermal seasonal trivalent-influenza vaccine (TIV) delivered by a microneedle injection system and a virosomal-TIV intramuscularly delivered for prevention of influenza hospitalization in non-institutionalized adults aged ≥65 years. We obtained administrative data on immunization status and influenza hospitalization for the 2011-2012 influenza season, and used Cox regression models to assess comparative effectiveness. We estimated crude and adjusted (age, sex, comorbidity, pharmaceutical claims, recent pneumococcal vaccination and number of hospitalizations for all causes other than influenza between the previous and current influenza seasons) hazard ratios (HR). Overall, 164,021 vaccinated subjects were evaluated. There were 127 hospitalizations for influenza among 62,058 subjects, contributing 914,740 person-weeks at risk in the virosomal-TIV group, and 133 hospitalizations for influenza among 101,963 subjects, contributing 1,504,570 person-weeks at risk in the intradermal-TIV group. The crude HR of intradermal-TIV relative to virosomal-TIV was 0.64 (95% confidence interval (CI): 0.50-0.81), and the adjusted Cox estimated HR was 0.67 (95% CI: 0.52-0.85). During the 2011-2012 influenza season the risk of hospitalization for influenza was reduced by 33% in non-institutionalized elderly adults who were vaccinated with intradermal-TIV compared with virosomal-TIV. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Bayesian dynamic regression models for interval censored survival data with application to children dental health.

PubMed

Wang, Xiaojing; Chen, Ming-Hui; Yan, Jun

2013-07-01

Cox models with time-varying coefficients offer great flexibility in capturing the temporal dynamics of covariate effects on event times, which could be hidden from a Cox proportional hazards model. Methodology development for varying coefficient Cox models, however, has been largely limited to right censored data; only limited work on interval censored data has been done. In most existing methods for varying coefficient models, analysts need to specify which covariate coefficients are time-varying and which are not at the time of fitting. We propose a dynamic Cox regression model for interval censored data in a Bayesian framework, where the coefficient curves are piecewise constant but the number of pieces and the jump points are covariate specific and estimated from the data. The model automatically determines the extent to which the temporal dynamics is needed for each covariate, resulting in smoother and more stable curve estimates. The posterior computation is carried out via an efficient reversible jump Markov chain Monte Carlo algorithm. Inference of each coefficient is based on an average of models with different number of pieces and jump points. A simulation study with three covariates, each with a coefficient of different degree in temporal dynamics, confirmed that the dynamic model is preferred to the existing time-varying model in terms of model comparison criteria through conditional predictive ordinate. When applied to a dental health data of children with age between 7 and 12 years, the dynamic model reveals that the relative risk of emergence of permanent tooth 24 between children with and without an infected primary predecessor is the highest at around age 7.5, and that it gradually reduces to one after age 11. These findings were not seen from the existing studies with Cox proportional hazards models.

Derivation of the linear-logistic model and Cox's proportional hazard model from a canonical system description.

PubMed

Voit, E O; Knapp, R G

1997-08-15

The linear-logistic regression model and Cox's proportional hazard model are widely used in epidemiology. Their successful application leaves no doubt that they are accurate reflections of observed disease processes and their associated risks or incidence rates. In spite of their prominence, it is not a priori evident why these models work. This article presents a derivation of the two models from the framework of canonical modeling. It begins with a general description of the dynamics between risk sources and disease development, formulates this description in the canonical representation of an S-system, and shows how the linear-logistic model and Cox's proportional hazard model follow naturally from this representation. The article interprets the model parameters in terms of epidemiological concepts as well as in terms of general systems theory and explains the assumptions and limitations generally accepted in the application of these epidemiological models.

Lifetime comorbidities between phobic disorders and major depression in Japan: Results from the World Mental Health Japan 2002-2004 Survey

PubMed Central

Tsuchiya, Masao; Kawakami, Norito; Ono, Yutaka; Nakane, Yoshibumi; Nakamura, Yosikazu; Tachimori, Hisateru; Iwata, Noboru; Uda, Hidenori; Nakane, Hideyuki; Watanabe, Makoto; Naganuma, Yoichi; Furukawa, Toshiaki A.; Hata, Yukihiro; Kobayashi, Masayo; Miyake, Yuko; Takeshima, Tadashi; Kikkawa, Takehiko; Kessler, Ronald C.

2013-01-01

Background Although often considered of minor significance in themselves, evidence exists that early-onset phobic disorders might be predictors of later more serious disorders, such as major depressive disorder (MDD). The purpose of this study was to investigate the association of phobic disorders with the onset of MDD in the community in Japan. Methods Data from the World Mental Health Japan 2002-2004 Survey were analyzed. A total of 2,436 community residents aged 20 and older were interviewed using the WHO Composite International Diagnostic Interview 3.0 (response rate, 58.4%). A Cox proportional hazards model was used to predict the onset of MDD as a function of prior history of DSM-IV specific phobia, agoraphobia, or social phobia, adjusting for gender, birth cohort, other anxiety disorders, education, and marital status at survey. Results Social phobia was strongly associated with the subsequent onset of MDD (hazard ratio [HR] = 4.1 [95%CI: 2.0-8.7]) after adjusting for sex, birth cohort, and the number of other anxiety disorders. The association between agoraphobia or specific phobia and MDD was not statistically significant after adjusting for these variables. Conclusions Social phobia is a powerful predictor of the subsequent first onset of MDD in Japan. While this finding argues against a simple neurobiological model and in favor of a model in which the cultural meanings of phobia play a part in promoting MDD, an elucidation of causal pathways will require more fine-grained comparative research. PMID:19195005

Higher Serum Direct Bilirubin Levels Were Associated with a Lower Risk of Incident Chronic Kidney Disease in Middle Aged Korean Men

PubMed Central

Ryu, Seungho; Chang, Yoosoo; Zhang, Yiyi; Woo, Hee-Yeon; Kwon, Min-Jung; Park, Hyosoon; Lee, Kyu-Beck; Son, Hee Jung; Cho, Juhee; Guallar, Eliseo

2014-01-01

Background The association between serum bilirubin levels and incident chronic kidney disease (CKD) in the general population is unknown. We aimed to examine the association between serum bilirubin concentration (total, direct, and indirect) and the risk of incident CKD. Methods and Findings Longitudinal cohort study of 12,823 Korean male workers 30 to 59 years old without CKD or proteinuria at baseline participating in medical health checkup program in a large worksite. Study participants were followed for incident CKD from 2002 through 2011. Estimated glomerular filtration rate (eGFR) was estimated by using the CKD-EPI equation. CKD was defined as eGFR <60 mL/min per 1.73 m2. Parametric Cox models and pooled logistic regression models were used to estimate adjusted hazard ratios for incident CKD. We observed 238 incident cases of CKD during 70,515.8 person-years of follow-up. In age-adjusted models, the hazard ratios for CKD comparing quartiles 2–4 vs. quartile 1 of serum direct bilirubin were 0.93 (95% CI 0.67–1.28), 0.88 (0.60–1.27) and 0.60 (0.42–0.88), respectively. In multivariable models, the adjusted hazard ratio for CKD comparing the highest to the lowest quartile of serum direct bilirubin levels was 0.60 (95% CI 0.41–0.87; P trend = 0.01). Neither serum total nor indirect bilirubin levels were significantly associated with the incidence of CKD. Conclusions Higher serum direct bilirubin levels were significantly associated with a lower risk of developing CKD, even adjusting for a variety of cardiometabolic parameters. Further research is needed to elucidate the mechanisms underlying this association and to establish the role of serum direct bilirubin as a marker for CKD risk. PMID:24586219

Prevalent digoxin use and subsequent risk of death or hospitalization in ambulatory heart failure patients with a reduced ejection fraction-Findings from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized controlled trial.

PubMed

Ambrosy, Andrew P; Bhatt, Ankeet S; Stebbins, Amanda L; Wruck, Lisa M; Fudim, Marat; Greene, Stephen J; Kraus, William E; O'Connor, Christopher M; Piña, Ileana L; Whellan, David J; Mentz, Robert J

2018-05-01

Despite more than 200 years of clinical experience and a pivotal trial, recently published research has called into question the safety and efficacy of digoxin therapy in heart failure (HF). HF-ACTION (ClinicalTrials.gov Number: NCT00047437) enrolled 2331 outpatients with HF and an EF ≤35% between April 2003 and February 2007 and randomized them to aerobic exercise training versus usual care. Patients were grouped according to prevalent digoxin status at baseline. The association between digoxin therapy and outcomes was assessed using Cox proportional hazard and inverse-probability weighted (IPW) regression models adjusted for demographics, medical history, medications, laboratory values, quality of life, and exercise parameters. The prevalence of digoxin therapy decreased from 52% during the first 6 months of enrollment to 35% at the end of the HF-ACTION trial (P <0.0001). Study participants were 59± 13 years of age, 72% were male, and approximately half had an ischemic etiology of HF. Patients receiving digoxin at baseline tended to be younger and were more likely to report New York Heart Association functional class III/IV symptoms (rather than class II) compared to those not receiving digoxin. Patients taking digoxin had worse baseline exercise capacity as measured by peak VO 2 and 6-min walk test and greater impairments in health status as reflected by the Kansas City Cardiomyopathy Questionnaire. The association between digoxin and the risk of death or hospitalization differed depending on whether Cox proportional hazard (Hazard Ratio 1.03, 95% Confidence Interval 0.92-1.16; P = .62) or IPW regression models (HR 1.08, 95% CI 1.00-1.17; P = .057) were used to adjust for potential confounders. Although digoxin use was associated with high-risk clinical features, the association between digoxin therapy and outcomes was dependent on the statistical methods used for multivariable adjustment. Clinical equipoise exists and additional prospective research is required to clarify the role of digoxin in contemporary clinical practice including its effects on functional capacity, quality of life, and long-term outcomes. Copyright © 2018. Published by Elsevier Inc.

77 FR 62263 - Investigations Regarding Eligibility to Apply for Worker Adjustment Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-12

... and Training Administration, U.S. Department of Labor, Room N-5428, 200 Constitution Avenue NW., Washington, DC 20210. Signed at Washington, DC, this 3rd day of October 2012. Elliott S. Kushner, Certifying... Electronics & Safety Kokomo, IN 09/24/12 09/20/12 (Company). 81992 Cox Media Group Ohio, Dayton, OH 09/24/12...

Accounting for individual differences and timing of events: estimating the effect of treatment on criminal convictions in heroin users

PubMed Central

2014-01-01

Background The reduction of crime is an important outcome of opioid maintenance treatment (OMT). Criminal intensity and treatment regimes vary among OMT patients, but this is rarely adjusted for in statistical analyses, which tend to focus on cohort incidence rates and rate ratios. The purpose of this work was to estimate the relationship between treatment and criminal convictions among OMT patients, adjusting for individual covariate information and timing of events, fitting time-to-event regression models of increasing complexity. Methods National criminal records were cross linked with treatment data on 3221 patients starting OMT in Norway 1997–2003. In addition to calculating cohort incidence rates, criminal convictions was modelled as a recurrent event dependent variable, and treatment a time-dependent covariate, in Cox proportional hazards, Aalen’s additive hazards, and semi-parametric additive hazards regression models. Both fixed and dynamic covariates were included. Results During OMT, the number of days with criminal convictions for the cohort as a whole was 61% lower than when not in treatment. OMT was associated with reduced number of days with criminal convictions in all time-to-event regression models, but the hazard ratio (95% CI) was strongly attenuated when adjusting for covariates; from 0.40 (0.35, 0.45) in a univariate model to 0.79 (0.72, 0.87) in a fully adjusted model. The hazard was lower for females and decreasing with older age, while increasing with high numbers of criminal convictions prior to application to OMT (all p < 0.001). The strongest predictors were level of criminal activity prior to entering into OMT, and having a recent criminal conviction (both p < 0.001). The effect of several predictors was significantly time-varying with their effects diminishing over time. Conclusions Analyzing complex observational data regarding to fixed factors only overlooks important temporal information, and naïve cohort level incidence rates might result in biased estimates of the effect of interventions. Applying time-to-event regression models, properly adjusting for individual covariate information and timing of various events, allows for more precise and reliable effect estimates, as well as painting a more nuanced picture that can aid health care professionals and policy makers. PMID:24886472

Evaluating cardiovascular mortality in type 2 diabetes patients: an analysis based on competing risks Markov chains and additive regression models.

PubMed

Rosato, Rosalba; Ciccone, G; Bo, S; Pagano, G F; Merletti, F; Gregori, D

2007-06-01

Type 2 diabetes represents a condition significantly associated with increased cardiovascular mortality. The aims of the study are: (i) to estimate the cumulative incidence function for cause-specific mortality using Cox and Aalen model; (ii) to describe how the prediction of cardiovascular or other causes mortality changes for patients with different pattern of covariates; (iii) to show if different statistical methods may give different results. Cox and Aalen additive regression model through the Markov chain approach, are used to estimate the cause-specific hazard for cardiovascular or other causes mortality in a cohort of 2865 type 2 diabetic patients without insulin treatment. The models are compared in the estimation of the risk of death for patients of different severity. For younger patients with a better covariates profile, the Cumulative Incidence Function estimated by Cox and Aalen model was almost the same; for patients with the worst covariates profile, models gave different results: at the end of follow-up cardiovascular mortality rate estimated by Cox and Aalen model was 0.26 [95% confidence interval (CI) = 0.21-0.31] and 0.14 (95% CI = 0.09-0.18). Standard Cox and Aalen model capture the risk process for patients equally well with average profiles of co-morbidities. The Aalen model, in addition, is shown to be better at identifying cause-specific risk of death for patients with more severe clinical profiles. This result is relevant in the development of analytic tools for research and resource management within diabetes care.

Elevated pulmonary artery systolic pressure predicts heart failure admissions in African Americans: Jackson Heart Study.

PubMed

Choudhary, Gaurav; Jankowich, Matthew; Wu, Wen-Chih

2014-07-01

Although elevated pulmonary artery systolic pressure (PASP) is associated with heart failure (HF), whether PASP measurement can help predict future HF admissions is not known, especially in African Americans who are at increased risk for HF. We hypothesized that elevated PASP is associated with increased risk of HF admission and improves HF prediction in African American population. We conducted a longitudinal analysis using the Jackson Heart Study cohort (n=3125; 32.2% men) with baseline echocardiography-derived PASP and follow-up for HF admissions. Hazard ratio for HF admission was estimated using Cox proportional hazard model adjusted for variables in the Atherosclerosis Risk in Community (ARIC) HF prediction model. During a median follow-up of 3.46 years, 3.42% of the cohort was admitted for HF. Subjects with HF had a higher PASP (35.6±11.4 versus 27.6±6.9 mm Hg; P<0.001). The hazard of HF admission increased with higher baseline PASP (adjusted hazard ratio per 10 mm Hg increase in PASP: 2.03; 95% confidence interval, 1.67-2.48; adjusted hazard ratio for highest [≥33 mm Hg] versus lowest quartile [<24 mm Hg] of PASP: 2.69; 95% confidence interval, 1.43-5.06) and remained significant irrespective of history of HF or preserved/reduced ejection fraction. Addition of PASP to the ARIC model resulted in a significant improvement in model discrimination (area under the curve=0.82 before versus 0.84 after; P=0.03) and improved net reclassification index (11-15%) using PASP as a continuous or dichotomous (cutoff=33 mm Hg) variable. Elevated PASP predicts HF admissions in African Americans and may aid in early identification of at-risk subjects for aggressive risk factor modification. © 2014 American Heart Association, Inc.

Adjusting for multiple prognostic factors in the analysis of randomised trials

PubMed Central

2013-01-01

Background When multiple prognostic factors are adjusted for in the analysis of a randomised trial, it is unclear (1) whether it is necessary to account for each of the strata, formed by all combinations of the prognostic factors (stratified analysis), when randomisation has been balanced within each stratum (stratified randomisation), or whether adjusting for the main effects alone will suffice, and (2) the best method of adjustment in terms of type I error rate and power, irrespective of the randomisation method. Methods We used simulation to (1) determine if a stratified analysis is necessary after stratified randomisation, and (2) to compare different methods of adjustment in terms of power and type I error rate. We considered the following methods of analysis: adjusting for covariates in a regression model, adjusting for each stratum using either fixed or random effects, and Mantel-Haenszel or a stratified Cox model depending on outcome. Results Stratified analysis is required after stratified randomisation to maintain correct type I error rates when (a) there are strong interactions between prognostic factors, and (b) there are approximately equal number of patients in each stratum. However, simulations based on real trial data found that type I error rates were unaffected by the method of analysis (stratified vs unstratified), indicating these conditions were not met in real datasets. Comparison of different analysis methods found that with small sample sizes and a binary or time-to-event outcome, most analysis methods lead to either inflated type I error rates or a reduction in power; the lone exception was a stratified analysis using random effects for strata, which gave nominal type I error rates and adequate power. Conclusions It is unlikely that a stratified analysis is necessary after stratified randomisation except in extreme scenarios. Therefore, the method of analysis (accounting for the strata, or adjusting only for the covariates) will not generally need to depend on the method of randomisation used. Most methods of analysis work well with large sample sizes, however treating strata as random effects should be the analysis method of choice with binary or time-to-event outcomes and a small sample size. PMID:23898993

Cancer Survival Estimates Due to Non-Uniform Loss to Follow-Up and Non-Proportional Hazards

PubMed

K M, Jagathnath Krishna; Mathew, Aleyamma; Sara George, Preethi

2017-06-25

Background: Cancer survival depends on loss to follow-up (LFU) and non-proportional hazards (non-PH). If LFU is high, survival will be over-estimated. If hazard is non-PH, rank tests will provide biased inference and Cox-model will provide biased hazard-ratio. We assessed the bias due to LFU and non-PH factor in cancer survival and provided alternate methods for unbiased inference and hazard-ratio. Materials and Methods: Kaplan-Meier survival were plotted using a realistic breast cancer (BC) data-set, with >40%, 5-year LFU and compared it using another BC data-set with <15%, 5-year LFU to assess the bias in survival due to high LFU. Age at diagnosis of the latter data set was used to illustrate the bias due to a non-PH factor. Log-rank test was employed to assess the bias in p-value and Cox-model was used to assess the bias in hazard-ratio for the non-PH factor. Schoenfeld statistic was used to test the non-PH of age. For the non-PH factor, we employed Renyi statistic for inference and time dependent Cox-model for hazard-ratio. Results: Five-year BC survival was 69% (SE: 1.1%) vs. 90% (SE: 0.7%) for data with low vs. high LFU respectively. Age (<45, 46-54 & >54 years) was a non-PH factor (p-value: 0.036). However, survival by age was significant (log-rank p-value: 0.026), but not significant using Renyi statistic (p=0.067). Hazard ratio (HR) for age using Cox-model was 1.012 (95%CI: 1.004 -1.019) and the same using time-dependent Cox-model was in the other direction (HR: 0.997; 95% CI: 0.997- 0.998). Conclusion: Over-estimated survival was observed for cancer with high LFU. Log-rank statistic and Cox-model provided biased results for non-PH factor. For data with non-PH factors, Renyi statistic and time dependent Cox-model can be used as alternate methods to obtain unbiased inference and estimates. Creative Commons Attribution License

Cell-type-specific roles for COX-2 in UVB-induced skin cancer

PubMed Central

Herschman, Harvey

2014-01-01

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2 flox/flox mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2 flox/flox;K14Cre + mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2 flox/flox;K14Cre + papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2 flox/flox; LysMCre + myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID:24469308

Cell-type-specific roles for COX-2 in UVB-induced skin cancer.

PubMed

Jiao, Jing; Mikulec, Carol; Ishikawa, Tomo-o; Magyar, Clara; Dumlao, Darren S; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey

2014-06-01

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

PubMed Central

Wang, Xiao-Min; Wu, Tian-Xia; Hamza, May; Ramsay, Edward S.; Wahl, Sharon M.; Dionne, Raymond A.

2007-01-01

New insights into the biological properties of cyclooxygenase-2 (COX-2) and its response pathway challenge the hypothesis that COX-2 is simply pro-inflammatory and inhibition of COX-2 solely prevents the development of inflammation and ameliorates inflammatory pain. The present study performed a comprehensive analysis of gene/protein expression induced by a selective inhibitor of COX-2, rofecoxib, compared with a non-selective COX inhibitor, ibuprofen, and placebo in a clinical model of acute inflammatory pain (the surgical extraction of impacted third molars) using microarray analysis followed by quantitative RT-PCR verification and Western blotting. Inhibition of COX-2 modulated gene expression related to inflammation and pain, the arachidonic acid pathway, apoptosis/angiogenesis, cell adhesion and signal transduction. Compared to placebo, rofecoxib treatment increased the gene expression of ANXA3 (annexin 3), SOD2 (superoxide dismutase 2), SOCS3 (suppressor of cytokine signaling 3) and IL1RN (IL1 receptor antagonist) which are associated with inhibition of phospholipase A2 and suppression of cytokine signaling cascades, respectively. Both rofecoxib and ibuprofen treatment increased the gene expression of the pro-inflammatory mediators, IL6 and CCL2 (chemokine C-C motif ligand 2), following tissue injury compared to the placebo treatment. These results indicate a complex role for COX-2 in the inflammatory cascade in addition to the well-characterized COX-dependent pathway, as multiple pathways are also involved in rofecoxib-induced anti-inflammatory and analgesic effects at the gene expression level. These findings may also suggest an alternative hypothesis for the adverse effects attributed to selective inhibition of COX-2. PMID:17070997

Prevention of posterior capsular opacification through cyclooxygenase-2 inhibition

PubMed Central

Barden, Curtis A; Lu, Ping; Kusewitt, Donna F.; Colitz, Carmen M. H.

2007-01-01

Purpose To determine if cyclooxygenase-2 (COX-2) is upregulated when lens epithelial cells (LEC) in clinical samples of cataracts and posterior capsule opacification (PCO) undergo epithelial-mesenchymal transition (EMT)-like changes. We also wanted to learn if inhibition of the enzymatic activity of COX-2 could prevent PCO formation. Methods To ensure that EMT-like changes were occurring in LEC, real-time RT-PCR was used to examine expression of EMT markers. Clinical samples of canine cataracts and PCO were examined for COX-2 expression using immunohistochemistry, western blot analysis, and real-time RT-PCR. The COX-2 inhibitors, rofecoxib and celecoxib, were used in an ex vivo model of PCO formation, and the effects on cellular migration, proliferation, and apoptosis were analyzed using immunohistochemistry and western blots. Prostaglandin E2 (PGE2) expression was examined with ELISA. Results Markers of EMT, such as lumican, Snail, Slug, and COX-2 were expressed in LEC. In clinical samples of cataracts and PCO, there was overexpression of COX-2 protein and mRNA. Both rofecoxib and celecoxib were effective at inhibiting PCO formation in our ex vivo model. Prevention of PCO with the COX-2 inhibitors appeared to work through decreased migration and proliferation, and increased apoptosis. Neither of the drugs had a toxic effect on confluent LEC and appeared to inhibit PCO through their pharmacologic action. Synthesis of PGE2 was inhibiting in the capsules treated with the COX-2 inhibiting drugs. Conclusions Extracapsular phacoemulsification cataract surgery is the most common surgical procedure performed in human and veterinary ophthalmology. The most frequent postoperative complication is PCO. The LEC that remain adhered to the lens capsule undergo EMT-like changes, proliferate, and migrate across the posterior lens capsule causing opacities. We have shown that COX-2, a protein associated with EMT, is upregulated in canine cataracts and PCO. Inhibiting the enzymatic activity effectively prevented EMT of LEC in our ex vivo model of PCO through pharmacologic action, and not acute toxicity. These findings indicate that using COX-2 inhibitors in vivo may be an effective technique in preventing PCO. PMID:17563718

A Box-Cox normal model for response times.

PubMed

Klein Entink, R H; van der Linden, W J; Fox, J-P

2009-11-01

The log-transform has been a convenient choice in response time modelling on test items. However, motivated by a dataset of the Medical College Admission Test where the lognormal model violated the normality assumption, the possibilities of the broader class of Box-Cox transformations for response time modelling are investigated. After an introduction and an outline of a broader framework for analysing responses and response times simultaneously, the performance of a Box-Cox normal model for describing response times is investigated using simulation studies and a real data example. A transformation-invariant implementation of the deviance information criterium (DIC) is developed that allows for comparing model fit between models with different transformation parameters. Showing an enhanced description of the shape of the response time distributions, its application in an educational measurement context is discussed at length.

Cyclooxygenase 2 Promotes Parathyroid Hyperplasia in ESRD

PubMed Central

Zhang, Qian; Qiu, Junsi; Li, Haiming; Lu, Yanwen; Wang, Xiaoyun; Yang, Junwei; Wang, Shaoqing; Zhang, Liyin; Gu, Yong; Hao, Chuan-Ming

2011-01-01

Hyperplasia of the PTG underlies the secondary hyperparathyroidism (SHPT) observed in CKD, but the mechanism underlying this hyperplasia is incompletely understood. Because aberrant cyclooxygenase 2 (COX2) expression promotes epithelial cell proliferation, we examined the effects of COX2 on the parathyroid gland in uremia. In patients with ESRD who underwent parathyroidectomy, clusters of cells within the parathyroid glands had increased COX2 expression. Some COX2-positive cells exhibited two nuclei, consistent with proliferation. Furthermore, nearly 78% of COX2-positive cells expressed proliferating cell nuclear antigen (PCNA). In the 5/6-nephrectomy rat model, rats fed a high-phosphate diet had significantly higher serum PTH levels and larger parathyroid glands than sham-operated rats. Compared with controls, the parathyroid glands of uremic rats exhibited more PCNA-positive cells and greater COX2 expression in the chief cells. Treatment with COX2 inhibitor celecoxib significantly reduced PCNA expression, attenuated serum PTH levels, and reduced the size of the glands. In conclusion, COX2 promotes the pathogenesis of hyperparathyroidism in ESRD, suggesting that inhibiting the COX2 pathway could be a potential therapeutic target. PMID:21335517

A Cluster Randomized Trial of Tailored Breastfeeding Support for Women with Gestational Diabetes.

PubMed

Stuebe, Alison M; Bonuck, Karen; Adatorwovor, Reuben; Schwartz, Todd A; Berry, Diane C

2016-12-01

Women with gestational diabetes mellitus (GDM) and their infants are at increased risk of developing metabolic disease; however, longer breastfeeding is associated with a reduction in these risks. We tested an intervention to increase breastfeeding duration among women with GDM. We conducted a cluster randomized trial to determine the efficacy of a breastfeeding education and support program for women with GDM. Women were enrolled between 22 and 36 weeks of pregnancy and cluster randomized to an experimental lifestyle intervention or wait-list control group. Breastfeeding duration and intensity were prespecified secondary outcomes of the trial. Duration of exclusive and any breastfeeding was assessed at 6 weeks and at 4, 7, and 10 months postpartum. We quantified differences in breastfeeding rates using Kaplan-Meier estimates, log-rank tests, and Cox regression models. We enrolled 100 women, of whom 52% were African American, 31% non-Hispanic white, 11% Hispanic, 9% American Indian or Alaskan Native, 2% Asian, 2% other, and 4% more than one race. In models accounting for within-cluster correlation and adjusted for study site, breastfeeding intention, and African American race, women allocated to the intervention group were less likely to stop breastfeeding (adjusted hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.21-0.74) or to introduce formula (adjusted HR 0.50, 95% CI 0.34-0.72). Our results suggest that targeted breastfeeding education for women with GDM is feasible and efficacious. http://clinicaltrials.gov/ct2/show/NCT01809431.

The relationship of brachial-ankle pulse wave velocity to future cardiovascular disease events in the general Japanese population: the Takashima Study.

PubMed

Takashima, N; Turin, T C; Matsui, K; Rumana, N; Nakamura, Y; Kadota, A; Saito, Y; Sugihara, H; Morita, Y; Ichikawa, M; Hirose, K; Kawakani, K; Hamajima, N; Miura, K; Ueshima, H; Kita, Y

2014-05-01

Brachial-ankle pulse wave velocity (baPWV) is a non-invasive measure of arterial stiffness obtained using an automated system. Although baPWVs have been widely used as a non-invasive marker for evaluation of arterial stiffness, evidence for the prognostic value of baPWV in the general population is scarce. In this study, we assessed the association between baPWV and future cardiovascular disease (CVD) incidence in a Japanese population. From 2002 to 2009, baPWV was measured in a total of 4164 men and women without a history of CVD, and they were followed up until the end of 2009 with a median follow-up period of 6.5 years. Hazard ratios (HRs) for CVD incidence according to baPWV levels were calculated using a Cox proportional hazards model adjusted for potential confounding factors, including seated or supine blood pressure (BP). During the follow-up period, we observed 40 incident cases of CVD. In multivariable-adjusted model, baPWV as a continuous variable was not significantly associated with future CVD risk after adjustment for supine BP. However, compared with lower baPWV category (<18 m s(-1)), higher baPWV (< or = 18.0 m s(-1)) was significantly associated with an increased CVD risk (HR: 2.70, 95% confidence interval: 1.18-6.19). Higher baPWV (< or = 18.0 m s(-1)) would be an independent predictor of future CVD event in the general Japanese population.

Lung Quality and Utilization in Controlled Donation After Circulatory Determination of Death Within the United States.

PubMed

Mooney, J J; Hedlin, H; Mohabir, P K; Vazquez, R; Nguyen, J; Ha, R; Chiu, P; Patel, K; Zamora, M R; Weill, D; Nicolls, M R; Dhillon, G S

2016-04-01

Although controlled donation after circulatory determination of death (cDCDD) could increase the supply of donor lungs within the United States, the yield of lungs from cDCDD donors remains low compared with donation after neurologic determination of death (DNDD). To explore the reason for low lung yield from cDCDD donors, Scientific Registry of Transplant Recipient data were used to assess the impact of donor lung quality on cDCDD lung utilization by fitting a logistic regression model. The relationship between center volume and cDCDD use was assessed, and the distance between center and donor hospital was calculated by cDCDD status. Recipient survival was compared using a multivariable Cox regression model. Lung utilization was 2.1% for cDCDD donors and 21.4% for DNDD donors. Being a cDCDD donor decreased lung donation (adjusted odds ratio 0.101, 95% confidence interval [CI] 0.085-0.120). A minority of centers have performed cDCDD transplant, with higher volume centers generally performing more cDCDD transplants. There was no difference in center-to-donor distance or recipient survival (adjusted hazard ratio 1.03, 95% CI 0.78-1.37) between cDCDD and DNDD transplants. cDCDD lungs are underutilized compared with DNDD lungs after adjusting for lung quality. Increasing transplant center expertise and commitment to cDCDD lung procurement is needed to improve utilization. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Depressive symptoms are associated with incident coronary heart disease or revascularization among Blacks but not among Whites in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) Study

PubMed Central

Sims, Mario; Redmond, Nicole; Khodneva, Yulia; Durant, Raegan W.; Halanych, Jewell; Safford, Monika M.

2015-01-01

Purpose To examine the association of depressive symptoms with coronary heart disease (CHD) endpoints by race and income. Methods Study participants were Blacks and Whites (n=24,443) without CHD at baseline from the national REasons for Geographical and Racial Differences in Stroke (REGARDS) cohort. Outcomes included acute CHD and CHD or revascularization. We estimated race-stratified multivariable Cox proportional hazards models of incident CHD and incident CHD or revascularization with the 4-item Center for Epidemiological Studies-Depression scale, adjusting for risk factors. Results Mean follow-up was 4.2+1.5 years, CHD incidence was 8.3 events per 1000 person years (n=366) among Blacks and 8.8 events per 1000 person years (n=613) among Whites. After adjustment for age, sex, marital status, region, and socioeconomic status, depressive symptoms were significantly associated with incident CHD among Blacks [HR 1.39 (95%CI 1.00-1.91)], but not among Whites [HR 1.10 (95%CI 0.74-1.64)]. In the fully-adjusted model, compared to Blacks who reported no depressive symptoms, those reporting depressive symptoms had greater risk for the composite endpoint of CHD or revascularization [HR 1.36 (95%CI 1.01-1.81)]. Depressive symptoms were not associated with incident CHD endpoints among Whites. Conclusions High depressive symptoms were associated with higher risk of CHD or revascularization for Blacks but not Whites. PMID:25891100

Green space and mortality following ischemic stroke.

PubMed

Wilker, Elissa H; Wu, Chih-Da; McNeely, Eileen; Mostofsky, Elizabeth; Spengler, John; Wellenius, Gregory A; Mittleman, Murray A

2014-08-01

Residential proximity to green space has been associated with physical and mental health benefits, but whether green space is associated with post-stroke survival has not been studied. Patients ≥ 21 years of age admitted to the Beth Israel Deaconess Medical Center (BIDMC) between 1999 and 2008 with acute ischemic stroke were identified. Demographics, presenting symptoms, medical history and imaging results were abstracted from medical records at the time of hospitalization for stroke onset. Addresses were linked to average Normalized Difference Vegetation Index, distance to roadways with more than 10,000 cars/day, and US census block group. Deaths were identified through June 2012 using the Social Security Death Index. There were 929 deaths among 1645 patients with complete data (median follow up: 5 years). In multivariable Cox models adjusted for indicators of medical history, demographic and socioeconomic factors, the hazard ratio for patients living in locations in the highest quartile of green space compared to the lowest quartile was 0.78 (95% Confidence Interval: 0.63-0.97) (p-trend = 0.009). This association remained statistically significant after adjustment for residential proximity to a high traffic road. Residential proximity to green space is associated with higher survival rates after ischemic stroke in multivariable adjusted models. Further work is necessary to elucidate the underlying mechanisms for this association, and to better understand the exposure-response relationships and susceptibility factors that may contribute to higher mortality in low green space areas. Copyright © 2014 Elsevier Inc. All rights reserved.

Analgesic Effect of the Newly Developed S(+)-Flurbiprofen Plaster on Inflammatory Pain in a Rat Adjuvant-Induced Arthritis Model.

PubMed

Sugimoto, Masanori; Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Hirose, Takuya; Endo, Hiromi; Futaki, Nobuko; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

2016-02-01

Preclinical Research This article describes the properties of a novel topical NSAID (Nonsteroidal anti-inflammatory drug) patch, SFPP (S(+)-flurbiprofen plaster), containing the potent cyclooxygenase (COX) inhibitor, S(+)-flurbiprofen (SFP). The present studies were conducted to confirm human COX inhibition and absorption of SFP and to evaluate the analgesic efficacy of SFPP in a rat adjuvant-induced arthritis (AIA) model. COX inhibition by SFP, ketoprofen and loxoprofen was evaluated using human recombinant COX proteins. Absorption of SFPP, ketoprofen and loxoprofen from patches through rat skin was assessed 24 h after application. The AIA model was induced by injecting Mycobacterium tuberculosis followed 20 days later by the evaluation of the prostaglandin PGE2 content of the inflamed paw and the pain threshold. SFP exhibited more potent inhibitory activity against COX-1 (IC50  = 8.97 nM) and COX-2 (IC50  = 2.94 nM) than the other NSAIDs evaluated. Absorption of SFP was 92.9%, greater than that of ketoprofen and loxoprofen from their respective patches. Application of SFPP decreased PGE2 content from 15 min to 6 h and reduced paw hyperalgesia compared with the control, ketoprofen and loxoprofen patches. SFPP showed analgesic efficacy, and was superior to the ketoprofen and loxoprofen patches, which could be through the potent COX inhibitory activity of SFP and greater skin absorption. The results suggested SFPP can be expected to exert analgesic effect clinically. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc.

An integrated epidemiological and neural net model of the warfarin effect in managed care patients.

PubMed

Jacobs, David M; Stefanovic, Filip; Wilton, Greg; Gomez-Caminero, Andres; Schentag, Jerome J

2017-01-01

Risk assessment tools are utilized to estimate the risk for stroke and need of anticoagulation therapy for patients with atrial fibrillation (AF). These risk stratification scores are limited by the information inputted into them and a reliance on time-independent variables. The objective of this study was to develop a time-dependent neural net model to identify AF populations at high risk of poor clinical outcomes and evaluate the discriminatory ability of the model in a managed care population. We performed a longitudinal, cohort study within a health-maintenance organization from 1997 to 2008. Participants were identified with incident AF irrespective of warfarin status and followed through their duration within the database. Three clinical outcome measures were evaluated including stroke, myocardial infarction, and hemorrhage. A neural net model was developed to identify patients at high risk of clinical events and defined to be an "enriched" patient. The model defines the enrichment based on the top 10 minimum mean square error output parameters that describe the three clinical outcomes. Cox proportional hazard models were utilized to evaluate the outcome measures. Among 285 patients, the mean age was 74±12 years with a mean follow-up of 4.3±2.6 years, and 154 (54%) were treated with warfarin. After propensity score adjustment, warfarin use was associated with a slightly increased risk of adverse outcomes (including stroke, myocardial infarction, and hemorrhage), though it did not attain statistical significance (adjusted hazard ratio [aHR] =1.22; 95% confidence interval [CI] 0.75-1.97; p =0.42). Within the neural net model, subjects at high risk of adverse outcomes were identified and labeled as "enriched." Following propensity score adjustment, enriched subjects were associated with an 81% higher risk of adverse outcomes as compared to nonenriched subjects (aHR=1.81; 95% CI, 1.15-2.88; p =0.01). Enrichment methodology improves the statistical discrimination of meaningful endpoints when used in a health records-based analysis.

Bootstrap investigation of the stability of a Cox regression model.

PubMed

Altman, D G; Andersen, P K

1989-07-01

We describe a bootstrap investigation of the stability of a Cox proportional hazards regression model resulting from the analysis of a clinical trial of azathioprine versus placebo in patients with primary biliary cirrhosis. We have considered stability to refer both to the choice of variables included in the model and, more importantly, to the predictive ability of the model. In stepwise Cox regression analyses of 100 bootstrap samples using 17 candidate variables, the most frequently selected variables were those selected in the original analysis, and no other important variable was identified. Thus there was no reason to doubt the model obtained in the original analysis. For each patient in the trial, bootstrap confidence intervals were constructed for the estimated probability of surviving two years. It is shown graphically that these intervals are markedly wider than those obtained from the original model.

Choice of time-scale in Cox's model analysis of epidemiologic cohort data: a simulation study.

PubMed

Thiébaut, Anne C M; Bénichou, Jacques

2004-12-30

Cox's regression model is widely used for assessing associations between potential risk factors and disease occurrence in epidemiologic cohort studies. Although age is often a strong determinant of disease risk, authors have frequently used time-on-study instead of age as the time-scale, as for clinical trials. Unless the baseline hazard is an exponential function of age, this approach can yield different estimates of relative hazards than using age as the time-scale, even when age is adjusted for. We performed a simulation study in order to investigate the existence and magnitude of bias for different degrees of association between age and the covariate of interest. Age to disease onset was generated from exponential, Weibull or piecewise Weibull distributions, and both fixed and time-dependent dichotomous covariates were considered. We observed no bias upon using age as the time-scale. Upon using time-on-study, we verified the absence of bias for exponentially distributed age to disease onset. For non-exponential distributions, we found that bias could occur even when the covariate of interest was independent from age. It could be severe in case of substantial association with age, especially with time-dependent covariates. These findings were illustrated on data from a cohort of 84,329 French women followed prospectively for breast cancer occurrence. In view of our results, we strongly recommend not using time-on-study as the time-scale for analysing epidemiologic cohort data. 2004 John Wiley & Sons, Ltd.

The Multidisciplinary Swallowing Team Approach Decreases Pneumonia Onset in Acute Stroke Patients.

PubMed

Aoki, Shiro; Hosomi, Naohisa; Hirayama, Junko; Nakamori, Masahiro; Yoshikawa, Mineka; Nezu, Tomohisa; Kubo, Satoshi; Nagano, Yuka; Nagao, Akiko; Yamane, Naoya; Nishikawa, Yuichi; Takamoto, Megumi; Ueno, Hiroki; Ochi, Kazuhide; Maruyama, Hirofumi; Yamamoto, Hiromi; Matsumoto, Masayasu

2016-01-01

Dysphagia occurs in acute stroke patients at high rates, and many of them develop aspiration pneumonia. Team approaches with the cooperation of various professionals have the power to improve the quality of medical care, utilizing the specialized knowledge and skills of each professional. In our hospital, a multidisciplinary participatory swallowing team was organized. The aim of this study was to clarify the influence of a team approach on dysphagia by comparing the rates of pneumonia in acute stroke patients prior to and post team organization. All consecutive acute stroke patients who were admitted to our hospital between April 2009 and March 2014 were registered. We analyzed the difference in the rate of pneumonia onset between the periods before team organization (prior period) and after team organization (post period). Univariate and multivariate analyses were performed using a Cox proportional hazards model to determine the predictors of pneumonia. We recruited 132 acute stroke patients from the prior period and 173 patients from the post period. Pneumonia onset was less frequent in the post period compared with the prior period (6.9% vs. 15.9%, respectively; p = 0.01). Based on a multivariate analysis using a Cox proportional hazards model, it was determined that a swallowing team approach was related to pneumonia onset independent from the National Institutes of Health Stroke Scale score on admission (adjusted hazard ratio 0.41, 95% confidence interval 0.19-0.84, p = 0.02). The multidisciplinary participatory swallowing team effectively decreased the pneumonia onset in acute stroke patients.

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy.

PubMed

Braadland, Peder R; Giskeødegård, Guro; Sandsmark, Elise; Bertilsson, Helena; Euceda, Leslie R; Hansen, Ailin F; Guldvik, Ingrid J; Selnæs, Kirsten M; Grytli, Helene H; Katz, Betina; Svindland, Aud; Bathen, Tone F; Eri, Lars M; Nygård, Ståle; Berge, Viktor; Taskén, Kristin A; Tessem, May-Britt

2017-11-21

Robust biomarkers that identify prostate cancer patients with high risk of recurrence will improve personalised cancer care. In this study, we investigated whether tissue metabolites detectable by high-resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) were associated with recurrence following radical prostatectomy. We performed a retrospective ex vivo study using HR-MAS MRS on tissue samples from 110 radical prostatectomy specimens obtained from three different Norwegian cohorts collected between 2002 and 2010. At the time of analysis, 50 patients had experienced prostate cancer recurrence. Associations between metabolites, clinicopathological variables, and recurrence-free survival were evaluated using Cox proportional hazards regression modelling, Kaplan-Meier survival analyses and concordance index (C-index). High intratumoural spermine and citrate concentrations were associated with longer recurrence-free survival, whereas high (total-choline+creatine)/spermine (tChoCre/Spm) and higher (total-choline+creatine)/citrate (tChoCre/Cit) ratios were associated with shorter time to recurrence. Spermine concentration and tChoCre/Spm were independently associated with recurrence in multivariate Cox proportional hazards modelling after adjusting for clinically relevant risk factors (C-index: 0.769; HR: 0.72; P=0.016 and C-index: 0.765; HR: 1.43; P=0.014, respectively). Spermine concentration and tChoCre/Spm ratio in prostatectomy specimens were independent prognostic markers of recurrence. These metabolites can be noninvasively measured in vivo and may thus offer predictive value to establish preoperative risk assessment nomograms.

Increased risk of avascular necrosis in patients with psoriatic disease: A nationwide population-based matched cohort study.

PubMed

Chiu, Hsien-Yi; Wang, I-Ting; Huang, Weng-Foung; Tsai, Yi-Wen; Shiu, Ming-Neng; Tsai, Tsen-Fang

2017-05-01

Avascular necrosis (AVN) and psoriasis have some pathogenic mechanisms and associated conditions in common. To examine the association between psoriasis and AVN. This study used data from the Taiwan National Health Insurance Research Database for the period 2004-2006 and identified 28,268 patients with psoriasis, who were then matched for age and sex with 113,072 controls without psoriasis from the Taiwan Longitudinal Health Insurance Database 2000. Multivariate Cox proportional hazards models were used for the analysis. The unadjusted risk of AVN was significantly higher for patients with psoriasis than for controls (hazard ratio [HR] 2.29) and remained significant after adjustment for other risk factors (adjusted HR 1.96; 95% confidence interval 1.62-2.38). The risk for AVN increased in relation to psoriasis severity and was higher for patients with psoriasis and arthritis than for patients without arthritis. The adjusted HRs were higher for male patients than for female patients and for patients younger than 30 years compared with older patients. We lacked information on daily tobacco use, alcohol consumption, and physical activity. The risk for AVN increased with the disease severity of psoriasis. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Lifecourse social conditions and racial disparities in incidence of first stroke.

