Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Hormonal contraceptive use before and after conception in relation to preterm birth and small for gestational age: an observational cohort study.

OBJECTIVE: To evaluate whether hormonal contraceptives, used before or in early pregnancy, confer increased risk of preterm birth or reduced fetal growth. DESIGN: Population-based cohort study conducted by the Norwegian Institute of Public Health (Mother and Child Cohort Study, 1998-2008) with linkage to the Norwegian Prescription Registry and to the Medical Birth Registry of Norway. SETTING: Norway. POPULATION: Of the 48,615 pregnancies meeting study inclusion criteria, 44,734 pregnancies were included in the complete case analysis. METHODS: We characterised hormonal contraception by type (combination oral, progestin-only oral, vaginal ring, transdermal, and injectable) and specific progestin component. We used generalised estimating equations to estimate the odds of adverse outcome according to formulation used. Several sensitivity analyses were conducted. MAIN OUTCOME MEASURES: Preterm birth, small for gestational age. RESULTS: We observed a positive association between use of a combination oral contraceptive and preterm birth for all exposure periods (e.g. adjusted odds ratio 1.21, 95% confidence interval 1.04-1.41 for last use 12 to >4 months before conception); combination contraceptives containing the progestin norethisterone were consistently related to risk. Other types of hormonal contraception were generally not associated with preterm birth; none were related to small for gestational age. Observed associations were robust to sensitivity analyses. CONCLUSION: Hormonally active agents may exert dose-, agent-, and timing-specific effects on growth and development. We found that the particular progestin component is important when assessing the potential for adverse effects among former users of hormonal contraceptives.

Propensity scores for confounder adjustment when assessing the effects of medical interventions using nonexperimental study designs.

Treatment effects, especially when comparing two or more therapeutic alternatives as in comparative effectiveness research, are likely to be heterogeneous across age, gender, co-morbidities and co-medications. Propensity scores (PSs), an alternative to multivariable outcome models to control for measured confounding, have specific advantages in the presence of heterogeneous treatment effects. Implementing PSs using matching or weighting allows us to estimate different overall treatment effects in differently defined populations. Heterogeneous treatment effects can also be due to unmeasured confounding concentrated in those treated contrary to prediction. Sensitivity analyses based on PSs can help to assess such unmeasured confounding. PSs should be considered a primary or secondary analytic strategy in nonexperimental medical research, including pharmacoepidemiology and nonexperimental comparative effectiveness research.

Maternal hormonal contraceptive use and offspring overweight or obesity.

BACKGROUND/OBJECTIVES: Experiments in animal models have shown a positive association between in utero exposure to pharmacologic sex hormones and offspring obesity. The developmental effects of such hormones on human obesity are unknown. SUBJECTS/METHODS: Using data from a large, prospective pregnancy cohort study (n=19 652), with linkage to a national prescription registry, we evaluated the association between use of hormonal contraceptives before and after conception (defined from dispensed prescription data and characterized by last date of use relative to conception, 12 to >4 months before (n=3392), 4 to >1 months before (n=2541), 1 to >0 months before (n=2997) and 0-12 weeks after (n=567)) in relation to offspring overweight or obesity at age 3 years. RESULTS: We observed a weak, inverse association between early pregnancy use of a combination oral contraceptive and offspring overweight or obesity at age 3 (adjusted odds ratio (OR): 0.75, 95% confidence interval (CI): 0.53, 1.08) and a positive, but imprecise, association with use of a progestin-only oral contraceptive in early pregnancy (adjusted OR: 1.26, 95% CI: 0.79, 2.02). In general, no association was observed between the use of a hormonal contraceptive before conception and offspring overweight or obesity. A sensitivity analysis comparing combination oral contraceptive users in early pregnancy to other unplanned pregnancies without hormonal contraceptive use further strengthened the inverse association (adjusted OR: 0.70, 95% CI: 0.48, 1.02). Other sensitivity analyses were conducted to evaluate the robustness of the associations observed given varying assumptions. CONCLUSIONS: Pharmacologic sex hormones in early pregnancy may be inversely or positively associated with offspring overweight or obesity at age 3, depending on the specific formulation used. The present study provides support for the potential for environmental sources of hormonally active agents to exert developmental effects.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

The psychiatric vulnerability gene CACNA1C and its sex-specific relationship with personality traits, resilience factors and depressive symptoms in the general population.