PubMed

Glymour, M Maria; Avendaño, Mauricio; Haas, Steven; Berkman, Lisa F

2008-12-01

Some previous studies found excess stroke rates among black subjects persisted after adjustment for socioeconomic status (SES), fueling speculation regarding racially patterned genetic predispositions to stroke. Previous research was hampered by incomplete SES assessments, without measures of childhood conditions or adult wealth. We assess the role of lifecourse SES in explaining stroke risk and stroke disparities. Health and Retirement Study participants age 50+ (n = 20,661) were followed on average 9.9 years for self- or proxy-reported first stroke (2175 events). Childhood social conditions (southern state of birth, parental SES, self-reported fair/poor childhood health, and attained height), adult SES (education, income, wealth, and occupational status) and traditional cardiovascular risk factors were used to predict first stroke onset using Cox proportional hazards models. Black subjects had a 48% greater risk of first stroke incidence than whites (95% confidence interval, 1.33-1.65). Childhood conditions predicted stroke risk in both blacks and whites, independently of adult SES. Adjustment for both childhood social conditions and adult SES measures attenuated racial differences to marginal significance (hazard ratio, 1.13; 95% CI, 1.00-1.28). Childhood social conditions predict stroke risk in black and White American adults. Additional adjustment for adult SES, in particular wealth, nearly eliminated the disparity in stroke risk between black and white subjects.

Nativity and neighborhood characteristics and cervical cancer stage at diagnosis and survival outcomes among Hispanic women in California.

PubMed

Gomez, Nicole; Guendelman, Sylvia; Harley, Kim G; Gomez, Scarlett Lin

2015-03-01

We examined stage of diagnosis and survival after cervical cancer among Hispanic women, and their associations with Hispanic nativity, and explored whether neighborhood socioeconomic status (SES) and residence in a Hispanic enclave modify the association of nativity with stage and survival. We used California Cancer Registry data (1994-2009) to identify 7958 Hispanic women aged 21 years and older with invasive cervical cancer. We used logistic and Cox proportional hazards models to estimate the associations between stage and mortality with nativity, neighborhood factors, and other covariates. Foreign-born women had similar adjusted relative odds of being diagnosed with stages II through IV (vs stage I) cervical cancer compared with US-born Hispanic women. However, among foreign-born women, those in low-SES-low-enclave neighborhoods were more likely to have late-stage disease than those in high-SES-low-enclave neighborhoods (adjusted odds ratio=1.91; 95% confidence interval=1.18, 3.07). Foreign-born women had lower cervical cancer mortality (adjusted hazard ratio=0.67; 95% confidence interval=0.58, 0.76) than US-born women, but only in high enclaves. Among Hispanic women, nativity, neighborhood enclaves, and SES interact in their influence on stage and survival of cervical cancer.

Preoperative atrial fibrillation and long-term survival after open heart surgery in a rural tertiary heart institute.

PubMed

O'Neal, Wesley T; Efird, Jimmy T; Davies, Stephen W; Choi, Yuk Ming; Anderson, Curtis A; Kindell, Linda C; O'Neal, Jason B; Ferguson, T Bruce; Chitwood, W Randolph; Kypson, Alan P

2013-01-01

Preoperative atrial fibrillation (AF) is associated with increased morbidity and mortality after open heart surgery. However, the impact of preoperative AF on long-term survival after open heart surgery has not been widely examined in rural populations. Patients from rural regions are less likely to receive treatment for cardiac conditions and to have adequate medical insurance coverage. To examine the influence of preoperative AF on long-term survival following open heart surgery in rural eastern North Carolina. Long-term survival was compared in patients with and without preoperative AF after coronary artery bypass grafting (CABG) and CABG plus valve (CABG + V) surgery between 2002 and 2011. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. The study population consisted of 5438 patients. A total of 263 (5%) patients had preoperative AF. Preoperative AF was an independent predictor of long-term survival (open heart surgery: adjusted HR = 1.6, 95% CI = 1.3-2.0; CABG: adjusted HR = 1.6, 95% CI = 1.3-2.1; CABG + V: adjusted HR = 1.6, 95% CI = 1.1-2.3). Preoperative AF is an important predictor of long-term survival after open heart surgery in this rural population. Copyright © 2013 Elsevier Inc. All rights reserved.

Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus.

PubMed

Chen, Weiqi; Pan, Yuesong; Jing, Jing; Zhao, Xingquan; Liu, Liping; Meng, Xia; Wang, Yilong; Wang, Yongjun

2017-06-01

We aimed to determine the risk conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent stroke in patients with minor ischemic stroke or transient ischemic attack from the CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events) trial. In total, 3044 patients were included. Patients were stratified into 4 groups: neither, METS only, DM only, or both. METS was defined using the Chinese Diabetes Society (CDS) and International Diabetes Foundation (IDF) definitions. The primary outcome was new stroke (including ischemic and hemorrhagic) at 90 days. A multivariable Cox regression model was used to assess the relationship of METS and DM status to the risk of recurrent stroke adjusted for potential covariates. Using the CDS criteria of METS, 53.2%, 17.2%, 19.8%, and 9.8% of patients were diagnosed as neither, METS only, DM only, and both, respectively. After 90 days of follow-up, there were 299 new strokes (293 ischemic, 6 hemorrhagic). Patients with DM only (16.1% versus 6.8%; adjusted hazard ratio 2.50, 95% CI 1.89-3.39) and both (17.1% versus 6.8%; adjusted hazard ratio 2.76, 95% CI 1.98-3.86) had significantly increased rates of recurrent stroke. No interaction effect of antiplatelet therapy by different METS or DM status for the risk of recurrent stroke ( P =0.82 for interaction in the fully adjusted model of CDS) was observed. Using the METS (IDF) criteria demonstrated similar results. Concurrent METS and DM was associated with an increased risk of recurrent stroke in patients with minor stroke and transient ischemic attack. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

A Prospective Investigation of Coffee Drinking and Bladder Cancer Incidence in the United States.

PubMed

Loftfield, Erikka; Freedman, Neal D; Inoue-Choi, Maki; Graubard, Barry I; Sinha, Rashmi

2017-09-01

In 1991, coffee was classified as a group 2B carcinogen, possibly carcinogenic to humans, based on limited epidemiologic evidence of a positive association with bladder cancer. In 2016, the International Agency for Research on Cancer downgraded this classification due to lack of evidence from prospective studies particularly for never smokers. Baseline coffee drinking was assessed with a food frequency questionnaire in the NIH-AARP prospective cohort study. Among 469,047 US adults, who were cancer free at baseline, 6,012 bladder cancer cases (5,088 men and 924 women) were identified during >6.3 million person-years of follow-up. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), with non-coffee drinkers as the reference group. Coffee drinking was positively associated with bladder cancer in models adjusted for age and sex (HR for ≥4 cups/d relative to coffee nondrinkers = 1.91, 95% CI = 1.70, 2.14; P trend < 0.0001). However, the association was substantially attenuated after adjustment for cigarette smoking and other potential confounders (HR for ≥4 cups/d relative to coffee nondrinkers = 1.18, 95% CI = 1.05, 1.33; P trend = 0.0007). Associations were further attenuated after additional adjustment for lifetime smoking patterns among the majority of the cohort with this available data (P trend = 0.16). There was no evidence of an association among never smokers (P trend = 0.84). Positive associations between coffee drinking and bladder cancer among ever smokers but not never smokers suggest that residual confounding from imperfect measurement of smoking or unmeasured risk factors may be an explanation for our positive findings.

Hospital-level Variation in Utilization of Surgery for Clinical Stage I-II Pancreatic Adenocarcinoma.

PubMed

Swords, Douglas S; Mulvihill, Sean J; Skarda, David E; Finlayson, Samuel R G; Stoddard, Gregory J; Ott, Mark J; Firpo, Matthew A; Scaife, Courtney L

2017-07-11

To (1) evaluate rates of surgery for clinical stage I-II pancreatic ductal adenocarcinoma (PDAC), (2) identify predictors of not undergoing surgery, (3) quantify the degree to which patient- and hospital-level factors explain differences in hospital surgery rates, and (4) evaluate the association between adjusted hospital-specific surgery rates and overall survival (OS) of patients treated at different hospitals. Curative-intent surgery for potentially resectable PDAC is underutilized in the United States. Retrospective cohort study of patients ≤85 years with clinical stage I-II PDAC in the 2004 to 2014 National Cancer Database. Mixed effects multivariable models were used to characterize hospital-level variation across quintiles of hospital surgery rates. Multivariable Cox proportional hazards models were used to estimate the effect of adjusted hospital surgery rates on OS. Of 58,553 patients without contraindications or refusal of surgery, 63.8% underwent surgery, and the rate decreased from 2299/3528 (65.2%) in 2004 to 4412/7092 (62.2%) in 2014 (P < 0.001). Adjusted hospital rates of surgery varied 6-fold (11.4%-70.9%). Patients treated at hospitals with higher rates of surgery had better unadjusted OS (median OS 10.2, 13.3, 14.2, 16.5, and 18.4 months in quintiles 1-5, respectively, P < 0.001, log-rank). Treatment at hospitals in lower surgery rate quintiles 1-3 was independently associated with mortality [Hazard ratio (HR) 1.10 (1.01, 1.21), HR 1.08 (1.02, 1.15), and HR 1.09 (1.04, 1.14) for quintiles 1-3, respectively, compared with quintile 5] after adjusting for patient factors, hospital type, and hospital volume. Quality improvement efforts are needed to help hospitals with low rates of surgery ensure that their patients have access to appropriate surgery.

Relationship Between Attention-Deficit/Hyperactivity Disorder Care and Medication Continuity.

PubMed

Brinkman, William B; Baum, Rebecca; Kelleher, Kelly J; Peugh, James; Gardner, William; Lichtenstein, Phil; Langberg, Joshua; Epstein, Jeffery N

2016-04-01

To describe the relationships between attention-deficit/hyperactivity disorder (ADHD) care practices and subsequent medication use. A retrospective cohort from a random sample of medical records in 50 pediatric practices with 188 providers, including 1,352 children who started ADHD medication, was studied. Independent variables included physician behaviors related to medication titration and monitoring of treatment response. Primary outcomes were number of days covered with ADHD medication during the first year of treatment and time from starting medicine to the first 30-day gap in medication supply. Multilevel modeling and Cox proportional hazards regression models were conducted. Children had an average medication supply of 217 days in the first year. Half experienced a 30-day gap in medication supply in the first 3 months. Nearly three-fourths had a medication adjustment in the first year with the first adjustment usually being a dosage change. The average time to the first medication adjustment was over 3 months. Physician's first contact with parents occurred in the first month of treatment for less than half, with the average time being over 2 months. Little variation related to ADHD care quality was accounted for at the physician level. Early titration and early contact were related to greater medication supply and continuity of treatment. Earlier physician-delivered ADHD care (e.g., contact with parent after starting medication and medication adjustment) is related to greater medication supply and continuity. It remains to be determined whether interventions that improve the quality of titration and monitoring practices for children with ADHD would also improve medication continuity. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Risk of Intracranial Hemorrhage From Statin Use in Asians: A Nationwide Cohort Study.

PubMed

Chang, Chia-Hsuin; Lin, Chin-Hsien; Caffrey, James L; Lee, Yen-Chieh; Liu, Ying-Chun; Lin, Jou-Wei; Lai, Mei-Shu

2015-06-09

Reports of statin usage and increased risk of intracranial hemorrhage (ICH) have been inconsistent. This study examined potential associations between statin usage and the risk of ICH in subjects without a previous history of stroke. Patients initiating statin therapy between 2005 and 2009 without a previous history of ischemic or hemorrhagic stroke were identified from Taiwan's National Health Insurance database. Participants were stratified by advanced age (≥70 years), sex, and diagnosed hypertension. The outcome of interest was hospital admission for ICH (International Classification of Diseases, Ninth Revision, Clinical Modification codes 430, 431, 432). Cox regression models were applied to estimate the hazard ratio of ICH. The cumulative statin dosage stratified by quartile and adjusted for baseline disease risk score served as the primary variable using the lowest quartile of cumulative dosage as a reference. There were 1 096 547 statin initiators with an average follow-up of 3.3 years. The adjusted hazard ratio for ICH between the highest and the lowest quartile was nonsignificant at 1.06 with a 95% confidence interval spanning 1.00 (0.94-1.19). Similar nonsignificant results were found in sensitivity analyses using different outcome definitions or model adjustments, reinforcing the robustness of the study findings. Subgroup analysis identified an excess of ICH frequency in patients without diagnosed hypertension (adjusted hazard ratio 1.36 [1.11-1.67]). In general, no association was observed between cumulative statin use and the risk of ICH among subjects without a previous history of stroke. An increased risk was identified among the nonhypertensive cohort, but this finding should be interpreted with caution. © 2015 American Heart Association, Inc.

Enzymologic and pharmacologic profile of loxoprofen sodium and its metabolites.

PubMed

Noguchi, Masahiro; Kimoto, Aishi; Gierse, James Kevin; Walker, Mark Crossfield; Zweifel, Ben Scott; Nozaki, Kazutoshi; Sasamata, Masao

2005-11-01

We investigated the mechanism of inhibition of loxoprofen sodium, a non-steroidal anti-inflammatory drug (NSAID), and its active metabolite (loxoprofen-SRS) on cyclooxygenase (COX). In in vitro assays, loxoprofen sodium appeared inactive against recombinant human COX-1 and COX-2, whereas loxoprofen-SRS inhibited both. In the investigation of kinetic behavior, loxoprofen-SRS showed time-dependent inhibition for both isozymes. Human whole blood assay also showed that loxoprofen-SRS possesses the profile of a non-selective inhibitor for COX. In a rat air pouch model, oral administration of loxoprofen sodium lowered prostaglandin (PG) E2 in both fluid exudates of the inflammatory pouch and stomach tissue with ED50 values of 2.0 and 2.1 mg/kg, respectively. Additionally, platelet thromboxane B2 production was also inhibited by loxoprofen sodium (ED50 of 0.34 mg/kg). In a rat carrageenan-induced paw edema model, loxoprofen sodium dose-dependently reduced the paw edema, accompanied by a decrease in PGE2 content in inflamed paw exudates. These findings suggest that the COX inhibitory activity of loxoprofen sodium is attributable to its active metabolite, loxoprofen-SRS, and that loxoprofen-SRS shows non-selective inhibition for COX.

Training artificial neural networks directly on the concordance index for censored data using genetic algorithms.

PubMed

Kalderstam, Jonas; Edén, Patrik; Bendahl, Pär-Ola; Strand, Carina; Fernö, Mårten; Ohlsson, Mattias

2013-06-01

The concordance index (c-index) is the standard way of evaluating the performance of prognostic models in the presence of censored data. Constructing prognostic models using artificial neural networks (ANNs) is commonly done by training on error functions which are modified versions of the c-index. Our objective was to demonstrate the capability of training directly on the c-index and to evaluate our approach compared to the Cox proportional hazards model. We constructed a prognostic model using an ensemble of ANNs which were trained using a genetic algorithm. The individual networks were trained on a non-linear artificial data set divided into a training and test set both of size 2000, where 50% of the data was censored. The ANNs were also trained on a data set consisting of 4042 patients treated for breast cancer spread over five different medical studies, 2/3 used for training and 1/3 used as a test set. A Cox model was also constructed on the same data in both cases. The two models' c-indices on the test sets were then compared. The ranking performance of the models is additionally presented visually using modified scatter plots. Cross validation on the cancer training set did not indicate any non-linear effects between the covariates. An ensemble of 30 ANNs with one hidden neuron was therefore used. The ANN model had almost the same c-index score as the Cox model (c-index=0.70 and 0.71, respectively) on the cancer test set. Both models identified similarly sized low risk groups with at most 10% false positives, 49 for the ANN model and 60 for the Cox model, but repeated bootstrap runs indicate that the difference was not significant. A significant difference could however be seen when applied on the non-linear synthetic data set. In that case the ANN ensemble managed to achieve a c-index score of 0.90 whereas the Cox model failed to distinguish itself from the random case (c-index=0.49). We have found empirical evidence that ensembles of ANN models can be optimized directly on the c-index. Comparison with a Cox model indicates that near identical performance is achieved on a real cancer data set while on a non-linear data set the ANN model is clearly superior. Copyright © 2013 Elsevier B.V. All rights reserved.

Immunohistochemical and morphometric evaluation of COX-1 and COX-2 in the remodeled lung in idiopathic pulmonary fibrosis and systemic sclerosis* ,**

PubMed Central

Parra, Edwin Roger; Lin, Flavia; Martins, Vanessa; Rangel, Maristela Peres; Capelozzi, Vera Luiza

2013-01-01

OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients, correlating that expression with patient survival. METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP) in SSc patients and usual interstitial pneumonia (UIP) in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival. RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc-NSIP lung tissue than in the control tissue. No difference was found between IPF-UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP), and low COX-1 expression in alveolar septa. CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that. PMID:24473763

Association Between Metabolic Syndrome and the Serum Uric Acid: a Cohort Study.

PubMed

Ren, Ping; Gao, Mengna

2018-05-01

Metabolic syndrome (MS) consists of a cluster of metabolic diseases, and the association between serum uric acid (SUA) and MS has recently been reported in several studies; however, whether SUA is a susceptibility or risk biomarker for the development of MS among Chinese adults is unclear. This study was designed to investigate the relationship between SUA and MS. This study involved 4,988 subjects who were followed up for 9 years. Cox regression model was used to analyze the risk factors of MS. Of the 4,988 subjects, 1,192 subjects developed MS over 9 years of follow-up. The overall 9-year cumulative incidence of MS was 23.9%, ranging from 16.6% in quartile 1 to 35.1% in quartile 4 (p for trend < 0.001). Cox regression analyses indicated that SUA was significantly associated with incident MS (HR comparing quartile 2, 3, and 4 vs. quartile 1, 1.11, 1.33, and 1.78, respectively; p < 0.001) after adjusting for multiple associated parameters. In receiver operating characteristic curve analysis, the cutoff levels for SUA to predict incident MS were 350 μmol/L and 268 μmol/L in males and females, respectively. The results of this study demonstrated that high SUA concentrations may increase the risk of MS among Chinese adults.

Survival of adults with systemic autoimmune rheumatic diseases and pulmonary arterial hypertension after lung transplantation.

PubMed

Bernstein, Elana J; Bathon, Joan M; Lederer, David J

2018-05-01

Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in adults with systemic autoimmune rheumatic diseases (ARDs). The aim of this study was to determine whether adults with ARDs and PAH on right-sided heart catheterization (ARD-PAH) have increased mortality following lung transplantation compared with those with PAH not due to an ARD. We conducted a retrospective cohort study of 93 adults with ARD-PAH and 222 adults with PAH who underwent lung transplantation in the USA between 4 May 2005 and 9 March 2015 using data from the United Network for Organ Sharing. We examined associations between diagnosis and survival after lung transplantation using stratified Cox models adjusted for potential confounding recipient factors. Among adults undergoing lung transplantation in the USA, we did not detect a difference in the multivariable-adjusted mortality rate between those with ARD-PAH and those with PAH [hazard ratio 0.75 (95% CI 0.47, 1.19)]. The presence of an ARD was not associated with increased mortality after lung transplantation in adults with PAH.

Aortic Valve Calcification and Risk of Stroke: The Rotterdam Study.

PubMed

Bos, Daniel; Bozorgpourniazi, Atefeh; Mutlu, Unal; Kavousi, Maryam; Vernooij, Meike W; Moelker, Adriaan; Franco, Oscar H; Koudstaal, Peter J; Ikram, M Arfan; van der Lugt, Aad

2016-11-01

It remains uncertain whether aortic valve calcification (AVC) is a risk factor for stroke. From the population-based Rotterdam Study, 2471 participants (mean age: 69.6 years; 51.8% women) underwent computed tomography to quantify AVC. We assessed prevalent stroke and continuously monitored the remaining participants for the incidence of stroke. Logistic and Cox regression models were used to investigate associations of AVC with prevalent stroke and risk of incident stroke. AVC was present in 33.1% of people. At baseline, 97 participants had ever suffered a stroke. During 18 665 person-years of follow-up (mean: 7.9 years), 135 people experienced a first-ever stroke. The presence of AVC was not associated with prevalent stroke (fully adjusted odds ratio: 0.97 (95% confidence interval, 0.61-1.53]) or with an increased risk of stroke (fully adjusted hazard ratio: 0.99 (95% confidence interval, 0.69-1.44]). Although AVC is a common finding in middle-aged and elderly community-dwelling people, our results suggest that AVC is not associated with an increased risk of stroke. © 2016 American Heart Association, Inc.

Urate levels predict survival in amyotrophic lateral sclerosis: Analysis of the expanded Pooled Resource Open-Access ALS clinical trials database.

PubMed

Paganoni, Sabrina; Nicholson, Katharine; Chan, James; Shui, Amy; Schoenfeld, David; Sherman, Alexander; Berry, James; Cudkowicz, Merit; Atassi, Nazem

2018-03-01

Urate has been identified as a predictor of amyotrophic lateral sclerosis (ALS) survival in some but not all studies. Here we leverage the recent expansion of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to study the association between urate levels and ALS survival. Pooled data of 1,736 ALS participants from the PRO-ACT database were analyzed. Cox proportional hazards regression models were used to evaluate associations between urate levels at trial entry and survival. After adjustment for potential confounders (i.e., creatinine and body mass index), there was an 11% reduction in risk of reaching a survival endpoint during the study with each 1-mg/dL increase in uric acid levels (adjusted hazard ratio 0.89, 95% confidence interval 0.82-0.97, P < 0.01). Our pooled analysis provides further support for urate as a prognostic factor for survival in ALS and confirms the utility of the PRO-ACT database as a powerful resource for ALS epidemiological research. Muscle Nerve 57: 430-434, 2018. © 2017 Wiley Periodicals, Inc.

Sleep duration, cognitive decline, and dementia risk in older women

PubMed Central

Chen, Jiu-Chiuan; Espeland, Mark A.; Brunner, Robert L.; Lovato, Laura C.; Wallace, Robert B.; Leng, Xiaoyan; Phillips, Lawrence S.; Robinson, Jennifer G.; Kotchen, Jane M.; Johnson, Karen C.; Manson, JoAnn E.; Stefanick, Marcia L.; Sarto, Gloria E.; Mysiw, W. Jerry

2015-01-01

Background Consistent evidence linking habitual sleep duration with risks of mild cognitive impairment (MCI) and dementia is lacking. Methods We conducted a prospective study on 7444 community-dwelling women (aged 65–80) with self-reported sleep duration, within the Women’s Health Initiative Memory Study in 1995–2008. Incident MCI/dementia cases were ascertained by validated protocols. Cox models were used to adjust for multiple sociodemographic and lifestyle factors, depression, cardiovascular disease (CVD), and other clinical characteristics. Results We found a statistically significant (p=0.03) V-shaped association, with a higher MCI/dementia risk in women with either short (≤6 hours/night) or long (≥8 hours/night) sleep duration (vs.7 hours/night). The multicovariate-adjusted hazard for MCI/dementia was increased by 36% in short sleepers irrespective of CVD, and by 35% in long sleepers without CVD. A similar V-shaped association was found with cognitive decline. Conclusion In older women, habitual sleep duration predicts the future risk for cognitive impairments including dementia, independent of vascular risk factors. PMID:26086180

Statistical modelling for recurrent events: an application to sports injuries

PubMed Central

Ullah, Shahid; Gabbett, Tim J; Finch, Caroline F

2014-01-01

Background Injuries are often recurrent, with subsequent injuries influenced by previous occurrences and hence correlation between events needs to be taken into account when analysing such data. Objective This paper compares five different survival models (Cox proportional hazards (CoxPH) model and the following generalisations to recurrent event data: Andersen-Gill (A-G), frailty, Wei-Lin-Weissfeld total time (WLW-TT) marginal, Prentice-Williams-Peterson gap time (PWP-GT) conditional models) for the analysis of recurrent injury data. Methods Empirical evaluation and comparison of different models were performed using model selection criteria and goodness-of-fit statistics. Simulation studies assessed the size and power of each model fit. Results The modelling approach is demonstrated through direct application to Australian National Rugby League recurrent injury data collected over the 2008 playing season. Of the 35 players analysed, 14 (40%) players had more than 1 injury and 47 contact injuries were sustained over 29 matches. The CoxPH model provided the poorest fit to the recurrent sports injury data. The fit was improved with the A-G and frailty models, compared to WLW-TT and PWP-GT models. Conclusions Despite little difference in model fit between the A-G and frailty models, in the interest of fewer statistical assumptions it is recommended that, where relevant, future studies involving modelling of recurrent sports injury data use the frailty model in preference to the CoxPH model or its other generalisations. The paper provides a rationale for future statistical modelling approaches for recurrent sports injury. PMID:22872683

Racial differences in the outcome of patients with urothelial carcinoma of the upper urinary tract: an international study.

PubMed

Matsumoto, Kazumasa; Novara, Giacomo; Gupta, Amit; Margulis, Vitaly; Walton, Thomas J; Roscigno, Marco; Ng, Casey; Kikuchi, Eiji; Zigeuner, Richard; Kassouf, Wassim; Fritsche, Hans-Martin; Ficarra, Vincenzo; Martignoni, Guido; Tritschler, Stefan; Rodriguez, Joaquin Carballido; Seitz, Christian; Weizer, Alon; Remzi, Mesut; Raman, Jay D; Bolenz, Christian; Bensalah, Karim; Koppie, Theresa M; Karakiewicz, Pierre I; Wood, Christopher G; Montorsi, Francesco; Iwamura, Masatsugu; Shariat, Shahrokh F

2011-10-01

•To assess the impact of differences in ethnicity on clinico-pathological characteristics and outcomes of patients with upper urinary tract urothelial carcinoma (UTUC) in a large multi-center series of patients treated with radical nephroureterectomy (RNU). •We retrospectively collected the data of 2163 patients treated with RNU at 20 academic centres in America, Asia, and Europe. •Univariable and multivariable Cox regression models addressed recurrence-free survival (RFS) and cancer-specific survival (CSS). •In all, 1794 (83%) patients were Caucasian and 369 (17%) were Japanese. All the main clinical and pathological features were significantly different between the two ethnicities. •The median follow-up of the whole cohort was 36 months. At last follow-up, 554 patients (26%) developed disease recurrence and 461 (21%) were dead from UTUC. •The 5-year RFS and CSS estimates were 71.5% and 74.2%, respectively, for Caucasian patients compared with 68.8% and 75.4%, respectively, for Japanese patients. •On univariable Cox regression analyses, ethnicity was not significantly associated with either RFS (P= 0.231) or CSS (P= 0.752). •On multivariable Cox regression analyses that adjusted for the effects of age, gender, surgical type, T stage, grade, tumour architecture, presence of concomitant carcinoma in situ, lymphovascular invasion, tumour necrosis, and lymph node status, ethnicity was not associated with either RFS (hazard ratio [HR] 1.1; P= 0.447) or CSS (HR 1.0; P= 0.908). •There were major differences in the clinico-pathological characteristics of Caucasian and Japanese patients. •However, RFS and CSS probabilities were not affected by ethnicity and race was not an independent predictor of either recurrence or cancer-related death. © 2011 THE AUTHORS; BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.

Long-term reduction of health care costs & utilization after epilepsy surgery

PubMed Central

Schiltz, Nicholas K.; Kaiboriboon, Kitti; Koroukian, Siran M.; Singer, Mendel E.; Love, Thomas E.

2015-01-01

SUMMARY Objective To assess long-term direct medical costs, health care utilization, and mortality following resective surgery in persons with uncontrolled epilepsy. Methods Retrospective longitudinal cohort study of Medicaid beneficiaries with epilepsy from 2000 - 2008. The study population included 7,835 persons with uncontrolled focal epilepsy age 18 to 64 years, with an average follow-up time of 5 years. Of these, 135 received surgery during the study period. To account for selection bias, we used risk-set optimal pairwise matching on a time-varying propensity score, and inverse probability of treatment weighting. Repeated measures generalized linear models were used to model utilization and cost outcomes. Cox proportional hazard was used to model survival. Results The mean direct medical cost difference between the surgical group and control group was $6,806 after risk-set matching. The incidence rate ratio of inpatient, emergency room, and outpatient utilization was lower among the surgical group in both unadjusted and adjusted analyses. There was no significant difference in mortality after adjustment. Among surgical cases, mean annual costs per subject were on average $6,484 lower, and all utilization measures were lower after surgery compared to before. Significance Subjects that underwent epilepsy surgery had lower direct medical care costs and health care utilization. These findings support that epilepsy surgery yield substantial health care cost savings. PMID:26693701

Periconceptional Over-the-Counter Nonsteroidal Anti-inflammatory Drug Exposure and Risk for Spontaneous Abortion

PubMed Central

Velez Edwards, Digna R.; Aldridge, Tiara; Baird, Donna D.; Funk, Michele Jonsson; Savitz, David A.; Hartmann, Katherine E.

2012-01-01

Objective To estimate the association between over-the-counter nonsteroidal anti-inflammatory drug (NSAID) exposure during the early first-trimester and risk for spontaneous abortion (gestation prior to 20 weeks) in a prospective cohort. Methods Women were enrolled in the Right from the Start study (2004–2010). Exposure data regarding over-the-counter NSAID use from the last menstrual period through the 6th week of pregnancy were obtained from intake and first-trimester interviews. Pregnancy outcomes were self-reported and verified by medical records. Gestational age was determined from last menstrual period. Stage of development prior to loss was determined from study ultrasound. Cox proportional hazards regression models were used to estimate the association between NSAID exposure and pregnancy outcome, taking into account candidate confounders. Results Among 2,780 pregnancies, 367 women (13%) experienced an spontaneous abortion. NSAID exposure was reported by 1,185 (43%) women. NSAID exposure was not associated with spontaneous abortion risk in unadjusted models (hazard ratio [HR] = 1.01, 95% confidence interval [CI] 0.82, 1.24) or models adjusted for maternal age (adjusted [aHR] = 1.00, 95% CI 0.81, 1.23). Conclusions Our findings suggest that use of non-prescription over-the-counter NSAIDs in early pregnancy does not put women at increased risk of spontaneous abortion. PMID:22914399

Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

PubMed

Otgonsuren, Munkhzul; Estep, Michael J; Hossain, Nayeem; Younossi, Elena; Frost, Spencer; Henry, Linda; Hunt, Sharon; Fang, Yun; Goodman, Zachary; Younossi, Zobair M

2014-12-01

Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD). A liver biopsy is considered the "gold standard" for diagnosing/staging NASH. Identification of NAFLD/NASH using non-invasive tools is important for intervention. The study aims were to: develop/validate the predictive performance of a non-invasive model (index of NASH [ION]); assess the performance of a recognized non-invasive model (fatty liver index [FLI]) compared with ION for NAFLD diagnosis; determine which non-invasive model (FLI, ION, or NAFLD fibrosis score [NFS]) performed best in predicting age-adjusted mortality. From the National Health and Nutrition Examination Survey III database, anthropometric, clinical, ultrasound, laboratory, and mortality data were obtained (n = 4458; n = 861 [19.3%] NAFLD by ultrasound) and used to develop the ION model, and then to compare the ION and FLI models for NAFLD diagnosis. For validation and diagnosis of NASH, liver biopsy data were used (n = 152). Age-adjusted Cox proportional hazard modeling estimated the association among the three non-invasive tests (FLI, ION, and NFS) and mortality. FLI's threshold score > 60 and ION's threshold score > 22 had similar specificity (FLI = 80% vs ION = 82%) for NAFLD diagnosis; FLI < 30 (80% sensitivity) and ION < 11 (81% sensitivity) excluded NAFLD. An ION score > 50 predicted histological NASH (92% specificity); the FLI model did not predict NASH or mortality. The ION model was best in predicting cardiovascular/diabetes-related mortality; NFS predicted overall or diabetes-related mortality. The ION model was superior in predicting NASH and mortality compared with the FLI model. Studies are needed to validate ION. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

An Incident Cohort Study Comparing Survival on Home Hemodialysis and Peritoneal Dialysis (Australia and New Zealand Dialysis and Transplantation Registry)

PubMed Central

Nadeau-Fredette, Annie-Claire; Hawley, Carmel M.; Pascoe, Elaine M.; Chan, Christopher T.; Clayton, Philip A.; Polkinghorne, Kevan R.; Boudville, Neil; Leblanc, Martine

2015-01-01

Background and objectives Home dialysis is often recognized as a first-choice therapy for patients initiating dialysis. However, studies comparing clinical outcomes between peritoneal dialysis and home hemodialysis have been very limited. Design, setting, participants, & measurements This Australia and New Zealand Dialysis and Transplantation Registry study assessed all Australian and New Zealand adult patients receiving home dialysis on day 90 after initiation of RRT between 2000 and 2012. The primary outcome was overall survival. The secondary outcomes were on-treatment survival, patient and technique survival, and death-censored technique survival. All results were adjusted with three prespecified models: multivariable Cox proportional hazards model (main model), propensity score quintile–stratified model, and propensity score–matched model. Results The study included 10,710 patients on incident peritoneal dialysis and 706 patients on incident home hemodialysis. Treatment with home hemodialysis was associated with better patient survival than treatment with peritoneal dialysis (5-year survival: 85% versus 44%, respectively; log-rank P<0.001). Using multivariable Cox proportional hazards analysis, home hemodialysis was associated with superior patient survival (hazard ratio for overall death, 0.47; 95% confidence interval, 0.38 to 0.59) as well as better on-treatment survival (hazard ratio for on-treatment death, 0.34; 95% confidence interval, 0.26 to 0.45), composite patient and technique survival (hazard ratio for death or technique failure, 0.34; 95% confidence interval, 0.29 to 0.40), and death-censored technique survival (hazard ratio for technique failure, 0.34; 95% confidence interval, 0.28 to 0.41). Similar results were obtained with the propensity score models as well as sensitivity analyses using competing risks models and different definitions for technique failure and lag period after modality switch, during which events were attributed to the initial modality. Conclusions Home hemodialysis was associated with superior patient and technique survival compared with peritoneal dialysis. PMID:26068181

Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation.

PubMed

Badie, Behnam; Schartner, Jill M; Hagar, Aaron R; Prabakaran, Sakthivel; Peebles, Todd R; Bartley, Becky; Lapsiwala, Samir; Resnick, Daniel K; Vorpahl, Jessica

2003-02-01

Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. To examine the role of inflammatory cells in brain edema formation, we studied the expression cyclooxygenase (COX)-2, a key enzyme in arachidonic acid metabolism, by microglia in the C6 rodent glioma model. The expression of COX-2 in primary microglia cultures obtained from intracranial rat C6 gliomas was examined using reverse transcription-PCR, Western analysis, and prostaglandin E(2) (PGE(2)) enzyme immunoassay. Blood-tumor barrier permeability was studied in the same tumor model using magnetic resonance imaging. In contrast to C6 glioma cells, microglia isolated from intracranial C6 tumors produced high levels of PGE(2) through a COX-2-dependent pathway. To test whether the observed microglia COX-2 activity played a role in brain edema formation in gliomas, tumor-bearing rats were treated with rofecoxib, a selective COX-2 inhibitor. Rofecoxib was as effective as dexamethasone in decreasing the diffusion of contrast material into the brain parenchyma (P = 0.01, rofecoxib versus control animals), suggesting a reduction in blood-tumor barrier permeability. These findings suggest that glioma-infiltrating microglia are a major source of PGE(2) production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors.

Symptoms of depression and all-cause mortality in farmers, a cohort study: the HUNT study, Norway

PubMed Central

Letnes, Jon Magne; Hilt, Bjørn; Bjørngaard, Johan Håkon; Krokstad, Steinar

2016-01-01

Objectives To explore all-cause mortality and the association between symptoms of depression and all-cause mortality in farmers compared with other occupational groups, using a prospective cohort design. Methods We included adult participants with a known occupation from the second wave of the Nord-Trøndelag Health Study (Helseundersøkelsen i Nord-Trøndelag 2 (HUNT2) 1995–1997), Norway. Complete information on emigration and death from all causes was obtained from the National Registries. We used the depression subscale of the Hospital Anxiety and Depression Scale (HADS) to measure symptoms of depression. We compared farmers to 4 other occupational groups. Our baseline study population comprised 32 618 participants. Statistical analyses were performed using the Cox proportional hazards models. Results The estimated mortality risk in farmers was lower than in all other occupations combined, with a sex and age-adjusted HR (0.91, 95% CI 0.82 to 1.00). However, farmers had an 11% increased age-adjusted and sex-adjusted mortality risk compared with the highest ranked socioeconomic group (HR 1.11, 95% CI 0.98 to 1.25). In farmers, symptoms of depression were associated with a 13% increase in sex-adjusted and age-adjusted mortality risk (HR 1.13, 95% CI 0.88 to 1.45). Compared with other occupations this was the lowest HR, also after adjusting for education, marital status, long-lasting limiting somatic illness and lifestyle factors (HR 1.08, 95% CI 0.84 to 1.39). Conclusions Farmers had lower all-cause mortality compared with the other occupational groups combined. Symptoms of depression were associated with an increased mortality risk in farmers, but the risk increase was smaller compared with the other occupational groups. PMID:27188811

Comparison of long-term outcomes between older Asian and white patients with non-ST-segment elevation myocardial infarction: findings from CRUSADE-CMS database.

PubMed

Xu, Weixian; Holmes, Dajuanicia N; Becker, Richard C; Roe, Matthew T; Peterson, Eric D; Wang, Tracy Y

2013-12-01

In the United States as well as globally, Asians are a growing proportion of patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI), yet little is known about their longitudinal outcomes. We linked Centers for Medicare & Medicaid claims data to detailed clinical data for 37,702 NSTEMI patients ≥65 years old treated at 444 CRUSADE hospitals between 2003 and 2006 to examine longitudinal outcomes. We used Cox proportional hazards modeling to compared outcomes between Asian and white patients, adjusting for differences in baseline patient characteristics. Compared with white NSTEMI patients, Asians (n = 307) were younger; more frequently had hypertension, diabetes and renal insufficiency; and were less likely to have had a prior myocardial infarction, but there were no significant differences in rates of cardiac catheterization or revascularization during the index hospitalization between the 2 groups. At 30 days, Asian and white patients had a similar risk-adjusted mortality (9.5% vs 9.9%, P = .77), but by 1 year, Asian patients had a significantly lower risk-adjusted mortality (20.9% vs 24.5%, adjusted hazard ratio 0.64, 95% CI 0.50-0.82). Compared with white patients, Asians also had a lower adjusted 1-year cardiovascular readmission risk (37.1% vs 42.1%, adjusted hazard ratio 0.79, 95% CI 0.64-0.98). Despite similar inhospital treatments, Asian NSTEMI patients had lower mortality and cardiovascular readmission risks at 1 year, compared with white patients. Further study is needed to determine whether intrinsic ethnic differences or differential longitudinal prevention strategies explain these differences in long-term outcomes. © 2013.

[Suppression of COX-2 protein to cell apoptosis in non-small cell lung cancer].

PubMed

Sun, Limei; Zhao, Yue; Wang, Lujian; Song, Min; Song, Jiye

2007-06-20

One of mechanisms of carcinogenesis is suppression of cell apoptosis which leads to accumulation of aberrant cells. The aim of this study is to investigate cell apoptosis and COX-2 protein expression in non-small cell lung cancer (NSCLC). Cell apoptosis, expression of COX-2 and microvessel density (MVD) were detcted in 111 NSCLC samples by TdT-mediated dUTP nick end labeling (TUNEL) technique and immunohistochemical staining. The positive rate of COX-2 protein expression was 67.6% (75/111), and there were 53 patients with high level cell apoptosis (47.7%). Expression of COX-2 protien was significantly related to TNM stages (P=0.025) and lymph node metastasis (P=0.018). The MVD in NSCLC tissues with positive COX-2 expression was significantly higher than that in negative expression ones (P=0.000). COX model showed that lymph node metastasis (P=0.006) and positive expression of COX-2 protein (P=0.000) were independent prognostic factors of NSCLC. The expression of COX-2 protein may suppress cell apoptosis of tumor, and it may serve as a potential marker of prognosis for NSCLC.

Inhibitory activity of tryptanthrin on prostaglandin and leukotriene synthesis.

PubMed

Danz, Henning; Stoyanova, Stefka; Thomet, Olivier A R; Simon, Hans-Uwe; Dannhardt, Gerd; Ulbrich, Holger; Hamburger, Matthias

2002-10-01

The indolo[2,1- b]quinazoline alkaloid tryptanthrin has previously been identified as the cyclooxygenase-2 (COX-2) inhibitory principle in the extract ZE550 prepared from the medicinal plant Isatis tinctoria (Brassicaceae). We here investigated the potential inhibitory activity of tryptanthrin and ZE550 on COX-2, COX-1 in cellular and cell-free systems. A certain degree of selectivity towards COX-2 was observed when COX-1-dependent formation of thromboxane B(2) (TxB(2)) in HEL cells and COX-2-dependent formation of 6-ketoprostaglandin F(1alpha) (6-keto-PGF(1alpha)) in Mono Mac 6 and RAW 264.7 cells were compared. Preferential inhibition of COX-2 by two orders of magnitude was found in phorbol myristate acetate (PMA) activated bovine aortic coronary endothelial cells (BAECs). Assays with purified COX isoenzymes from sheep confirmed the high selectivity towards COX-2. The leukotriene B(4) (LTB(4)) release from calcium ionophore-stimulated human granulocytes (neutrophils) was used as a model to determine 5-lipoxygenase (5-LOX) activity. Tryptanthrin and the extract ZE550 inhibited LTB(4) release in a dose dependent manner and with a potency comparable to that of the clinically used 5-LOX inhibitor zileuton.

Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.

PubMed Central

Masferrer, J L; Zweifel, B S; Manning, P T; Hauser, S D; Leahy, K M; Smith, W G; Isakson, P C; Seibert, K

1994-01-01

We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammation in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by high levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of COX-2 mRNA and protein coincided with the production of PGs in the pouch tissue and cellular infiltrate. Carrageenan-induced COX-2 immunoreactivity was localized to macrophages obtained from the fluid exudate as well as to the inner surface layer of cells within the pouch lining. Dexamethasone inhibited both COX-2 expression and PG synthesis in the fluid exudate but failed to inhibit PG synthesis in the stomach. Furthermore, NS-398, a selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, blocked proinflammatory PG synthesis in the air pouch. In contrast, only indomethacin blocked gastric PG and, additionally, produced gastric lesions. These results suggest that inhibitors of COX-2 are potent antiinflammatory agents which do not produce the typical side effects (e.g., gastric ulcers) associated with the nonselective, COX-1-directed antiinflammatory drugs. Images PMID:8159730

Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors.

PubMed

Vernieri, Ermelinda; Gomez-Monterrey, Isabel; Milite, Ciro; Grieco, Paolo; Musella, Simona; Bertamino, Alessia; Scognamiglio, Ilaria; Alcaro, Stefano; Artese, Anna; Ortuso, Francesco; Novellino, Ettore; Sala, Marina; Campiglia, Pietro

2013-01-01

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 20(3) possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents.

PubMed

Lin, Chun-Kuang; Tseng, Chin-Kai; Wu, Yu-Hsuan; Liaw, Chih-Chuang; Lin, Chun-Yu; Huang, Chung-Hao; Chen, Yen-Hsu; Lee, Jin-Ching

2017-03-20

Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E 2 (PGE 2 ) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE 2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection.

Ku80 cooperates with CBP to promote COX-2 expression and tumor growth

PubMed Central

Qin, Yu; Xuan, Yang; Jia, Yunlu; Hu, Wenxian; Yu, Wendan; Dai, Meng; Li, Zhenglin; Yi, Canhui; Zhao, Shilei; Li, Mei; Du, Sha; Cheng, Wei; Xiao, Xiangsheng; Chen, Yiming; Wu, Taihua; Meng, Songshu; Yuan, Yuhui; Liu, Quentin; Huang, Wenlin; Guo, Wei; Wang, Shusen; Deng, Wuguo

2015-01-01

Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer. PMID:25797267

Heterogeneity in 14-year Dementia Incidence Between Asian American Subgroups.

PubMed

Mayeda, Elizabeth R; Glymour, M Maria; Quesenberry, Charles P; Whitmer, Rachel A

2017-01-01

Asian Americans are a rapidly growing and diverse population. Prior research on dementia among Asian Americans focused on Japanese Americans or Asian Americans overall, although marked differences in cardiometabolic conditions between subgroups have been documented. We compared dementia incidence among 4 Asian American subgroups (n=8384 Chinese; n=4478 Japanese; n=6210 Filipino; n=197 South Asian) and whites (n=206,490) who were Kaiser Permanente Northern California members aged 64 years and above with no dementia diagnoses as of January 1, 2000. Dementia diagnoses were collected from medical records January 1, 2000 to December 31, 2013. Baseline medical utilization and comorbidities (diabetes, depression, hypertension, stroke, cardiovascular disease) were abstracted from medical records January 1, 1996 to December 31, 1999. We calculated age-standardized dementia incidence rates and Cox models adjusted for age, sex, medical utilization, and comorbidities. Mean baseline age was 71.7 years; mean follow-up was 9.6 years. Age-standardized dementia incidence rates were higher among whites than "All Asian-Americans" or any subgroup. Compared with Chinese (13.7/1000 person-years), dementia incidence was slightly higher among Japanese [14.8/1000 person-years; covariate-adjusted hazard ratio (adjusted-HR)=1.08; 95% confidence interval (CI), 0.99-1.18] and Filipinos (17.3/1000 person-years; adjusted-HR=1.20; 95% CI, 1.11-1.31), and lower among South Asians (12.1/1000 person-years; adjusted-HR=0.81; 95% CI, 0.53-1.25). Future studies are needed to understand how immigration history, social, environmental, and genetic factors contribute to dementia risk in the growing and diverse Asian American population.

Phobic anxiety symptom scores and incidence of type 2 diabetes in US men and women

PubMed Central

Farvid, Maryam S; Qi, Lu; Hu, Frank B; Kawachi, Ichiro; Okereke, Olivia I; Kubzansky, Laura; Willett, Walter C

2013-01-01

Context Emotional stress may be a risk factor for type 2 diabetes (T2D), but the relation between phobic anxiety symptom scores and risk of T2D is uncertain. Objective To evaluate prospectively the association between phobic anxiety symptom scores and incident T2D in three cohorts of US men and women. Design, Setting and Patients We followed 30,830 men in the Health Professional’s Follow-Up Study (HPFS) (1988–2008), 69,336 women in the Nurses’ Health Study (NHS) (1988–2008), and 80,120 women in the Nurses’ Health Study II (NHS II) (1993–2011). Phobic anxiety symptom scores, as measured by the Crown-Crisp index (CCI), calculated from 8 questions, was administered at baseline and updated in 2004 for NHS, in 2005 for NHS II, and in 2000 for HPFS. Incident T2D was confirmed by a validated supplementary questionnaire. We used Cox proportional hazards analysis to evaluate associations with incident T2D. Results During 3,110,248 person-years of follow-up, we documented 12,876 incident T2D cases. In multivariable Cox regression models with adjustment for major lifestyle and dietary risk factors, the HRs of T2D across categories of increasing levels of CCI (scores= 2-<3, 3-<4, 4-<6, 6), compared with a score of <2, were increased significantly by 6%, 10%, 11% and 13% (Ptrend =0.0005) for NHS; and by 19%, 11%, 22%, and 29% (Ptrend <0.0001) for NHS II. Each score increment in CCI was associated with 3% higher risk of T2D in NHS (HRs, 1.03, 95%CI:1.02-1.04) and 4% higher risk of T2D in NHS II (HRs, 1.04, 95%CI:1.03-1.05). Further adjustment for self-reported depression and antidepressant use did not change the results. In HPFS, the association between CCI and T2D was not significant after adjusting for lifestyle variables. Conclusion Our results suggest that higher phobic anxiety symptom scores are associated with an increased risk of T2D in women. PMID:24184473

Do heads of government age more quickly? Observational study comparing mortality between elected leaders and runners-up in national elections of 17 countries

PubMed Central

Olenski, Andrew R; Abola, Matthew V

2015-01-01

Objectives To determine whether being elected to head of government is associated with accelerated mortality by studying survival differences between people elected to office and unelected runner-up candidates who never served. Design Observational study. Setting Historical survival data on elected and runner-up candidates in parliamentary or presidential elections in Australia, Austria, Canada, Denmark, Finland, France, Germany, Greece, Ireland, Italy, New Zealand, Norway, Poland, Spain, Sweden, United Kingdom, and United States, from 1722 to 2015. Participants Elected and runner-up political candidates. Main outcome measure Observed number of years alive after each candidate’s last election, relative to what would be expected for an average person of the same age and sex as the candidate during the year of the election, based on historical French and British life tables. Observed post-election life years were compared between elected candidates and runners-up, adjusting for life expectancy at time of election. A Cox proportional hazards model (adjusted for candidate’s life expectancy at the time of election) considered years until death (or years until end of study period for those not yet deceased by 9 September 2015) for elected candidates versus runners-up. Results The sample included 540 candidates: 279 winners and 261 runners-up who never served. A total of 380 candidates were deceased by 9 September 2015. Candidates who served as a head of government lived 4.4 (95% confidence interval 2.1 to 6.6) fewer years after their last election than did candidates who never served (17.8 v 13.4 years after last election; adjusted difference 2.7 (0.6 to 4.8) years). In Cox proportional hazards analysis, which considered all candidates (alive or deceased), the mortality hazard for elected candidates relative to runners-up was 1.23 (1.00 to 1.52). Conclusions Election to head of government is associated with a substantial increase in mortality risk compared with candidates in national elections who never served. PMID:26666894

Do heads of government age more quickly? Observational study comparing mortality between elected leaders and runners-up in national elections of 17 countries.

PubMed

Olenski, Andrew R; Abola, Matthew V; Jena, Anupam B

2015-12-14

To determine whether being elected to head of government is associated with accelerated mortality by studying survival differences between people elected to office and unelected runner-up candidates who never served. Observational study. Historical survival data on elected and runner-up candidates in parliamentary or presidential elections in Australia, Austria, Canada, Denmark, Finland, France, Germany, Greece, Ireland, Italy, New Zealand, Norway, Poland, Spain, Sweden, United Kingdom, and United States, from 1722 to 2015. Elected and runner-up political candidates. Observed number of years alive after each candidate's last election, relative to what would be expected for an average person of the same age and sex as the candidate during the year of the election, based on historical French and British life tables. Observed post-election life years were compared between elected candidates and runners-up, adjusting for life expectancy at time of election. A Cox proportional hazards model (adjusted for candidate's life expectancy at the time of election) considered years until death (or years until end of study period for those not yet deceased by 9 September 2015) for elected candidates versus runners-up. The sample included 540 candidates: 279 winners and 261 runners-up who never served. A total of 380 candidates were deceased by 9 September 2015. Candidates who served as a head of government lived 4.4 (95% confidence interval 2.1 to 6.6) fewer years after their last election than did candidates who never served (17.8 v 13.4 years after last election; adjusted difference 2.7 (0.6 to 4.8) years). In Cox proportional hazards analysis, which considered all candidates (alive or deceased), the mortality hazard for elected candidates relative to runners-up was 1.23 (1.00 to 1.52). Election to head of government is associated with a substantial increase in mortality risk compared with candidates in national elections who never served. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Phobic anxiety symptom scores and incidence of type 2 diabetes in US men and women.

PubMed

Farvid, Maryam S; Qi, Lu; Hu, Frank B; Kawachi, Ichiro; Okereke, Olivia I; Kubzansky, Laura D; Willett, Walter C

2014-02-01

Emotional stress may be a risk factor for type 2 diabetes (T2D), but the relation between phobic anxiety symptoms and risk of T2D is uncertain. To evaluate prospectively the association between phobic anxiety symptoms and incident T2D in three cohorts of US men and women. We followed 30,791 men in the Health Professional's Follow-Up Study (HPFS) (1988-2008), 68,904 women in the Nurses' Health Study (NHS) (1988-2008), and 79,960 women in the Nurses' Health Study II (NHS II) (1993-2011). Phobic anxiety symptom scores, as measured by the Crown-Crisp index (CCI), calculated from 8 questions, were administered at baseline and updated in 2004 for NHS, in 2005 for NHS II, and in 2000 for HPFS. Incident T2D was confirmed by a validated supplementary questionnaire. We used Cox proportional hazards analysis to evaluate associations with incident T2D. During 3,099,651 person-years of follow-up, we documented 12,831 incident T2D cases. In multivariate Cox proportional-hazards models with adjustment for major lifestyle and dietary risk factors, the hazard ratios (HRs) of T2D across categories of increasing levels of CCI (scores=2 to <3, 3 to <4, 4 to <6, ⩾6), compared with a score of <2, were increased significantly by 6%, 10%, 10% and 13% (Ptrend=0.001) for NHS; and by 19%, 11%, 21%, and 29% (Ptrend<0.0001) for NHS II. Each score increment in CCI was associated with 2% higher risk of T2D in NHS (HRs, 1.02, 95% confidence intervals: 1.01-1.03) and 4% higher risk of T2D in NHS II (HRs, 1.04, 95% confidence intervals: 1.02-1.05). Further adjustment for depression did not change the results. In HPFS, the association between CCI and T2D was not significant after adjusting for lifestyle variables. Our results suggest that higher phobic anxiety symptoms are associated with an increased risk of T2D in women. Copyright © 2013 Elsevier Inc. All rights reserved.

Flexible mixture modeling via the multivariate t distribution with the Box-Cox transformation: an alternative to the skew-t distribution

PubMed Central

Lo, Kenneth

2011-01-01

Cluster analysis is the automated search for groups of homogeneous observations in a data set. A popular modeling approach for clustering is based on finite normal mixture models, which assume that each cluster is modeled as a multivariate normal distribution. However, the normality assumption that each component is symmetric is often unrealistic. Furthermore, normal mixture models are not robust against outliers; they often require extra components for modeling outliers and/or give a poor representation of the data. To address these issues, we propose a new class of distributions, multivariate t distributions with the Box-Cox transformation, for mixture modeling. This class of distributions generalizes the normal distribution with the more heavy-tailed t distribution, and introduces skewness via the Box-Cox transformation. As a result, this provides a unified framework to simultaneously handle outlier identification and data transformation, two interrelated issues. We describe an Expectation-Maximization algorithm for parameter estimation along with transformation selection. We demonstrate the proposed methodology with three real data sets and simulation studies. Compared with a wealth of approaches including the skew-t mixture model, the proposed t mixture model with the Box-Cox transformation performs favorably in terms of accuracy in the assignment of observations, robustness against model misspecification, and selection of the number of components. PMID:22125375

Flexible mixture modeling via the multivariate t distribution with the Box-Cox transformation: an alternative to the skew-t distribution.

PubMed

Lo, Kenneth; Gottardo, Raphael

2012-01-01

Cluster analysis is the automated search for groups of homogeneous observations in a data set. A popular modeling approach for clustering is based on finite normal mixture models, which assume that each cluster is modeled as a multivariate normal distribution. However, the normality assumption that each component is symmetric is often unrealistic. Furthermore, normal mixture models are not robust against outliers; they often require extra components for modeling outliers and/or give a poor representation of the data. To address these issues, we propose a new class of distributions, multivariate t distributions with the Box-Cox transformation, for mixture modeling. This class of distributions generalizes the normal distribution with the more heavy-tailed t distribution, and introduces skewness via the Box-Cox transformation. As a result, this provides a unified framework to simultaneously handle outlier identification and data transformation, two interrelated issues. We describe an Expectation-Maximization algorithm for parameter estimation along with transformation selection. We demonstrate the proposed methodology with three real data sets and simulation studies. Compared with a wealth of approaches including the skew-t mixture model, the proposed t mixture model with the Box-Cox transformation performs favorably in terms of accuracy in the assignment of observations, robustness against model misspecification, and selection of the number of components.

Erectile Dysfunction in Male Adults With Atopic Dermatitis and Psoriasis.

PubMed

Egeberg, Alexander; Hansen, Peter R; Gislason, Gunnar H; Skov, Lone; Thyssen, Jacob P

2017-03-01

Patients with psoriasis have increased risk of cardiovascular disease, but data on atopic dermatitis (AD) are less clear-cut. However, it is well-established that erectile dysfunction (ED) can serve as a risk marker for coronary disease. To investigate the incidence, prevalence, and risk of ED in men with psoriasis and AD. The sample included all Danish men at least 30 years old. In patients with AD and psoriasis, we determined disease severity based on use of systemic therapy. We performed a cross-sectional study (January 1, 2008) using logistic regression to estimate the prevalence and odds ratio of ED. Moreover, in a cohort study design, patients were followed from January 1, 2008 through December 31, 2012, and Cox regression models were used to estimate adjusted hazard ratios of new-onset ED. Models were adjusted for potential confounding factors, including age, socioeconomic status, health care consumption, smoking, alcohol abuse, diabetes, and cholesterol-lowering drug use. The outcome was initiation of pharmacotherapy used for treatment of ED. The sample consisted of 1,756,679 Danish men (age range = 30-100 years), of which 2,373 and 26,536 had adult AD (mild = 1,072; severe = 1,301) and psoriasis (mild = 21,775; severe = 4,761), respectively. Mean ages (SDs) were 53.0 (14.6), 46.7 (12.0), and 56.3 (13.8) years for the general population, patients with AD, and patients with psoriasis, respectively. Prevalences of ED were 8.7%, 6.7%, and 12.8% for the general population, patients with AD, and patients with psoriasis, respectively. Adjusted odds ratios (logistic regression) of ED were decreased in patients with AD (0.68; 0.57-0.80) but increased in those with psoriasis (1.15; 1.11-1.20). Adjusted odds ratios for mild and severe AD were 0.63 (0.48-0.82) and 0.72 (0.58-0.88), respectively, and those for psoriasis these were 1.16 (1.11-1.21) and 1.13 (1.03-1.23). Adjusted hazard ratios (Cox regression) were 0.92 (0.76-1.11) for AD and 1.14 (1.08-1.20) for psoriasis. The ED risk was not increased in men with mild AD (0.85; 0.63-1.14) or severe AD (0.97; 0.76-1.24) but was significantly increased in men with mild psoriasis (1.13; 1.09-1.20) and severe psoriasis (1.17; 1.04-1.32). We found an increased prevalence and risk of ED in men with psoriasis, whereas the risk was comparable to (and even slightly lower than) the general population for men with AD. Egeberg A, Hansen PR, Gislason GH, et al. Erectile Dysfunction in Male Adults With Atopic Dermatitis and Psoriasis. J Sex Med 2017;14:380-386. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Heart failure in women and men during acute coronary syndrome and long-term cardiovascular mortality (the ABC-3* Study on Heart Disease) (*Adria, Bassano, Conegliano, and Padova Hospitals).

PubMed

Berton, Giuseppe; Cordiano, Rocco; Cavuto, Fiorella; Bagato, Francesco; Pellegrinet, Marco; Cati, Arianna

2016-10-01

We investigated the gender-based differences in the association between heart failure (HF) during acute coronary syndrome (ACS) and post-discharge, long-term cardiovascular (CV) mortality. The present study included 557 patients enrolled in three intensive coronary care units and discharged alive. HF during ACS was evaluated by Killip class and left ventricular ejection fraction (LVEF). Interaction between gender and HF after 15years of follow up was studied using Cox models including a formal interaction term. Median age was 67 (interquartile range [IQR], 59-75) years, 29% were females, 37% had non-ST elevation myocardial infarction and 32% Killip class>1, and median LVEF was 53% (IQR 46-61). All but five patients were followed up to 15years, representing 5332 person-years. Of these, 40.2% died of CV-related causes. Crude CV mortality rate was higher among women (52.2%) than men (35.3%; P<0.0001). At a univariable level, a negative interaction between female gender and Killip class for CV mortality was found [hazard ratio (HR)=0.51 (0.34-0.77), P=0.002]. In five multivariable models after controlling for age, main CV risk factors, clinical features, post-discharge medical treatment, and mechanical coronary reperfusion, the interaction was significant across all models [HR=0.63 (0.42-0.95), P=0.02 in the fully adjusted model]. LVEF showed no significant hazard associated with female gender on univariable analysis [HR=1.4 (0.9-0.2.0), P=0.11] but did so in all adjusted models [HR=1.7 (1.2-2.5), P=0.005 in the fully adjusted model]. Gender is a consistent, independent effect modifier in the association between HF and long-term CV mortality after ACS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cyclooxygenase-2 inhibitors modulate skin aging in a catalytic activity-independent manner

PubMed Central

Lee, Mi Eun; Kim, So Ra; Lee, Seungkoo; Jung, Yu-Jin; Choi, Sun Shim; Kim, Woo Jin

2012-01-01

It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2 inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1. PMID:22771771

Yogurt consumption, weight change and risk of overweight/obesity: the SUN cohort study.

PubMed

Martinez-Gonzalez, M A; Sayon-Orea, C; Ruiz-Canela, M; de la Fuente, C; Gea, A; Bes-Rastrollo, M

2014-11-01

Epidemiological studies on the association between yogurt consumption and the risk of overweight/obesity are scarce. We prospectively examined the association of yogurt consumption with overweight/obesity and average annual weight gain. Prospective cohort study of 8516 men and women (mean age 37.1, SD: 10.8 y). Participants were followed-up every two years. Participants were classified in 5 categories of yogurt consumption at baseline: 0-2, >2-<5, 5-<7, 7 and ≥ 7 servings/week. Outcomes were: 1) average yearly weight change during follow-up; and 2) incidence of overweight/obesity. Linear regression models and Cox models were used to adjust for potential confounders. After a median follow-up of 6.6 years, 1860 incident cases of overweight/obesity were identified. A high (>7 servings/week) consumption of total and whole-fat yogurt was associated with lower incidence of overweight/obesity [multivariable adjusted hazard ratios = 0.80 (95% CI: 0.68-0.94); and 0.62 (0.47-0.82) respectively] in comparison with low consumption (0-2 servings/week). This inverse association was stronger among participants with higher fruit consumption. In this Mediterranean cohort, yogurt consumption was inversely associated with the incidence of overweight/obesity, especially among participants with higher fruit consumption. Copyright © 2014 Elsevier B.V. All rights reserved.

Work disability following major organisational change: the Whitehall II study.

PubMed

Virtanen, M; Kivimäki, M; Singh-Manoux, A; Gimeno, D; Shipley, M J; Vahtera, J; Akbaraly, T N; Marmot, M G; Ferrie, J E

2010-05-01

Privatisation and private sector practices have been increasingly applied to the public sector in many industrialised countries. Over the same period, long-term work disability has risen substantially. We examined whether a major organisational change--the transfer of public sector work to executive agencies run on private sector lines--was associated with an increased risk of work disability. The study uses self-reported data from the prospective Whitehall II cohort study. Associations between transfer to an executive agency assessed at baseline (1991-1994) and work disability ascertained over a period of approximately 8 years at three follow-up surveys (1995-1996, 1997-1999 and 2001) were examined using Cox proportional hazard models. In age- and sex-adjusted models, risk of work disability was higher among the 1263 employees who were transferred to an executive agency (HR 1.90, 95% CI 1.46 to 2.48) compared with the 3419 employees whose job was not transferred. These findings were robust to additional adjustment for physical and mental health and health behaviours at baseline. Increased work disability was observed among employees exposed to the transfer of public sector work to executive agencies run on private sector lines. This may highlight an unintentional cost for employees, employers and society.

The prognostic role of body mass index on mortality amongst the middle-aged and elderly: a competing risk analysis.

PubMed

Ghaem Maralani, Haleh; Tai, Bee Choo; Wong, Tien Y; Tai, E Shyong; Li, Jialiang; Wang, Jie Jin; Mitchell, Paul

2014-01-01

To determine the relationship between body mass index (BMI) including its 5-year changes and mortality, and compare the results obtained using Cox and competing risks models. Our study subjects included 2216 persons aged ≥49 years who participated in the Blue Mountains Eye Study, Australia between 1992 and 1994, and returned for further follow-up examinations between 1997 and 1999. We examined the relationship between BMI and mortality using cubic spline. The Cox and competing risks models were used to assess the associations between baseline BMI and its 5-year changes with all-cause and cause-specific mortality. Amongst subjects aged ≤70 years, the relationship between BMI and all-cause mortality was U-shaped. For those aged >70 years, an L-shaped relationship was seen with no elevation in risk amongst the overweight/obese. Based on the competing risks model, obesity at baseline was associated with increased risk of cardiovascular death and reduction in BMI at 5-year was linked to an increase risk of cancer death amongst those aged ≤70 years. The cause-specific Cox model showed that reduction in BMI at 5-year was associated with cancer-death regardless of age, and with cardiovascular deaths among subjects aged ≤70 years. Cox regression model showed larger magnitude of effect with wider confidence interval as compared with competing risks model. Conditions associated with obesity are more likely to affect mortality among subjects aged ≤70 years, but not among those aged over 70 years. Cox model shows larger magnitude of effect in comparison with competing risks model. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

A simple approach to power and sample size calculations in logistic regression and Cox regression models.

PubMed

Vaeth, Michael; Skovlund, Eva

2004-06-15

For a given regression problem it is possible to identify a suitably defined equivalent two-sample problem such that the power or sample size obtained for the two-sample problem also applies to the regression problem. For a standard linear regression model the equivalent two-sample problem is easily identified, but for generalized linear models and for Cox regression models the situation is more complicated. An approximately equivalent two-sample problem may, however, also be identified here. In particular, we show that for logistic regression and Cox regression models the equivalent two-sample problem is obtained by selecting two equally sized samples for which the parameters differ by a value equal to the slope times twice the standard deviation of the independent variable and further requiring that the overall expected number of events is unchanged. In a simulation study we examine the validity of this approach to power calculations in logistic regression and Cox regression models. Several different covariate distributions are considered for selected values of the overall response probability and a range of alternatives. For the Cox regression model we consider both constant and non-constant hazard rates. The results show that in general the approach is remarkably accurate even in relatively small samples. Some discrepancies are, however, found in small samples with few events and a highly skewed covariate distribution. Comparison with results based on alternative methods for logistic regression models with a single continuous covariate indicates that the proposed method is at least as good as its competitors. The method is easy to implement and therefore provides a simple way to extend the range of problems that can be covered by the usual formulas for power and sample size determination. Copyright 2004 John Wiley & Sons, Ltd.

Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome.

PubMed

Morgan, Thomas M; House, John A; Cresci, Sharon; Jones, Philip; Allayee, Hooman; Hazen, Stanley L; Patel, Yesha; Patel, Riyaz S; Eapen, Danny J; Waddy, Salina P; Quyyumi, Arshed A; Kleber, Marcus E; März, Winfried; Winkelmann, Bernhard R; Boehm, Bernhard O; Krumholz, Harlan M; Spertus, John A

2011-09-29

Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated. We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients. After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086). We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.

Selective cyclooxygenase-2 inhibitor suppresses renal thromboxane production but not proliferative lesions in the MRL/lpr murine model of lupus nephritis.

PubMed

Oates, Jim C; Halushka, Perry V; Hutchison, Florence N; Ruiz, Philip; Gilkeson, Gary S

2011-02-01

Proliferative lupus nephritis (LN) is marked by increased renal thromboxane (TX) A₂ production. Targeting the TXA₂ receptor or TXA₂ synthase effectively improves renal function in humans with LN and improves glomerular pathology in murine LN. This study was designed to address the following hypotheses: (1) TXA₂ production in the MRL/MpJ-Tnfrsf6(lpr)/J (MRL/lpr) model of proliferative LN is cyclooxygenase (COX)-2 dependent and (2) COX2 inhibitor therapy improves glomerular filtration rate (GFR), proteinuria, markers of innate immune response and glomerular pathology. Twenty female MRL/lpr and 20 BALB/cJ mice were divided into 2 equal treatment groups: (1) SC-236, a moderately selective COX2 inhibitor or (2) vehicle. After treatment from the age of 10 to 20 weeks, the effectiveness of inhibition of TXA₂ was determined by measuring urine TXB₂. Response endpoints measured at the age of 20 weeks were renal function (GFR), proteinuria, urine nitrate + nitrite (NO(x)) and glomerular histopathology. SC-236 therapy reduced surrogate markers of renal TXA₂ production during early, active glomerulonephritis. When this pharmacodynamic endpoint was reached, therapy improved GFR. Parallel reductions in markers of the innate immune response (urine NO(x)) during therapy were observed. However, the beneficial effect of SC-236 therapy on GFR was only transient, and renal histopathology was not improved in late disease. These data demonstrate that renal TXA2 production is COX2 dependent in murine LN and suggest that NO production is directly or indirectly COX2 dependent. However, COX2 inhibitor therapy in this model failed to improve renal pathology, making COX2 inhibition a less attractive approach for treating LN.

The bitter barricading of prostaglandin biosynthesis pathway: understanding the molecular mechanism of selective cyclooxygenase-2 inhibition by amarogentin, a secoiridoid glycoside from Swertia chirayita.

PubMed

Shukla, Shantanu; Bafna, Khushboo; Sundar, Durai; Thorat, Sunil S

2014-01-01

Swertia chirayita, a medicinal herb inhabiting the challenging terrains and high altitudes of the Himalayas, is a rich source of essential phytochemical isolates. Amarogentin, a bitter secoiridoid glycoside from S. chirayita, shows varied activity in several patho-physiological conditions, predominantly in leishmaniasis and carcinogenesis. Experimental analysis has revealed that amarogentin downregulates the cyclooxygenase-2 (COX-2) activity and helps to curtail skin carcinogenesis in mouse models; however, there exists no account on selective inhibition of the inducible cyclooxygenase (COX) isoform by amarogentin. Hence the computer-aided drug discovery methods were used to unravel the COX-2 inhibitory mechanism of amarogentin and to check its selectivity for the inducible isoform over the constitutive one. The generated theoretical models of both isoforms were subjected to molecular docking analysis with amarogentin and twenty-one other Food and Drug Authority (FDA) approved lead molecules. The post-docking binding energy profile of amarogentin was comparable to the binding energy profiles of the FDA approved selective COX-2 inhibitors. Subsequent molecular dynamics simulation analysis delineated the difference in the stability of both complexes, with amarogentin-COX-2 complex being more stable after 40ns simulation. The total binding free energy calculated by MMGBSA for the amarogentin-COX-2 complex was -52.35 KCal/mol against a binding free energy of -8.57 KCal/mol for amarogentin-COX-1 complex, suggesting a possible selective inhibition of the COX-2 protein by the natural inhibitor. Amarogentin achieves this potential selectivity by small, yet significant, structural differences inherent to the binding cavities of the two isoforms. Hypothetically, it might block the entry of the natural substrates in the hydrophobic binding channel of the COX-2, inhibiting the cyclooxygenation step. To sum up briefly, this work highlights the mechanism of the possible selective COX-2 inhibition by amarogentin and endorses the possibility of obtaining efficient, futuristic and targeted therapeutic agents for relieving inflammation and malignancy from this phytochemical source.

The Application of Extended Cox Proportional Hazard Method for Estimating Survival Time of Breast Cancer

NASA Astrophysics Data System (ADS)

Husain, Hartina; Astuti Thamrin, Sri; Tahir, Sulaiha; Mukhlisin, Ahmad; Mirna Apriani, M.

2018-03-01

Breast cancer is one type of cancer that is the leading cause of death worldwide. This study aims to model the factors that affect the survival time and rate of cure of breast cancer patients. The extended cox model, which is a modification of the proportional hazard cox model in which the proportional hazard assumptions are not met, is used in this study. The maximum likelihood estimation approach is used to estimate the parameters of the model. This method is then applied to medical record data of breast cancer patient in 2011-2016, which is taken from Hasanuddin University Education Hospital. The results obtained indicate that the factors that affect the survival time of breast cancer patients are malignancy and leukocyte levels.

Antidepressant Medication Use and its Association with Cardiovascular Disease and All-Cause Mortality in the Reasons for Geographic and Ethnic Differences in Stroke (REGARDS) Study

PubMed Central

Hansen, Richard A.; Khodneva, Yulia; Glasser, Stephen P.; Qian, Jingjing; Redmond, Nicole; Safford, Monika M.

2018-01-01

Background Mixed evidence suggests second-generation antidepressants may increase risk of cardiovascular and cerebrovascular events. Objective Assess whether antidepressant use is associated with acute coronary heart disease, stroke, cardiovascular disease death, and all-cause mortality. Methods Secondary analyses of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) longitudinal cohort study were conducted. Use of selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, bupropion, nefazodone, and trazodone was measured during the baseline (2003-2007) in-home visit. Outcomes of coronary heart disease, stroke, cardiovascular disease death, and all-cause mortality were assessed every 6 months and adjudicated by medical record review. Cox proportional hazards time-to-event analysis followed patients until their first event on or before December 31, 2011, iteratively adjusting for covariates. Results Among 29,616 participants, 3,458 (11.7%) used an antidepressant of interest. Intermediate models adjusting for everything but physical and mental health found an increased risk of acute coronary heart disease (Hazard Ratio=1.21; 95% CI 1.04-1.41), stroke (Hazard Ratio=1.28; 95% CI 1.02-1.60), cardiovascular disease death (Hazard Ratio =1.29; 95% CI 1.09-1.53), and all-cause mortality (Hazard Ratio=1.27; 95% CI 1.15-1.41) for antidepressant users. Risk estimates trended in this direction for all outcomes in the fully adjusted model, but only remained statistically associated with increased risk of all-cause mortality (Hazard Ratio=1.12; 95% CI 1.01-1.24). This risk was attenuated in sensitivity analyses censoring follow-up time at 2-years (Hazard Ratio=1.37; 95% CI 1.11-1.68). Conclusions In fully adjusted models antidepressant use was associated with a small increase in all-cause mortality. PMID:26783360

Urinary Tract Stones and Osteoporosis: Findings From the Women’s Health Initiative

PubMed Central

Carbone, Laura D; Hovey, Kathleen M; Andrews, Christopher A; Thomas, Fridtjof; Sorensen, Mathew D; Crandall, Carolyn J; Watts, Nelson B; Bethel, Monique; Johnson, Karen C

2017-01-01

Kidney and bladder stones (urinary tract stones) and osteoporosis are prevalent, serious conditions for postmenopausal women. Men with kidney stones are at increased risk of osteoporosis; however, the relationship of urinary tract stones to osteoporosis in postmenopausal women has not been established. The purpose of this study was to determine whether urinary tract stones are an independent risk factor for changes in bone mineral density (BMD) and incident fractures in women in the Women’s Health Initiative (WHI). Data were obtained from 150,689 women in the Observational Study and Clinical Trials of the WHI with information on urinary tract stones status: 9856 of these women reported urinary tract stones at baseline and/or incident urinary tract stones during follow-up. Cox regression models were used to determine the association of urinary tract stones with incident fractures and linear mixed models were used to investigate the relationship of urinary tract stones with changes in BMD that occurred during WHI. Follow-up was over an average of 8 years. Models were adjusted for demographic and clinical factors, medication use, and dietary histories. In unadjusted models there was a significant association of urinary tract stones with incident total fractures (HR 1.10; 95% CI, 1.04 to 1.17). However, in covariate adjusted analyses, urinary tract stones were not significantly related to changes in BMD at any skeletal site or to incident fractures. In conclusion, urinary tract stones in postmenopausal women are not an independent risk factor for osteoporosis. PMID:25990099

Metabolic syndrome, impaired fasting glucose and obesity, as predictors of incident diabetes in 14 120 hypertensive patients of ASCOT-BPLA: comparison of their relative predictability using a novel approach.

PubMed

Gupta, A K; Prieto-Merino, D; Dahlöf, B; Sever, P S; Poulter, N R

2011-08-01

To evaluate, in hypertensive patients, whether the metabolic syndrome is a better predictor of new-onset diabetes compared with impaired fasting glucose, obesity or its other individual components alone, or collectively. Cox models were developed to assess the risk of new-onset diabetes associated with the metabolic syndrome after adjusting for a priori confounders (age, sex, ethnicity and concomitant use of non-cardiovascular medications), its individual components and other determinants of new-onset diabetes. Area under receiver operator curves using the metabolic syndrome or models of impaired fasting glucose were compared, and the ability of these models to correctly identify those who (after 5-years of follow-up) would or would not develop diabetes was assessed. The metabolic syndrome adjusted for a priori confounders and its individual components, and further adjusted for other determinants, was associated with significantly increased risk of new-onset diabetes [1.19 (1.00-1.40), P = 0.05 and 1.22 (1.03-1.44), P = 0.02, respectively]. The discriminative ability of the metabolic syndrome model [area under receiver operating curve: 0.764 (0.750-0.778)] was significantly better than the model of impaired fasting glucose [0.742 (0.727-0.757)] (P < 0.001). The metabolic syndrome correctly allocates the risk of new-onset diabetes in a significantly higher proportion of patients (62.3%) than impaired fasting glucose status (37.7%) (P < 0.001). The presence of both the metabolic syndrome and impaired fasting glucose were associated with an approximately 9-fold (7.47-10.45) increased risk of new-onset diabetes. Among normoglycaemic patients, the metabolic syndrome was also associated with significantly increased risk of new-onset diabetes, after adjusting for BMI and a priori confounders [1.66 (1.29-2.13)]. Both impaired fasting glucose and the metabolic syndrome predict the risk of new-onset diabetes; however, the metabolic syndrome is a better predictor than impaired fasting glucose in assigning the risk of new-onset diabetes in hypertensive patients, and among those with normoglycaemia. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Delayed heart rate recovery after exercise as a risk factor of incident type 2 diabetes mellitus after adjusting for glycometabolic parameters in men.

PubMed

Yu, Tae Yang; Jee, Jae Hwan; Bae, Ji Cheol; Hong, Won-Jung; Jin, Sang-Man; Kim, Jae Hyeon; Lee, Moon-Kyu

2016-10-15

Some studies have reported that delayed heart rate recovery (HRR) after exercise is associated with incident type 2 diabetes mellitus (T2DM). This study aimed to investigate the longitudinal association of delayed HRR following a graded exercise treadmill test (GTX) with the development of T2DM including glucose-associated parameters as an adjusting factor in healthy Korean men. Analyses including fasting plasma glucose, HOMA-IR, HOMA-β, and HbA1c as confounding factors and known confounders were performed. HRR was calculated as peak heart rate minus heart rate after a 1-min rest (HRR 1). Cox proportional hazards model was used to quantify the independent association between HRR and incident T2DM. During 9082 person-years of follow-up between 2006 and 2012, there were 180 (10.1%) incident cases of T2DM. After adjustment for age, BMI, systolic BP, diastolic BP, smoking status, peak heart rate, peak oxygen uptake, TG, LDL-C, HDL-C, fasting plasma glucose, HOMA-IR, HOMA-β, and HbA1c, the hazard ratios (HRs) [95% confidence interval (CI)] of incident T2DM comparing the second and third tertiles to the first tertile of HRR 1 were 0.867 (0.609-1.235) and 0.624 (0.426-0.915), respectively (p for trend=0.017). As a continuous variable, in the fully-adjusted model, the HR (95% CI) of incident T2DM associated with each 1 beat increase in HRR 1 was 0.980 (0.960-1.000) (p=0.048). This study demonstrated that delayed HRR after exercise predicts incident T2DM in men, even after adjusting for fasting glucose, HOMA-IR, HOMA-β, and HbA1c. However, only HRR 1 had clinical significance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inflammation as a Mediator of the Association Between Race and Atrial Fibrillation: Results from the Health, Aging, and Body Composition Study

PubMed Central

Dewland, Thomas A.; Vittinghoff, Eric; Harris, Tamara B.; Magnani, Jared W.; Liu, Yongmei; Hsu, Fang-Chi; Satterfield, Suzanne; Wassel, Christina; Marcus, Gregory M.

2015-01-01

Background Despite a lower prevalence of established atrial fibrillation (AF) risk factors, Whites exhibit substantially higher rates of this arrhythmia compared to Blacks. The mechanism underlying this observation is not known. Both inflammation and obesity are risk factors for AF, and adipose tissue is a known contributor to systemic inflammation. Objectives We sought to determine the degree to which racial differences in AF risk are explained by differences in inflammation and adiposity. Methods Baseline serum inflammatory biomarker concentrations and abdominal adiposity (assessed by computed tomography) were quantified in a subset of Black and White participants without prevalent AF in the Health, Aging, and Body Composition (Health ABC) Study. Participants were prospectively followed for the diagnosis of AF using study ECGs and Medicare claims data. Cox proportional hazards models were used to determine the adjusted relative hazard of incident AF between races before and after biomarker adjustment. Results Among 2,768 participants (43% Black), 721 developed incident AF over a median follow up of 10.9 years. White race was associated with a heightened adjusted risk of incident AF (HR 1.55, 95% CI 1.30 to 1.84, p < 0.001). Abdominal adiposity was not associated with AF when added to the adjusted model. Among the studied biomarkers, adiponectin, TNF-α, TNF-α SR I, and TNF-α SR II concentrations were each higher among Whites and independently associated with a greater risk of incident AF. Together, these inflammatory cytokines mediated 42% (95% CI 15 to 119%, p = 0.004) of the adjusted race-AF association. Conclusions Systemic inflammatory pathways significantly mediate the heightened risk of AF among Whites. The higher level of systemic inflammation and concomitant increased AF risk in Whites is not explained by racial differences in abdominal adiposity or the presence of other pro-inflammatory cardiovascular comorbidities. PMID:26501131

Somatic gene mutations in African Americans may predict worse outcomes in colorectal cancer.

PubMed

Kang, Melissa; Shen, Xiang J; Kim, Sangmi; Araujo-Perez, Felix; Galanko, Joseph A; Martin, Chris F; Sandler, Robert S; Keku, Temitope O

2013-01-01

African Americans have worse outcomes in colorectal cancer (CRC) than Caucasians. We sought to determine if KRAS, BRAF and PIK3CA mutations might contribute to the racial differences in CRC outcome. DNA was extracted from tissue microarrays made from CRC samples from 67 African Americans and 237 Caucasians. Mutations in KRAS, BRAF, and PIK3CA were evaluated by PCR sequencing. We also examined microsatellite instability (MSI) status. Associations of mutation status with tumor stage and grade were examined using a logistic regression model. Cox proportional hazards models were used to estimate the all-cause mortality associated with mutational status, race and other clinicopathologic features. KRAS mutations were more common in African Americans than among Caucasians (37% vs 21%, p=0.01) and were associated with advanced stage (unadjusted odds ratio (OR)=3.31, 95% confidence interval (CI) 1.03-10.61) and grade (unadjusted OR=5.60, 95% CI 1.01-31.95) among African Americans. Presence of BRAF mutations was also positively associated with advanced tumor stage (adjusted OR=3.99, 95%CI 1.43-11.12) and grade (adjusted OR=3.93, 95%CI 1.05-14.69). PIK3CA mutations showed a trend toward an association with an increased risk of death compared to absence of those mutations (adjusted for age, sex and CRC site HR=1.89, 95% CI 0.98-3.65). Among African Americans, the association was more evident (adjusted for age, sex and CRC site HR=3.92, 95% CI 1.03-14.93) and remained significant after adjustment for MSI-H status and combined education-income level, with HR of 12.22 (95%CI 1.32-121.38). Our results suggest that African Americans may have different frequencies of somatic genetic alterations that may partially explain the worse prognosis among African Americans with CRC compared to whites.

Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program

PubMed Central

Zacharia, Brad E.; Bruce, Samuel S.; Goldstein, Hannah; Malone, Hani R.; Neugut, Alfred I.; Bruce, Jeffrey N.

2012-01-01

Craniopharyngioma is a rare primary central nervous system neoplasm. Our objective was to determine factors associated with incidence, treatment, and survival of craniopharyngiomas in the United States. We used the surveillance, epidemiology and end results program (SEER) database to identify patients who received a diagnosis of craniopharyngioma during 2004–2008. We analyzed clinical and demographic information, including age, race, sex, tumor histology, and treatment. Age-adjusted incidence rates and age, sex, and race-adjusted expected survival rates were calculated. We used Cox proportional hazards models to determine the association between covariates and overall survival. We identified 644 patients with a diagnosis of craniopharyngioma. Black race was associated with an age-adjusted relative risk for craniopharyngioma of 1.26 (95% confidence interval [CI], 0.98–1.59), compared with white race. One- and 3-year survival rates of 91.5% (95% CI, 88.9%–93.5%), and 86.2% (95% CI, 82.7%–89.0%) were observed for the cohort; relative survival rates were 92.1% (95% CI, 89.5%–94.0%) and 87.6% (95% CI, 84.1%–90.4%) for 1- and 3-years, respectively. In the multivariable model, factors associated with prolonged survival included younger age, smaller tumor size, subtotal resection, and radiation therapy. Black race, on the other hand, was associated with worse overall survival in the final model. We demonstrated that >85% of patients survived 3 years after diagnosis and that subtotal resection and radiation therapy were associated with prolonged survival. We also noted a higher incidence rate and worse 1- and 3-year survival rates in the black population. Future investigations should examine these racial disparities and focus on evaluating the efficacy of emerging treatment paradigms. PMID:22735773

Area-Level Deprivation and Overall and Cause-Specific Mortality: 12 Years’ Observation on British Women and Systematic Review of Prospective Studies

PubMed Central

Sánchez-Santos, Maria T.; Mesa-Frias, Marco; Choi, Minkyoung; Nüesch, Eveline; Asunsolo-Del Barco, Angel; Amuzu, Antoinette; Smith, George Davey; Ebrahim, Shah; Prieto-Merino, David; Casas, Juan P.

2013-01-01

Background Prospective studies have suggested a negative impact of area deprivation on overall mortality, but its effect on cause-specific mortality and the mechanisms that account for this association remain unclear. We investigate the association of area deprivation, using Index of Multiple deprivation (IMD), with overall and cause-specific mortality, contextualising findings within a systematic review. Methods And Findings We used data from 4,286 women from the British Women’s Heart Health Study (BWHHS) recruited at 1999-2001 to examine the association of IMD with overall and cause-specific mortality using Cox regression models. One standard deviation (SD) increase in the IMD score had a hazard ratio (HR) of 1.21 (95% CI: 1.13-1.30) for overall mortality after adjustment for age and lifecourse individual deprivation, which was attenuated to 1.15 (95% CI: 1.04-1.26) after further inclusion of mediators (health behaviours, biological factors and use of statins and blood pressure-lowering medications). A more pronounced association was observed for respiratory disease and vascular deaths. The meta-analysis, based on 20 published studies plus the BWHHS (n=21), yielded a summary relative risk (RR) of 1.15 (95% CI: 1.11-1.19) for area deprivation (top [least deprived; reference] vs. bottom tertile) with overall mortality in an age and sex adjusted model, which reduced to 1.06 (95% CI: 1.04-1.08) in a fully adjusted model. Conclusions Health behaviours mediate the association between area deprivation and cause-specific mortality. Efforts to modify health behaviours may be more successful if they are combined with measures that tackle area deprivation. PMID:24086262

Readmissions After Colon Cancer Surgery: Does It Matter Where Patients Are Readmitted?

PubMed Central

Hussain, Tanvir; Chang, Hsien-Yen; Pfoh, Elizabeth; Pollack, Craig Evan

2016-01-01

Purpose: Readmissions to a different hospital may place patients at increased risk for poor outcomes and may increase their overall costs of care. We evaluated whether mortality and costs differ for patients with colon cancer on the basis of whether patients are readmitted to the index hospital or to a different hospital within 30 days of discharge. Methods: We conducted a retrospective analysis using SEER-Medicare linked claims data for patients with stage I to III colon cancer diagnosed between 2000 and2009 who were readmitted within 30 days (N = 3,399). Our primary outcome was all-cause mortality, which was modeled by using Cox proportional hazards. Secondary outcomes included colon cancer–specific mortality, 90-day mortality, and costs of care. We used subhazard ratios for colon cancer– specific mortality and generalized linear models for costs. For each model, we used a propensity score–weighted doubly robust approach to adjust for patient, physician, and hospital characteristics. Results: Approximately 23% (n = 769) of readmitted patients were readmitted to a different hospital than where they were initially discharged. After adjustment, there was no difference in all-cause mortality, colon cancer–specific mortality, or cost of care for patients readmitted to a different hospital. Patient readmitted to a different hospital did have a higher risk of short-term mortality (90-day all-cause mortality; adjusted hazard ratio, 1.18; 95% CI, 1.02 to 1.38). Conclusion: Readmission to a different hospital after colon cancer surgery is associated with short-term mortality but not with long-term mortality nor with post-discharge costs of care. Additional investigation is needed to determine how to improve short-term mortality among patients readmitted to different hospitals. PMID:27048614

Utility of serum lipid ratios for predicting incident type 2 diabetes: the Isfahan Diabetes Prevention Study.

PubMed

Janghorbani, Mohsen; Amini, Masoud

2016-09-01

In this study, we evaluate the association between triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio and total cholesterol (TC) to HDL (TC/HDL) ratio and the risks of type 2 diabetes (T2D) in an Iranian high-risk population. We analysed 7-year follow-up data (n = 1771) in non-diabetic first-degree relatives of consecutive patients with T2D 30-70 years old. The primary outcome was the diagnosis of T2D based on repeated oral glucose tolerance tests. We used Cox proportional hazard models to estimate hazard ratio for incident T2D across tertiles of TG/HDL and TC/HDL ratios and plotted a receiver operating characteristic (ROC) curve to assess discrimination. The highest tertile of TG/HDL and TC/HDL ratios compared with the lowest tertile was not associated with T2D in age- and gender-adjusted models (HR 0.99, 95% CI: 0.88, 1.11 for TG/HDL ratio and 1.10, 95% CI: 0.97, 1.23 for TC/HDL ratio). Further adjustment for waist circumference or body mass index, fasting plasma glucose, and low-density lipoprotein cholesterol did not appreciably alter the hazard ratio compared with the age- and gender-adjusted model. The area under the ROC curve for TG/HDL ratio was 57.7% (95% CI: 54.0, 61.5) and for TC/HDL ratio was 55.1% (95% CI: 51.2, 59.0). TG/HDL and TC/HDL ratios were not robust predictors of T2D in high-risk individuals in Iran. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Comparative Outcome Analysis of Penicillin-Based Versus Fluoroquinolone-Based Antibiotic Therapy for Community-Acquired Pneumonia

PubMed Central

Wang, Chi-Chuan; Lin, Chia-Hui; Lin, Kuan-Yin; Chuang, Yu-Chung; Sheng, Wang-Huei

2016-01-01

Abstract Community-acquired pneumonia (CAP) is a common but potentially life-threatening condition, but limited information exists on the effectiveness of fluoroquinolones compared to β-lactams in outpatient settings. We aimed to compare the effectiveness and outcomes of penicillins versus respiratory fluoroquinolones for CAP at outpatient clinics. This was a claim-based retrospective cohort study. Patients aged 20 years or older with at least 1 new pneumonia treatment episode were included, and the index penicillin or respiratory fluoroquinolone therapies for a pneumonia episode were at least 5 days in duration. The 2 groups were matched by propensity scores. Cox proportional hazard models were used to compare the rates of hospitalizations/emergence service visits and 30-day mortality. A logistic model was used to compare the likelihood of treatment failure between the 2 groups. After propensity score matching, 2622 matched pairs were included in the final model. The likelihood of treatment failure of fluoroquinolone-based therapy was lower than that of penicillin-based therapy (adjusted odds ratio [AOR], 0.88; 95% confidence interval [95%CI], 0.77–0.99), but no differences were found in hospitalization/emergence service (ES) visits (adjusted hazard ratio [HR], 1.27; 95% CI, 0.92–1.74) and 30-day mortality (adjusted HR, 0.69; 95% CI, 0.30–1.62) between the 2 groups. The likelihood of treatment failure of fluoroquinolone-based therapy was lower than that of penicillin-based therapy for CAP on an outpatient clinic basis. However, this effect may be marginal. Further investigation into the comparative effectiveness of these 2 treatment options is warranted. PMID:26871827

Adjusting for reverse causation to estimate the effect of obesity on mortality after incident heart failure in the Atherosclerosis Risk in Communities (ARIC) study.

PubMed

Shakiba, Maryam; Soori, Hamid; Mansournia, Mohammad Ali; Nazari, Seyed Saeed Hashemi; Salimi, Yahya

2016-01-01

The lower mortality rate of obese patients with heart failure (HF) has been partly attributed to reverse causation bias due to weight loss caused by disease. Using data about weight both before and after HF, this study aimed to adjust for reverse causation and examine the association of obesity both before and after HF with mortality. Using the Atherosclerosis Risk in Communities (ARIC) study, 308 patients with data available from before and after the incidence of HF were included. Pre-morbid and post-morbid obesity were defined based on body mass index measurements at least three months before and after incident HF. The associations of pre-morbid and post-morbid obesity and weight change with survival after HF were evaluated using a Cox proportional hazard model. Pre-morbid obesity was associated with higher mortality (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.04 to 2.49) but post-morbid obesity was associated with increased survival (HR, 0.57; 95% CI, 0.37 to 0.88). Adjusting for weight change due to disease as a confounder of the obesity-mortality relationship resulted in the absence of any significant associations between post-morbid obesity and mortality. This study demonstrated that controlling for reverse causality by adjusting for the confounder of weight change may remove or reverse the protective effect of obesity on mortality among patients with incident HF.

Density of calcium in the ascending thoracic aorta and risk of incident cardiovascular disease events.

PubMed

Thomas, Isac C; McClelland, Robyn L; Michos, Erin D; Allison, Matthew A; Forbang, Nketi I; Longstreth, W T; Post, Wendy S; Wong, Nathan D; Budoff, Matthew J; Criqui, Michael H

2017-10-01

The volume and density of coronary artery calcium (CAC) both independently predict cardiovascular disease (CVD) beyond standard risk factors, with CAC density inversely associated with incident CVD after accounting for CAC volume. We tested the hypothesis that ascending thoracic aorta calcium (ATAC) volume and density predict incident CVD events independently of CAC. The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of participants without clinical CVD at baseline. ATAC and CAC were measured from baseline cardiac computed tomography (CT). Cox regression models were used to estimate the associations of ATAC volume and density with incident coronary heart disease (CHD) events and CVD events, after adjustment for standard CVD risk factors and CAC volume and density. Among 6811 participants, 234 (3.4%) had prevalent ATAC and 3395 (49.8%) had prevalent CAC. Over 10.3 years, 355 CHD and 562 CVD events occurred. One-standard deviation higher ATAC density was associated with a lower risk of CHD (HR 0.48 [95% CI 0.29-0.79], p<0.01) and CVD (HR 0.56 [0.37-0.84], p<0.01) after full adjustment. ATAC volume was not associated with outcomes after full adjustment. ATAC was uncommon in a cohort free of clinical CVD at baseline. However, ATAC density was inversely associated with incident CHD and CVD after adjustment for CVD risk factors and CAC volume and density. Copyright © 2017 Elsevier B.V. All rights reserved.

Statins Improve Long Term Patency of Arteriovenous Fistula for Hemodialysis

PubMed Central

Chang, Hao-Hsiang; Chang, Yu-Kang; Lu, Chia-Wen; Huang, Chi-Ting; Chien, Chiang-Ting; Hung, Kuan-Yu; Huang, Kuo-Chin; Hsu, Chih-Cheng

2016-01-01

The protective effects of statins against stenosis for permanent hemodialysis access have been repeatedly demonstrated in animal studies, but remain controversial in human studies. This study aims to evaluate the association between statin use and permanent hemodialysis access patency using a nationwide hemodialysis cohort. A total of 9862 pairs of statin users and non-users, matched by age and gender, were selected for investigation from 75404 new hemodialysis patients during 2000–2008. The effect of statins on permanent hemodialysis access patency was evaluated using Cox proportional hazards models. Compared with non-users, statin users had an overall 18% risk reduction in the composite endpoint in which angioplasty and recreation were combined (adjusted hazard ratio = 0.82 [95%CI, 0.78–0.87]) and 21% in recreation of permanent hemodialysis access (adjusted hazard ratio = 0.79 [95%CI, 0.69–0.80]). Specifically, the protective effect was found for arteriovenous fistula (adjusted hazard ratio = 0.78[95% CI, 0.73–0.82] for composite endpoint and 0.74 [95% CI, 0.69–0.80] for vascular recreation), but not for arteriovenous grafts (adjusted hazard ratio = 1.10 [95% CI, 0.98–1.24] and 0.94 [95% CI, 0.83–1.07]). Statins possess a protective effect for arteriovenous fistula against the recreation of permanent hemodialysis access. The results provide a pharmaco-epidemiologic link between basic research and clinical evidence. PMID:26902330

Modeling time-to-event (survival) data using classification tree analysis.

PubMed

Linden, Ariel; Yarnold, Paul R

2017-12-01

Time to the occurrence of an event is often studied in health research. Survival analysis differs from other designs in that follow-up times for individuals who do not experience the event by the end of the study (called censored) are accounted for in the analysis. Cox regression is the standard method for analysing censored data, but the assumptions required of these models are easily violated. In this paper, we introduce classification tree analysis (CTA) as a flexible alternative for modelling censored data. Classification tree analysis is a "decision-tree"-like classification model that provides parsimonious, transparent (ie, easy to visually display and interpret) decision rules that maximize predictive accuracy, derives exact P values via permutation tests, and evaluates model cross-generalizability. Using empirical data, we identify all statistically valid, reproducible, longitudinally consistent, and cross-generalizable CTA survival models and then compare their predictive accuracy to estimates derived via Cox regression and an unadjusted naïve model. Model performance is assessed using integrated Brier scores and a comparison between estimated survival curves. The Cox regression model best predicts average incidence of the outcome over time, whereas CTA survival models best predict either relatively high, or low, incidence of the outcome over time. Classification tree analysis survival models offer many advantages over Cox regression, such as explicit maximization of predictive accuracy, parsimony, statistical robustness, and transparency. Therefore, researchers interested in accurate prognoses and clear decision rules should consider developing models using the CTA-survival framework. © 2017 John Wiley & Sons, Ltd.

Comparative economic evaluation of home-based and hospital-based palliative care for terminal cancer patients.

PubMed

Kato, Koki; Fukuda, Haruhisa

2017-11-01

To quantify the difference between adjusted costs for home-based palliative care and hospital-based palliative care in terminally ill cancer patients. We carried out a case-control study of home-care patients (cases) who had died at home between January 2009 and December 2013, and hospital-care patients (controls) who had died at a hospital between April 2008 and December 2013. Data on patient characteristics were obtained from insurance claims data and medical records. We identified the determinants of home care using a multivariate logistic regression analysis. Cox proportional hazards analysis was used to examine treatment duration in both types of care, and a generalized linear model was used to estimate the reduction in treatment costs associated with home care. The case and control groups comprised 48 and 99 patients, respectively. Home care was associated with one or more person(s) living with the patient (adjusted OR 6.54, 95% CI 1.18-36.05), required assistance for activities of daily living (adjusted OR 3.61, 95% CI 1.12-10.51), non-use of oxygen inhalation therapy (adjusted OR 12.75, 95% CI 3.53-46.02), oral or suppository opioid use (adjusted OR 5.74, 95% CI 1.11-29.54) and transdermal patch opioid use (adjusted OR 8.30, 95% CI 1.97-34.93). The adjusted hazard ratio of home care for treatment duration was not significant (adjusted OR 0.95, 95% CI 0.59-1.53). However, home care was significantly associated with a reduction of $7523 (95% CI $7093-7991, P = 0.015) in treatment costs. Despite similar treatment durations between the groups, treatment costs were substantially lower in the home-care group. These findings might inform the policymaking process for improving the home-care support system. Geriatr Gerontol Int 2017; 17: 2247-2254. © 2017 Japan Geriatrics Society.

Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort.

PubMed

López-Cortés, L E; Almirante, B; Cuenca-Estrella, M; Garnacho-Montero, J; Padilla, B; Puig-Asensio, M; Ruiz-Camps, I; Rodríguez-Baño, J

2016-08-01

We compared the clinical efficacy of fluconazole and echinocandins in the treatment of candidemia in real practice. The CANDIPOP study is a prospective, population-based cohort study on candidemia carried out between May 2010 and April 2011 in 29 Spanish hospitals. Using strict inclusion criteria, we separately compared the impact of empirical and targeted therapy with fluconazole or echinocandins on 30-day mortality. Cox regression, including a propensity score (PS) for receiving echinocandins, stratified analysis on the PS quartiles and PS-based matched analyses, were performed. The empirical and targeted therapy cohorts comprised 316 and 421 cases, respectively; 30-day mortality was 18.7% with fluconazole and 33.9% with echinocandins (p 0.02) in the empirical therapy group and 19.8% with fluconazole and 27.7% with echinocandins (p 0.06) in the targeted therapy group. Multivariate Cox regression analysis including PS showed that empirical therapy with fluconazole was associated with better prognosis (adjusted hazard ratio 0.38; 95% confidence interval 0.17-0.81; p 0.01); no differences were found within each PS quartile or in cases matched according to PS. Targeted therapy with fluconazole did not show a significant association with mortality in the Cox regression analysis (adjusted hazard ratio 0.77; 95% confidence interval 0.41-1.46; p 0.63), in the PS quartiles or in PS-matched cases. The results were similar among patients with severe sepsis and septic shock. Empirical or targeted treatment with fluconazole was not associated with increased 30-day mortality compared to echinocandins among adults with candidemia. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

VEGF expression and the effect of NSAIDs on ascites cell proliferation in the hen model of ovarian cancer.

PubMed

Urick, M E; Giles, J R; Johnson, P A

2008-09-01

We aimed to determine the expression of vascular endothelial growth factor (VEGF) and the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the proliferation of cells isolated from ascites in the hen model of ovarian cancer. Ovarian tumor and normal ovary were collected from hens and ascites cells were isolated from hens with ovarian cancer. Quantitative real-time PCR was used to quantify mRNA expression. Immunohistochemical and/or Western blot analyses were used to localize protein expression in ovarian tumors, normal ovaries, and ascites cells. Cells were treated with a nonspecific, COX-1-specific, or COX-2-specific NSAID and proliferation was determined. VEGF mRNA was increased in ascites cells and there was a trend for a correlation between VEGF mRNA in ascites cells and ascites volume. VEGF protein was localized to theca cells of normal ovaries, in glandular areas of tumors, and to the cytoplasm of ascites cells. Aspirin and a COX-1-specific inhibitor decreased the proliferation of ascites cells, whereas a COX-2-specific inhibitor did not. VEGF may play a role in ovarian cancer progression in the hen and the proliferation of ascites cells can be decreased by targeting the COX-1 but not COX-2 pathway.

Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents

PubMed Central

Lin, Chun-Kuang; Tseng, Chin-Kai; Wu, Yu-Hsuan; Liaw, Chih-Chuang; Lin, Chun-Yu; Huang, Chung-Hao; Chen, Yen-Hsu; Lee, Jin-Ching

2017-01-01

Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E2 (PGE2) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection. PMID:28317866

Azoxymethane protects intestinal stem cells and reduces crypt epithelial mitosis through a COX-1-dependent mechanism.

PubMed

Riehl, Terrence E; George, Robert J; Sturmoski, Mark A; May, Randal; Dieckgraefe, Brian; Anant, Shrikant; Houchen, Courtney W

2006-12-01

Azoxymethane (AOM) is a potent DNA-damaging agent and carcinogen that induces intestinal and colonic tumors in rodents. Evaluation of the stem cell population by colony formation assay reveals that, within 8 h after treatment, AOM (10 mg/kg) elicited a prosurvival response. In wild-type (WT) mice, AOM treatment induced a 2.5-fold increase in intestinal crypt stem cell survival. AOM treatment increased stem cell survival in cyclooxygenase (COX)-2(-/-) but not COX-1(-/-) mice, confirming a role of COX-1 in the AOM-induced increase in stem cell survival. COX-1 mRNA and protein expression as well as COX-1-derived PGE(2) synthesis were increased 8 h after AOM treatment. Immunohistochemical staining of COX-1 demonstrated expression of the enzyme in the crypt epithelial cells, especially in the columnar epithelial cells between the Paneth cells adjacent to the stem cell zone. WT mice receiving AOM exhibited increased intestinal apoptosis and a simultaneous reduction in crypt mitotic figures within 8 h of injection. There were no significant differences in baseline or AOM-induced intestinal epithelial apoptosis between WT and COX-1(-/-) mice, but there was a complete reversal of the AOM-mediated reduction in mitosis in COX-1(-/-) mice. This suggests that COX-1-derived PGE(2) may play a key role in the early phase of intestinal tumorigenesis in response to DNA damage and suggests that COX-1 may be a potential therapeutic target in this model of colon cancer.

Albuminuria and Rapid Loss of GFR and Risk of New Hip and Pelvic Fractures

PubMed Central

Gao, Peggy; Clase, Catherine M.; Mente, Andrew; Mann, Johannes F.E.; Sleight, Peter; Yusuf, Salim; Teo, Koon K.

2013-01-01

Summary Background and objectives The microvascular circulation plays an important role in bone health. This study examines whether albuminuria, a marker of renal microvascular disease, is associated with incident hip and pelvic fractures. Design, setting, participants, & measurements This study reanalyzed data from the Ongoing Telmisartan Alone and in combination with Ramipril Global End Point Trial/Telmisartan Randomized Assessment Study in Angiotensin-Converting Enzyme Intolerant Subjects with Cardiovascular Disease trials, which examined the impact of renin angiotensin system blockade on cardiovascular outcomes (n=28,601). Albuminuria was defined as an albumin-to-creatinine ratio≥30 mg/g (n=4597). Cox proportional hazards models were used to determine the association of albuminuria with fracture risk adjusted for known risk factors for fractures, estimated GFR, and rapid decline in estimated GFR (≥5%/yr). Results There were 276 hip and pelvic fractures during a mean of 4.6 years of follow-up. Participants with baseline albuminuria had a significantly increased risk of fracture compared with participants without albuminuria (unadjusted hazard ratio=1.62 [1.22, 2.15], P<0.001; adjusted hazard ratio=1.36 [1.01, 1.84], P=0.05). A dose-dependent relationship was observed, with macroalbuminuria having a large fracture risk (unadjusted hazard ratio=2.01 [1.21, 3.35], P=0.007; adjusted hazard ratio=1.71 [1.007, 2.91], P=0.05) and microalbuminuria associating with borderline or no statistical significance (unadjusted hazard ratio=1.52 [1.10, 2.09], P=0.01; adjusted hazard ratio=1.28 [0.92, 1.78], P=0.15). Estimated GFR was not a predictor of fracture in any model, but rapid loss of estimated GFR over the first 2 years of follow-up predicted subsequent fracture (adjusted hazard ratio=1.47 [1.05, 2.04], P=0.02). Conclusions Albuminuria, especially macroalbuminuria, and rapid decline of estimated GFR predict hip and pelvic fractures. These findings support a theoretical model of a relationship between underlying causes of microalbuminuria and bone disease. PMID:23184565

Immunohistochemical localization of cyclooxygenase isoforms in the organ of Corti and the spiral ganglion cells of guinea pig cochlea.

PubMed

Ziegler, E A; Brieger, J; Heinrich, U R; Mann, W J

2004-01-01

Prostaglandins have been used in experimental models and clinical studies for the therapy of sudden hearing loss and tinnitus with conflicting results. However, little is known about the rate-limiting enzymes of prostaglandin synthesis in the inner ear, the generally constitutively expressed cyclooxygenase 1 (COX-1) and the distress-inducible cyclooxygenase 2 (COX-2). To extend our knowledge concerning the physiological expression and localization of these two enzymes, immunohistochemical stainings of the guinea pig cochlea were performed. Light microscopical analysis revealed a homogenous distribution of COX-1 within nearly all cell types of the organ of Corti, but no COX-1 expression in the cuticular plates of pillar cells. COX-2 was found to be expressed in all cell types, with much stronger expression in Hensen cells, neighboring Deiters cells and cuticular plates of outer hair cells. Both COX-1 and COX-2 immunoreactions were also found in the spiral ganglion. We conclude that both COX subtypes are expressed in the guinea pig cochlea under physiological conditions. The prominent expression of the distress-inducible COX-2 isoform in cell types under mechanical stress during noise reception might support the hypothesis of a cytoprotective function of COX products in hearing and in cellular stress situations like intense noise exposure. Copyright (c) 2004 S. Karger AG, Basel.

Prescription channeling of COX-2 inhibitors and traditional nonselective nonsteroidal anti-inflammatory drugs: a population-based case-control study.

PubMed

Moride, Yola; Ducruet, Thierry; Boivin, Jean-François; Moore, Nicholas; Perreault, Sylvie; Zhao, Sean

2005-01-01

This pharmacoepidemiologic study was conducted to determine whether risk factors for upper gastrointestinal bleeding influenced the prescription of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at the time when COX-2 inhibitors were first included in the formulary of reimbursed medications. A population-based case-control study was conducted in which the prevalence of risk factors and the medical histories of patients prescribed COX-2 inhibitors and traditional nonselective NSAIDs were compared. The study population consisted of a random sample of members of the Quebec drug plan (age 18 years or older) who received at least one dispensation of celecoxib (n = 42,422; cases), rofecoxib (n = 25,674; cases), or traditional nonselective NSAIDs (n = 12,418; controls) during the year 2000. All study data were obtained from the Quebec health care databases. Adjusting for income level, Chronic Disease Score, prior use of low-dose acetylsalicylic acid, acetaminophen, antidepressants, benzodiazepines, prescriber specialty, and time period, the following factors were significantly associated with the prescription of COX-2 inhibitors: age 75 years or older (odds ratio [OR] 4.22, 95% confidence interval [CI] 3.95-4.51), age 55-74 years (OR 3.23, 95% CI 3.06-3.40), female sex (OR 1.52, 95% CI 1.45-1.58), prior diagnosis of gastropathy (OR 1.21, 95% CI 1.08-1.36) and prior dispensation of gastroprotective agents (OR 1.57, 95% CI 1.47-1.67). Patients who received a traditional nonselective NSAID recently were more likely to switch to a coxib, especially first-time users (OR 2.17, 95% CI 1.93-2.43). Associations were significantly greater for celecoxib than rofecoxib for age, chronic NSAID use, and last NSAID use between 1 and 3 months before the index date. At the time of introduction of COX-2 inhibitors into the formulary, prescription channeling could confound risk comparisons across products.

Disease Characteristics, Patterns of Care, and Survival in Very Elderly Patients with Diffuse Large B-Cell Lymphoma

PubMed Central

Williams, Jessica N.; Rai, Ashish; Lipscomb, Joseph; Koff, Jean L.; Nastoupil, Loretta J.; Flowers, Christopher R.

2015-01-01

Background Although rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered standard therapy for diffuse large B-cell lymphoma (DLBCL), patterns of use and the impact of R-CHOP on survival in patients >80 years are less clear. Methods We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to characterize presentation, treatment, and survival patterns in DLBCL patients diagnosed from 2002–2009. Chi-squared tests compared characteristics and initial treatments of DLBCL patients >80 years and ≤80 years. Multivariable logistic regression models examined factors associated with treatment selection in patients >80 years; standard and propensity score-adjusted multivariable Cox proportional hazards models examined relationships between treatment regimen, treatment duration, and survival. Results Among 4,635 patients with DLBCL, 1,156 (25%) were >80 years. Patients >80 were less likely to receive R-CHOP and more likely to be observed or receive rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP); both p<0.0001. Marital status, stage, disease site, performance status, radiation therapy, and growth factor support were associated with initial R-CHOP in patients >80. In propensity score-matched multivariable Cox proportional hazards models examining relationships between treatment regimen and survival, R-CHOP was the only regimen associated with improved OS (hazard ratio (HR) = 0.45, 95% confidence interval (CI) = 0.33–0.62) and LRS (HR=0.58, 95% CI 0.38–0.88). Conclusions Although DLBCL patients >80 years were less likely to receive R-CHOP, this regimen conferred the longest survival and should be considered for this population. Further studies are needed to characterize the impact of DLBCL treatment on quality of life in this age group. PMID:25675909

High Body Mass Index is an Important Risk Factor for the Development of Type 2 Diabetes

PubMed Central

Sanada, Hironobu; Yokokawa, Hirohide; Yoneda, Minoru; Yatabe, Junichi; Yatabe, Midori Sasaki; Williams, Scott M.; Felder, Robin A; Jose, Pedro A

2012-01-01

OBJECTIVE The aim of this study is to establish a causal relationship between excess body weight and the onset of diabetes in a retrospective cohort study. METHODS This 10-year observational cohort study investigated 969 men and 585 women (23 to 80 years of age), who underwent voluntary complete medical check-ups and an annual 75-g oral glucose tolerance test (75g-OGTT). Participants with fasting plasma glucose ≥ 126 mg/dl, 2-h glucose level in a 75g-OGTT ≥ 200 mg/dl and/or received medical treatment for type 2 diabetes during the previous year were counted as new-onset diabetics. We assessed the independent contribution of increased BMI to the risk of developing type 2 diabetes with Cox proportional hazard model. RESULT During the follow-up period, we diagnosed 86 men and 49 women with new-onset type 2 diabetes. In the Cox proportional hazards model, the risk of diabetes mellitus increased with increasing BMI, even after adjusting for age, sex, blood pressure, metabolic profiles, and insulin resistance. In the final model, setting BMI less than 25 as a reference group, the Hazard ratios for diabetes mellitus was 3.12 for those with a BMI of 25–27.4 and increased to 3.80 for participants with a BMI of 27.5 or higher. CONCLUSION Overweight/obesity (high BMI) is an independent and dose-dependent risk factor for type 2 diabetes in overweight Japanese patients. Our results confirmed the usefulness of BMI as a classic parameter, and the importance of lifestyle modification and better management among people with overweight/obesity for prevention of type 2 diabetes mellitus PMID:22821094

Structural brain changes and all-cause mortality in the elderly population-the mediating role of inflammation.

PubMed

Hanning, Uta; Roesler, Andreas; Peters, Annette; Berger, Klaus; Baune, Bernhard T

2016-12-01

While MRI brain changes have been related to mortality during ageing, the role of inflammation in this relationship remains poorly understood. Hence, this study aimed to investigate the impact of MRI changes on all-cause mortality and the mediating role of cytokines. All-cause mortality was evaluated in 268 community dwelling elderly (age 65-83 years) in the MEMO study (Memory and Morbidity in Augsburg elderly). MRI markers of brain atrophy and cerebral small vessel disease (SVD), C-reactive protein (CRP) and a panel of cytokines in serum were assessed. Cox proportional hazard models were used to estimate the association of MRI changes with survival over 9 years. Regression models were used to assess the hypothesis that inflammation is mediating the relationship between MRI-brain changes and mortality. In total, 77 (29 %) deaths occurred during a mean follow up of 9 years. After adjusting for confounders, the degree of global cortical atrophy and the level of the cytokines CRP, TNF-α and IL-8 were of higher significance in study participants who had died at follow-up in comparison to survivors. In Cox proportional hazard models, higher degrees of global cortical atrophy (HR 1.56, p = 0.003) and regional atrophy of the temporal lobe (HR 1.38, p = 0.011) were associated with a significantly increased risk of mortality. Mediation analyses revealed a partial mediation by IL-6 and IL-8 of the effects of global cortical atrophy on mortality. Global cortical brain atrophy is a significant indicator of survival in the elderly. Our study supports a possible role for inflammation in the atrophy pathogenesis. If replicated in other samples, IL-6 and IL-8 level assessment may improve risk prognosis for mortality.

Hemoglobin Concentration and Risk of Incident Stroke in Community-Living Adults.

PubMed

Panwar, Bhupesh; Judd, Suzanne E; Warnock, David G; McClellan, William M; Booth, John N; Muntner, Paul; Gutiérrez, Orlando M

2016-08-01

In previous observational studies, hemoglobin concentrations have been associated with an increased risk of stroke. However, these studies were limited by a relatively low number of stroke events, making it difficult to determine whether the association of hemoglobin and stroke differed by demographic or clinical factors. Using Cox proportional hazards analysis and Kaplan-Meier plots, we examined the association of baseline hemoglobin concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults aged ≥45 years. A total of 518 participants developed stroke over a mean 7±2 years of follow-up. There was a statistically significant interaction between hemoglobin and sex (P=0.05) on the risk of incident stroke. In Cox regression models adjusted for demographic and clinical variables, there was no association of baseline hemoglobin concentration with incident stroke in men, whereas in women, the lowest (<12.4 g/dL) and highest (>14.0 g/dL) quartiles of hemoglobin were associated with higher risk of stroke when compared with the second quartile (12.4-13.2 g/dL; quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.09-2.31; quartile 2: referent; quartile 3: hazard ratio, 0.91; 95% confidence interval, 0.59-1.38; quartile 4: hazard ratio, 1.59; 95% confidence interval, 1.08-2.35). Similar results were observed in models stratified by hemoglobin and sex and when hemoglobin was modeled as a continuous variable using restricted quadratic spline regression. Lower and higher hemoglobin concentrations were associated with a higher risk of incident stroke in women. No such associations were found in men. © 2016 American Heart Association, Inc.

Design, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors

PubMed Central

Ahmaditaba, Mohammad Ali; Houshdar Tehrani, Mohammad Hassan; Zarghi, Afshin; Shahosseini, Sorayya; Daraei, Bahram

2018-01-01

A new series of peptide-like derivatives containing different aromatic amino acids and possessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para position of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method using Wang resin. One of the analogues, i.e., compound 2d, as the representative of these series was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value of 0.08 μM and COX-2 selectivity index of 351.2, among the other synthesized compounds. Molecular docking study was operated to determine possible binding models of compound 2d to COX-2 enzyme. The study showed that the p-azido-phenyl fragment of 2d occupied inside the secondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquired disclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine as amino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with high selectivity. Compound 2d can be a good candidate for the development of new hits of COX-2 inhibitors.

Long-Term Ozone Exposure and Mortality in a Large Prospective Study

PubMed Central

Jerrett, Michael; Pope, C. Arden; Krewski, Daniel; Gapstur, Susan M.; Diver, W. Ryan; Beckerman, Bernardo S.; Marshall, Julian D.; Su, Jason; Crouse, Daniel L.; Burnett, Richard T.

2016-01-01

Rationale: Tropospheric ozone (O3) is potentially associated with cardiovascular disease risk and premature death. Results from long-term epidemiological studies on O3 are scarce and inconclusive. Objectives: In this study, we examined associations between chronic ambient O3 exposure and all-cause and cause-specific mortality in a large cohort of U.S. adults. Methods: Cancer Prevention Study II participants were enrolled in 1982. A total of 669,046 participants were analyzed, among whom 237,201 deaths occurred through 2004. We obtained estimates of O3 concentrations at the participant’s residence from a hierarchical Bayesian space–time model. Estimates of fine particulate matter (particulate matter with an aerodynamic diameter of up to 2.5 μm [PM2.5]) and NO2 concentrations were obtained from land use regression. Cox proportional hazards regression models were used to examine mortality associations adjusted for individual- and ecological-level covariates. Measurements and Main Results: In single-pollutant models, we observed significant positive associations between O3, PM2.5, and NO2 concentrations and all-cause and cause-specific mortality. In two-pollutant models adjusted for PM2.5, significant positive associations remained between O3 and all-cause (hazard ratio [HR] per 10 ppb, 1.02; 95% confidence interval [CI], 1.01–1.04), circulatory (HR, 1.03; 95% CI, 1.01–1.05), and respiratory mortality (HR, 1.12; 95% CI, 1.08–1.16) that were unchanged with further adjustment for NO2. We also observed positive mortality associations with both PM2.5 (both near source and regional) and NO2 in multipollutant models. Conclusions: Findings derived from this large-scale prospective study suggest that long-term ambient O3 contributes to risk of respiratory and circulatory mortality. Substantial health and environmental benefits may be achieved by implementing further measures aimed at controlling O3 concentrations. PMID:26680605

Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II

PubMed Central

Krewski, Daniel; Diver, W. Ryan; Pope, C. Arden; Burnett, Richard T.; Jerrett, Michael; Marshall, Julian D.; Gapstur, Susan M.

2017-01-01

Background: The International Agency for Research on Cancer classified both outdoor air pollution and airborne particulate matter as carcinogenic to humans (Group 1) for lung cancer. There may be associations with cancer at other sites; however, the epidemiological evidence is limited. Objective: The aim of this study was to clarify whether ambient air pollution is associated with specific types of cancer other than lung cancer by examining associations of ambient air pollution with nonlung cancer death in the Cancer Prevention Study II (CPS-II). Methods: Analysis included 623,048 CPS-II participants who were followed for 22 y (1982–2004). Modeled estimates of particulate matter with aerodynamic diameter <2.5µm (PM2.5) (1999–2004), nitrogen dioxide (NO2) (2006), and ozone (O3) (2002–2004) concentrations were linked to the participant residence at enrollment. Cox proportional hazards models were used to estimate associations per each fifth percentile–mean increment with cancer mortality at 29 anatomic sites, adjusted for individual and ecological covariates. Results: We observed 43,320 nonlung cancer deaths. PM2.5 was significantly positively associated with death from cancers of the kidney {adjusted hazard ratio (HR) per 4.4 μg/m3=1.14 [95% confidence interval (CI): 1.03, 1.27]} and bladder [HR=1.13 (95% CI: 1.03, 1.23)]. NO2 was positively associated with colorectal cancer mortality [HR per 6.5 ppb=1.06 (95% CI: 1.02, 1.10). The results were similar in two-pollutant models including PM2.5 and NO2 and in three-pollutant models with O3. We observed no statistically significant positive associations with death from other types of cancer based on results from adjusted models. Conclusions: The results from this large prospective study suggest that ambient air pollution was not associated with death from most nonlung cancers, but associations with kidney, bladder, and colorectal cancer death warrant further investigation. https://doi.org/10.1289/EHP1249 PMID:28886601

Non-Asymptotic Oracle Inequalities for the High-Dimensional Cox Regression via Lasso.

PubMed

Kong, Shengchun; Nan, Bin

2014-01-01

We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz.We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses.

Non-Asymptotic Oracle Inequalities for the High-Dimensional Cox Regression via Lasso

PubMed Central

Kong, Shengchun; Nan, Bin

2013-01-01

We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz.We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses. PMID:24516328

Confidence intervals for the first crossing point of two hazard functions.

PubMed

Cheng, Ming-Yen; Qiu, Peihua; Tan, Xianming; Tu, Dongsheng

2009-12-01

The phenomenon of crossing hazard rates is common in clinical trials with time to event endpoints. Many methods have been proposed for testing equality of hazard functions against a crossing hazards alternative. However, there has been relatively few approaches available in the literature for point or interval estimation of the crossing time point. The problem of constructing confidence intervals for the first crossing time point of two hazard functions is considered in this paper. After reviewing a recent procedure based on Cox proportional hazard modeling with Box-Cox transformation of the time to event, a nonparametric procedure using the kernel smoothing estimate of the hazard ratio is proposed. The proposed procedure and the one based on Cox proportional hazard modeling with Box-Cox transformation of the time to event are both evaluated by Monte-Carlo simulations and applied to two clinical trial datasets.

In Vivo Physiological Experiments in the Random Positioning Macine: A Study on the Rat Intestinal Transit

NASA Astrophysics Data System (ADS)

Peana, A. T.; Marzocco, S.; Bianco, G.; Autore, G.; Pinto, A.; Pippia, P.

2008-06-01

The aim of this work is to evaluate the rat intestinal transit as well as the expression of enzymes involved in this process and in gastrointestinal homeostasis as ciclooxygenase (COX-1 and COX-2), the inducibile isoform of nitric oxide synthase (iNOS), ICAM-1 and heat shock proteins HSP70 and HSP90. The modeled microgravity conditions were performed utilizing a three-dimensional clinostat, the Random Positioning Machine (RPM). Our results indicate that modeled microgravity significantly reduce rat intestinal transit. Western blot analysis on small intestine tissues of RPM rats reveals a significant increase in iNOS expression, a significant reduction in COX-2 levels, while COX-1 expression remains unaltered, and a significant increase in ICAM-1 and HSP 70 expression. Also a significant increase in HSP 90 stomach expression indicates a strong effect of simulated low g on gastrointestinal homeostasis.

Hydroxychloroquine Use Is Associated With Decreased Incident Cardiovascular Events in Rheumatoid Arthritis Patients.

PubMed

Sharma, Tarun S; Wasko, Mary Chester M; Tang, Xiaoqin; Vedamurthy, Deepak; Yan, Xiaowei; Cote, Jonida; Bili, Androniki

2016-01-04

Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA) patients. This study is the first to report the association of hydroxychloroquine (an antirheumatic medication that has been associated with decreased risk of diabetes, a less atherogenic lipid profile, and antithrombotic properties) with CVD in RA. A retrospective incident RA cohort from January 1, 2001, to October 31, 2013, excluding patients with CVD prior to RA diagnosis, was constructed. Patients were categorized as hydroxychloroquine users versus nonusers and were allowed to contribute time to either group according to hydroxychloroquine exposure. The primary outcome was adjudicated incident CVD defined as a composite of coronary artery disease, stroke, transient ischemic attack, sudden cardiac death, and peripheral artery disease with arterial revascularization procedure. The secondary outcome was a composite of incident coronary artery disease, stroke, and transient ischemic attack. Cox time-varying regression models were used to estimate the association between hydroxychloroquine exposure and development of CVD, after adjusting for propensity score and relevant confounders, including demographics, CVD-related comorbidities, RA severity, and activity indicators and medications. We included 1266 RA patients, 547 hydroxychloroquine users, and 719 nonusers. During the observation period, 102 CVD events occurred, 3 in hydroxychloroquine users and 99 in nonusers. The fully adjusted Cox model showed a hazard ratio of 0.28 (95% CI 0.12-0.63, P=0.002) for incident CVD and 0.30 (95% CI 0.13-0.68, P=0.004) for incident composite coronary artery disease, stroke, and transient ischemic attack for hydroxychloroquine users versus nonusers, respectively. In this hypothesis-generating study, hydroxychloroquine use was associated with a 72% decrease in the risk of incident CVD in RA patients. If these preliminary results are confirmed in larger studies, our findings may be used as a rationale for a randomized study of hydroxychloroquine use for primary prevention of CVD in RA or nonrheumatic high-risk patients. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Apigenin inhibits COX-2, PGE2, and EP1 and also initiates terminal differentiation in the epidermis of tumor bearing mice.

PubMed

Kiraly, Alex J; Soliman, Eman; Jenkins, Audrey; Van Dross, Rukiyah T

2016-01-01

Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States. NMSC overexpresses cyclooxygenase-2 (COX-2). COX-2 synthesizes prostaglandins such as PGE2 which promote proliferation and tumorigenesis by engaging G-protein-coupled prostaglandin E receptors (EP). Apigenin is a bioflavonoid that blocks mouse skin tumorigenesis induced by the chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the effect of apigenin on the COX-2 pathway has not been examined in the DMBA/TPA skin tumor model. In the present study, apigenin decreased tumor multiplicity and incidence in DMBA/TPA-treated SKH-1 mice. Analysis of the non-tumor epidermis revealed that apigenin reduced COX-2, PGE2, EP1, and EP2 synthesis and also increased terminal differentiation. In contrast, apigenin did not inhibit the COX-2 pathway or promote terminal differentiation in the tumors. Since fewer tumors developed in apigenin-treated animals which contained reduced epidermal COX-2 levels, our data suggest that apigenin may avert skin tumor development by blocking COX-2. Copyright © 2015 Elsevier Ltd. All rights reserved.

Structural Basis for Certain Naturally Occurring Bioflavonoids to Function as Reducing Co-Substrates of Cyclooxygenase I and II

PubMed Central

Zhu, Bao Ting

2010-01-01

Background Recent studies showed that some of the dietary bioflavonoids can strongly stimulate the catalytic activity of cyclooxygenase (COX) I and II in vitro and in vivo, presumably by facilitating enzyme re-activation. In this study, we sought to understand the structural basis of COX activation by these dietary compounds. Methodology/Principal Findings A combination of molecular modeling studies, biochemical analysis and site-directed mutagenesis assay was used as research tools. Three-dimensional quantitative structure-activity relationship analysis (QSAR/CoMFA) predicted that the ability of bioflavonoids to activate COX I and II depends heavily on their B-ring structure, a moiety known to be associated with strong antioxidant ability. Using the homology modeling and docking approaches, we identified the peroxidase active site of COX I and II as the binding site for bioflavonoids. Upon binding to this site, bioflavonoid can directly interact with hematin of the COX enzyme and facilitate the electron transfer from bioflavonoid to hematin. The docking results were verified by biochemical analysis, which reveals that when the cyclooxygenase activity of COXs is inhibited by covalent modification, myricetin can still stimulate the conversion of PGG2 to PGE2, a reaction selectively catalyzed by the peroxidase activity. Using the site-directed mutagenesis analysis, we confirmed that Q189 at the peroxidase site of COX II is essential for bioflavonoids to bind and re-activate its catalytic activity. Conclusions/Significance These findings provide the structural basis for bioflavonoids to function as high-affinity reducing co-substrates of COXs through binding to the peroxidase active site, facilitating electron transfer and enzyme re-activation. PMID:20808785

A Cluster Randomized Trial of Tailored Breastfeeding Support for Women with Gestational Diabetes

PubMed Central

Bonuck, Karen; Adatorwovor, Reuben; Schwartz, Todd A.; Berry, Diane C.

2016-01-01

Abstract Background: Women with gestational diabetes mellitus (GDM) and their infants are at increased risk of developing metabolic disease; however, longer breastfeeding is associated with a reduction in these risks. We tested an intervention to increase breastfeeding duration among women with GDM. Materials and Methods: We conducted a cluster randomized trial to determine the efficacy of a breastfeeding education and support program for women with GDM. Women were enrolled between 22 and 36 weeks of pregnancy and cluster randomized to an experimental lifestyle intervention or wait-list control group. Breastfeeding duration and intensity were prespecified secondary outcomes of the trial. Duration of exclusive and any breastfeeding was assessed at 6 weeks and at 4, 7, and 10 months postpartum. We quantified differences in breastfeeding rates using Kaplan–Meier estimates, log-rank tests, and Cox regression models. Results: We enrolled 100 women, of whom 52% were African American, 31% non-Hispanic white, 11% Hispanic, 9% American Indian or Alaskan Native, 2% Asian, 2% other, and 4% more than one race. In models accounting for within-cluster correlation and adjusted for study site, breastfeeding intention, and African American race, women allocated to the intervention group were less likely to stop breastfeeding (adjusted hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.21–0.74) or to introduce formula (adjusted HR 0.50, 95% CI 0.34–0.72). Conclusion: Our results suggest that targeted breastfeeding education for women with GDM is feasible and efficacious. Clinical Trials Registration: http://clinicaltrials.gov/ct2/show/NCT01809431 PMID:27782758

Cognitive ability in young adulthood predicts risk of early-onset dementia in Finnish men.

PubMed

Rantalainen, Ville; Lahti, Jari; Henriksson, Markus; Kajantie, Eero; Eriksson, Johan G; Räikkönen, Katri

2018-06-06

To test if the Finnish Defence Forces Basic Intellectual Ability Test scores at 20.1 years predicted risk of organic dementia or Alzheimer disease (AD). Dementia was defined as inpatient or outpatient diagnosis of organic dementia or AD risk derived from Hospital Discharge or Causes of Death Registers in 2,785 men from the Helsinki Birth Cohort Study, divided based on age at first diagnosis into early onset (<65 years) or late onset (≥65 years). The Finnish Defence Forces Basic Intellectual Ability Test comprises verbal, arithmetic, and visuospatial subtests and a total score (scores transformed into a mean of 100 and SD of 15). We used Cox proportional hazard models and adjusted for age at testing, childhood socioeconomic status, mother's age at delivery, parity, participant's birthweight, education, and stroke or coronary heart disease diagnosis. Lower cognitive ability total and verbal ability (hazard ratio [HR] per 1 SD disadvantage >1.69, 95% confidence interval [CI] 1.01-2.63) scores predicted higher early-onset any dementia risk across the statistical models; arithmetic and visuospatial ability scores were similarly associated with early-onset any dementia risk, but these associations weakened after covariate adjustments (HR per 1 SD disadvantage >1.57, 95% CI 0.96-2.57). All associations were rendered nonsignificant when we adjusted for participant's education. Cognitive ability did not predict late-onset dementia risk. These findings reinforce previous suggestions that lower cognitive ability in early life is a risk factor for early-onset dementia. © 2018 American Academy of Neurology.

Menopause and risk of diabetes in the Diabetes Prevention Program

PubMed Central

Kim, Catherine; Edelstein, Sharon L.; Crandall, Jill P.; Dabelea, Dana; Kitabchi, Abbas E.; Hamman, Richard F.; Montez, Maria G.; Perreault, Leigh; Foulkes, Mary A.; Barrett-Connor, Elizabeth

2012-01-01

Objective The study objective was to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopausal status modifies response to diabetes prevention interventions. Methods The study population included women in premenopause (n=708), natural postmenopause (n=328), and bilateral oophorectomy (n=201) in the Diabetes Prevention Program (DPP), a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy (HT) use. Results After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (HR 0.19, 95% CI 0.04, 0.94), although observations were too few to determine if this was independent of HT use. No significant differences were seen in the metformin (HR 1.29, 95% CI 0.63, 2.64) or placebo arms (HR 1.37, 95% CI 0.74, 2.55). Conclusions Among women at high-risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with decreased diabetes risk. PMID:21709591

Menopause and risk of diabetes in the Diabetes Prevention Program.

PubMed

Kim, Catherine; Edelstein, Sharon L; Crandall, Jill P; Dabelea, Dana; Kitabchi, Abbas E; Hamman, Richard F; Montez, Maria G; Perreault, Leigh; Foulkes, Mary A; Barrett-Connor, Elizabeth

2011-08-01

The study objectives were to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopause status modifies response to diabetes prevention interventions. The study population included women in premenopause (n = 708), women in natural postmenopause (n = 328), and women with bilateral oophorectomy (n = 201) in the Diabetes Prevention Program, a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose-intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance, and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy use. After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (hazard ratio [HR], 0.19; 95% CI, 0.04-0.94), although observations were too few to determine if this was independent of hormone therapy use. No significant differences were seen in the metformin (HR, 1.29; 95% CI, 0.63-2.64) or placebo arms (HR, 1.37; 95% CI, 0.74-2.55). Among women at high risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with a decreased diabetes risk.

Ibrutinib versus previous standard of care: an adjusted comparison in patients with relapsed/refractory chronic lymphocytic leukaemia.

PubMed

Hansson, Lotta; Asklid, Anna; Diels, Joris; Eketorp-Sylvan, Sandra; Repits, Johanna; Søltoft, Frans; Jäger, Ulrich; Österborg, Anders

2017-10-01

This study explored the relative efficacy of ibrutinib versus previous standard-of-care treatments in relapsed/refractory patients with chronic lymphocytic leukaemia (CLL), using multivariate regression modelling to adjust for baseline prognostic factors. Individual patient data were collected from an observational Stockholm cohort of consecutive patients (n = 144) diagnosed with CLL between 2002 and 2013 who had received at least second-line treatment. Data were compared with results of the RESONATE clinical trial. A multivariate Cox proportional hazards regression model was used which estimated the hazard ratio (HR) of ibrutinib versus previous standard of care. The adjusted HR of ibrutinib versus the previous standard-of-care cohort was 0.15 (p < 0.0001) for progression-free survival (PFS) and 0.36 (p < 0.0001) for overall survival (OS). A similar difference was observed also when patients treated late in the period (2012-) were compared separately. Multivariate analysis showed that later line of therapy, male gender, older age and poor performance status were significant independent risk factors for worse PFS and OS. Our results suggest that PFS and OS with ibrutinib in the RESONATE study were significantly longer than with previous standard-of-care regimens used in second or later lines in routine healthcare. The approach used, which must be interpreted with caution, compares patient-level data from a clinical trial with outcomes observed in a daily clinical practice and may complement results from randomised trials or provide preliminary wider comparative information until phase 3 data exist.

Estimation of variance in Cox's regression model with shared gamma frailties.

PubMed

Andersen, P K; Klein, J P; Knudsen, K M; Tabanera y Palacios, R

1997-12-01

The Cox regression model with a shared frailty factor allows for unobserved heterogeneity or for statistical dependence between the observed survival times. Estimation in this model when the frailties are assumed to follow a gamma distribution is reviewed, and we address the problem of obtaining variance estimates for regression coefficients, frailty parameter, and cumulative baseline hazards using the observed nonparametric information matrix. A number of examples are given comparing this approach with fully parametric inference in models with piecewise constant baseline hazards.

Joint modelling of repeated measurement and time-to-event data: an introductory tutorial.

PubMed

Asar, Özgür; Ritchie, James; Kalra, Philip A; Diggle, Peter J

2015-02-01

The term 'joint modelling' is used in the statistical literature to refer to methods for simultaneously analysing longitudinal measurement outcomes, also called repeated measurement data, and time-to-event outcomes, also called survival data. A typical example from nephrology is a study in which the data from each participant consist of repeated estimated glomerular filtration rate (eGFR) measurements and time to initiation of renal replacement therapy (RRT). Joint models typically combine linear mixed effects models for repeated measurements and Cox models for censored survival outcomes. Our aim in this paper is to present an introductory tutorial on joint modelling methods, with a case study in nephrology. We describe the development of the joint modelling framework and compare the results with those obtained by the more widely used approaches of conducting separate analyses of the repeated measurements and survival times based on a linear mixed effects model and a Cox model, respectively. Our case study concerns a data set from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS). We also provide details of our open-source software implementation to allow others to replicate and/or modify our analysis. The results for the conventional linear mixed effects model and the longitudinal component of the joint models were found to be similar. However, there were considerable differences between the results for the Cox model with time-varying covariate and the time-to-event component of the joint model. For example, the relationship between kidney function as measured by eGFR and the hazard for initiation of RRT was significantly underestimated by the Cox model that treats eGFR as a time-varying covariate, because the Cox model does not take measurement error in eGFR into account. Joint models should be preferred for simultaneous analyses of repeated measurement and survival data, especially when the former is measured with error and the association between the underlying error-free measurement process and the hazard for survival is of scientific interest. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Simultaneous confidence bands for Cox regression from semiparametric random censorship.

PubMed

Mondal, Shoubhik; Subramanian, Sundarraman

2016-01-01

Cox regression is combined with semiparametric random censorship models to construct simultaneous confidence bands (SCBs) for subject-specific survival curves. Simulation results are presented to compare the performance of the proposed SCBs with the SCBs that are based only on standard Cox. The new SCBs provide correct empirical coverage and are more informative. The proposed SCBs are illustrated with two real examples. An extension to handle missing censoring indicators is also outlined.

Assessing the effect of quantitative and qualitative predictors on gastric cancer individuals survival using hierarchical artificial neural network models.

PubMed

Amiri, Zohreh; Mohammad, Kazem; Mahmoudi, Mahmood; Parsaeian, Mahbubeh; Zeraati, Hojjat

2013-01-01

There are numerous unanswered questions in the application of artificial neural network models for analysis of survival data. In most studies, independent variables have been studied as qualitative dichotomous variables, and results of using discrete and continuous quantitative, ordinal, or multinomial categorical predictive variables in these models are not well understood in comparison to conventional models. This study was designed and conducted to examine the application of these models in order to determine the survival of gastric cancer patients, in comparison to the Cox proportional hazards model. We studied the postoperative survival of 330 gastric cancer patients who suffered surgery at a surgical unit of the Iran Cancer Institute over a five-year period. Covariates of age, gender, history of substance abuse, cancer site, type of pathology, presence of metastasis, stage, and number of complementary treatments were entered in the models, and survival probabilities were calculated at 6, 12, 18, 24, 36, 48, and 60 months using the Cox proportional hazards and neural network models. We estimated coefficients of the Cox model and the weights in the neural network (with 3, 5, and 7 nodes in the hidden layer) in the training group, and used them to derive predictions in the study group. Predictions with these two methods were compared with those of the Kaplan-Meier product limit estimator as the gold standard. Comparisons were performed with the Friedman and Kruskal-Wallis tests. Survival probabilities at different times were determined using the Cox proportional hazards and a neural network with three nodes in the hidden layer; the ratios of standard errors with these two methods to the Kaplan-Meier method were 1.1593 and 1.0071, respectively, revealed a significant difference between Cox and Kaplan-Meier (P < 0.05) and no significant difference between Cox and the neural network, and the neural network and the standard (Kaplan-Meier), as well as better accuracy for the neural network (with 3 nodes in the hidden layer). Probabilities of survival were calculated using three neural network models with 3, 5, and 7 nodes in the hidden layer, and it has been observed that none of the predictions was significantly different from results with the Kaplan-Meier method and they appeared more comparable towards the last months (fifth year). However, we observed better accuracy using the neural network with 5 nodes in the hidden layer. Using the Cox proportional hazards and a neural network with 3 nodes in the hidden layer, we found enhanced accuracy with the neural network model. Neural networks can provide more accurate predictions for survival probabilities compared to the Cox proportional hazards mode, especially now that advances in computer sciences have eliminated limitations associated with complex computations. It is not recommended in order to adding too many hidden layer nodes because sample size related effects can reduce the accuracy. We recommend increasing the number of nodes to a point that increased accuracy continues (decrease in mean standard error), however increasing nodes should cease when a change in this trend is observed.

Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

PubMed

Vannini, Federica; Chattopadhyay, Mitali; Kodela, Ravinder; Rao, Praveen P N; Kashfi, Khosrow

2015-12-01

We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

ASP6537, a novel highly selective cyclooxygenase-1 inhibitor, exerts potent antithrombotic effect without "aspirin dilemma".

PubMed

Sakata, Chinatsu; Kawasaki, Tomihisa; Kato, Yasuko; Abe, Masaki; Suzuki, Ken-ichi; Ohmiya, Makoto; Funatsu, Toshiyuki; Morita, Yoshiaki; Okada, Masamichi

2013-07-01

Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were >142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥100 mg/kg. ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genomic selection for slaughter age in pigs using the Cox frailty model.

PubMed

Santos, V S; Martins Filho, S; Resende, M D V; Azevedo, C F; Lopes, P S; Guimarães, S E F; Glória, L S; Silva, F F

2015-10-19

The aim of this study was to compare genomic selection methodologies using a linear mixed model and the Cox survival model. We used data from an F2 population of pigs, in which the response variable was the time in days from birth to the culling of the animal and the covariates were 238 markers [237 single nucleotide polymorphism (SNP) plus the halothane gene]. The data were corrected for fixed effects, and the accuracy of the method was determined based on the correlation of the ranks of predicted genomic breeding values (GBVs) in both models with the corrected phenotypic values. The analysis was repeated with a subset of SNP markers with largest absolute effects. The results were in agreement with the GBV prediction and the estimation of marker effects for both models for uncensored data and for normality. However, when considering censored data, the Cox model with a normal random effect (S1) was more appropriate. Since there was no agreement between the linear mixed model and the imputed data (L2) for the prediction of genomic values and the estimation of marker effects, the model S1 was considered superior as it took into account the latent variable and the censored data. Marker selection increased correlations between the ranks of predicted GBVs by the linear and Cox frailty models and the corrected phenotypic values, and 120 markers were required to increase the predictive ability for the characteristic analyzed.

Long term mortality in critically ill burn survivors.

PubMed

Nitzschke, Stephanie; Offodile, Anaeze C; Cauley, Ryan P; Frankel, Jason E; Beam, Andrew; Elias, Kevin M; Gibbons, Fiona K; Salim, Ali; Christopher, Kenneth B

2017-09-01

Little is known about long term survival risk factors in critically ill burn patients who survive hospitalization. We hypothesized that patients with major burns who survive hospitalization would have favorable long term outcomes. We performed a two center observational cohort study in 365 critically ill adult burn patients who survived to hospital discharge. The exposure of interest was major burn defined a priori as >20% total body surface area burned [TBSA]. The modified Baux score was determined by age + %TBSA+ 17(inhalational injury). The primary outcome was all-cause 5year mortality based on the US Social Security Administration Death Master File. Adjusted associations were estimated through fitting of multivariable logistic regression models. Our final model included adjustment for inhalational injury, presence of 3rd degree burn, gender and the acute organ failure score, a validated ICU risk-prediction score derived from age, ethnicity, surgery vs. medical patient type, comorbidity, sepsis and acute organ failure covariates. Time-to-event analysis was performed using Cox proportional hazard regression. Of the cohort patients studied, 76% were male, 29% were non white, 14% were over 65, 32% had TBSA >20%, and 45% had inhalational injury. The mean age was 45, 92% had 2nd degree burns, 60% had 3rd degree burns, 21% received vasopressors, and 26% had sepsis. The mean TBSA was 20.1%. The mean modified Baux score was 72.8. Post hospital discharge 5year mortality rate was 9.0%. The 30day hospital readmission rate was 4%. Patients with major burns were significantly younger (41 vs. 47 years) had a significantly higher modified Baux score (89 vs. 62), and had significantly higher comorbidity, acute organ failure, inhalational injury and sepsis (all P<0.05). There were no differences in gender and the acute organ failure score between major and non-major burns. In the multivariable logistic regression model, major burn was associated with a 3 fold decreased odds of 5year post-discharge mortality compared to patients with TBSA<20% [OR=0.29 (95%CI 0.11-0.78; P=0.014)]. The adjusted model showed good discrimination [AUC 0.81 (95%CI 0.74-0.89)] and calibration (Hosmer-Lemeshow χ 2 P=0.67). Cox proportional hazard multivariable regression modeling, adjusting for inhalational injury, presence of 3rd degree burn, gender and the acute organ failure score, showed that major burn was predictive of lower mortality following hospital admission [HR=0.34 (95% CI 0.15-0.76; P=0.009)]. The modified Baux score was not predictive for mortality following hospital discharge [OR 5year post-discharge mortality=1.00 (95%CI 0.99-1.02; P=0.74); HR for post-discharge mortality=1.00 (95% CI 0.99-1.02; P=0.55)]. Critically ill patients with major burns who survive to hospital discharge have decreased 5year mortality compared to those with less severe burns. ICU Burn unit patients who survive to hospital discharge are younger with less comorbidities. The observed relationship is likely due to the relatively higher physiological reserve present in those who survive a Burn ICU course which may provide for a survival advantage during recovery after major burn. Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.

Reproductive Risk Factors and Coronary Heart Disease in the Women’s Health Initiative Observational Study

PubMed Central

Parikh, Nisha I.; Jeppson, Rebecca P.; Berger, Jeffrey S.; Eaton, Charles B.; Kroenke, Candyce H.; LeBlanc, Erin S.; Lewis, Cora E.; Loucks, Eric B.; Parker, Donna R.; Rillamas-Sun, Eileen; Ryckman, Kelli K; Waring, Molly E.; Schenken, Robert S.; Johnson, Karen C; Edstedt-Bonamy, Anna-Karin; Allison, Matthew A.; Howard, Barbara V.

2016-01-01

Background Reproductive factors provide an early window into a woman’s coronary heart disease (CHD) risk, however their contribution to CHD risk stratification is uncertain. Methods and Results In the Women’s Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥ 1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C-statistic, net reclassification index (or NRI with risk categories of <5%, 5–<10%, and ≥10% 10-year risk of CHD) and integrated discriminatory index (IDI) were assessed. Among 72,982 women [n=4607 CHD events, median follow-up=12.0 (IQR=8.3–13.7) years, mean (SD) age 63.2 (7.2) years], an age-adjusted reproductive risk factor model had a C-statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C-statistic increased from 0.726 to 0.730; IDI=0.0013, p-value < 0.0001). Net reclassification for women with events was not improved (NRI events=0.007, p-value=0.18); and for women without events was marginally improved (NRI non-events=0.002, p-value=0.04) Conclusions Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination and do not materially improve net reclassification. PMID:27143682

Bootstrap-based methods for estimating standard errors in Cox's regression analyses of clustered event times.

PubMed

Xiao, Yongling; Abrahamowicz, Michal

2010-03-30

We propose two bootstrap-based methods to correct the standard errors (SEs) from Cox's model for within-cluster correlation of right-censored event times. The cluster-bootstrap method resamples, with replacement, only the clusters, whereas the two-step bootstrap method resamples (i) the clusters, and (ii) individuals within each selected cluster, with replacement. In simulations, we evaluate both methods and compare them with the existing robust variance estimator and the shared gamma frailty model, which are available in statistical software packages. We simulate clustered event time data, with latent cluster-level random effects, which are ignored in the conventional Cox's model. For cluster-level covariates, both proposed bootstrap methods yield accurate SEs, and type I error rates, and acceptable coverage rates, regardless of the true random effects distribution, and avoid serious variance under-estimation by conventional Cox-based standard errors. However, the two-step bootstrap method over-estimates the variance for individual-level covariates. We also apply the proposed bootstrap methods to obtain confidence bands around flexible estimates of time-dependent effects in a real-life analysis of cluster event times.

Mining gene link information for survival pathway hunting.

PubMed

Jing, Gao-Jian; Zhang, Zirui; Wang, Hong-Qiang; Zheng, Hong-Mei

2015-08-01

This study proposes a gene link-based method for survival time-related pathway hunting. In this method, the authors incorporate gene link information to estimate how a pathway is associated with cancer patient's survival time. Specifically, a gene link-based Cox proportional hazard model (Link-Cox) is established, in which two linked genes are considered together to represent a link variable and the association of the link with survival time is assessed using Cox proportional hazard model. On the basis of the Link-Cox model, the authors formulate a new statistic for measuring the association of a pathway with survival time of cancer patients, referred to as pathway survival score (PSS), by summarising survival significance over all the gene links in the pathway, and devise a permutation test to test the significance of an observed PSS. To evaluate the proposed method, the authors applied it to simulation data and two publicly available real-world gene expression data sets. Extensive comparisons with previous methods show the effectiveness and efficiency of the proposed method for survival pathway hunting.

Collagen Triple Helix Repeat Containing-1 (CTHRC1) Expression in Oral Squamous Cell Carcinoma (OSCC): Prognostic Value and Clinico-Pathological Implications

PubMed Central

Lee, Chia Ee; Vincent-Chong, Vui King; Ramanathan, Anand; Kallarakkal, Thomas George; Karen-Ng, Lee Peng; Ghani, Wan Maria Nabillah; Rahman, Zainal Ariff Abdul; Ismail, Siti Mazlipah; Abraham, Mannil Thomas; Tay, Keng Kiong; Mustafa, Wan Mahadzir Wan; Cheong, Sok Ching; Zain, Rosnah Binti

2015-01-01

BACKGROUND: Collagen Triple Helix Repeat Containing 1 (CTHRC1) is a protein often found to be over-expressed in various types of human cancers. However, correlation between CTHRC1 expression level with clinico-pathological characteristics and prognosis in oral cancer remains unclear. Therefore, this study aimed to determine mRNA and protein expression of CTHRC1 in oral squamous cell carcinoma (OSCC) and to evaluate the clinical and prognostic impact of CTHRC1 in OSCC. METHODS: In this study, mRNA and protein expression of CTHRC1 in OSCCs were determined by quantitative PCR and immunohistochemistry, respectively. The association between CTHRC1 and clinico-pathological parameters were evaluated by univariate and multivariate binary logistic regression analyses. Correlation between CTHRC1 protein expressions with survival were analysed using Kaplan-Meier and Cox regression models. RESULTS: Current study demonstrated CTHRC1 was significantly overexpressed at the mRNA level in OSCC. Univariate analyses indicated a high-expression of CTHRC1 that was significantly associated with advanced stage pTNM staging, tumour size ≥ 4 cm and positive lymph node metastasis (LNM). However, only positive LNM remained significant after adjusting with other confounder factors in multivariate logistic regression analyses. Kaplan-Meier survival analyses and Cox model demonstrated that patients with high-expression of CTHRC1 protein were associated with poor prognosis and is an independent prognostic factor in OSCC. CONCLUSION: This study indicated that over-expression of CTHRC1 potentially as an independent predictor for positive LNM and poor prognosis in OSCC. PMID:26664254

Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer

PubMed Central

Kim, Eric S.; Lee, J. Jack; He, Guangan; Chow, Chi-Wan; Fujimoto, Junya; Kalhor, Neda; Swisher, Stephen G.; Wistuba, Ignacio I.; Stewart, David J.; Siddik, Zahid H.

2012-01-01

Purpose Platinum resistance is a major limitation in the treatment of advanced non–small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC. Patients and Methods We measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post- versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis. Results Tissue platinum concentration correlated significantly with percent reduction in tumor size (P < .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P = .034), progression-free survival (P = .018), and overall survival (P = .005) in the multicovariate Cox model analysis after adjusting for number of cycles. Conclusion This clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted. PMID:22891266

Dietary sodium to potassium ratio and the incidence of hypertension and cardiovascular disease: A population-based longitudinal study.

PubMed

Mirmiran, Parvin; Bahadoran, Zahra; Nazeri, Pantea; Azizi, Fereidoun

2018-01-30

There is an interaction between dietary sodium/potassium intake in the pathogenesis of hypertension (HTN) and cardiovascular disease (CVD). The aim of this study was to investigate the association of dietary sodium to potassium (Na/K) ratio and the risk of HTN and CVD in a general population of Iranian adults. In this prospective cohort study, adults men and women with complete baseline data were selected from among participants of the Tehran Lipid and Glucose Study and were followed up for 6.3 years for incidence of HTN and CVD outcomes. Dietary sodium and potassium were assessed using a valid and reliable 168-item food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between dietary sodium, potassium and their ratio and risk of outcomes. During the study follow-up, 291 (15.1%) and 79 (5.0%) new cases of HTN and CVD were identified, respectively. No significant association was observed between usual intakes of sodium, potassium and dietary Na/K ratio with the incidence of HTN. There was no significant association between dietary intakes of sodium and potassium per se and the risk of CVD, whereas when dietary sodium to potassium ratio was considered as exposure in the fully-adjusted Cox regression model, and participants in the highest compared to lowest tertile had a significantly increased risk of CVD (HR = 2.19, 95% CI = 1.16-4.14). Our findings suggest that high dietary Na/K ratio could contribute to increased risk of CVD events.

No evidence of a causal relationship between hypothyroidism and glaucoma: A Danish nationwide register-based cohort study.

PubMed

Thvilum, Marianne; Brandt, Frans; Brix, Thomas Heiberg; Hegedüs, Laszlo

2018-01-01

An interrelationship between hypothyroidism and glaucoma, due to a shared autoimmune background or based on deposition of mucopolysaccharides in the trabecular meshwork in the eye, has been suggested but is at present unsubstantiated. Therefore, our objective was to investigate, at a nationwide and population-based level, whether there is such an association. Observational cohort study using record-linkage data from nationwide Danish health registers. 121,799 individuals diagnosed with a first episode of hypothyroidism were identified and were matched with 4 non-hypothyroid controls according to age and sex. Prevalence of glaucoma was recorded and cases and controls were followed over a mean of 7.1 years (range 0-17). Logistic and Cox regression models were used to assess the risk of glaucoma before and after the diagnosis of hypothyroidism, respectively. Overall, we found a higher prevalence of glaucoma in subjects with hypothyroidism as compared to controls (4.6% vs. 4.3%, p < 0.001). Prior to the diagnosis of hypothyroidism, the odds ratio (OR) was significantly increased for glaucoma [1.09; 95% confidence interval (CI): 1.04-1.13]. Based on the Cox regression model, there was no increased risk of glaucoma after the diagnosis of hypothyroidism [hazard ratio (HR) 1.00; 95% CI: 0.96-1.06], and the HR decreased further after adjusting for pre-existing co-morbidity (0.88; 95% CI: 0.84-0.93). There was an increased risk of glaucoma before but not after the diagnosis of hypothyroidism, suggesting that screening for glaucoma in hypothyroid individuals is unwarranted.

Usefulness of the admission electrocardiogram to predict long-term outcomes after non-ST-elevation acute coronary syndrome (from the FRISC II, ICTUS, and RITA-3 [FIR] Trials).

PubMed

Damman, Peter; Holmvang, Lene; Tijssen, Jan G P; Lagerqvist, Bo; Clayton, Tim C; Pocock, Stuart J; Windhausen, Fons; Hirsch, Alexander; Fox, Keith A A; Wallentin, Lars; de Winter, Robbert J

2012-01-01

The aim of this study was to evaluate the independent prognostic value of qualitative and quantitative admission electrocardiographic (ECG) analysis regarding long-term outcomes after non-ST-segment elevation acute coronary syndromes (NSTE-ACS). From the Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II), Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS), and Randomized Intervention Trial of Unstable Angina 3 (RITA-3) patient-pooled database, 5,420 patients with NSTE-ACS with qualitative ECG data, of whom 2,901 had quantitative data, were included in this analysis. The main outcome was 5-year cardiovascular death or myocardial infarction. Hazard ratios (HRs) were calculated with Cox regression models, and adjustments were made for established outcome predictors. The additional discriminative value was assessed with the category-less net reclassification improvement and integrated discrimination improvement indexes. In the 5,420 patients, the presence of ST-segment depression (≥1 mm; adjusted HR 1.43, 95% confidence interval [CI] 1.25 to 1.63) and left bundle branch block (adjusted HR 1.64, 95% CI 1.18 to 2.28) were independently associated with long-term cardiovascular death or myocardial infarction. Risk increases were short and long term. On quantitative ECG analysis, cumulative ST-segment depression (≥5 mm; adjusted HR 1.34, 95% CI 1.05 to 1.70), the presence of left bundle branch block (adjusted HR 2.15, 95% CI 1.36 to 3.40) or ≥6 leads with inverse T waves (adjusted HR 1.22, 95% CI 0.97 to 1.55) was independently associated with long-term outcomes. No interaction was observed with treatment strategy. No improvements in net reclassification improvement and integrated discrimination improvement were observed after the addition of quantitative characteristics to a model including qualitative characteristics. In conclusion, in the FRISC II, ICTUS, and RITA-3 NSTE-ACS patient-pooled data set, admission ECG characteristics provided long-term prognostic value for cardiovascular death or myocardial infarction. Quantitative ECG characteristics provided no incremental discrimination compared to qualitative data. Copyright © 2012 Elsevier Inc. All rights reserved.

Expectation Maximization Algorithm for Box-Cox Transformation Cure Rate Model and Assessment of Model Misspecification Under Weibull Lifetimes.

PubMed

Pal, Suvra; Balakrishnan, Narayanaswamy

2018-05-01

In this paper, we develop likelihood inference based on the expectation maximization algorithm for the Box-Cox transformation cure rate model assuming the lifetimes to follow a Weibull distribution. A simulation study is carried out to demonstrate the performance of the proposed estimation method. Through Monte Carlo simulations, we also study the effect of model misspecification on the estimate of cure rate. Finally, we analyze a well-known data on melanoma with the model and the inferential method developed here.

Association of Cataract Surgery With Mortality in Older Women: Findings from the Women's Health Initiative.

PubMed

Tseng, Victoria L; Chlebowski, Rowan T; Yu, Fei; Cauley, Jane A; Li, Wenjun; Thomas, Fridtjof; Virnig, Beth A; Coleman, Anne L

2018-01-01

Previous studies have suggested an association between cataract surgery and decreased risk for all-cause mortality potentially through a mechanism of improved health status and functional independence, but the association between cataract surgery and cause-specific mortality has not been previously studied and is not well understood. To examine the association between cataract surgery and total and cause-specific mortality in older women with cataract. This prospective cohort study included nationwide data collected from the Women's Health Initiative (WHI) clinical trial and observational study linked with the Medicare claims database. Participants in the present study were 65 years or older with a diagnosis of cataract in the linked Medicare claims database. The WHI data were collected from January 1, 1993, through December 31, 2015. Data were analyzed for the present study from July 1, 2014, through September 1, 2017. Cataract surgery as determined by Medicare claims codes. The outcomes of interest included all-cause mortality and mortality attributed to vascular, cancer, accidental, neurologic, pulmonary, and infectious causes. Mortality rates were compared by cataract surgery status using the log-rank test and Cox proportional hazards regression models adjusting for demographics, systemic and ocular comorbidities, smoking, alcohol use, body mass index, and physical activity. A total of 74 044 women with cataract in the WHI included 41 735 who underwent cataract surgery. Mean (SD) age was 70.5 (4.6) years; the most common ethnicity was white (64 430 [87.0%]), followed by black (5293 [7.1%]) and Hispanic (1723 [2.3%]). The mortality rate was 2.56 per 100 person-years in both groups. In covariate-adjusted Cox models, cataract surgery was associated with lower all-cause mortality (adjusted hazards ratio [AHR], 0.40; 95% CI, 0.39-0.42) as well as lower mortality specific to vascular (AHR, 0.42; 95% CI, 0.39-0.46), cancer (AHR, 0.31; 95% CI, 0.29-0.34), accidental (AHR, 0.44; 95% CI, 0.33-0.58), neurologic (AHR, 0.43; 95% CI, 0.36-0.53), pulmonary (AHR, 0.63; 95% CI, 0.52-0.78), and infectious (AHR, 0.44; 95% CI, 0.36-0.54) diseases. In older women with cataract in the WHI, cataract surgery is associated with lower risk for total and cause-specific mortality, although whether this association is explained by the intervention of cataract surgery is unclear. Further study of the interplay of cataract surgery, systemic disease, and disease-related mortality would be informative for improved patient care.

Coffee intake, cardiovascular disease and all-cause mortality: observational and Mendelian randomization analyses in 95 000-223 000 individuals.

PubMed

Nordestgaard, Ask Tybjærg; Nordestgaard, Børge Grønne

2016-12-01

Coffee has been associated with modestly lower risk of cardiovascular disease and all-cause mortality in meta-analyses; however, it is unclear whether these are causal associations. We tested first whether coffee intake is associated with cardiovascular disease and all-cause mortality observationally; second, whether genetic variations previously associated with caffeine intake are associated with coffee intake; and third, whether the genetic variations are associated with cardiovascular disease and all-cause mortality. First, we used multivariable adjusted Cox proportional hazard regression models evaluated with restricted cubic splines to examine observational associations in 95 366 White Danes. Second, we estimated mean coffee intake according to five genetic variations near the AHR (rs4410790; rs6968865) and CYP1A1/2 genes (rs2470893; rs2472297; rs2472299). Third, we used sex- and age adjusted Cox proportional hazard regression models to examine genetic associations with cardiovascular disease and all-cause mortality in 112 509 Danes. Finally, we used sex and age-adjusted logistic regression models to examine genetic associations with ischaemic heart disease including the Cardiogram and C4D consortia in a total of up to 223 414 individuals. We applied similar analyses to ApoE genotypes associated with plasma cholesterol levels, as a positive control. In observational analyses, we observed U-shaped associations between coffee intake and cardiovascular disease and all-cause mortality; lowest risks were observed in individuals with medium coffee intake. Caffeine intake allele score (rs4410790 + rs2470893) was associated with a 42% higher coffee intake. Hazard ratios per caffeine intake allele were 1.02 (95% confidence interval: 1.00-1.03) for ischaemic heart disease, 1.02 (0.99-1.02) for ischaemic stroke, 1.02 (1.00-1.03) for ischaemic vascular disease, 1.02 (0.99-1.06) for cardiovascular mortality and 1.01 (0.99-1.03) for all-cause mortality. Including international consortia, odds ratios per caffeine intake allele for ischaemic heart disease were 1.00 (0.98-1.02) for rs4410790, 1.01 (0.99-1.03) for rs6968865, 1.02 (1.00-1.04) for rs2470893, 1.02 (1.00-1.04) for rs2472297 and 1.03 (0.99-1.06) for rs2472299. Conversely, 5% lower cholesterol level caused by ApoE genotype had a corresponding odds ratio for ischaemic heart disease of 0.93 (0.89-0.97). Observationally, coffee intake was associated with U-shaped lower risk of cardiovascular disease and all-cause mortality; however, genetically caffeine intake was not associated with risk of cardiovascular disease or all-cause mortality. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

Does vagotomy protect against multiple sclerosis?

PubMed

Sundbøll, Jens; Horváth-Puhó, Erzsébet; Adelborg, Kasper; Svensson, Elisabeth

2017-07-01

To examine the association between vagotomy and multiple sclerosis. We conducted a matched cohort study of all patients who underwent truncal or super-selective vagotomy and a comparison cohort, by linking Danish population-based medical registries (1977-1995). Hazard ratios (HRs) for multiple sclerosis, adjusting for potential confounders were computed by means of Cox regression analysis. Median age of multiple sclerosis onset corresponded to late onset multiple sclerosis. No association with multiple sclerosis was observed for truncal vagotomy (0-37 year adjusted HR=0.91, 95% confidence interval [CI]: 0.48-1.74) or super-selective vagotomy (0-37 year adjusted HR=1.28, 95% CI: 0.79-2.09) compared with the general population. We found no association between vagotomy and later risk of late onset multiple sclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

The Bitter Barricading of Prostaglandin Biosynthesis Pathway: Understanding the Molecular Mechanism of Selective Cyclooxygenase-2 Inhibition by Amarogentin, a Secoiridoid Glycoside from Swertia chirayita

PubMed Central

Sundar, Durai; Thorat, Sunil S.

2014-01-01

Swertia chirayita, a medicinal herb inhabiting the challenging terrains and high altitudes of the Himalayas, is a rich source of essential phytochemical isolates. Amarogentin, a bitter secoiridoid glycoside from S. chirayita, shows varied activity in several patho-physiological conditions, predominantly in leishmaniasis and carcinogenesis. Experimental analysis has revealed that amarogentin downregulates the cyclooxygenase-2 (COX-2) activity and helps to curtail skin carcinogenesis in mouse models; however, there exists no account on selective inhibition of the inducible cyclooxygenase (COX) isoform by amarogentin. Hence the computer-aided drug discovery methods were used to unravel the COX-2 inhibitory mechanism of amarogentin and to check its selectivity for the inducible isoform over the constitutive one. The generated theoretical models of both isoforms were subjected to molecular docking analysis with amarogentin and twenty-one other Food and Drug Authority (FDA) approved lead molecules. The post-docking binding energy profile of amarogentin was comparable to the binding energy profiles of the FDA approved selective COX-2 inhibitors. Subsequent molecular dynamics simulation analysis delineated the difference in the stability of both complexes, with amarogentin-COX-2 complex being more stable after 40ns simulation. The total binding free energy calculated by MMGBSA for the amarogentin-COX-2 complex was −52.35 KCal/mol against a binding free energy of −8.57 KCal/mol for amarogentin-COX-1 complex, suggesting a possible selective inhibition of the COX-2 protein by the natural inhibitor. Amarogentin achieves this potential selectivity by small, yet significant, structural differences inherent to the binding cavities of the two isoforms. Hypothetically, it might block the entry of the natural substrates in the hydrophobic binding channel of the COX-2, inhibiting the cyclooxygenation step. To sum up briefly, this work highlights the mechanism of the possible selective COX-2 inhibition by amarogentin and endorses the possibility of obtaining efficient, futuristic and targeted therapeutic agents for relieving inflammation and malignancy from this phytochemical source. PMID:24603686

Direct Lentiviral-Cyclooxygenase 2 Application to the Tendon-Bone Interface Promotes Osteointegration and Enhances Return of the Pull-Out Tensile Strength of the Tendon Graft in a Rat Model of Biceps Tenodesis

PubMed Central

Wergedal, Jon E.; Stiffel, Virginia; Lau, Kin-Hing William

2014-01-01

This study sought to determine if direct application of the lentiviral (LV)-cyclooxygenase 2 (COX2) vector to the tendon-bone interface would promote osteointegration of the tendon graft in a rat model of biceps tenodesis. The LV-COX2 gene transfer strategy was chosen for investigation because a similar COX2 gene transfer strategy promoted bony bridging of the fracture gap during bone repair, which involves similar histologic transitions that occur in osteointegration. Briefly, a 1.14-mm diameter tunnel was drilled in the mid-groove of the humerus of adult Fischer 344 rats. The LV-COX2 or βgal control vector was applied directly into the bone tunnel and onto the end of the tendon graft, which was then pulled into the bone tunnel. A poly-L-lactide pin was press-fitted into the tunnel as interference fixation. Animals were sacrificed at 3, 5, or 8 weeks for histology analysis of osteointegration. The LV-COX2 gene transfer strategy enhanced neo-chondrogenesis at the tendon-bone interface but with only marginal effect on de novo bone formation. The tendon-bone interface of the LV-COX2-treated tenodesis showed the well-defined tendon-to-fibrocartilage-to-bone histologic transitions that are indicative of osteointegration of the tendon graft. The LV-COX2 in vivo gene transfer strategy also significantly enhanced angiogenesis at the tendon-bone interface. To determine if the increased osteointegration was translated into an improved pull-out mechanical strength property, the pull-out tensile strength of the LV-COX2-treated tendon grafts was determined with a pull-out mechanical testing assay. The LV-COX2 strategy yielded a significant improvement in the return of the pull-out strength of the tendon graft after 8 weeks. In conclusion, the COX2-based in vivo gene transfer strategy enhanced angiogenesis, osteointegration and improved return of the pull-out strength of the tendon graft. Thus, this strategy has great potential to be developed into an effective therapy to promote tendon-to-bone healing after tenodesis or related surgeries. PMID:24848992

The impact of stroke unit care on outcome in a Scottish stroke population, taking into account case mix and selection bias.

PubMed

Turner, Melanie; Barber, Mark; Dodds, Hazel; Dennis, Martin; Langhorne, Peter; Macleod, Mary Joan

2015-03-01

Randomised trials indicate that stroke unit care reduces morbidity and mortality after stroke. Similar results have been seen in observational studies but many have not corrected for selection bias or independent predictors of outcome. We evaluated the effect of stroke unit compared with general ward care on outcomes after stroke in Scotland, adjusting for case mix by incorporating the six simple variables (SSV) model, also taking into account selection bias and stroke subtype. We used routine data from National Scottish datasets for acute stroke patients admitted between 2005 and 2011. Patients who died within 3 days of admission were excluded from analysis. The main outcome measures were survival and discharge home. Multivariable logistic regression was used to estimate the OR for survival, and adjustment was made for the effect of the SSV model and for early mortality. Cox proportional hazards model was used to estimate the hazard of death within 365 days. There were 41 692 index stroke events; 79% were admitted to a stroke unit at some point during their hospital stay and 21% were cared for in a general ward. Using the SSV model, we obtained a receiver operated curve of 0.82 (SE 0.002) for mortality at 6 months. The adjusted OR for survival at 7 days was 3.11 (95% CI 2.71 to 3.56) and at 1 year 1.43 (95% CI 1.34 to 1.54) while the adjusted OR for being discharged home was 1.19 (95% CI 1.11 to 1.28) for stroke unit care. In routine practice, stroke unit admission is associated with a greater likelihood of discharge home and with lower mortality up to 1 year, after correcting for known independent predictors of outcome, and excluding early non-modifiable mortality. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Albumin-induced podocyte injury and protection are associated with regulation of COX-2.

PubMed Central

Agrawal, Shipra; Guess, Adam J.; Chanley, Melinda A.; Smoyer, and William E.

2014-01-01

Albuminuria is both a hallmark and a risk factor for progressive glomerular disease, and results in increased exposure of podocytes to serum albumin with its associated factors. Here in vivo and in vitro models of serum albumin overload were used to test the hypothesis that albumin-induced proteinuria and podocyte injury directly correlate with COX-2 induction. Albumin induced COX-2, MCP-1, CXCL1 and the stress protein HSP25 in both rat glomeruli and cultured podocytes, while B7-1 and HSP70i were also induced in podocytes. Podocyte exposure to albumin induced both mRNA and protein and enhanced the mRNA stability of COX-2, a key regulator of renal hemodynamics and inflammation, which renders podocytes susceptible to injury. Podocyte exposure to albumin also stimulated several kinases (p38 MAPK, MK2, JNK/SAPK and ERK1/2), inhibitors of which (except JNK/SAPK) down-regulated albumin-induced COX-2. Inhibition of AMPK, PKC and NFκB also down-regulated albumin-induced COX-2. Critically, albumin-induced COX-2 was also inhibited by glucocorticoids and thiazolidinediones, both of which directly protect podocytes against injury. Furthermore, specific albumin-associated fatty acids were identified as important contributors to COX-2 induction, podocyte injury and proteinuria. Thus, COX-2 is associated with podocyte injury during albuminuria, as well as with the known podocyte protection imparted by glucocorticoids and thiazolidinediones. Moreover, COX-2 induction, podocyte damage and albuminuria appear mediated largely by serum albumin-associated fatty acids. PMID:24918154

Association of Race With Mortality and Cardiovascular Events in a Large Cohort of US Veterans.

PubMed

Kovesdy, Csaba P; Norris, Keith C; Boulware, L Ebony; Lu, Jun L; Ma, Jennie Z; Streja, Elani; Molnar, Miklos Z; Kalantar-Zadeh, Kamyar

2015-10-20

In the general population, blacks experience higher mortality than their white peers, attributed in part to their lower socioeconomic status, reduced access to care, and possibly intrinsic biological factors. Patients with kidney disease are a notable exception, among whom blacks experience lower mortality. It is unclear if similar differences affecting outcomes exist in patients with no kidney disease but with equal or similar access to health care. We compared all-cause mortality, incident coronary heart disease, and incident ischemic stroke using multivariable-adjusted Cox models in a nationwide cohort of 547 441 black and 2 525 525 white patients with baseline estimated glomerular filtration rate ≥ 60 mL·min⁻¹·1.73 m⁻² receiving care from the US Veterans Health Administration. In parallel analyses, we compared outcomes in black versus white individuals in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. After multivariable adjustments in veterans, black race was associated with 24% lower all-cause mortality (adjusted hazard ratio, 0.76; 95% confidence interval, 0.75-0.77; P<0.001) and 37% lower incidence of coronary heart disease (adjusted hazard ratio, 0.63; 95% confidence interval, 0.62-0.65; P<0.001) but a similar incidence of ischemic stroke (adjusted hazard ratio, 0.99; 95% confidence interval, 0.97-1.01; P=0.3). Black race was associated with a 42% higher adjusted mortality among individuals with estimated glomerular filtration rate ≥ 60 mL·min⁻¹·1.73 m⁻² in NHANES (adjusted hazard ratio, 1.42; 95% confidence interval, 1.09-1.87). Black veterans with normal estimated glomerular filtration rate and equal access to healthcare have lower all-cause mortality and incidence of coronary heart disease and a similar incidence of ischemic stroke. These associations are in contrast to the higher mortality experienced by black individuals in the general US population. © 2015 American Heart Association, Inc.

ELASTIC NET FOR COX'S PROPORTIONAL HAZARDS MODEL WITH A SOLUTION PATH ALGORITHM.

PubMed

Wu, Yichao

2012-01-01

For least squares regression, Efron et al. (2004) proposed an efficient solution path algorithm, the least angle regression (LAR). They showed that a slight modification of the LAR leads to the whole LASSO solution path. Both the LAR and LASSO solution paths are piecewise linear. Recently Wu (2011) extended the LAR to generalized linear models and the quasi-likelihood method. In this work we extend the LAR further to handle Cox's proportional hazards model. The goal is to develop a solution path algorithm for the elastic net penalty (Zou and Hastie (2005)) in Cox's proportional hazards model. This goal is achieved in two steps. First we extend the LAR to optimizing the log partial likelihood plus a fixed small ridge term. Then we define a path modification, which leads to the solution path of the elastic net regularized log partial likelihood. Our solution path is exact and piecewise determined by ordinary differential equation systems.

[Application of SAS macro to evaluated multiplicative and additive interaction in logistic and Cox regression in clinical practices].

PubMed

Nie, Z Q; Ou, Y Q; Zhuang, J; Qu, Y J; Mai, J Z; Chen, J M; Liu, X Q

2016-05-01

Conditional logistic regression analysis and unconditional logistic regression analysis are commonly used in case control study, but Cox proportional hazard model is often used in survival data analysis. Most literature only refer to main effect model, however, generalized linear model differs from general linear model, and the interaction was composed of multiplicative interaction and additive interaction. The former is only statistical significant, but the latter has biological significance. In this paper, macros was written by using SAS 9.4 and the contrast ratio, attributable proportion due to interaction and synergy index were calculated while calculating the items of logistic and Cox regression interactions, and the confidence intervals of Wald, delta and profile likelihood were used to evaluate additive interaction for the reference in big data analysis in clinical epidemiology and in analysis of genetic multiplicative and additive interactions.

The structure of DSM-IV-TR personality disorder diagnoses in NESARC: a reanalysis.

PubMed

Trull, Timothy J; Vergés, Alvaro; Wood, Phillip K; Sher, Kenneth J

2013-12-01

Cox, Clara, Worobec, and Grant (2012) recently presented results from a series of analyses aimed at identifying the factor structure underlying the DSM-IV-TR (APA, 2000) personality diagnoses assessed in the large NESARC study. Cox et al. (2012) concluded that the best fitting model was one that modeled three lower-order factors (the three clusters of PDs as outlined by DSM-IV-TR), which in turn loaded on a single PD higher-order factor. Our reanalyses of the NESARC Wave 1 and Wave 2 data for personality disorder diagnoses revealed that the best fitting model was that of a general PD factor that spans each of the ten DSM-IV PD diagnoses, and our reanalyses do not support the three-cluster hierarchical structure outlined by Cox et al. (2012) and DSM-IV-TR. Finally, we note the importance of modeling the Wave 2 assessment method factor in analyses of NESARC PD data.

Changes in survival patterns in urban Chinese patients with liver cancer

PubMed Central

Hao, Xi-Shan; Chen, Ke-Xin; Wang, Peizhong Peter; Rohan, Tom

2003-01-01

AIM: To examine the survival patterns and determinants of primary liver cancer in a geographically defined Chinese population. METHODS: Primary liver cancer cases (n = 13685) diagnosed between 1981 and 2000 were identified by the Tianjin Cancer Registry. Age-adjusted and age-specific incidence rates were examined in both males and females. Proportional hazards (Cox) regression was utilized to explore the effects of time of diagnosis, sex, age, occupation, residence, and hospital of diagnosis on survival. RESULTS: Crude and age-adjusted incidence rates in the study period were: 27.4/100000 and 26.3/100000 in males; and 11.5/100000 and 10.4/100000 in females, respectively. Cox regression analyses indicated that there was a significant improvement in survival rates over time. Industrial workers and older people had relatively poor survival rates. The hospital in which the liver cancer was diagnosed was a statistically significant predictor of survival; patients diagnosed in city hospitals were more likely to have better survival than those diagnosed in community/district hospitals. CONCLUSION: Patients diagnosed in recent years appeared to have a better outcome than those diagnosed in early times. There were also significant survival disparities with respect to occupation and hospital of diagnosis, which suggest that socioeconomic status may play an important role in determining prognosis. PMID:12800226

Work-family conflicts and subsequent sleep medication among women and men: a longitudinal registry linkage study.

PubMed

Lallukka, T; Arber, S; Laaksonen, M; Lahelma, E; Partonen, T; Rahkonen, O

2013-02-01

Work and family are two key domains of life among working populations. Conflicts between paid work and family life can be detrimental to sleep and other health-related outcomes. This study examined longitudinally the influence of work-family conflicts on subsequent sleep medication. Questionnaire data were derived from the Helsinki Health Study mail surveys in 2001-2002 (2929 women, 793 men) of employees aged 40-60 years. Data concerning sleep medication were derived from the Finnish Social Insurance Institution's registers covering all prescribed medication from 1995 to 2007. Four items measured whether job responsibilities interfered with family life (work to family conflicts), and four items measured whether family responsibilities interfered with work (family to work conflicts). Cox proportional hazard models were fitted, adjusting for age, sleep medication five years before baseline, as well as various family- and work-related covariates. During a five-year follow-up, 17% of women and 10% of men had at least one purchase of prescribed sleep medication. Among women, family to work conflicts were associated with sleep medication over the following 5 years after adjustment for age and prior medication. The association remained largely unaffected after adjusting for family-related and work-related covariates. Work to family conflicts were also associated with subsequent sleep medication after adjustment for age and prior medication. The association attenuated after adjustment for work-related factors. No associations could be confirmed among men. Thus reasons for men's sleep medication likely emerge outside their work and family lives. Concerning individual items, strain-based ones showed stronger associations with sleep medication than more concrete time-based items. In conclusion, in particular family to work conflicts, but also work to family conflicts, are clear determinants of women's sleep medication. Copyright © 2012 Elsevier Ltd. All rights reserved.

Serum calcium changes and risk of type 2 diabetes mellitus in Asian population.

PubMed

Suh, Sunghwan; Bae, Ji Cheol; Jin, Sang-Man; Jee, Jae Hwan; Park, Mi Kyoung; Kim, Duk Kyu; Kim, Jae Hyeon

2017-11-01

We examined the association between changes in serum calcium levels with the incidence of type 2 diabetes mellitus (T2DM) in apparently healthy South Korean subjects. A retrospective longitudinal analysis was conducted with subjects who had participated in comprehensive health check-ups at least four times over a 7-year period (between 2006 and 2012). In total, 23,121 subjects were categorized into tertiles based on changes in their albumin-adjusted serum calcium levels. Multivariate Cox regression models were fitted to assess the association between changes in serum calcium levels during follow-up and the relative risk of diabetes incidence. After a median follow-up of 57.4months, 1,929 (8.3%) new cases of T2DM occurred. Simple linear regression analysis showed serum calcium level changes correlated positively with changes in HbA1c and fasting plasma glucose (FPG) levels (B=5.72, p<0.001 for FPG; B=0.13, p<0.001 for HbA1c). An increase in albumin-adjusted serum calcium levels during follow-up was related to an increased risk of T2DM. After adjustment for potential confounders, the risk of T2DM was 1.6 times greater for subjects whose albumin-adjusted serum calcium levels were in the highest change tertile during follow-up than for subjects whose levels were in the lowest tertile (HR 1.65, 95% CI 1.44-1.88, P<0.001). The elevation of albumin-adjusted serum calcium levels was associated with an increased risk of T2DM, independent of baseline glycemic status. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigation of risk factors for mortality in aged guide dogs: A retrospective cohort study.

PubMed

Hoummady, S; Hua, J; Muller, C; Pouchelon, J L; Blondot, M; Gilbert, C; Desquilbet, L

2016-09-15

The overall median lifespan of domestic dogs has been estimated to 9-12 years, but little is known about risk factors for mortality in aged and a priori healthy dogs. The objective of this retrospective cohort study was to determine which characteristics are associated with mortality in aged and a priori healthy guide dogs, in a retrospective cohort study of 116 guide dogs followed from a systematic geriatric examination at the age of 8-10 years old. A geriatric grid collected the clinical data and usual biological parameters were measured at the time of examination. Univariate (Kaplan-Meier estimates) and multivariable (Cox proportional hazard model) survival analyses were used to assess the associations with time to all-cause death. The majority of dogs were Golden Retrievers (n=48) and Labrador Retrievers (n=27). Median age at geriatric examination was 8.9 years. A total of 76 dogs died during follow-up, leading to a median survival time from geriatric examination of 4.4 years. After adjustment for demographic and biological variables, an increased alanine amionotransferase level (adjusted Hazard Ratio (adjusted HR), 6.2; 95% confidence interval [95%CI], 2.0-19.0; P<0.01), presenting skin nodules (adjusted HR, 1.9; 95% CI, 1.0-3.4; P=0.04), and not being a Labrador Retriever (adjusted HR, 3.3; 95%CI, 1.4-10; P<0.01) were independently associated with a shorter time to death. This study documents independent associations of alanine aminotransferase level, skin nodules and breed with mortality in aged guide dogs. These results may be useful for preventive medical care when conducting a geriatric examination in working dogs. Copyright © 2016 Elsevier B.V. All rights reserved.

Nut consumption and 5-y all-cause mortality in a Mediterranean cohort: the SUN project.

PubMed

Fernández-Montero, A; Bes-Rastrollo, M; Barrio-López, M T; Fuente-Arrillaga, C de la; Salas-Salvadó, J; Moreno-Galarraga, L; Martínez-González, M A

2014-09-01

The aim of this study was to assess the association between nut consumption and all-cause mortality after 5-y follow-up in a Spanish cohort. The SUN (Seguimiento Universidad de Navarra, University of Navarra Follow-up) project is a prospective cohort study, formed by Spanish university graduates. Information is gathered by mailed questionnaires collected biennially. In all, 17 184 participants were followed for up to 5 y. Baseline nut consumption was collected by self-reported data, using a validated 136-item semi-quantitative food frequency questionnaire. Information on mortality was collected by permanent contact with the SUN participants and their families, postal authorities, and the National Death Index. The association between baseline nut consumption and all-cause mortality was assessed using Cox proportional hazards models to adjust for potential confounding. Baseline nut consumption was categorized in two ways. In a first analysis energy-adjusted quintiles of nut consumption (measured in g/d) were used. To adjust for total energy intake the residuals method was used. In a second analysis, participants were categorized into four groups according to pre-established categories of nut consumption (servings/d or servings/wk). Both analyses were adjusted for potential confounding factors. Participants who consumed nuts ≥2/wk had a 56% lower risk for all-cause mortality than those who never or almost never consumed nuts (adjusted hazard ratio, 0.44; 95% confidence intervals, 0.23-0.86). Nut consumption was significantly associated with a reduced risk for all-cause mortality after the first 5 y of follow-up in the SUN project. Copyright © 2014 Elsevier Inc. All rights reserved.

Neighborhood-Level Racial/Ethnic Residential Segregation and Incident Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

Kershaw, Kiarri N.; Osypuk, Theresa L.; Do, D. Phuong; De Chavez, Peter J.; Roux, Ana V. Diez

2014-01-01

Background Previous research suggests neighborhood-level racial/ethnic residential segregation is linked to health, but it has not been studied prospectively in relation to cardiovascular disease (CVD). Methods and Results Participants were 1,595 non-Hispanic Black, 2,345 non-Hispanic White, and 1,289 Hispanic adults from the Multi-Ethnic Study of Atherosclerosis free of CVD at baseline (ages 45-84). Own-group racial/ethnic residential segregation was assessed using the Gi∗ statistic, a measure of how the neighborhood racial/ethnic composition deviates from surrounding counties’ racial/ethnic composition. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios (HR) for incident CVD (first definite angina, probable angina followed by revascularization, myocardial infarction, resuscitated cardiac arrest, CHD death, stroke, or stroke death) over 10.2 median years of follow-up. Among Blacks, each standard deviation increase in Black segregation was associated with a 12% higher hazard of developing CVD after adjusting for demographics (95% Confidence Interval (CI): 1.02, 1.22). This association persisted after adjustment for neighborhood-level characteristics, individual socioeconomic position, and CVD risk factors (HR: 1.12; 95% CI: 1.02, 1.23). For Whites, higher White segregation was associated with lower CVD risk after adjusting for demographics (HR: 0.88; 95% CI: 0.81, 0.96), but not after further adjustment for neighborhood characteristics. Segregation was not associated with CVD risk among Hispanics. Similar results were obtained after adjusting for time-varying segregation and covariates. Conclusions The association of residential segregation with cardiovascular risk varies according to race/ethnicity. Further work is needed to better characterize the individual- and neighborhood-level pathways linking segregation to CVD risk. PMID:25447044

Social participation and coronary heart disease risk in a large prospective study of UK women

PubMed Central

Balkwill, Angela; Canoy, Dexter; Reeves, Gillian K; Green, Jane; Beral, Valerie; Cairns, Benjamin J

2015-01-01

Background Participation in social activities is thought to prevent heart disease, but evidence is inconclusive. Design We assessed whether participating in social activities reduces the risk of coronary heart disease (CHD) in a large prospective study of 735,159 middle-aged UK women. Methods Women reported their participation in eight social activities (religious group, voluntary work, adult education, art/craft/music, dancing, sports club, yoga, bingo) and were followed for first CHD event (hospital admission or death) over the next 8.6 years. Cox regression models were used to estimate relative risks for CHD incidence by participation in each and in any of the social activities. Results After adjustment for age and region only, every activity except bingo was associated with a reduced risk of CHD (n = 30,756 cases in total). However, after additional adjustment for 11 factors (deprivation, education, smoking, physical activity, body mass index, alcohol, marital status, self-rated health, happiness, hypertension, diabetes), every relative risk estimate moved close to 1.0. For example, for participation in any of the activities compared with none, the relative risk adjusted for age and region only was 0.83 (99% confidence interval 0.81–0.86), but changed to 1.06 (99% confidence interval 1.02–1.09) after additional adjustment. Adjustment for education, self-rated health, smoking and physical activity attenuated the associations most strongly. Residual confounding and other unmeasured factors may well account for any small remaining associations. Conclusions Associations between participation in various social activities and CHD risk appear to be largely or wholly due to confounding by personal characteristics of the participants. PMID:26416995

Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.

PubMed

Gulløv, A L; Koefoed, B G; Petersen, P; Pedersen, T S; Andersen, E D; Godtfredsen, J; Boysen, G

1998-07-27

Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation, many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients. The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study was a randomized, controlled trial examining the following therapies: warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; and aspirin, 300 mg/d. These were compared with adjusted-dose warfarin therapy (international normalized ratio of prothrombin time [INR], 2.0-3.0). Stroke or a systemic thromboembolic event was the primary outcome event. Transient ischemic attack, acute myocardial infarction, and death were secondary events. Data were handled as survival data, and risk factors were identified using the Cox proportional hazards model. The trial was scheduled for 6 years from May 1, 1993, but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study, our trial was prematurely terminated on October 2, 1996. We included 677 patients (median age, 74 years). The cumulative primary event rate after 1 year was 5.8% in patients receiving minidose warfarin; 7.2%, warfarin plus aspirin; 3.6%, aspirin; and 2.8%, adjusted-dose warfarin (P = .67). After 3 years, no difference among the groups was seen. Major bleeding events were rare. Although the difference was insignificant, adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment. The results do not justify a change in the current recommendation of adjusted-dose warfarin (INR, 2.0-3.0) for stroke prevention in atrial fibrillation.

Coffee consumption and incidence of lung cancer in the NIH-AARP Diet and Health Study

PubMed Central

Guertin, Kristin A; Freedman, Neal D; Loftfield, Erikka; Graubard, Barry I; Caporaso, Neil E; Sinha, Rashmi

2016-01-01

Background: Coffee drinkers had a higher risk of lung cancer in some previous studies, but as heavy coffee drinkers tend to also be cigarette smokers, such findings could be confounded. Therefore, we examined this association in the nearly half a million participants of the US NIH-AARP Diet and Health Study. Methods: Typical coffee intake and smoking history were queried at baseline. During 4 155 256 person-years of follow-up, more than 9000 incident lung cancer cases occurred. We used Cox proportional hazards regression to estimate hazard ratios (HRs)and 95% confidence intervals for coffee intake and subsequent incidence of lung cancer. We also comprehensively adjusted for tobacco smoking and examined associations by detailed strata of tobacco use. Results: Coffee drinkers were far more likely to smoke than non-drinkers. Although coffee drinking was associated with lung cancer in age- and sex- adjusted models (HR for ≥ 6 cups/day compared with none: 4.56, 4.08-5.10), this association was substantially attenuated after adjusting for smoking (HR: 1.27, 1.14-1.42). Similar findings were observed for each different histological type of lung cancer, and for participants drinking predominantly caffeinated or decaffeinated coffee. Little evidence for an association was observed in our stratified analyses, either within never smokers or in most categories of tobacco use. Conclusions: Coffee drinking was positively associated with lung cancer in our study, although the association was substantially attenuated after adjustment for tobacco smoking. As our adjustment for lifetime tobacco use was imperfect, it is likely that the remaining association is due to residual confounding by smoking, although other explanations are possible. PMID:26082405

Social participation and coronary heart disease risk in a large prospective study of UK women.

PubMed

Floud, Sarah; Balkwill, Angela; Canoy, Dexter; Reeves, Gillian K; Green, Jane; Beral, Valerie; Cairns, Benjamin J

2016-06-01

Participation in social activities is thought to prevent heart disease, but evidence is inconclusive. We assessed whether participating in social activities reduces the risk of coronary heart disease (CHD) in a large prospective study of 735,159 middle-aged UK women. Women reported their participation in eight social activities (religious group, voluntary work, adult education, art/craft/music, dancing, sports club, yoga, bingo) and were followed for first CHD event (hospital admission or death) over the next 8.6 years. Cox regression models were used to estimate relative risks for CHD incidence by participation in each and in any of the social activities. After adjustment for age and region only, every activity except bingo was associated with a reduced risk of CHD (n = 30,756 cases in total). However, after additional adjustment for 11 factors (deprivation, education, smoking, physical activity, body mass index, alcohol, marital status, self-rated health, happiness, hypertension, diabetes), every relative risk estimate moved close to 1.0. For example, for participation in any of the activities compared with none, the relative risk adjusted for age and region only was 0.83 (99% confidence interval 0.81-0.86), but changed to 1.06 (99% confidence interval 1.02-1.09) after additional adjustment. Adjustment for education, self-rated health, smoking and physical activity attenuated the associations most strongly. Residual confounding and other unmeasured factors may well account for any small remaining associations. Associations between participation in various social activities and CHD risk appear to be largely or wholly due to confounding by personal characteristics of the participants. © The European Society of Cardiology 2015.

Triglyceride to high-density lipoprotein cholesterol ratio predicts cardiovascular outcomes in prevalent dialysis patients.

PubMed

Chen, Hung-Yuan; Tsai, Wan-Chuan; Chiu, Yen-Ling; Hsu, Shih-Ping; Pai, Mei-Fen; Yang, Ju-Yeh; Peng, Yu-Sen

2015-03-01

Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, an indicator of atherogenic dyslipidemia, is a predictor of cardiovascular (CV) outcomes in the general population and has been correlated with atherosclerotic events. Whether the TG/HDL-C ratio can predict CV outcomes and survival in dialysis patients is unknown. We performed this prospective, observational cohort study and enrolled 602 dialysis patients (539 hemodialysis and 63 peritoneal dialysis) from a single center in Taiwan followed up for a median of 3.9 years. The outcomes were the occurrence of CV events, CV death, and all-cause mortality during follow-up. The association of baseline TG/HDL-C ratio with outcomes was explored with Cox regression models, which were adjusted for demographic parameters and inflammatory/nutritional markers. Overall, 203 of the patients experienced CV events and 169 patients died, of whom 104 died due to CV events. Two hundred fifty-four patients reached the composite CV outcome. Patients with higher TG/HDL-C levels (quintile 5) had a higher incidence of CV events (adjusted hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.19-3.47), CV mortality (adjusted HR 1.91, 95% CI 1.07-3.99), composite CV outcome (adjusted HR 2.2, 95% CI 1.37-3.55), and all-cause mortality (adjusted HR 1.94, 95% CI 1.1-3.39) compared with the patients in quintile 1. However, in diabetic dialysis patients, the TG/HDL-C ratio did not predict the outcomes. The TG/HDL-C ratio is a reliable and easily accessible predictor to evaluate CV outcomes and survival in prevalent nondiabetic dialysis patients. ClinicalTrials.gov: NCT01457625.

Triglyceride to High-Density Lipoprotein Cholesterol Ratio Predicts Cardiovascular Outcomes in Prevalent Dialysis Patients

PubMed Central

Chen, Hung-Yuan; Tsai, Wan-Chuan; Chiu, Yen-Ling; Hsu, Shih-Ping; Pai, Mei-Fen; Yang, Ju-Yeh; Peng, Yu-Sen

2015-01-01

Abstract Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, an indicator of atherogenic dyslipidemia, is a predictor of cardiovascular (CV) outcomes in the general population and has been correlated with atherosclerotic events. Whether the TG/HDL-C ratio can predict CV outcomes and survival in dialysis patients is unknown. We performed this prospective, observational cohort study and enrolled 602 dialysis patients (539 hemodialysis and 63 peritoneal dialysis) from a single center in Taiwan followed up for a median of 3.9 years. The outcomes were the occurrence of CV events, CV death, and all-cause mortality during follow-up. The association of baseline TG/HDL-C ratio with outcomes was explored with Cox regression models, which were adjusted for demographic parameters and inflammatory/nutritional markers. Overall, 203 of the patients experienced CV events and 169 patients died, of whom 104 died due to CV events. Two hundred fifty-four patients reached the composite CV outcome. Patients with higher TG/HDL-C levels (quintile 5) had a higher incidence of CV events (adjusted hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.19–3.47), CV mortality (adjusted HR 1.91, 95% CI 1.07–3.99), composite CV outcome (adjusted HR 2.2, 95% CI 1.37–3.55), and all-cause mortality (adjusted HR 1.94, 95% CI 1.1–3.39) compared with the patients in quintile 1. However, in diabetic dialysis patients, the TG/HDL-C ratio did not predict the outcomes. The TG/HDL-C ratio is a reliable and easily accessible predictor to evaluate CV outcomes and survival in prevalent nondiabetic dialysis patients. ClinicalTrials.gov: NCT01457625 PMID:25761189

Anger Proneness, Gender, and the Risk of Heart Failure

PubMed Central

Kucharska-Newton, Anna M.; Williams, Janice E.; Chang, Patricia P.; Stearns, Sally C.; Sueta, Carla A.; Blecker, Saul B.; Mosley, Thomas H.

2014-01-01

Background Evidence concerning the association of anger-proneness with incidence of heart failure is lacking. Methods Anger proneness was ascertained among 13,171 black and white participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort using the Spielberger Trait Anger Scale. Incident heart failure events, defined as occurrence of ICD-9-CM code 428.x, were ascertained from participants’ medical records during follow-up 1990–2010. Relative hazard of heart failure across categories of trait anger was estimated from Cox proportional hazard models. Results Study participants (mean age 56.9 (SD 5.7) years) experienced 1,985 incident HF events during 18.5 (SD 4.9) years of follow-up. Incidence of HF was greater among those with high, as compared to those with low or moderate trait anger, with higher incidence observed for men as compared to women. The relative hazard of incident HF was modestly high among those with high trait anger, as compared to those with low or moderate trait anger (age-adjusted HR for men=1.44 (95% CI 1.23, 1.69). Adjustment for comorbidities and depressive symptoms attenuated the estimated age-adjusted relative hazard in men to 1.26 (95% CI 1.00, 1.60). Conclusion Assessment of anger proneness may be necessary in successful prevention and clinical management of heart failure, especially in men. PMID:25284390

Heart Rate Response to a Timed Walk & Cardiovascular Outcomes in Older Adults: The Cardiovascular Health Study

PubMed Central

Girotra, Saket; Kitzman, Dalane W.; Kop, Willem J.; Stein, Phyllis K.; Gottdiener, John S.; Mukamal, Kenneth J.

2012-01-01

OBJECTIVES To determine the relationship between heart rate response during low-grade physical exertion (six-minute walk) with mortality and adverse cardiovascular outcomes in the elderly. METHODS Participants in the Cardiovascular Health Study, who completed a six-minute walk test, were included. We used delta heart rate (difference between post-walk heart rate and resting heart rate) as a measure of chronotropic response and examined its association with 1) all-cause mortality and 2) incident coronary heart disease (CHD) event, using multivariable Cox regression models. RESULTS We included 2224 participants (mean age 77±4 years; 60% women, 85% white). The average delta heart rate was 26 beats/min. Participants in the lowest tertile of delta heart rate (<20 beats/min) had higher risk-adjusted mortality (hazard ratio [HR] 1.18; 95% confidence interval [CI][1.00, 1.40]) and incident CHD (HR 1.37; 95% CI[1.05, 1.78]) compared to subjects in the highest tertile (≥30 beats/min), with a significant linear trend across tertiles (P for trend <0.05 for both outcomes). This relationship was not significant after adjustment for distance walked. CONCLUSION Impaired chronotropic response during six-minute walk test was associated with an increased risk of mortality and incident CHD among the elderly. This association was attenuated after adjusting for distance walked. PMID:22722364

Mode of detection: an independent prognostic factor for women with breast cancer.

PubMed

Hofvind, Solveig; Holen, Åsne; Román, Marta; Sebuødegård, Sofie; Puig-Vives, Montse; Akslen, Lars

2016-06-01

To investigate breast cancer survival and risk of breast cancer death by detection mode (screen-detected, interval, and detected outside the screening programme), adjusting for prognostic and predictive tumour characteristics. Information about detection mode, prognostic (age, tumour size, histologic grade, lymph node status) and predictive factors (molecular subtypes based on immunohistochemical analyses of hormone receptor status (estrogen and progesterone) and Her2 status) were available for 8344 women in Norway aged 50-69 at diagnosis of breast cancer, 2005-2011. A total of 255 breast cancer deaths were registered by the end of 2011. Kaplan-Meier method was used to estimate six years breast cancer specific survival and Cox proportional hazard model to estimate hazard ratio (HR) for breast cancer death by detection mode, adjusting for prognostic and predictive factors. Women with screen-detected cancer had favourable prognostic and predictive tumour characteristics compared with interval cancers and those detected outside the screening programme. The favourable characteristics were present for screen-detected cancers, also within the subtypes. Adjusted HR of dying from breast cancer was two times higher for women with symptomatic breast cancer (interval or outside the screening), using screen-detected tumours as the reference. Detection mode is an independent prognostic factor for women diagnosed with breast cancer. Information on detection mode might be relevant for patient management to avoid overtreatment. © The Author(s) 2015.

Statin use after esophageal cancer diagnosis and survival: A population based cohort study.

PubMed

Cardwell, Chris R; Spence, Andrew D; Hughes, Carmel M; Murray, Liam J

2017-06-01

A recent epidemiological study of esophageal cancer patients concluded statin use post-diagnosis was associated with large (38%) and significant reductions in cancer-specific mortality. We investigated statin use and cancer-specific mortality in a large population-based cohort of esophageal cancer patients. Newly diagnosed [2009-2012] esophageal cancer patients were identified from the Scottish Cancer Registry and linked with the Prescribing Information System and Scotland Death Records (to January 2015). Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by post-diagnostic statin use (using a 6 month lag to reduce reverse causation) and to adjust these HRs for potential confounders. 1921 esophageal cancer patients were included in the main analysis, of whom 651 (34%) used statins after diagnosis. There was little evidence of a reduction in esophageal cancer-specific mortality in statin users compared with non-users after diagnosis (adjusted HR=0.93, 95% CI, 0.81, 1.07) and no dose response associations were seen. However, statin users compared with non-users in the year before diagnosis had a weak reduction in esophageal cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.79, 0.99). In this large population-based esophageal cancer cohort, there was little evidence of a reduction in esophageal cancer-specific mortality with statin use after diagnosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hyperkalemia is Associated with Increased 30-Day Mortality in Hip Fracture Patients.

PubMed

Norring-Agerskov, Debbie; Madsen, Christian Medom; Abrahamsen, Bo; Riis, Troels; Pedersen, Ole B; Jørgensen, Niklas Rye; Bathum, Lise; Lauritzen, Jes Bruun; Jørgensen, Henrik L

2017-07-01

Abnormal plasma concentrations of potassium in the form of hyper- and hypokalemia are frequent among hospitalized patients and have been linked to poor outcomes. In this study, we examined the prevalence of hypo- and hyperkalemia in patients admitted with a fractured hip as well as the association with 30-day mortality in these patients. A total of 7293 hip fracture patients (aged 60 years or above) with admission plasma potassium measurements were included. Data on comorbidity, medication, and death was retrieved from national registries. The association between plasma potassium and mortality was examined using Cox proportional hazards models adjusted for age, sex, and comorbidities. The prevalence of hypo- and hyperkalemia on admission was 19.8% and 6.6%, respectively. The 30-day mortality rates were increased for patients with hyperkalemia (21.0%, p < 0.0001) compared to normokalemic patients (9.5%), whereas hypokalemia was not significantly associated with mortality. After adjustment for age, sex, and individual comorbidities, hyperkalemia was still associated with increased risk of death 30 days after admission (HR = 1.93 [1.55-2.40], p < 0.0001). After the same adjustments, hypokalemia remained non-associated with increased risk of 30-day mortality (HR = 1.06 [0.87-1.29], p = 0.6). Hyperkalemia, but not hypokalemia, at admission is associated with increased 30-day mortality after a hip fracture.

Zoster vaccination is associated with a reduction of zoster in elderly patients with chronic kidney disease.

PubMed

Langan, Sinéad M; Thomas, Sara L; Smeeth, Liam; Margolis, David J; Nitsch, Dorothea

2016-12-01

Growing epidemiological evidence demonstrates increased zoster risks in people with chronic kidney disease (CKD). Study objectives were to determine zoster vaccine effectiveness in individuals with CKD in pragmatic use. A population-based cohort study was undertaken in a 5% random sample of US Medicare from 2007 to 2009 involving 766 330 eligible individuals aged ≥65 years who were (29 785) and were not (736 545) exposed to the zoster vaccine. Incidence rates for zoster in vaccinated and unvaccinated individuals and hazard ratios for zoster comparing vaccinated with unvaccinated were determined for individuals with CKD. Time-updated Cox proportional hazards models were used, adjusting for relevant confounders. CKD was present in 183 762 (24%) of individuals (15% of vaccinees). Adjusted vaccine effectiveness [95% confidence intervals (CIs)] in individuals with CKD was 0.49 (0.36-0.65). The adjusted vaccine effectiveness in participants with both CKD and diabetes mellitus was 0.46 (95% CI 0.09-0.68). Vaccine effectiveness estimates were similar to those previously reported for the general population [vaccine effectiveness 0.48 (95% CI 0.39-0.56)]. Zoster vaccine is effective against incident zoster in older individuals with CKD. Extra efforts are warranted to increase vaccine uptake in individuals with CKD given the known low uptake in these higher risk individuals. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

Trends and outcomes of cardiac transplantation from donors dying of drug intoxication.

PubMed

Warraich, Haider J; Lu, Di; Cobb, Stacy; Cooper, Lauren B; DeVore, Adam; Patel, Chetan B; Rosenberg, Paul B; Schroder, Jacob N; Daneshmand, Mani A; Milano, Carmelo A; Hernandez, Adrian F; Rogers, Joseph G; Mentz, Robert J

2018-05-01

Deaths from drug intoxication have increased in the United States but outcomes of recipients of orthotopic heart transplantation (OHT) from these donors are not well characterized. We performed a retrospective analysis of the United Network for Organ Sharing's STAR database between January 2000 and March 2014 and assessed mortality and retransplantation using adjusted Cox models by mechanism of donor death. Of the 31,660 OHTs from 2000 to 2014, 1233 (3.9%) were from drug intoxication. These donors were more likely to be female, white, with greater tobacco use and higher BMI compared to donors who died of other mechanisms. Drug intoxication accounted for 1.1% of OHT donors in 2000 and 6.2% in March 2014. No significant difference was observed in 10-year mortality (adjusted hazard ratio [HR], 95% confidence interval [CI]: 0.99, 0.87-1.13), 10-year retransplantation (adjusted HR 0.84, 0.49-1.41) or 1-year and 3-year rehospitalization with other mechanisms of death compared to drug intoxication. There has been a large increase in OHT donors who die of drug intoxication in the United States. OHT outcomes from these donors are similar to those dying from other mechanisms. These data have important implications for donor selection in context of the ongoing opioid epidemic. Copyright © 2018. Published by Elsevier Inc.

Scabies is strongly associated with acute rheumatic fever in a cohort study of Auckland children.

PubMed

Thornley, Simon; Marshall, Roger; Jarrett, Paul; Sundborn, Gerhard; Reynolds, Edwin; Schofield, Grant

2018-02-14

This study sought to determine whether scabies infection is associated with acute rheumatic fever (ARF) or chronic rheumatic heart disease (CRHD). A cohort study was undertaken using health records of children aged 3-12 years attending an oral health service for the first time. Subjects were then linked to hospital diagnoses of scabies and ARF or CRHD. A total of 213 957 children free of rheumatic heart disease at baseline were available for analysis. During a mean follow-up time of 5.1 years, 440 children were diagnosed with ARF or CRHD in hospital records. Children diagnosed with scabies during follow-up were 23 times more likely to develop ARF or CRHD, compared with children who had no scabies diagnosis. After adjustment for confounders in a Cox model, the association reduced but remained strong (adjusted hazard ratio: 8.98; 95% confidence interval: 6.33-20.2). In an analysis restricted to children hospitalised at least once during follow-up, the adjusted hazard ratio for the same comparison was 3.43 (95% confidence interval: 1.85-6.37). A recent diagnosis of scabies from hospital records is strongly associated with a subsequent diagnosis of ARF. Further investigation of the role that scabies infestation may play in the aetiology of ARF is warranted. © 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Flow cytometric analysis of platelet cyclooxygenase-1 and -2 and surface glycoproteins in patients with immune thrombocytopenia and healthy individuals.

PubMed

Rubak, Peter; Kristensen, Steen D; Hvas, Anne-Mette

2017-06-01

Immature platelets may contain more platelet enzymes such as cyclooxygenase (COX)-1 and COX-2 than mature platelets. Patients with immune thrombocytopenia (ITP) have a higher fraction of immature platelets and can therefore be utilized as a biological model for investigating COX-1 and COX-2 platelet expression. The aims were to develop flow cytometric assays for platelet COX-1 and COX-2 and to investigate the COX-1 and COX-2 platelet expression, platelet turnover, and platelet glycoproteins in ITP patients (n = 10) compared with healthy individuals (n = 30). Platelet count and platelet turnover parameters (mean platelet volume (MPV), immature platelet fraction (IPF), and immature platelet count (IPC)) were measured by flow cytometry (Sysmex XE-5000). Platelet COX-1, COX-2, and the glycoproteins (GP)IIb, IX, Ib, Ia, and IIIa were all analyzed by flow cytometry (Navios) and expressed as median fluorescence intensity. COX analyses were performed in both whole blood and platelet rich plasma (PRP), whereas platelet glycoproteins were analyzed in whole blood only. ITP patients had significantly lower platelet count (55 × 10 9 /L) than healthy individuals (240 × 10 9 /L, p < 0.01), but a higher MPV (p = 0.03) and IPF (p < 0.01). IPC was similar for the two groups (p = 0.74). PRP had significantly lower MPV (p < 0.01) and significantly higher platelet count and IPC (both p-values <0.03) when compared with whole blood. IPF was similar for PRP and whole blood (p = 0.18). COX-1 expression was 10 times higher and COX-2 expression was 50% higher in PRP than in whole blood (p COX-1 < 0.01, p COX-2 < 0.01). Platelet COX-1 expression was higher in ITP patients than healthy individuals using whole blood (p COX-1 < 0.01) and PRP, though this was nonsignificant in PRP (p COX-1 = 0.17). In ITP patients, positive correlations were found between platelet turnover and COX-1 expression (all p-values <0.01, rho = 0.80-0.94), whereas healthy individuals showed significant though weaker correlations between platelet turnover and COX-1 and COX-2 expressions (all p-values <0.03, rho = 0.44-0.71). GPIIb, IX, and Ib expression was increased in ITP patients compared with healthy individuals (all p-values < 0.03). GPIIb, IX, Ib, and IIIa showed positive correlations with platelet turnover in ITP patients (all p-values <0.02, rho = 0.71-0.94), but weak and nonsignificant correlations in healthy individuals (all p-values >0.14, rho = 0.11-0.28). In conclusion, ITP patients expressed higher COX-1 and platelet glycoprotein levels than healthy individuals. COX-1 and platelet glycoproteins demonstrated positive correlations with platelet turnover in ITP patients. In healthy individuals, COX-1 and COX-2 expression correlated positively with platelet turnover. PRP was more sensitive compared with whole blood as regards determination of COX. Therefore, PRP is the recommended matrix for investigating COX-1 and COX-2 in platelets.

Comparison of Weibull and Lognormal Cure Models with Cox in the Survival Analysis Of Breast Cancer Patients in Rafsanjan.

PubMed

Hoseini, Mina; Bahrampour, Abbas; Mirzaee, Moghaddameh

2017-02-16

Breast cancer is the most common cancer after lung cancer and the second cause of death. In this study we compared Weibull and Lognormal Cure Models with Cox regression on the survival of breast cancer. A cohort study. The current study retrospective cohort study was conducted on 140 patients referred to Ali Ibn Abitaleb Hospital, Rafsanjan southeastern Iran from 2001 to 2015 suffering from breast cancer. We determined and analyzed the effective survival causes by different models using STATA14. According to AIC, log-normal model was more consistent than Weibull. In the multivariable Lognormal model, the effective factors like smoking, second -hand smoking, drinking herbal tea and the last breast-feeding period were included. In addition, using Cox regression factors of significant were the disease grade, size of tumor and its metastasis (p-value<0.05). As Rafsanjan is surrounded by pistachio orchards and pesticides applied by farmers, people of this city are exposed to agricultural pesticides and its harmful consequences. The effect of the pesticide on breast cancer was studied and the results showed that the effect of pesticides on breast cancer was not in agreement with the models used in this study. Based on different methods for survival analysis, researchers can decide how they can reach a better conclusion. This comparison indicates the result of semi-parametric Cox method is closer to clinical experiences evidences.

Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

PubMed Central

2011-01-01

Background Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated. Methods We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients. Results After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086). Conclusions We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease. PMID:21957892

The Effect of Cyclooxygenase Inhibition on Tendon-Bone Healing in an In Vitro Coculture Model

PubMed Central

Schwarting, Tim; Pretzsch, Sebastian; Debus, Florian; Ruchholtz, Steffen; Lechler, Philipp

2015-01-01

The effects of cyclooxygenase (COX) inhibition following the reconstruction of the anterior cruciate ligament remain unclear. We examined the effects of selective COX-2 and nonselective COX inhibition on bone-tendon integration in an in vitro model. We measured the dose-dependent effects of ibuprofen and parecoxib on the viability of lipopolysaccharide- (LPS-) stimulated and unstimulated mouse MC3T3-E1 and 3T3 cells, the influence on gene expression at the osteoblast, interface, and fibroblast regions measured by quantitative PCR, and cellular outgrowth assessed on histological sections. Ibuprofen led to a dose-dependent suppression of MC3T3 cell viability, while parecoxib reduced the viability of 3T3 cultures. Exposure to ibuprofen significantly suppressed expression of Alpl (P < 0.01), Bglap (P < 0.001), and Runx2 (P < 0.01), and although parecoxib reduced expression of Alpl (P < 0.001), Fmod (P < 0.001), and Runx2 (P < 0.01), the expression of Bglap was increased (P < 0.01). Microscopic analysis showed a reduction in cellular outgrowth in LPS-stimulated cultures following exposure to ibuprofen and parecoxib. Nonselective COX inhibition and the specific inhibition of COX-2 led to region-specific reductions in markers of calcification and cell viability. We suggest further in vitro and in vivo studies examining the biologic and biomechanical effects of selective and nonselective COX inhibition. PMID:26063979

Prostanoid receptor EP2 as a therapeutic target.

PubMed

Ganesh, Thota

2014-06-12

Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.

Early increased density of cyclooxygenase-2 (COX-2) immunoreactive neurons in Down syndrome.

PubMed

Mulet, Maria; Blasco-Ibáńez, José Miguel; Crespo, Carlos; Nácher, Juan; Varea, Emilio

2017-01-01

Neuroinflammation is one of the hallmarks of Alzheimer's disease. One of the enzymes involved in neuroinflammation, even in early stages of the disease, is COX-2, an inducible cyclooxygenase responsible for the generation of eicosanoids and for the generation of free radicals. Individuals with Down syndrome develop Alzheimer's disease early in life. Previous studies pointed to the possible overexpression of COX-2 and correlated it to brain regions affected by the disease. We analysed the COX-2 expression levels in individuals with Down syndrome and in young, adult and old mice of the Ts65Dn mouse model for Down syndrome. We have observed an overexpression of COX-2 in both, Down syndrome individuals and mice. Importantly, mice already presented an overexpression of COX-2 at postnatal day 30, before neurodegeneration begins; which suggests that neuroinflammation may underlie the posterior neurodegeneration observed in individuals with Down syndrome and in Ts65Dn mice and could be a factor for the premature appearance of Alzheimer's disease..

RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

PubMed

Aslanukov, Azamat; Bhowmick, Reshma; Guruju, Mallikarjuna; Oswald, John; Raz, Dorit; Bush, Ronald A; Sieving, Paul A; Lu, Xinrong; Bock, Cheryl B; Ferreira, Paulo A

2006-10-01

The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/-) are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/-) mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.

Post-approval safety issues with innovative drugs: a European cohort study.

PubMed

Mol, Peter G M; Arnardottir, Arna H; Motola, Domenico; Vrijlandt, Patrick J; Duijnhoven, Ruben G; Haaijer-Ruskamp, Flora M; de Graeff, Pieter A; Denig, Petra; Straus, Sabine M J M

2013-11-01

At time of approval, knowledge of the full benefit risk of any drug is limited, in particular with regards to safety. Post-approval surveillance of potential drug safety concerns is recognized as an important task of regulatory agencies. For innovative, often first-in-class drugs, safety knowledge at time of approval is often even less extensive and these may require tighter scrutiny post approval. We evaluated whether more post-approval serious safety issues were identified for drugs with a higher level of innovation. A cohort study was performed that included all new active substances approved under the European Centralized Procedure and for which serious safety issues were identified post-approval from 1 January 1999 to 1 January 2012. Serious safety issues were defined as issues requiring a Direct Healthcare Professional Communication to alert individual healthcare professionals of a new serious safety issue, or a safety-related drug withdrawal. Data were retrieved from publicly available websites of the Dutch Medicines Evaluation Board and the European Medicines Agency. The level of innovation was scored using a validated algorithm, grading drugs as important (A), moderate (B) or modest (C) innovations or as pharmacological or technological (pharm/tech) innovations. The data were analyzed using appropriate descriptive statistics and Kaplan-Meier analysis, with a Mantel-Cox log-rank test, and Cox-regression models correcting for follow-up duration, to identify a possible trend in serious safety issues with an increasing level of innovation. In Europe, 279 new drugs were approved between 1999 and 2011. Fifty-nine (21 %) were graded as important, 63 (23 %) moderate, or 34 (12 %) modest innovations and 123 (44 %) as non-innovative (pharm/tech), while 15 (25 %), 13 (21 %), 8 (24 %) and 17 (14 %) had post-approval safety issues, respectively (p = 0.06, linear-by-linear test). Five drugs were withdrawn from the market. The Kaplan-Meier-derived probability for having a first serious safety issue was statistically significant, log-rank (Mantel-Cox) p = 0.036. In the final adjusted Cox proportional hazard model there was no statistically significant difference in occurrence of a first serious safety issue for important, moderate and modest innovations versus non-innovative drugs; hazard ratios 1.76 (95 % CI 0.82-3.77), 1.61 (95 % CI 0.76-3.41)], and 1.25 (95 % CI 0.51-3.06), respectively. A higher level of innovation was not clearly related to an increased risk of serious safety issues identified after approval.

Multiple recent horizontal transfers of the cox1 intron in Solanaceae and extended co-conversion of flanking exons

PubMed Central

2011-01-01

Background The most frequent case of horizontal transfer in plants involves a group I intron in the mitochondrial gene cox1, which has been acquired via some 80 separate plant-to-plant transfer events among 833 diverse angiosperms examined. This homing intron encodes an endonuclease thought to promote the intron's promiscuous behavior. A promising experimental approach to study endonuclease activity and intron transmission involves somatic cell hybridization, which in plants leads to mitochondrial fusion and genome recombination. However, the cox1 intron has not yet been found in the ideal group for plant somatic genetics - the Solanaceae. We therefore undertook an extensive survey of this family to find members with the intron and to learn more about the evolutionary history of this exceptionally mobile genetic element. Results Although 409 of the 426 species of Solanaceae examined lack the cox1 intron, it is uniformly present in three phylogenetically disjunct clades. Despite strong overall incongruence of cox1 intron phylogeny with angiosperm phylogeny, two of these clades possess nearly identical intron sequences and are monophyletic in intron phylogeny. These two clades, and possibly the third also, contain a co-conversion tract (CCT) downstream of the intron that is extended relative to all previously recognized CCTs in angiosperm cox1. Re-examination of all published cox1 genes uncovered additional cases of extended co-conversion and identified a rare case of putative intron loss, accompanied by full retention of the CCT. Conclusions We infer that the cox1 intron was separately and recently acquired by at least three different lineages of Solanaceae. The striking identity of the intron and CCT from two of these lineages suggests that one of these three intron captures may have occurred by a within-family transfer event. This is consistent with previous evidence that horizontal transfer in plants is biased towards phylogenetically local events. The discovery of extended co-conversion suggests that other cox1 conversions may be longer than realized but obscured by the exceptional conservation of plant mitochondrial sequences. Our findings provide further support for the rampant-transfer model of cox1 intron evolution and recommend the Solanaceae as a model system for the experimental analysis of cox1 intron transfer in plants. PMID:21943226

Depression and incident dementia. An 8-year population-based prospective study.

PubMed

Luppa, Melanie; Luck, Tobias; Ritschel, Franziska; Angermeyer, Matthias C; Villringer, Arno; Riedel-Heller, Steffi G

2013-01-01

The aim of the study was to investigate the impact of depression (categorical diagnosis; major depression, MD) and depressive symptoms (dimensional diagnosis and symptom patterns) on incident dementia in the German general population. Within the Leipzig Longitudinal Study of the Aged (LEILA 75+), a representative sample of 1,265 individuals aged 75 years and older were interviewed every 1.5 years over 8 years (mean observation time 4.3 years; mean number of visits 4.2). Cox proportional hazards and binary logistic regressions were used to estimate the effect of baseline depression and depressive symptoms on incident dementia. The incidence of dementia was 48 per 1,000 person-years (95% confidence interval (CI) 45-51). Depressive symptoms (Hazard ratio HR 1.03, 95% CI 1.01-1.05), and in particular mood-related symptoms (HR 1.08, 95% CI 1.03-1.14), showed a significant impact on the incidence of dementia only in univariate analysis, but not after adjustment for cognitive and functional impairment. MD showed only a significant impact on incidence of dementia in Cox proportional hazards regression, but not in binary logistic regression models. The present study using different diagnostic measures of depression on future dementia found no clear significant associations of depression and incident dementia. Further in-depth investigation would help to understand the nature of depression in the context of incident dementia.

Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

PubMed

Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

2015-09-03

Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.

Serum Uric Acid Is Associated with Poor Outcome in Black Africans in the Acute Phase of Stroke

PubMed Central

Ayeah, Chia Mark; Ba, H.; Mbahe, Salomon

2017-01-01

Background Prognostic significance of serum uric acid (SUA) in acute stroke still remains controversial. Objectives To determine the prevalence of hyperuricemia and its association with outcome of stroke patients in the Douala General Hospital (DGH). Methods This was a hospital based prospective cohort study which included acute stroke patients with baseline SUA levels and 3-month poststroke follow-up data. Associations between high SUA levels and stroke outcomes were analyzed using multiple logistic regression and survival analysis (Cox regression and Kaplan-Meier). Results A total of 701 acute stroke patients were included and the prevalence of hyperuricemia was 46.6% with a mean SUA level of 68.625 ± 24 mg/l. Elevated SUA after stroke was associated with death (OR = 2.067; 95% CI: 1.449–2.950; p < 0.001) but did not predict this issue. However, an independent association between increasing SUA concentration and mortality was noted in a Cox proportional hazards regression model (adjusted HR = 1.740; 95% CI: 1.305–2.320; p < 0.001). Furthermore, hyperuricemia was an independent predictor of poor functional outcome within 3 months after stroke (OR = 2.482; 95% CI: 1.399–4.404; p = 0.002). Conclusion The prevalence of hyperuricemia in black African stroke patients is quite high and still remains a predictor of poor outcome. PMID:29082062

Effect of late HIV diagnosis on HIV-related mortality among adults in general hospitals of Central Zone Tigray, northern Ethiopia: a retrospective cohort study.

PubMed

Belay, Hadera; Alemseged, Fessahaye; Angesom, Teklit; Hintsa, Solomon; Abay, Mebrahtu

2017-01-01

The global incidence of HIV infection is not significantly decreasing, especially in sub-Saharan African countries, including Ethiopia. Though there is availability and accessibility of free HIV services, people are not being diagnosed early for HIV, and hence patients are still dying of HIV-related causes. This research is aimed at verifying the effect of late diagnosis of HIV on HIV-related mortality in Central Zone Tigray, Ethiopia. A retrospective cohort study among adult (≥15 years old) HIV patients in three general hospitals of Tigray was conducted. Record reviews were carried out retrospectively from 2010 to 2015. Sample size was determined using stpower Cox in Stata software. Data were entered into EpiData version 3.1 software and transferred to Stata version 12 for analysis. Both bivariable and multivariable analyses were performed using Cox regression model to compare the HIV-related mortality of exposed (cluster of differentiation 4 cells count <350 cells/mm 3 ) and nonexposed (≥350 cells/mm 3 ) patients using adjusted hazard ratio (AHR) at 95% confidence interval (CI). In all, 638 HIV patients were analyzed, contributing 2,105.6 person-years. Forty-eight (7.5%) patients died of HIV-related causes with a mortality rate of 2.28 per 100 person-years. In the multivariable Cox regression model, patients with late diagnosis of HIV had a higher risk of mortality (AHR =3.22, 95% CI: 1.17-8.82) than patients with early diagnosis of HIV. Rural residence (AHR =1.96, 95% CI: 1.05-3.68), unemployment (AHR =2.70, 95% CI: 1.03-7.08), bedridden patients (AHR =2.98, 95% CI: 1.45-6.13), ambulatory patients (AHR =2.54, 95% CI: 1.05-6.15), and baseline hemoglobin level of <11 mg/dL (AHR =3.06, 95% CI: 1.51-6.23) were other independent predictors of mortality. Late diagnosis of HIV increased HIV-related mortality. Rural residence, unemployment, bedridden and ambulatory patients, and baseline hemoglobin level <11 mg/dL were also independent predictors of HIV-related mortality.

Compliance with guidelines and predictors of mortality in hemodialysis. Learning from Serbia patients.

PubMed

Djukanović, Ljubica; Dimković, Nada; Marinković, Jelena; Andrić, Branislav; Bogdanović, Jasmina; Budošan, Ivana; Cvetičanin, Anica; Djordjev, Kosta; Djordjević, Verica; Djurić, Živka; Lilić, Branimir Haviža; Jovanović, Nasta; Jelačić, Rosa; Knežević, Violeta; Kostić, Svetislav; Lazarević, Tatjana; Ljubenović, Stanimir; Marić, Ivko; Marković, Rodoljub; Milenković, Srboljub; Milićević, Olivera; Mitić, Igor; Mićunović, Vesna; Mišković, Milena; Pilipović, Dragana; Plješa, Steva; Radaković, Miroslava; Stanojević, Marina Stojanović; Janković, Biserka Tirmenštajn; Vojinović, Goran; Šefer, Kornelija

2015-01-01

The aims of the study were to determine the percentage of patients on regular hemodialysis (HD) in Serbia failing to meet KDOQI guidelines targets and find out factors associated with the risk of time to death and the association between guidelines adherence and patient outcome. A cohort of 2153 patients on regular HD in 24 centers (55.7% of overall HD population) in Serbia were followed from January 2010 to December 2012. The percentage of patients failing to meet KDOQI guidelines targets of dialysis dose (Kt/V>1.2), hemoglobin (>110g/L), serum phosphorus (1.1-1.8mmol/L), calcium (2.1-2.4mmol/L) and iPTH (150-300pg/mL) was determined. Cox proportional hazards analysis was used to select variables significantly associated with the risk of time to death. The patients were on regular HD for 5.3±5.3 years, dialyzed 11.8±1.9h/week. Kt/V<1.2 had 42.4% of patients, hemoglobin <110g/L had 66.1%, s-phosphorus <1.1mmol/L had 21.7% and >1.8mmol/L 28.6%, s-calcium <2.1mmol/L had 11.7% and >2.4mmol/L 25.3%, iPTH <150pg/mL had 40% and >300pg/mL 39.7% of patients. Using Cox model (adjustment for patient age, gender, duration of HD treatment) age, duration of HD treatment, hemoglobin, iPTH and diabetic nephropathy were selected as significant independent predictors of time to death. When targets of five examined parameters were included in Cox model, target for KtV, hemoglobin and iPTH were found to be significant independent predictors of time to death. Substantial proportion of patients examined failed to meet KDOQI guidelines targets. The relative risk of time to death was associated with being outside the targets for Kt/V, hemoglobin and iPTH. Copyright © 2015 The Authors. Published by Elsevier España, S.L.U. All rights reserved.

New Coumarin Derivatives as Potent Selective COX-2 Inhibitors: Synthesis, Anti-Inflammatory, QSAR, and Molecular Modeling Studies.

PubMed

Dawood, Dina H; Batran, Rasha Z; Farghaly, Thoraya A; Khedr, Mohammed A; Abdulla, Mohamed M

2015-12-01

Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti-inflammatory activities using the carrageenan-induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)-1 and COX-2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity and displayed superior GI safety profiles (0-7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX-2 isoenzyme, compared to the reference celecoxib with IC50 values ranging from 0.31 to 0.78 μM. The ethyl thiosemicarbazone 2b, thiazoline derivatives 3a, 3b, 5b, 6a, and 7f, and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti-inflammatory activities with remarkable COX-2 selectivity. Quantitative structure-activity relationship study (QSAR) was done and resulted in a highly predictive power R(2) (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers

PubMed Central

Hao, Jiajiao; Chen, Miao; Yu, Wendan; Guo, Wei; Chen, Yiming; Huang, Wenlin; Deng, Wuguo

2017-01-01

Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandins (PGs) biosynthesis. Previous studies indicate that COX-2, one of the isoforms of COX, is highly expressed in colon cancers and plays a key role in colon cancer carcinogenesis. Thus, searching for novel transcription factors regulating COX-2 expression will facilitate drug development for colon cancer. In this study, we identified XRCC5 as a binding protein of the COX-2 gene promoter in colon cancer cells with streptavidin-agarose pulldown assay and mass spectrometry analysis, and found that XRCC5 promoted colon cancer growth through modulation of COX-2 signaling. Knockdown of XRCC5 by siRNAs inhibited the growth of colon cancer cells in vitro and of tumor xenografts in a mouse model in vivo by suppressing COX-2 promoter activity and COX-2 protein expression. Conversely, overexpression of XRCC5 promoted the growth of colon cancer cells by activating COX-2 promoter and increasing COX-2 protein expression. Moreover, the role of p300 (a transcription co-activator) in acetylating XRCC5 to co-regulate COX-2 expression was also evaluated. Immunofluorescence assay and confocal microscopy showed that XRCC5 and p300 proteins were co-located in the nucleus of colon cancer cells. Co-immunoprecipitation assay also proved the interaction between XRCC5 and p300 in nuclear proteins of colon cancer cells. Cell viability assay indicated that the overexpression of wild-type p300, but not its histone acetyltransferase (HAT) domain deletion mutant, increased XRCC5 acetylation, thereby up-regulated COX-2 expression and promoted the growth of colon cancer cells. In contrast, suppression of p300 by a p300 HAT-specific inhibitor (C646) inhibited colon cancer cell growth by suppressing COX-2 expression. Taken together, our results demonstrated that XRCC5 promoted colon cancer growth by cooperating with p300 to regulate COX-2 expression, and suggested that the XRCC5/p300/COX-2 signaling pathway was a potential target in the treatment of colon cancers. PMID:29049411

NCC-AUC: an AUC optimization method to identify multi-biomarker panel for cancer prognosis from genomic and clinical data.

PubMed

Zou, Meng; Liu, Zhaoqi; Zhang, Xiang-Sun; Wang, Yong

2015-10-15

In prognosis and survival studies, an important goal is to identify multi-biomarker panels with predictive power using molecular characteristics or clinical observations. Such analysis is often challenged by censored, small-sample-size, but high-dimensional genomic profiles or clinical data. Therefore, sophisticated models and algorithms are in pressing need. In this study, we propose a novel Area Under Curve (AUC) optimization method for multi-biomarker panel identification named Nearest Centroid Classifier for AUC optimization (NCC-AUC). Our method is motived by the connection between AUC score for classification accuracy evaluation and Harrell's concordance index in survival analysis. This connection allows us to convert the survival time regression problem to a binary classification problem. Then an optimization model is formulated to directly maximize AUC and meanwhile minimize the number of selected features to construct a predictor in the nearest centroid classifier framework. NCC-AUC shows its great performance by validating both in genomic data of breast cancer and clinical data of stage IB Non-Small-Cell Lung Cancer (NSCLC). For the genomic data, NCC-AUC outperforms Support Vector Machine (SVM) and Support Vector Machine-based Recursive Feature Elimination (SVM-RFE) in classification accuracy. It tends to select a multi-biomarker panel with low average redundancy and enriched biological meanings. Also NCC-AUC is more significant in separation of low and high risk cohorts than widely used Cox model (Cox proportional-hazards regression model) and L1-Cox model (L1 penalized in Cox model). These performance gains of NCC-AUC are quite robust across 5 subtypes of breast cancer. Further in an independent clinical data, NCC-AUC outperforms SVM and SVM-RFE in predictive accuracy and is consistently better than Cox model and L1-Cox model in grouping patients into high and low risk categories. In summary, NCC-AUC provides a rigorous optimization framework to systematically reveal multi-biomarker panel from genomic and clinical data. It can serve as a useful tool to identify prognostic biomarkers for survival analysis. NCC-AUC is available at http://doc.aporc.org/wiki/NCC-AUC. ywang@amss.ac.cn Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Survival Disparity of African American Versus Non-African American Patients With ESRD Due to SLE.

PubMed

Nee, Robert; Martinez-Osorio, Jorge; Yuan, Christina M; Little, Dustin J; Watson, Maura A; Agodoa, Lawrence; Abbott, Kevin C

2015-10-01

A recent study showed an increased risk of death in African Americans compared with whites with end-stage renal disease (ESRD) due to lupus nephritis (LN). We assessed the impact of age stratification, socioeconomic factors, and kidney transplantation on the disparity in patient survival among African American versus non-African American patients with LN-caused ESRD, compared with other causes. Retrospective cohort study. Using the US Renal Data System database, we identified 12,352 patients with LN-caused ESRD among 1,132,202 patients who initiated maintenance dialysis therapy from January 1, 1995, through December 31, 2006, and were followed up until December 31, 2010. Baseline demographics and comorbid conditions, Hispanic ethnicity, socioeconomic factors (employment status, Medicare/Medicaid insurance, and area-level median household income based on zip code as obtained from the 2000 US census), and kidney transplantation as a time-dependent variable. All-cause mortality. Multivariable Cox and competing-risk regressions. Mean duration of follow-up in the LN-caused ESRD and other-cause ESRD cohorts were 6.24±4.20 (SD) and 4.06±3.61 years, respectively. 6,106 patients with LN-caused ESRD (49.43%) and 853,762 patients with other-cause ESRD (76.24%) died during the study period (P<0.001). Patients with LN-caused ESRD were significantly younger (mean age, 39.92 years) and more likely women (81.65%) and African American (48.13%) than those with other-cause ESRD. In the fully adjusted multivariable Cox regression model, African American (vs non-African American) patients with LN-caused ESRD had significantly increased risk of death at age 18 to 30 years (adjusted HR, 1.43; 95% CI, 1.24-1.65) and at age 31 to 40 years (adjusted HR, 1.17; 95% CI, 1.02-1.34). Among patients with other-cause ESRD, African Americans were at significantly increased risk at age 18 to 30 years (adjusted HR, 1.17; 95% CI, 1.11-1.22). We used zip code-based median household income as a surrogate for patient income. Residual socioeconomic confounders may exist. African Americans are at significantly increased risk of death compared with non-African Americans with LN-caused ESRD at age 18 to 40 years, a racial disparity risk that is 10 years longer than that in the general ESRD population. Accounting for area-level median household income and transplantation significantly attenuated the disparity in mortality of African American versus non-African American patients with LN-caused ESRD. Published by Elsevier Inc.

Development of a five-year mortality model in systemic sclerosis patients by different analytical approaches.

PubMed

Beretta, Lorenzo; Santaniello, Alessandro; Cappiello, Francesca; Chawla, Nitesh V; Vonk, Madelon C; Carreira, Patricia E; Allanore, Yannick; Popa-Diaconu, D A; Cossu, Marta; Bertolotti, Francesca; Ferraccioli, Gianfranco; Mazzone, Antonino; Scorza, Raffaella

2010-01-01

Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed. We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population. The NBC outperformed the Cox-based classifier and the other data mining algorithms after internal cross-validation (area under receiving operator characteristic curve, AUROC: NBC=0.759; RND-F=0.736; Log-Reg=0.754 and Cox= 0.724). The NBC had also a remarkable and better trade-off between sensitivity and specificity (e.g. Balanced accuracy, BA) than the Cox-based classifier, when tested on an independent population of SSc patients (BA: NBC=0.769, Cox=0.622). The NBC was also superior to domain experts in predicting 5-year survival in this population (AUROC=0.829 vs. AUROC=0.788 and BA=0.769 vs. BA=0.67). We provide a model to make consistent 5-year prognostic predictions in SSc patients. Its internal validity, as well as capability of generalisation and reduced uncertainty compared to human experts support its use at bedside. Available at: http://www.nd.edu/~nchawla/survival.xls.

APOL1 Nephropathy Risk Variants and Incident Cardiovascular Disease Events in Community-Dwelling Black Adults.

PubMed

Gutiérrez, Orlando M; Irvin, Marguerite R; Chaudhary, Ninad S; Cushman, Mary; Zakai, Neil A; David, Victor A; Limou, Sophie; Pamir, Nathalie; Reiner, Alex P; Naik, Rakhi P; Sale, Michele M; Safford, Monika M; Hyacinth, Hyacinth I; Judd, Suzanne E; Kopp, Jeffrey B; Winkler, Cheryl A

2018-06-01

APOL1 renal risk variants are strongly associated with chronic kidney disease in Black adults, but reported associations with cardiovascular disease (CVD) have been conflicting. We examined associations of APOL1 with incident coronary heart disease (n=323), ischemic stroke (n=331), and the composite CVD outcome (n=500) in 10 605 Black participants of the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Primary analyses compared individuals with APOL1 high-risk genotypes to APOL1 low-risk genotypes in Cox proportional hazards models adjusted for CVD risk factors and African ancestry. APOL1 high-risk participants were younger and more likely to have albuminuria at baseline than APOL1 low-risk participants. The risk of incident stroke, coronary heart disease, or composite CVD end point did not significantly differ by APOL1 genotype status in multivariable models. The association of APOL1 genotype with incident composite CVD differed by diabetes mellitus status ( P interaction =0.004). In those without diabetes mellitus, APOL1 high-risk genotypes associated with greater risk of incident composite CVD (hazard ratio, 1.67; 95% confidence interval, 1.12-2.47) compared with those with APOL1 low-risk genotypes in multivariable adjusted models. This latter association was driven by ischemic strokes (hazard ratio, 2.32; 95% confidence interval, 1.33-4.07), in particular, those related to small vessel disease (hazard ratio, 5.10; 95% confidence interval, 1.55-16.56). There was no statistically significant association of APOL1 genotypes with incident CVD in subjects with diabetes mellitus. The APOL1 high-risk genotype was associated with higher stroke risk in individuals without but not those with chronic kidney disease in fully adjusted models. APOL1 high-risk status is associated with CVD events in community-dwelling Black adults without diabetes mellitus. © 2018 American Heart Association, Inc.

Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study.

PubMed

Liu, Xinyang; Qin, Shukui; Wang, Zhichao; Xu, Jianming; Xiong, Jianping; Bai, Yuxian; Wang, Zhehai; Yang, Yan; Sun, Guoping; Wang, Liwei; Zheng, Leizhen; Xu, Nong; Cheng, Ying; Guo, Weijian; Yu, Hao; Liu, Tianshu; Lagiou, Pagona; Li, Jin

2017-09-05

Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan-Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64-0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53-0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival. Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.

Elevated risk of incarceration among street-involved youth who initiate drug dealing.

PubMed

Hoy, Carly; Barker, Brittany; Regan, Jackie; Dong, Huiru; Richardson, Lindsey; Kerr, Thomas; DeBeck, Kora

2016-11-22

Street-involved youth are known to be an economically vulnerable population that commonly resorts to risky activities such as drug dealing to generate income. While incarceration is common among people who use illicit drugs and associated with increased economic vulnerability, interventions among this population remain inadequate. Although previous research has documented the role of incarceration in further entrenching youth in both the criminal justice system and street life, less is known whether recent incarceration predicts initiating drug dealing among vulnerable youth. This study examines the relationship between incarceration and drug dealing initiation among street-involved youth. Between September 2005 and November 2014, data were collected through the At-Risk Youth Study, a cohort of street-involved youth who use illicit drugs, in Vancouver, Canada. An extended Cox model with time-dependent variables was used to examine the relationship between recent incarceration and initiation into drug dealing, controlling for relevant confounders. Among 1172 youth enrolled, only 194 (16.6%) were drug dealing naïve at baseline and completed at least one additional study visit to facilitate the assessment of drug dealing initiation. Among this sample, 56 (29%) subsequently initiated drug dealing. In final multivariable Cox regression analysis, recent incarceration was significantly associated with initiating drug dealing (adjusted hazard ratio = 2.31; 95% confidence interval (CI) 1.21-4.42), after adjusting for potential confounders. Measures of recent incarceration lagged to the prior study follow-up were not found to predict initiation of drug dealing (hazard ratio = 1.50; 95% CI 0.66-3.42). These findings suggest that among this study sample, incarceration does not appear to significantly propel youth to initiate drug dealing. However, the initiation of drug dealing among youth coincides with an increased risk of incarceration and their consequent vulnerability to the significant harms associated therein. Given that existing services tailored to street-involved youth are inadequate, evidence-based interventions should be invested and scaled up as a public health priority.

Risk of infective endocarditis in patients with systemic lupus erythematosus in Taiwan: a nationwide population-based study.

PubMed

Chang, Y S; Chang, C C; Chen, Y H; Chen, W S; Chen, J H

2017-10-01

Objectives Patients with systemic lupus erythematosus are considered vulnerable to infective endocarditis and prophylactic antibiotics are recommended before an invasive dental procedure. However, the evidence is insufficient. This nationwide population-based study evaluated the risk and related factors of infective endocarditis in systemic lupus erythematosus. Methods We identified 12,102 systemic lupus erythematosus patients from the National Health Insurance research-oriented database, and compared the incidence rate of infective endocarditis with that among 48,408 non-systemic lupus erythematosus controls. A Cox multivariable proportional hazards model was employed to evaluate the risk of infective endocarditis in the systemic lupus erythematosus cohort. Results After a mean follow-up of more than six years, the systemic lupus erythematosus cohort had a significantly higher incidence rate of infective endocarditis (42.58 vs 4.32 per 100,000 person-years, incidence rate ratio = 9.86, p < 0.001) than that of the control cohort. By contrast, the older systemic lupus erythematosus cohort had lower risk (adjusted hazard ratio 11.64) than that of the younger-than-60-years systemic lupus erythematosus cohort (adjusted hazard ratio 15.82). Cox multivariate proportional hazards analysis revealed heart disease (hazard ratio = 5.71, p < 0.001), chronic kidney disease (hazard ratio = 2.98, p = 0.034), receiving a dental procedure within 30 days (hazard ratio = 36.80, p < 0.001), and intravenous steroid therapy within 30 days (hazard ratio = 39.59, p < 0.001) were independent risk factors for infective endocarditis in systemic lupus erythematosus patients. Conclusions A higher risk of infective endocarditis was observed in systemic lupus erythematosus patients. Risk factors for infective endocarditis in the systemic lupus erythematosus cohort included heart disease, chronic kidney disease, steroid pulse therapy within 30 days, and a recent invasive dental procedure within 30 days.

Outcome of intracerebral hemorrhage associated with different oral anticoagulants

PubMed Central

Wilson, Duncan; Seiffge, David J.; Traenka, Christopher; Basir, Ghazala; Purrucker, Jan C.; Rizos, Timolaos; Sobowale, Oluwaseun A.; Sallinen, Hanne; Yeh, Shin-Joe; Wu, Teddy Y.; Ferrigno, Marc; Houben, Rik; Schreuder, Floris H.B.M.; Perry, Luke A.; Tanaka, Jun; Boulanger, Marion; Al-Shahi Salman, Rustam; Jäger, Hans R.; Ambler, Gareth; Shakeshaft, Clare; Yakushiji, Yusuke; Choi, Philip M.C.; Staals, Julie; Cordonnier, Charlotte; Jeng, Jiann-Shing; Veltkamp, Roland; Dowlatshahi, Dar; Engelter, Stefan T.; Parry-Jones, Adrian R.; Meretoja, Atte

2017-01-01

Objective: In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non–vitamin K antagonist oral anticoagulation–related ICH (NOAC-ICH) and vitamin K antagonist–associated ICH (VKA-ICH). Methods: We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours. Results: We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6–38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0–27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52–1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18–1.19 [p = 0.11]). Conclusions: In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH. PMID:28381513

Outcome of intracerebral hemorrhage associated with different oral anticoagulants.

PubMed

Wilson, Duncan; Seiffge, David J; Traenka, Christopher; Basir, Ghazala; Purrucker, Jan C; Rizos, Timolaos; Sobowale, Oluwaseun A; Sallinen, Hanne; Yeh, Shin-Joe; Wu, Teddy Y; Ferrigno, Marc; Houben, Rik; Schreuder, Floris H B M; Perry, Luke A; Tanaka, Jun; Boulanger, Marion; Al-Shahi Salman, Rustam; Jäger, Hans R; Ambler, Gareth; Shakeshaft, Clare; Yakushiji, Yusuke; Choi, Philip M C; Staals, Julie; Cordonnier, Charlotte; Jeng, Jiann-Shing; Veltkamp, Roland; Dowlatshahi, Dar; Engelter, Stefan T; Parry-Jones, Adrian R; Meretoja, Atte; Werring, David J

2017-05-02

In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non-vitamin K antagonist oral anticoagulation-related ICH (NOAC-ICH) and vitamin K antagonist-associated ICH (VKA-ICH). We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours. We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6-38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0-27.9) for VKA-ICH ( p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [ p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52-1.64] [ p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [ p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18-1.19 [ p = 0.11]). In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The influence of individual socioeconomic status on the clinical outcomes in ischemic stroke patients with different neighborhood status in Shanghai, China

PubMed Central

Yan, Han; Liu, Baoxin; Meng, Guilin; Shang, Bo; Jie, Qiqiang; Wei, Yidong; Liu, Xueyuan

2017-01-01

Objective: Socioeconomic status (SES) is being recognized as an important factor in both social and medical problems. The aim of present study is to examine the relationship between SES and ischemic stroke and investigate whether SES is a predictor of clinical outcomes among patients with different neighborhood status from Shanghai, China. Methods: A total of 471 first-ever ischemic stroke patients aged 18-80 years were enrolled in this retrospective study. The personal SES of each patient was evaluated using a summed score derived from his or her educational level, household income, occupation, and medical reimbursement rate. Clinical adverse events and all-cause mortality were analyzed to determine whether SES was a prognostic factor, its prognostic impact was then assessed based on different neighborhood status using multivariable Cox proportional hazard models after adjusting for other covariates. Results: The individual SES showed a significant positive correlation with neighborhood status (r = 0.370; P < 0.001). The incidence of clinical adverse events and mortality were significantly higher in low SES patients compared with middle and high SES patients (P = 0.001 and P = 0.037, respectively). After adjusting other risk factors and neighborhood status, Kaplan-Meier analysis showed clinical adverse events and deaths were still higher in the low SES patients (all P < 0.05). Multivariate Cox regression analysis demonstrated that both personal SES and neighborhood status are independent prognostic factors for ischemic stroke (all P < 0.05). Besides, among patients with low and middle neighborhood status, lower individual SES was significantly associated with clinical adverse events and mortality (all P < 0.05). Conclusion: Both individual SES and neighborhood status are significantly associated with the prognosis after ischemic stroke. A lower personal SES as well as poorer neighborhood status may significantly increase risk for adverse clinical outcomes among ischemic stroke patients. PMID:28138313

Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists.

PubMed

Hadianawala, Murtuza; Mahapatra, Amarjyoti Das; Yadav, Jitender K; Datta, Bhaskar

2018-02-26

Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ᅟ.

Chronic Rhinosinusitis Associated with Erectile Dysfunction: A Population-Based Study.

PubMed

Tai, Shu-Yu; Wang, Ling-Feng; Tai, Chih-Feng; Huang, Yu-Ting; Chien, Chen-Yu

2016-08-31

Few studies have investigated the relationship between chronic rhinosinusitis (CRS) and erectile dysfunction (ED). This case-control study aimed to investigate the association between CRS and the risk of ED in a large national sample. Tapping Taiwan's National Health Insurance Research Database, we identified people 30 years or older with a new primary diagnosis of CRS between 1996 and 2007. The cases were compared with sex- and age-matched controls. We identified 14 039 cases and recruited 140 387 matched controls. Both groups were followed up in the same database until the end of 2007 for instances of ED. Of those with CRS, 294 (2.1%) developed ED during a mean (SD) follow-up of 3.20 (2.33) years, while 1 661 (1.2%) of the matched controls developed ED, mean follow up 2.97 (2.39) years. Cox regression analyses were performed adjusting for sex, age, insurance premium, residence, hypertension, hyperlipidemia, diabetes, obesity, coronary heart disease, chronic kidney disease, chronic obstructive pulmonary disease, asthma, allergic rhinitis, arrhythmia, ischemic stroke, intracerebral hemorrhage, and medications. CRS was revealed to be an independent predictor of ED in the fully adjusted model (HR = 1.51; 95% CI = 1.33-1.73; P < 0.0001).

Frequent shopping by men and women increases survival in the older Taiwanese population.

PubMed

Chang, Yu-Hung; Chen, Rosalind Chia-Yu; Wahlqvist, Mark L; Lee, Meei-Shyuan

2012-07-01

Active ageing is a key to healthy ageing; shopping behaviour is an economically relevant activity of the elderly. Analysis was based on the NAHSIT 1999-2000 dataset. A total of 1841 representative free-living elderly Taiwanese people were selected and information included demographics, socioeconomic status, health behaviours, shopping frequencies, physical function and cognitive function. These data were linked to official death records. Cox proportional hazard models were used to evaluate shopping frequency on death from 1999-2008 with possible covariate adjustment. Highly frequent shopping compared to never or rarely predicted survival (HR 0.54, 95% CI 0.43 to 0.67) with adjustment for physical function and cognitive function and other covariates HR was 0.73 (95% CI 0.56 to 0.93). Elderly who shopped every day have 27% less risk of death than the least frequent shoppers. Men benefited more from everyday shopping than women with decreased HR 28% versus 23% compared to the least. Shopping behaviour favourably predicts survival. Highly frequent shopping may favour men more than women. Shopping captures several dimensions of personal well-being, health and security as well as contributing to the community's cohesiveness and economy and may represent or actually confer increased longevity.

Body mass index and outcomes in patients receiving chemotherapy for intermediate-grade B-cell non-Hodgkin lymphoma.

PubMed

Jones, Jeffrey A; Fayad, Luis E; Elting, Linda S; Rodriguez, Maria A

2010-09-01

We conducted a retrospective cohort study examining the influence of obesity on treatment outcome and survival among 712 patients with intermediate-grade B-cell NHL receiving frontline therapy between 1988 and 2001. Baseline adiposity was approximated by body mass index categorized according to the World Health Organization schema. Logistic and Cox proportional hazards regression modeling was used to adjust for baseline patient demographic, disease, and treatment variables. Approximately 37% of cohort patients were overweight (BMI 25 to <30 kg/m(2)) and more than 23% were obese (BMI >or= 30 kg/m(2)). Risk factors were similar across groups and treatment intensity did not vary by BMI. Median follow-up was 45.7 and 62.8 months for PFS and OS, respectively. After adjustment for other significant prognostic factors, BMI in the overweight range was associated with significantly reduced hazard for both PFS (OR 0.72, p = 0.011) and OS (OR 0.74, p = 0.030). Increased BMI is associated with significantly improved survival among patients with treatment-naive, intermediate-grade B-cell NHL. Prospective confirmation of these results is warranted given the increasing prevalence of both NHL and obesity.

No Trend in the Intergenerational Transmission of Divorce

PubMed Central

LI, JUI-CHUNG ALLEN; WU, LAWRENCE L.

2008-01-01

Previous studies on trends in the intergenerational transmission of divorce have produced mixed findings, with two studies (McLanahan and Bumpass 1988; Teachman 2002) reporting no trend in divorce transmission and one study (Wolfinger 1999) finding that divorce transmission has weakened substantially. Using a stratified Cox proportional hazard model, we analyze data from the National Survey of Families and Households and find no evidence for any trend in divorce transmission. To reconcile apparent differences in results, we note that the General Social Survey data used by Wolfinger lack information on marital duration, permitting analysis only for whether respondents have divorced by interview. As a result, an apparent decline in divorce transmission could be due to inadequate adjustments for the longer exposures to risk by earlier marriage cohorts, yielding a higher probability of divorce by interview for earlier cohorts relative to more recent cohorts even if divorce risks are identical across all marriage cohorts. We confirm this possibility by using a series of discrete-time hazard logistic regressions to investigate the sensitivity of estimates of trends in divorce transmission to different adjustments for exposure to risk. We conclude that there has been no trend in the intergenerational transmission of divorce. PMID:19110902

Urinary Tract Stones and Osteoporosis: Findings From the Women's Health Initiative.

PubMed

Carbone, Laura D; Hovey, Kathleen M; Andrews, Christopher A; Thomas, Fridtjof; Sorensen, Mathew D; Crandall, Carolyn J; Watts, Nelson B; Bethel, Monique; Johnson, Karen C

2015-11-01

Kidney and bladder stones (urinary tract stones) and osteoporosis are prevalent, serious conditions for postmenopausal women. Men with kidney stones are at increased risk of osteoporosis; however, the relationship of urinary tract stones to osteoporosis in postmenopausal women has not been established. The purpose of this study was to determine whether urinary tract stones are an independent risk factor for changes in bone mineral density (BMD) and incident fractures in women in the Women's Health Initiative (WHI). Data were obtained from 150,689 women in the Observational Study and Clinical Trials of the WHI with information on urinary tract stones status: 9856 of these women reported urinary tract stones at baseline and/or incident urinary tract stones during follow-up. Cox regression models were used to determine the association of urinary tract stones with incident fractures and linear mixed models were used to investigate the relationship of urinary tract stones with changes in BMD that occurred during WHI. Follow-up was over an average of 8 years. Models were adjusted for demographic and clinical factors, medication use, and dietary histories. In unadjusted models there was a significant association of urinary tract stones with incident total fractures (HR 1.10; 95% CI, 1.04 to 1.17). However, in covariate adjusted analyses, urinary tract stones were not significantly related to changes in BMD at any skeletal site or to incident fractures. In conclusion, urinary tract stones in postmenopausal women are not an independent risk factor for osteoporosis. © 2015 American Society for Bone and Mineral Research.

Targeted Deletions of COX-2 and Atherogenesis in Mice

PubMed Central

Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene; Yu, Zhou; Wang, Dairong; Stubbe, Jane; Wang, Miao; Puré, Ellen; FitzGerald, Garret A.

2010-01-01

Background While the dominant product of vascular cyclooxygenase (COX)-2, prostacyclin (PGI2), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages (Mac) and T cells (TC) to atherogenesis. Methods and Results Deletion of Mac COX-2 (MacKO) was attained using LysMCre mice and suppressed completely lipopolysaccharide (LPS) stimulated Mac prostaglandin (PG) formation and LPS evoked systemic PG biosynthesis by ∼ 30%. LPS stimulated COX-2 expression was suppressed in polymorphonuclear leucocytes (PMN) isolated from MacKOs, but PG formation was not even detected in PMN supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic LdlR KOs. Deletion of Mac COX-2 appeared to remove a restraint on COX-2 expression in lesional non-leukocyte (CD45 and CD11b negative) vascular cells that express vascular cell adhesion molecule and variably, α-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts (TCKOs) depressed its modest upregulation by anti-CD3ε. However, biosynthesis of PGs, TC composition in lymphatic organs and atherogenesis in LDLR KOs were unaltered in TCKOs. Conclusions Mac COX-2, primarily a source of thromboxane A2 and PGE2, promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective PGI2. TC COX-2 does not influence detectably TC development or function nor atherogenesis in mice. PMID:20530000

Houttuynia cordata, a novel and selective COX-2 inhibitor with anti-inflammatory activity.

PubMed

Li, Weifeng; Zhou, Ping; Zhang, Yanmin; He, Langchong

2011-01-27

Houttuynia cordata Thunb. (Saururaceae; HC) has been long used in traditional oriental medicine for the treatment of inflammation diseases. Modern research has implicated inducible cyclooxygenase-2 (COX-2) as a key regulator of the inflammatory process. In the present study, we aimed to investigate the effect of HC on COX-2. We examined the effects of HC on lipopolysaccharide (LPS)-induced prostaglandin (PG) E(2) production, an indirect indicator of COX-2 activity, and COX-2 gene and protein expression in mouse peritoneal macrophages. LPS-induced mouse peritoneal macrophages were employed as an in vitro model system. LPS-induced PGE(2) production was assessed by enzyme-linked immunosorbant assay and COX-2 protein expression was assessed by Western blot assay. The results showed that HC was able to inhibit the release of LPS-induced PGE(2) from mouse peritoneal macrophages (IC50 value: 44.8 μg/mL). Moreover, the inhibitory activity of HC essential oil elicited a dose-dependent inhibition of COX-2 enzyme activity (IC50 value: 30.9 μg/mL). HC was also found to cause reduction in LPS-induced COX-2 mRNA and protein expression, but did not affect COX-1 expression. The non-steroidal anti-inflammatory drug (NSAID) and specific COX-2 inhibitor NS398 functioned similarly in LPS-induced mouse peritoneal macrophages. Taken together, our data suggest HC mediates inhibition of COX-2 enzyme activity and can affect related gene and protein expression. HC works by a mechanism of action similar to that of NSAIDs. These results add a novel aspect to the biological profile of HC. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Identification of novel Cyclooxygenase-2-dependent genes in Helicobacter pylori infection in vivo

PubMed Central

Walduck, Anna K; Weber, Matthias; Wunder, Christian; Juettner, Stefan; Stolte, Manfred; Vieth, Michael; Wiedenmann, Bertram; Meyer, Thomas F; Naumann, Michael; Hoecker, Michael

2009-01-01

Background Helicobacter pylori is a crucial determining factor in the pathogenesis of benign and neoplastic gastric diseases. Cyclooxygenase-2 (Cox-2) is the inducible key enzyme of arachidonic acid metabolism and is a central mediator in inflammation and cancer. Expression of the Cox-2 gene is up-regulated in the gastric mucosa during H. pylori infection but the pathobiological consequences of this enhanced Cox-2 expression are not yet characterized. The aim of this study was to identify novel genes down-stream of Cox-2 in an in vivo model, thereby identifying potential targets for the study of the role of Cox- 2 in H. pylori pathogenesis and the initiation of pre- cancerous changes. Results Gene expression profiles in the gastric mucosa of mice treated with a specific Cox-2 inhibitor (NS398) or vehicle were analysed at different time points (6, 13 and 19 wk) after H. pylori infection. H. pylori infection affected the expression of 385 genes over the experimental period, including regulators of gastric physiology, proliferation, apoptosis and mucosal defence. Under conditions of Cox-2 inhibition, 160 target genes were regulated as a result of H. pylori infection. The Cox-2 dependent subset included those influencing gastric physiology (Gastrin, Galr1), epithelial barrier function (Tjp1, connexin45, Aqp5), inflammation (Icam1), apoptosis (Clu) and proliferation (Gdf3, Igf2). Treatment with NS398 alone caused differential expression of 140 genes, 97 of which were unique, indicating that these genes are regulated under conditions of basal Cox-2 expression. Conclusion This study has identified a panel of novel Cox-2 dependent genes influenced under both normal and the inflammatory conditions induced by H. pylori infection. These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity. PMID:19317916

Cyclooxygenase-2 inhibitor blocks the production of West Nile virus-induced neuroinflammatory markers in astrocytes.

PubMed

Verma, Saguna; Kumar, Mukesh; Nerurkar, Vivek R

2011-03-01

Inflammatory immune responses triggered initially to clear West Nile virus (WNV) infection later become detrimental and contribute to the pathological processes such as blood-brain barrier (BBB) disruption and neuronal death, thus complicating WNV-associated encephalitis (WNVE). It has been demonstrated previously that WNV infection in astrocytes results in induction of multiple matrix metalloproteinases (MMPs), which mediate BBB disruption. Cyclooxygenase (COX) enzymes and their product, prostaglandin E2 (PGE2), modulate neuroinflammation and regulate the production of multiple inflammatory molecules including MMPs. Therefore, this study determined and characterized the pathophysiological consequences of the expression of COX enzymes in human brain cortical astrocytes (HBCAs) following WNV infection. Whilst COX-1 mRNA expression did not change, WNV infection significantly induced RNA and protein expression of COX-2 in HBCAs. Similarly, PGE2 production was also enhanced significantly in infected HBCAs and was blocked in the presence of the COX-2-specific inhibitor NS-398, thus suggesting that COX-2, and not COX-1, was the source of the increased PGE2. Treatment of infected HBCAs with NS-398 attenuated the expression of MMP-1, -3 and -9 in a dose-dependent manner. Similarly, expression of interleukin-1β, -6 and -8, which were markedly elevated in infected HBCAs, exhibited a significant reduction in their levels in the presence of NS-398. These results provide direct evidence that WNV-induced COX-2/PGE2 is involved in modulating the expression of multiple neuroinflammatory mediators, thereby directly linking COX-2 with WNV disease pathogenesis. The ability of COX-2 inhibitors to modulate WNV-induced COX-2 and PGE2 signalling warrants further investigation in an animal model as a potential approach for clinical management of neuroinflammation associated with WNVE.

The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial

PubMed Central

Husted, Steen; James, Stefan K.; Bach, Richard G.; Becker, Richard C.; Budaj, Andrzej; Heras, Magda; Himmelmann, Anders; Horrow, Jay; Katus, Hugo A.; Lassila, Riita; Morais, Joao; Nicolau, José C.; Steg, Ph. Gabriel; Storey, Robert F.; Wojdyla, Daniel; Wallentin, Lars

2014-01-01

Aims The aim of this study was to assess the relationship between sex and clinical outcomes and treatment-related complications in patients with ST-elevation or non-ST-elevation acute coronary syndromes (ACS) randomized to treatment with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial. Methods The associations between sex subgroup and the primary composite outcomes, secondary outcomes, and major bleeding endpoints as well as interaction of sex subgroup with treatment effects were analysed using Cox proportional-hazards models. Results Sex was not significantly associated with the probability of the primary composite endpoint [adjusted hazard ratio (HR): 1.02 (0.91−1.16)], or other adverse cardiovascular endpoints. Ticagrelor was similarly more effective than clopidogrel in reducing rates of the primary endpoint in women 11.2 vs. 13.2% [adjusted HR: 0.88 (0.74−1.06)] and men 9.4 vs. 11.1% [adjusted HR: 0.86 (0.76−0.97)] (interaction P-value 0.78), all-cause death in women 5.8 vs. 6.8% [adjusted HR: 0.90 (0.69−1.16)] and men 4.0 vs. 5.7% [adjusted HR: 0.80 (0.67−0.96)] (interaction P-value 0.49), and definite stent thrombosis in women 1.2 vs. 1.4% [adjusted HR: 0.71 (0.36−1.38)] and men 1.4 vs. 2.1% [adjusted HR: 0.63 (0.45−0.89)] (interaction P-value 0.78). The treatments did not differ for PLATO-defined overall major bleeding complications in women [adjusted HR: 1.01 (0.83−1.23)] or men [adjusted HR: 1.10 (0.98−1.24)]. Sex had no significant association with these outcomes (interactions P = 0.43−0.88). Conclusion Female sex is not an independent risk factor for adverse clinical outcomes in moderate-to-high risk ACS patients. Ticagrelor has a similar efficacy and safety profile in men and women. PMID:24682844

Sex Differences in Functional Stress Test Versus CT Angiography in Symptomatic Patients With Suspected CAD: Insights From PROMISE

PubMed Central

Pagidipati, Neha J.; Hemal, Kshipra; Coles, Adrian; Mark, Daniel B.; Dolor, Rowena J.; Pellikka, Patricia A.; Hoffmann, Udo; Litwin, Sheldon E.; Udelson, James; Daubert, Melissa A.; Shah, Svati H.; Martinez, Beth; Lee, Kerry L.; Douglas, Pamela S.

2016-01-01

Background Risk stratification is an important goal of cardiac noninvasive tests (NITs), yet little contemporary data exist on the prognostic value of different NITs by patient sex. Objectives To compare the results and prognostic information derived from anatomic versus stress testing in stable men and women with suspected coronary artery disease. Methods In 8966 PROMISE trial patients tested as randomized (4500 computed tomographic angiography [CTA], 52% female; 4466 stress testing, 53% female), we assessed the relationship between sex and NIT results using logistic regression, and the relationship between sex and a composite of death, myocardial infarction, and unstable angina hospitalization using Cox proportional hazards models. Results In women, a positive CTA (≥70% stenosis) was less likely than a positive stress test (8% vs. 12%, adjusted OR 0.67 [95% CI 0.55-0.82]). Compared with negative tests, a positive CTA was more strongly associated with subsequent clinical events than a positive stress test (CTA adjusted HR 5.86 [95% CI 3.32-10.35]; stress adjusted HR 2.27 [95% CI 1.21-4.25]; adjusted p=0.028). Men were more likely to have a positive CTA than stress test (16% vs. 14%, adjusted OR 1.23 [95% CI 1.04-1.47]). Compared with negative tests, a positive CTA was less strongly associated with subsequent clinical events than a positive stress test in men, although this difference was not statistically significant (CTA adjusted HR 2.80 [95% CI 1.76-4.45]; stress adjusted HR 4.42 [95% CI 2.77-7.07]; adjusted p=0.168). Negative CTA and stress tests were equally likely to predict an event in both sexes (adjusted p-values=NS). A significant interaction between sex, NIT type, and test result (p=0.01) suggests that sex and NIT type jointly influence the relationship between test result and clinical events. Conclusions The prognostic value of an NIT result varies by test type and patient sex. Women appear to derive more prognostic information from a CTA, while men tend to derive similar prognostic value from both test types. PMID:27058908

First-trimester antihistamine exposure and risk of spontaneous abortion or preterm birth.

PubMed

Aldridge, Tiara D; Hartmann, Katherine E; Michels, Kara A; Velez Edwards, Digna R

2014-10-01

We tested whether antihistamine exposure during early pregnancy is associated with spontaneous abortion (SAB) or preterm birth (PTB). Women were enrolled in Right from the Start (2004-2010), a prospective pregnancy cohort. Data about first-trimester antihistamine use were obtained from screening and first-trimester interviews. Self-reported outcomes included SAB and PTB and were verified by medical records. Cox proportional hazards models were used to test for an association between antihistamine use and each outcome, both performed adjusting for confounders. Among the 2685 pregnancies analyzed, 14% (n = 377) reported use of antihistamines. Among antihistamine users, 12% (n = 44) experienced SABs, and 6% (n = 21) had PTBs. Antihistamine exposure was not associated with SAB (adjusted hazard ratio [aHR] = 0.88, 95% confidence interval [CI] 0.64, 1.21) or PTB, which was modified by maternal race (aHR = 1.03, 95%CI 0.61, 1.72 among White women and aHR = 0.43, 95%CI 0.14, 1.34 among Black women). Despite the biologic plausibility that antihistamine use may influence pregnancy outcomes, we did not detect evidence of an association with SAB or PTB. These data demonstrate the utility of large prospective cohorts for evaluating drug safety in pregnancy when concerns are raised from animal models. Copyright © 2014 John Wiley & Sons, Ltd.

Total daily physical activity and the risk of AD and cognitive decline in older adults

PubMed Central

Boyle, P.A.; Yu, L.; Shah, R.C.; Wilson, R.S.; Bennett, D.A.

2012-01-01

Objective: Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. Methods: Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. Results: During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273–0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). Conclusions: A higher level of total daily physical activity is associated with a reduced risk of AD. PMID:22517108

Insulin-Like Growth Factor-1 Bioactivity Plays a Prosurvival Role in Older Participants

PubMed Central

2013-01-01

The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second–third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population. PMID:23671288

Insulin-like growth factor-1 bioactivity plays a prosurvival role in older participants.

PubMed

Maggio, Marcello; Cattabiani, Chiara; Lauretani, Fulvio; Bandinelli, Stefania; De Vita, Francesca; Dall'Aglio, Elisabetta; Corsonello, Andrea; Lattanzio, Fabrizia; Paolisso, Giuseppe; Ferrucci, Luigi; Ceda, Gian Paolo

2013-11-01

The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second-third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population.

Psoriasis and the risk of foot and ankle tendinopathy or enthesopathy in the absence of psoriatic arthritis: a population-based study

PubMed Central

Lewinson, Ryan T; Vallerand, Isabelle A; Parsons, Laurie M; LaMothe, Jeremy M; Frolkis, Alexandra D; Lowerison, Mark W; Kaplan, Gilaad G; Patten, Scott B; Barnabe, Cheryl

2018-01-01

Objectives Imaging studies in patients with cutaneous psoriasis have demonstrated asymptomatic bone and tendon changes, commonly of the foot and ankle. We sought to determine if patients with cutaneous psoriasis have an increased risk of clinically significant foot and ankle tendinopathy or enthesopathy compared with the general population. Methods Patients with cutaneous psoriasis and a general population cohort were identified in The Health Improvement Network, a general practice medical records database from the UK. All patients with psoriatic arthritis were excluded. Cox proportional-hazards models (α=0.05) estimated the HR for development of foot and ankle tendinopathy or enthesopathy among patients with psoriasis, with adjustment for numerous covariates. Results In total, 78 630 patients with cutaneous psoriasis and 5 983 338 persons from the general population were identified. In an unadjusted model, patients with cutaneous psoriasis had a 25% increased risk of developing foot and ankle tendinopathy or enthesopathy compared with the general population (HR 1.25, 95% CI 1.20 to 1.30, p<0.0001). The HR remained unchanged and statistically significant after adjusting for covariates, and in sensitivity analyses. Conclusions These data suggest that patients with psoriasis can have foot and ankle tendinopathy or enthesopathy without having psoriatic arthritis, presenting a diagnostic challenge to physicians. Further research is needed to elucidate mechanisms contributing to this increased risk. PMID:29862046

Total daily physical activity and the risk of AD and cognitive decline in older adults.

PubMed

Buchman, A S; Boyle, P A; Yu, L; Shah, R C; Wilson, R S; Bennett, D A

2012-04-24

Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273-0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). A higher level of total daily physical activity is associated with a reduced risk of AD.

Age-adjusted Charlson comorbidity index score as predictor of survival of patients with digestive system cancer who have undergone surgical resection.

PubMed

Tian, Yaohua; Jian, Zhong; Xu, Beibei; Liu, Hui

2017-10-03

Comorbidities have considerable effects on survival outcomes. The primary objective of this retrospective study was to examine the association between age-adjusted Charlson comorbidity index (ACCI) score and postoperative in-hospital mortality in patients with digestive system cancer who have undergone surgical resection of their cancers. Using electronic hospitalization summary reports, we identified 315,464 patients who had undergone surgery for digestive system cancer in top-rank (Grade 3A) hospitals in China between 2013 and 2015. The Cox proportional hazard regression model was applied to evaluate the effect of ACCI score on postoperative mortality, with adjustments for sex, type of resection, anesthesia methods, and caseload of each healthcare institution. The postoperative in-hospital mortality rate in the study cohort was 1.2% (3,631/315,464). ACCI score had a positive graded association with the risk of postoperative in-hospital mortality for all cancer subtypes. The adjusted HRs for postoperative in-hospital mortality scores ≥ 6 for esophagus, stomach, colorectum, pancreas, and liver and gallbladder cancer were 2.05 (95% CI: 1.45-2.92), 2.00 (95% CI: 1.60-2.49), 2.54 (95% CI: 2.02-3.21), 2.58 (95% CI: 1.68-3.97), and 4.57 (95% CI: 3.37-6.20), respectively, compared to scores of 0-1. These findings suggested that a high ACCI score is an independent predictor of postoperative in-hospital mortality in Chinese patients with digestive system cancer who have undergone surgical resection.

Factor VII and incidence of myocardial infarction in a Japanese population: The Jichi Medical School Cohort Study.

PubMed

Shiraishi, Takuya; Ishikawa, Shizukiyo; Kario, Kazuomi; Kayaba, Kazunori; Kajii, Eiji

2017-11-01

The role of factor VII (FVII) as a risk factor in myocardial infarction (MI) has been the subject of numerous studies. However, it remains uncertain whether the FVII levels are associated with development of MI. The subjects were 4142 men and women whose activated FVII (FVIIa) and FVII coagulant (FVIIc) levels were measured in the Jichi Medical School Cohort Study. Subjects were divided into tertiles by FVIIa and FVIIc levels, and Cox's proportional hazard model was used to calculate hazard ratios (HRs) for MI. The multivariate-adjusted HRs (95% confidential interval [CI]) for FVIIa in men were 0.67 (0.67-1.78) in tertile 2 (T2), and 0.52 (0.17-1.60) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.18 (0.02-1.60) in T2, and 0.39 (0.07-2.20) in T3. The multivariate-adjusted HRs (95% CI) for FVIIc in men were 0.54 (0.21-1.36) in T2, and 0.20 (0.04-0.91) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.44 (0.07-2.85) in T2, and 0.35 (0.06-2.22) in T3. We used T1 as a reference for all measures. Our findings revealed a significant association between low FVIIc level and incidence of MI in men. The FVIIa and FVIIc levels were inversely related to increased MI risk, but did not reach statistical significance. Future studies are needed to confirm this association. © 2017 Wiley Periodicals, Inc.

Trauma, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study.

PubMed

Gradus, Jaimie L; Antonsen, Sussie; Svensson, Elisabeth; Lash, Timothy L; Resick, Patricia A; Hansen, Jens Georg

2015-09-01

Longitudinal outcomes following stress or trauma diagnoses are receiving attention, yet population-based studies are few. The aims of the present cohort study were to examine the cumulative incidence of traumatic events and psychiatric diagnoses following diagnoses of severe stress and adjustment disorders categorized using International Classification of Diseases, Tenth Revision, codes and to examine associations of these diagnoses with all-cause mortality and suicide. Data came from a longitudinal cohort of all Danes who received a diagnosis of reaction to severe stress or adjustment disorders (International Classification of Diseases, Tenth Revision, code F43.x) between 1995 and 2011, and they were compared with data from a general-population cohort. Cumulative incidence curves were plotted to examine traumatic experiences and psychiatric diagnoses during the study period. A Cox proportional hazards regression model was used to examine the associations of the disorders with mortality and suicide. Participants with stress diagnoses had a higher incidence of traumatic events and psychiatric diagnoses than did the comparison group. Each disorder was associated with a higher rate of all-cause mortality than that seen in the comparison cohort, and strong associations with suicide were found after adjustment. This study provides a comprehensive assessment of the associations of stress disorders with a variety of outcomes, and we found that stress diagnoses may have long-lasting and potentially severe consequences. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A higher incidence rate of acute coronary syndrome following radiation therapy in patients with breast cancer and a history of coronary artery diseases.

PubMed

Lee, Yen-Chien; Chuang, Jen-Pin; Hsieh, Pi-Ching; Chiou, Meng-Jiun; Li, Chung-Yi

2015-07-01

This study aims to investigate whether patients with breast cancer and a history of cardiovascular diseases (CADs) are at an increased incidence of acute coronary syndrome (ACS) after receiving radiation therapy (RT). In Taiwan, 5828 patients who had a history of CAD were newly diagnosed of breast cancer and received mastectomy between 1999 and 2009. Among these patients, 1851 also received RT. The study cohort was prospectively followed to the end of 2010 for estimating the incidence of ACS in association with exposure to RT. A Cox proportional hazard model that was adjusted for covariates was used to estimate the hazard ratio (HR) of ACS. Over the study period, the incident rates of ACS for RT and control patients were estimated at 1.51 and 1.77 per 100 person-years, respectively. Covariate-adjusted regression analysis indicated that the hazard of ACS significantly increased in RT patients at an adjusted HR of 1.48 [95% confidence interval (CI) 1.18-1.87]. Both hypertension and diabetes significantly increased the hazard of ACS in this patient cohort, with adjusted HRs of 3.31 (95% CI 1.94-5.66) and 1.50 (95% CI 1.19-1.89), respectively. This 12-year follow-up study suggested excess of ACS events in association with RT exposure in patients with breast cancer who had a higher cardiovascular risk. In consideration of the benefit associated with RT, intensive cardiac care should be given to patients with breast cancer and high cardiovascular risk.

The Association Between Broad Antigen HLA Mismatches, Eplet HLA Mismatches and Acute Rejection After Kidney Transplantation.

PubMed

Do Nguyen, Hung Thanh; Wong, Germaine; Chapman, Jeremy R; McDonald, Stephen P; Coates, Patrick T; Watson, Narelle; Russ, Graeme R; D'Orsogna, Lloyd; Lim, Wai Hon

2016-12-01

Epitope matching, which evaluates mismatched amino acids within antigen-antibody interaction sites (eplets), may better predict acute rejection than broad antigen matching alone. We aimed to determine the association between eplet mismatches and acute rejection in kidney transplant recipients. The association between eplet mismatches, broad antigen mismatches and acute rejection was assessed using adjusted Cox proportional hazard regression. Model discrimination for acute rejection was evaluated using the area under receiver operating characteristic curves. Of the 3,499 kidney transplant recipients from 2006 to 2011, the average (SD) number of broad antigen and eplet mismatches were 3.4 (1.7) and 22.8 (12.2), respectively. Compared with 0 to 2 eplet mismatches, the adjusted hazard ratio (HR) for acute rejection among those with 20 or greater eplet mismatches was 2.16 (95% confidence interval [CI], 1.33-3.52; P = 0.001). The adjusted area under the curve for broad antigen mismatches was 0.58 (95% CI, 0.56-0.61), similar to that for eplet mismatches (HR, 0.59; 95% CI, 0.56-0.61; P = 0.365). In recipients who were considered as low immunological risk (0-2 broad antigen HLA-ABDR mismatch), those with 20 or greater eplet mismatches experienced an increased risk of rejection compared to those with less than 20 mismatches (adjusted HR, 1.85; 95% CI, 1.11-3.08; P = 0.019). Increasing number of eplet mismatches is associated with acute rejection in kidney transplant recipients. Consideration of eplet HLA mismatches may improve risk stratification for acute rejection in a selected group of kidney transplant candidates.

Parametric Model Based On Imputations Techniques for Partly Interval Censored Data

NASA Astrophysics Data System (ADS)

Zyoud, Abdallah; Elfaki, F. A. M.; Hrairi, Meftah

2017-12-01

The term ‘survival analysis’ has been used in a broad sense to describe collection of statistical procedures for data analysis. In this case, outcome variable of interest is time until an event occurs where the time to failure of a specific experimental unit might be censored which can be right, left, interval, and Partly Interval Censored data (PIC). In this paper, analysis of this model was conducted based on parametric Cox model via PIC data. Moreover, several imputation techniques were used, which are: midpoint, left & right point, random, mean, and median. Maximum likelihood estimate was considered to obtain the estimated survival function. These estimations were then compared with the existing model, such as: Turnbull and Cox model based on clinical trial data (breast cancer data), for which it showed the validity of the proposed model. Result of data set indicated that the parametric of Cox model proved to be more superior in terms of estimation of survival functions, likelihood ratio tests, and their P-values. Moreover, based on imputation techniques; the midpoint, random, mean, and median showed better results with respect to the estimation of survival function.

Design, Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents

PubMed Central

Ghodsi, Razieh; Azizi, Ebrahim; Zarghi, Afshin

2016-01-01

A new group of 4-(Imidazolylmethyl)quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors and in-vitroanti breast cancer agents. In-vitro COX-1 and COX-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in the potent range 0.063-0.090 µM, and COX-2 selectivity indexes in the 179.9 to 547.6 range. Molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of COX-2 active site for interactions with Arg513. Cytotoxicity of quinolines 9a-e against human breast cancer MCF-7 and T47D cell lines were also evaluated. All the compounds 9a-e were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells.The data showed that the increase of lipophilic properties of substituents on the C-7 and C-8 quinoline ring increased their cytotoxicity on MCF-7cells andCOX-2 inhibitory activity. Among the quinolines 9a-e, 4-((1H-Imidazol-1-yl)methyl) 7,8,9,10-tetrahydro-2-(4-methylsulfonylphenyl)-benzo[h]quinoline (9d)was identified as the most potent andselective COX-2inhibitor as well as the most cytotoxic agent against MCF-7 cells. PMID:27610157

Anti-inflammatory, cyclooxygenase (COX)-2, COX-1 inhibitory, and free radical scavenging effects of Rumex nepalensis.

PubMed

Gautam, Raju; Karkhile, Kailas V; Bhutani, Kamlesh K; Jachak, Sanjay M

2010-10-01

Evaluation of the topical anti-inflammatory activity of chloroform and ethyl acetate extracts of RUMEX NEPALENSIS roots in a TPA-induced acute inflammation mouse model demonstrated a significant reduction in ear edema. The extracts were further tested on purified enzymes for COX-1 and COX-2 inhibition to elucidate their mechanism of action, and a strong inhibition was observed. Six anthraquinones and two naphthalene derivatives were isolated from the ethyl acetate extract. Among the isolated compounds, emodin was found to be a potent inhibitor with slight selectivity towards COX-2, and nepodin exhibited selectivity towards COX-1. Emodin, endocrocin, and nepodin also exhibited significant topical anti-inflammatory activity in mice. Interestingly, nepodin showed better radical scavenging activity than trolox and ascorbic acid against DPPH and ABTS radicals. The strong radical scavenging activity of chloroform and ethyl acetate extracts could be explained by the presence of nepodin as well as by the high phenolic content of the ethyl acetate extract. Thus, the anti-inflammatory effect of R. NEPALENSIS roots was assumed to be mediated through COX inhibition by anthraquinones and naphthalene derivatives and through the radical scavenging activities of naphthalene derivatives. © Georg Thieme Verlag KG Stuttgart · New York.

FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells.

PubMed

Liu, Shuo; Zhang, Cun; Zhang, Kuo; Gao, Yuan; Wang, Zhaowei; Li, Xiaoju; Cheng, Guang; Wang, Shuning; Xue, Xiaochang; Li, Weina; Zhang, Wei; Zhang, Yingqi; Xing, Xianghui; Li, Meng; Hao, Qiang

2017-07-04

Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFκB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFκB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells.

Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity

PubMed Central

Srivastava, Janmejai K; Pandey, Mitali; Gupta, Sanjay

2009-01-01

Aims Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. Main Methods We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. Key Findings Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. Significance These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer. PMID:19788894

Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity.

PubMed

Srivastava, Janmejai K; Pandey, Mitali; Gupta, Sanjay

2009-11-04

Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer.

Regularization Paths for Cox's Proportional Hazards Model via Coordinate Descent.

PubMed

Simon, Noah; Friedman, Jerome; Hastie, Trevor; Tibshirani, Rob

2011-03-01

We introduce a pathwise algorithm for the Cox proportional hazards model, regularized by convex combinations of ℓ 1 and ℓ 2 penalties (elastic net). Our algorithm fits via cyclical coordinate descent, and employs warm starts to find a solution along a regularization path. We demonstrate the efficacy of our algorithm on real and simulated data sets, and find considerable speedup between our algorithm and competing methods.

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.

PubMed

Praticò, D; Tillmann, C; Zhang, Z B; Li, H; FitzGerald, G A

2001-03-13

The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

Real-world impact of non-breast cancer-specific death on overall survival in resectable breast cancer.

PubMed

Fu, Jianfei; Wu, Lunpo; Jiang, Mengjie; Li, Dan; Jiang, Ting; Fu, Wei; Wang, Liangjing; Du, Jinlin

2017-07-01

The real-world occurrence rate of non-breast cancer-specific death (non-BCSD) and its impact on patients with breast cancer are poorly recognized. Women with resectable breast cancer from 1990 to 2007 in the Surveillance, Epidemiology, and End Results database (n = 199,963) were analyzed. The outcome events of breast cancer were classified as breast cancer-specific death (BCSD), non-BCSD, or survival. Binary logistics was used to estimate the occurrence rates of non-BCSD and BCSD with different clinicopathological factors. The Gray method was used to measure the cumulative incidence of non-BCSD and BCSD. The ratio of non-BCSDs to all causes of death and stacked cumulative incidence function plots were used to present the impact of non-BCSD on overall survival (OS). Models of Cox proportional hazards regression and competing risk regression were compared to highlight the suitable model. There were 12,879 non-BCSDs (6.44%) and 28,784 BCSDs (14.39%). The oldest age group (>62 years), black race, and a single or divorced marital status were associated with more non-BCSDs. With adjustments for age, a hormone receptor-positive (HoR+) status was no longer related to increased non-BCSDs. In patients with grade 1, stage I disease and an HoR+ status as well as the oldest subgroup, a great dilution of non-BCSD on all causes of death could be observed, and this led to incorrect interpretations. The inaccuracy, caused by the commonly used Cox proportional hazards model, could be corrected by a competing risk model. OS was largely impaired by non-BCSD during early breast cancer. For some future clinical trial planning, especially for the oldest patients and those with HoR+ breast cancer, non-BCSD should be considered a competing risk event. Cancer 2017;123:2432-43. © 2017 American Cancer Society. © 2017 American Cancer Society.

Predictive value of long-term changes of growth differentiation factor-15 over a 27-year-period for heart failure and death due to coronary heart disease.

PubMed

Fluschnik, Nina; Ojeda, Francisco; Zeller, Tanja; Jørgensen, Torben; Kuulasmaa, Kari; Becher, Peter Moritz; Sinning, Christoph; Blankenberg, Stefan; Westermann, Dirk

2018-01-01

Growth differentiation factor-15 (GDF-15), Cystatin C and C-reactive protein (CRP) have been discussed as biomarkers for prediction of cardiac diseases. The aim of this study was to investigate the predictive value of single and repeated measurements of GDF-15 compared to Cystatin C and CRP for incidence of heart failure (HF) and death due to coronary heart disease (CHD) in the general population. Levels of GDF-15, CRP and Cystatin C were determined in three repeated measurements collected 5 years apart in the DAN-MONICA (Danish-Multinational MONitoring of trends and determinants in Cardiovascular disease) cohort (participants at baseline n = 3785). Cox regression models adjusted for cardiovascular risk factors revealed significantly increased hazard ratios (HR) for GDF-15 for incident HF 1.36 (HR per interquartile range (IQR) increase, 95% confidence interval (CI): 1.16; 1.59) and for death from CHD 1.51 (HR per IQR increase, 95% CI: 1.31, 1.75) (both with p<0.001). Joint modeling of time-to-event and longitudinal GDF-15 over a median 27-year follow-up period showed that the marker evolution was positively associated with death of CHD (HR per IQR increase 3.02 95% CI: (2.26, 4.04), p < 0.001) and HF (HR per IQR increase 2.12 95% CI: (1.54, 2.92), p<0.001). However using Cox models with follow-up time starting at the time of the third examination, serial measurement of GDF-15, modeled as changes between the measurements, did not improve prediction over that of the most recent measurement. GDF-15 is a promising biomarker for prediction of HF and death due to CHD in the general population, which may provide prognostic information to already established clinical biomarkers. Repeated measurements of GDF-15 displayed only a slight improvement in the prediction of these endpoints compared to a single measurement.

A History of Falls is Associated with a Significant Increase in Acute Mortality in Women after Stroke.

PubMed

Foster, Emma J; Barlas, Raphae S; Wood, Adrian D; Bettencourt-Silva, Joao H; Clark, Allan B; Metcalf, Anthony K; Bowles, Kristian M; Potter, John F; Myint, Phyo K

2017-10-01

The risks of falls and fractures increase after stroke. Little is known about the prognostic significance of previous falls and fractures after stroke. This study examined whether having a history of either event is associated with poststroke mortality. We analyzed stroke register data collected prospectively between 2003 and 2015. Eight sex-specific models were analyzed, to which the following variables were incrementally added to examine their potential confounding effects: age, type of stroke, Oxfordshire Community Stroke Project classification, previous comorbidities, frailty as indicated by the prestroke modified Rankin Scale score, and acute illness parameters. Logistic regression was applied to investigate in-hospital and 30-day mortality, and Cox proportional-hazards models were applied to investigate longer-term outcomes of mortality. In total, 10,477 patients with stroke (86.1% ischemic) were included in the analysis. They were aged 77.7±11.9 years (mean±SD), and 52.2% were women. A history of falls was present in 8.6% of the men (n=430) and 20.2% of the women (n=1,105), while 3.8% (n=189) of the men and 12.9% of the women (n=706) had a history of both falls and fractures. Of the outcomes examined, a history of falls alone was associated with increased in-hospital mortality [odds ratio (OR)=1.33, 95% confidence interval (CI)=1.03-1.71] and 30-day mortality (OR=1.34, 95% CI=1.03-1.73) in women in the fully adjusted models. The Cox proportional-hazards models for longer-term outcomes and the history of falls and fractures combined showed no significant results. The history of falls is an important factor for acute stroke mortality in women. A previous history of falls may therefore be an important factor to consider in the short-term stroke prognosis, particularly in women. Copyright © 2017 Korean Neurological Association

Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas: modification by dietary curcumin and implications for clinical trials.

PubMed

Tunstall, R G; Sharma, R A; Perkins, S; Sale, S; Singh, R; Farmer, P B; Steward, W P; Gescher, A J

2006-02-01

The natural polphenol, curcumin, retards the growth of intestinal adenomas in the Apc(Min+) mouse model of human familial adenomatous polyposis. In other preclinical models, curcumin downregulates the transcription of the enzyme cyclooxygenase-2 (COX-2) and decreases levels of two oxidative DNA adducts, the pyrimidopurinone adduct of deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). We have studied COX-2 protein expression and oxidative DNA adduct levels in intestinal adenoma tissue from Apc(Min+) mice to try and differentiate between curcumin's direct pharmacodynamic effects and indirect effects via its inhibition of adenoma growth. Mice received dietary curcumin (0.2%) for 4 or 14 weeks. COX-2 protein, M1dG and 8-oxo-dG levels were measured by Western blot, immunochemical assay and liquid chromatography-mass spectrometry, respectively. In control Apc(Min+) mice, the levels of all three indices measured in adenoma tissue were significantly higher than levels in normal mucosa. Lifetime administration of curcumin reduced COX-2 expression by 66% (P = 0.01), 8-oxo-dG levels by 24% (P < 0.05) and M1dG levels by 39% (P < 0.005). Short-term feeding did not affect total adenoma number or COX-2 expression, but decreased M1dG levels by 43% (P < 0.01). COX-2 protein levels related to adenoma size. These results demonstrate the utility of measuring these oxidative DNA adduct levels to show direct antioxidant effects of dietary curcumin. The effects of long-term dietary curcumin on COX-2 protein levels appear to reflect retardation of adenoma development.

Heterotypic contact reveals a COX-2-mediated suppression of osteoblast differentiation by endothelial cells: A negative modulatory role for prostanoids in VEGF-mediated cell: cell communication?

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

Clarkin, Claire E.; Garonna, Elena; Pitsillides, Andrew A.

In bone, angiogenesis must be initiated appropriately, but limited once remodelling or repair is complete. Our recent findings have supported a role for prostaglandins (PG), known modulators of osteoblast (OB) and endothelial cell (EC) behaviour, in facilitating VEGF-mediated paracrine communication from OBs to 'remotely located' ECs, but the mechanism(s) regulating OB:EC crosstalk when these cells are closely opposed are undefined. In this study we have examined: (i) the effects of exogenous PGE{sub 2} on VEGF-driven events in ECs, and (ii) the role of endogenous COX-2-derived prostanoids in mediating communication between intimately opposed OBs and ECs in direct contact. Exposure ofmore » ECs to PGE{sub 2} increased ERK1/2 phosphorylation, COX-2 induction, 6-keto-PGF{sub 1{alpha}} release and EC proliferation. In contrast, PGE{sub 2} attenuated VEGF{sub 165}-induced VEGFR2/Flk1 phosphorylation, ERK1/2 activation and proliferation of ECs, suggesting that exogenous PGE{sub 2} restricts the actions of VEGF. However, the COX-2-selective inhibitor, NS398, also attenuated VEGF-induced proliferation, implying a distinct role for endogenous COX-2 activity in regulating EC behaviour. To examine the effect of OB:EC proximity and the role of COX-2 products further, we used a confrontational co-culture model. These studies showed that COX-2 blockade with NS398 enhanced EC-dependent increases in OB differentiation, that this effect was reversed by exogenous PGH{sub 2} (immediate COX-2 product), and that exogenous VEGF did not influence EC-dependent OB differentiation under these conditions. Our findings indicate that locally produced prostanoids may serve distinct roles depending on OB:EC proximity and negatively modulate VEGF-mediated changes in EC behaviour when these cells are closely opposed to control angiogenesis during bone (re)modelling.« less

A novel sulindac derivative lacking COX-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model

PubMed Central

Zhang, Yong; Zhang, Jinhui; Wang, Lei; Quealy, Emily; Gary, Bernard D.; Reynolds, Robert C.; Piazza, Gary A.; Lü, Junxuan

2016-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac are well-documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX) inhibitory activities cause severe gastrointestinal and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of the NSAIDs, and support the potential for development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution, referred to as sulindac sulfide amide (SSA) was recently identified to be devoid of COX inhibitory activity yet displays much more potent tumor cell growth inhibitory activity in vitro compared to sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the TRAMP mouse model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G1 arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption from 6 to 24 weeks of age dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression via repressing cell proliferation in the TRAMP mice, whereas it did not significantly impact neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis. PMID:20587701

Genetic deletion of COX-2 diminishes VEGF production in mouse retinal Müller cells.

PubMed

Yanni, Susan E; McCollum, Gary W; Penn, John S

2010-07-01

Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX activity, reduce the production of retinal VEGF and neovascularization in relevant models of ocular disease. We hypothesized that COX-2 mediates VEGF production in retinal Müller cells, one of its primary sources in retinal neovascular disease. The purpose of this study was to determine the role of COX-2 and its products in VEGF expression and secretion. These studies have more clearly defined the role of COX-2 and COX-2-derived prostanoids in retinal angiogenesis. Müller cells derived from wild-type and COX-2 null mice were exposed to hypoxia for 0-24 h. COX-2 protein and activity were assessed by western blot analysis and GC-MS, respectively. VEGF production was assessed by ELISA. Wild-type mouse Müller cells were treated with vehicle (0.1% DMSO), 10 microM PGE(2), or PGE(2) + 5 microM H-89 (a PKA inhibitor), for 12 h. VEGF production was assessed by ELISA. Hypoxia significantly increased COX-2 protein (p < 0.05) and activity (p < 0.05), and VEGF production (p < 0.0003). COX-2 null Müller cells produced significantly less VEGF in response to hypoxia (p < 0.05). Of the prostanoids, PGE(2) was significantly increased by hypoxia (p < 0.02). Exogenous PGE(2) significantly increased VEGF production by Müller cells (p < 0.0039), and this effect was inhibited by H-89 (p < 0.055). These data demonstrate that hypoxia induces COX-2, prostanoid production, and VEGF synthesis in Müller cells, and that VEGF production is at least partially COX-2-dependent. Our study suggests that PGE(2), signaling through the EP(2) and/or EP(4) receptor and PKA, mediates the VEGF response of Müller cells. Copyright 2010 Elsevier Ltd. All rights reserved.

Cystic Fibrosis Associated with Worse Survival After Liver Transplantation.

PubMed

Black, Sylvester M; Woodley, Frederick W; Tumin, Dmitry; Mumtaz, Khalid; Whitson, Bryan A; Tobias, Joseph D; Hayes, Don

2016-04-01

Survival in cystic fibrosis patients after liver transplantation and liver-lung transplantation is not well studied. To discern survival rates after liver transplantation and liver-lung transplantation in patients with and without cystic fibrosis. The United Network for Organ Sharing database was queried from 1987 to 2013. Univariate Cox proportional hazards, multivariate Cox models, and propensity score matching were performed. Liver transplant and liver-lung transplant were performed in 212 and 53 patients with cystic fibrosis, respectively. Univariate Cox proportional hazards regression identified lower survival in cystic fibrosis after liver transplant compared to a reference non-cystic fibrosis liver transplant cohort (HR 1.248; 95 % CI 1.012, 1.541; p = 0.039). Supplementary analysis found graft survival was similar across the 3 recipient categories (log-rank test: χ(2) 2.68; p = 0.262). Multivariate Cox models identified increased mortality hazard among cystic fibrosis patients undergoing liver transplantation (HR 2.439; 95 % CI 1.709, 3.482; p < 0.001) and liver-lung transplantation (HR 2.753; 95 % CI 1.560, 4.861; p < 0.001). Propensity score matching of cystic fibrosis patients undergoing liver transplantation to non-cystic fibrosis controls identified a greater mortality hazard in the cystic fibrosis cohort using a Cox proportional hazards model stratified on matched pairs (HR 3.167; 95 % CI 1.265, 7.929, p = 0.014). Liver transplantation in cystic fibrosis is associated with poorer long-term patient survival compared to non-cystic fibrosis patients, although the difference is not due to graft survival.

Long-term Survival Outcomes by Smoking Status in Surgical and Nonsurgical Patients With Non-small Cell Lung Cancer

PubMed Central

Meguid, Robert A.; Hooker, Craig M.; Harris, James; Xu, Li; Westra, William H.; Sherwood, J. Timothy; Sussman, Marc; Cattaneo, Stephen M.; Shin, James; Cox, Solange; Christensen, Joani; Prints, Yelena; Yuan, Nance; Zhang, Jennifer; Yang, Stephen C.

2010-01-01

Background: Survival outcomes of never smokers with non-small cell lung cancer (NSCLC) who undergo surgery are poorly characterized. This investigation compared surgical outcomes of never and current smokers with NSCLC. Methods: This investigation was a single-institution retrospective study of never and current smokers with NSCLC from 1975 to 2004. From an analytic cohort of 4,546 patients with NSCLC, we identified 724 never smokers and 3,822 current smokers. Overall, 1,142 patients underwent surgery with curative intent. For survival analysis by smoking status, hazard ratios (HRs) were estimated using Cox proportional hazard modeling and then further adjusted by other covariates. Results: Never smokers were significantly more likely than current smokers to be women (P < .01), older (P < .01), and to have adenocarcinoma (P < .01) and bronchioloalveolar carcinoma (P < .01). No statistically significant differences existed in stage distribution at presentation for the analytic cohort (P = .35) or for the subgroup undergoing surgery (P = .24). The strongest risk factors of mortality among patients with NSCLC who underwent surgery were advanced stage (adjusted hazard ratio, 3.43; 95% CI, 2.32-5.07; P < .01) and elevated American Society of Anesthesiologists classification (adjusted hazard ratio, 2.18; 95% CI, 1.40-3.40; P < .01). The minor trend toward an elevated risk of death on univariate analysis for current vs never smokers in the surgically treated group (hazard ratio, 1.20; 95% CI, 0.98-1.46; P = .07) was completely eliminated when the model was adjusted for covariates (P = .97). Conclusions: Our findings suggest that smoking status at time of lung cancer diagnosis has little impact on the long-term survival of patients with NSCLC, especially after curative surgery. Despite different etiologies between lung cancer in never and current smokers the prognosis is equally dismal. PMID:20507946

CD4/CD8 ratio, age, and risk of serious non-communicable diseases in HIV-infected adults on antiretroviral therapy

PubMed Central

CASTILHO, Jessica L.; SHEPHERD, Bryan E.; KOETHE, John; TURNER, Megan; BEBAWY, Sally; LOGAN, James; ROGERS, William B.; RAFFANTI, Stephen; STERLING, Timothy R.

2015-01-01

Objective In virologically suppressed HIV-infected adults, non-communicable diseases (NCDs) have been associated with immune senescence and low CD4/CD8 lymphocyte ratio. Age differences in the relationship between CD4/CD8 ratio and NCDs have not been described. Design Observational cohort study. Methods We assessed CD4/CD8 ratio and incident NCDs (cardiovascular, cancer, liver, and renal diseases) in HIV-infected adults started on antiretroviral therapy between 1998–2012. Study inclusion began once patients maintained virologic suppression for 12 months (defined as baseline). We examined age and baseline CD4/CD8 ratio and used Cox proportional hazard models to assess baseline CD4/CD8 ratio and NCDs. Results This study included 2,006 patients. Low baseline CD4/CD8 ratio was associated with older age, male sex, and low CD4 lymphocyte counts. In models adjusting for CD4 lymphocyte count, CD4/CD8 ratio was inversely associated with age (p <0.01). Among all patients, 182 had incident NCDs, including 46 with coronary artery disease (CAD) events. CD4/CD8 ratio was inversely associated with risk of CAD events (adjusted HR per 0.1 increase in CD4/CD8 ratio = 0.87, 95% CI: 0.76–0.99, p=0.03). This association was driven by those under age 50 years (adjusted HR 0.83 [0.70–0.97], p = 0.02) versus those over age 50 years (adjusted HR = 0.96 [0.79–1.18], p = 0.71). CD4/CD8 ratio was not significantly associated with incident non-cardiac NCDs. Conclusions Higher CD4/CD8 ratio after one year of HIV virologic suppression was independently predictive of decreased CAD risk, particularly among younger adults. Advanced immune senescence may contribute to CAD events in younger HIV patients on antiretroviral therapy. PMID:26959354

Longitudinal Change of Perceived Salt Intake and Stroke Risk in a Chinese Population.

PubMed

Li, Yun; Huang, Zhe; Jin, Cheng; Xing, Aijun; Liu, Yesong; Huangfu, Chunmei; Lichtenstein, Alice H; Tucker, Katherine L; Wu, Shouling; Gao, Xiang

2018-06-01

Data for a relationship between salt intake and stroke have been inconsistent. This inconstancy could be because of the majority of studies evaluated salt intake at a single time point, which may be insufficient to accurately characterize salt intake throughout the observation period. Included were 77 605 participants from the Kailuan study. We assessed perceived salt intake via questionnaire in 2006, 2008, and 2010. Salt intake trajectories from 2006 to 2010 were identified using latent mixture models. Incident stroke cases were identified from 2010 to 2015 and confirmed by review of medical records. Cox proportional hazards model was used to examine the association between salt intake trajectories and stroke risk after adjusting for possible confounders, including age, sex, lifestyle, social economic status, body mass index, use of medicines, blood pressure, and lipoprotein profiles. Identified were 5 distinct salt intake trajectories: moderate-stable (n=59 241), moderate-decreasing (n=9268), moderate-increasing (n=2975), low-increasing (n=2879), and high-decreasing (n=3242). During the 5-year follow-up period, there were 1564 incident strokes cases. Compared with individuals with the moderate-stable salt intake trajectory, individuals with moderate-decreasing salt intake trajectory had significantly lower cerebral infarction stroke risk (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.92) but not intracerebral hemorrhage risk (adjusted hazard ratio, 0.84; 95% confidence interval, 0.55-1.29). Further adjustment for 2006 or 2010 perceived salt intakes generated similar results. When baseline perceived salt intake only was used as the exposure, a significant dose-response relationship between higher perceived salt intake and higher stroke risk was observed ( P trend=0.006). Change in salt intake was associated with the stroke risk. These data support the dietary recommendation to the reduction of salt intake. © 2018 American Heart Association, Inc.

Influence of renal function on mortality and ventricular arrhythmias in patients undergoing first implantable cardioverter-defibrillator generator replacement.

PubMed

Waks, Jonathan W; Higgins, Angela Y; Mittleman, Murray A; Buxton, Alfred E

2015-03-01

Impaired renal function is associated with increased mortality among patients with implantable cardioverter-defibrillators (ICDs). The relationship between renal function at time of ICD generator replacement and subsequent appropriate ICD therapies is not known. We identified 441 patients who underwent first ICD generator replacement between 2000 and 2011 and had serum creatinine measured within 30 days of their procedure. Patients were divided into tertiles based on estimated glomerular filtration rate (eGFR). Adjusted Cox proportional hazard and competing risk models were used to assess relationships between eGFR and subsequent mortality and appropriate ICD therapy. Median eGFR was 37.6, 59.3, and 84.8 mL/min/1.73 m(2) for tertiles 1-3, respectively. Five-year Kaplan-Meier survival probability was 34.8%, 61.4%, and 84.5% for tertiles 1-3, respectively (P < 0.001). After multivariable adjustment, compared to tertile 3, worse eGFR tertile was associated with increased mortality (HR 2.84, 95% CI [1.36-5.94] for tertile 2; HR 3.84, 95% CI [1.81-8.12] for tertile 1). At 5 years, 57.0%, 58.1%, and 60.2% of patients remained free of appropriate ICD therapy in tertiles 1-3, respectively (P = 0.82). After adjustment, eGFR tertile was not associated with future appropriate ICD therapy. Results were unchanged in an adjusted competing risk model accounting for death. At time of first ICD generator replacement, lower eGFR is associated with higher mortality, but not with appropriate ICD therapies. The poorer survival of ICD patients with reduced eGFR does not appear to be influenced by arrhythmia status, and there is no clear proarrhythmic effect of renal dysfunction, even after accounting for the competing risk of death. © 2014 Wiley Periodicals, Inc.

Biological and Behavioral Risks for Incident Chlamydia trachomatis Infection in a Prospective Cohort

PubMed Central

Hwang, Loris Y.; Ma, Yifei; Moscicki, Anna-Barbara

2014-01-01

Objective To identify biological and behavioral risks for incident Chlamydia trachomatis among a prospective cohort of young women followed frequently. Methods Our cohort of 629 women from two outpatient sites was seen every 4 months (October 2000 through April 2012) for behavioral interviews and infection testing. C trachomatis was tested annually, and anytime patients reported symptoms or possible exposure using commercial nucleic acid amplification tests. Analyses excluded baseline prevalent C trachomatis infections. Risk factors for incident C trachomatis were assessed using Cox proportional hazards models. Significant risks (p<0.10) from bivariate models were entered in a multivariate model, adjusted for four covariates chosen a priori (age, race or ethnicity, condom use, study site). Backwards step-wise elimination produced a final parsimonious model retaining significant variables (p<0.05) and the four adjustment variables. Results The 629 women attended 9,594 total visits. Median follow-up time was 6.9 years (interquartile range 3.2-9.8), during which 97 (15%) women had incident C trachomatis . In the final multivariate model, incident C trachomatis was independently associated with HPV at the preceding visit (p<0.01), smoking (p=0.02), and weekly use of substances besides alcohol and marijuana (p<0.01) since prior visit. Among 207 women with available colpophotographs (1,742 visits), cervical ectopy was not a significant risk factor (p range=0.16-0.39 for ectopy as continuous and ordinal variables). Conclusion Novel risks for C trachomatis include preceding HPV, smoking, and substance use, which may reflect both biological and behavioral mechanisms of risk, such as immune modulation, higher-risk sexual networks, or both. Improved understanding of the biological bases for C trachomatis risk would inform our strategies for C trachomatis control. PMID:25437724

Early medication use in new-onset rheumatoid arthritis may delay joint replacement: results of a large population-based study.

PubMed

Moura, Cristiano S; Abrahamowicz, Michal; Beauchamp, Marie-Eve; Lacaille, Diane; Wang, Yishu; Boire, Gilles; Fortin, Paul R; Bessette, Louis; Bombardier, Claire; Widdifield, Jessica; Hanly, John G; Feldman, Debbie; Maksymowych, Walter; Peschken, Christine; Barnabe, Cheryl; Edworthy, Steve; Bernatsky, Sasha

2015-08-03

Use of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) may prevent joint damage and potentially reduce joint replacement surgeries. We assessed the association between RA drug use and joint replacement in Quebec, Canada. A cohort of new-onset RA patients was identified from Quebec's physician billing and hospitalization databases from 2002-2011. The outcome was defined using procedure codes submitted by orthopedic surgeons. Medication use was obtained from pharmacy databases. We used alternative Cox regression models with time-dependent variables measuring the cumulative effects of past use during different time windows (one model focussing on the first year after cohort entry) for methotrexate (MTX), and other DMARDs. Models were adjusted for baseline sociodemographics, co-morbidity and prior health service use, time-dependent cumulative use of other drugs (anti-tumor necrosis factor [anti-TNF] agents, other biologics, cyclooxygenase-2 inhibitors [COXIBs], nonselective nonsteroidal antiinflammatory drugs [NSAIDs], and systemic steroids), and markers of disease severity. During follow-up, 608 joint replacements occurred among 11,333 patients (median follow-up: 4.6 years). The best-fitting model relied on the cumulative early use (within the first year after cohort entry) of MTX and of other DMARDs, with an interaction between MTX and other DMARDs. In this model, greater exposure within the first year, to either MTX (adjusted hazard ratio, HR = 0.95 per 1 month, 95% confidence interval, 95% CI 0.93-0.97) or other DMARDs (HR = 0.97, 95% CI 0.95-0.99) was associated with longer time to joint replacement. Our results suggest that longer exposure to either methotrexate (MTX) or other DMARDs within the first year after RA diagnosis is associated with longer time to joint replacement surgery.