Genome-wide association studies have reported an association between the A-allele of rs1006737 within CACNA1C and affective disorders and schizophrenia. The aim of the present study was to investigate the relationship between rs1006737 and established and potential endophenotypes for these disorders in a population-based cohort of 3793 subjects, using an analytical method designed to assess a previously reported sex-specific effect of CACNA1C. The investigated endophenotypes included personality traits and resilience factors. At 10-year follow-up, subjects were screened for depressive symptoms. All subjects were genotyped for rs1006737. The direction of the effect and mode of inheritance of rs1006737 differed between the sexes. In men, the A-allele was associated with higher emotional lability and lower resilience, that is, lower sense of coherence (P=0.021), lower perceived social support (P=0.018), lower dispositional optimism (P=0.032) and more depressive symptoms at follow-up (P=0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is, higher sense of coherence (P=0.00028), higher perceived social support (P=0.010), lower neuroticism (P=0.022) and fewer depressive symptoms at follow-up (P=0.035). After conservative Bonferroni correction for 32 tests, results only remained significant for sense of coherence in women (P=0.009). These results suggest that CACNA1C is involved in the genetic architecture of endophenotypes for affective disorders and schizophrenia, and that it shows a distinct sex-specific effect. Comprehensive phenotype characterization in case-control samples and the general population, as well as an adequate modeling of sex-specific genetic effects, may be warranted to elucidate the pathogenetic mechanisms conferred by robustly identified susceptibility genes.

Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study.

AIM: To compare pancreatic cancer incidence and diagnostic evaluation among patients initiating dipeptidyl-peptidase-4 (DPP-4) inhibitor treatment with those initiating sulfonylureas (SU) and thiazolidinediones (TZD). METHODS: Medicare claims data were examined in a new-user active-comparator cohort study. Patients >65 years with no prescriptions for DPP-4 inhibitors, SU or TZD at baseline were included if they had at least two claims for the same drug within 180 days. Using an as-treated approach and propensity score-adjusted Cox models, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer. Diagnostic evaluations were compared using risk ratios. RESULTS: In the DPP-4 inhibitor versus SU comparison, there were 18 179 patients who initiated treatment with DPP-4 inhibitors, of whom 26 developed pancreatic cancer (interquartile range follow-up 5-18 months). In the DPP-4 inhibitor versus TZD comparison there were 29 366 people initiating DPP-4 inhibitor treatment and 52 of these developed pancreatic cancer. The risk of pancreatic cancer with DPP-4 inhibitor treatment was lower relative to SU treatment (HR: 0.6, CI: 0.4-0.9) and similar to TZD treatment (HR: 1.0, 95% CI: 0.7-1.4). After the first 6 months of follow-up were excluded to reduce the potential for reverse causality, the results were not altered. The probability of diagnostic evaluation after commencing DPP-4 inhibitor treatment (79.3%) was similar to that for TZD (74.1%, risk ratio 1.06, 95% CI: 1.05-1.07) and SU (74.6%) (risk ratio 1.06, 95% CI: 1.05-1.07). The probability of diagnostic evaluation before the index date (date of initiating treatment) was ∼80% for all cohorts. CONCLUSION: Although the present study was limited by sample size and the observed duration of treatment in the USA, our well-controlled population-based study suggests there is no higher short-term pancreatic cancer risk with DPP-4 inhibitor treatment relative to SU or TZD treatment.

Association between serum and urine biomarkers and lumbar spine individual radiographic features: the Johnston County Osteoarthritis Project.

OBJECTIVE: (1) To determine associations between radiographic features of lumbosacral (LS) spine disc space narrowing (DSN) and osteophytes (OST) and joint metabolism biomarkers (serum cartilage oligomeric matrix protein (COMP), hyaluronic acid (HA), collagen neoepitope (C2C), C-propeptide of type II procollagen (CP-II), urine C-terminal cross-linking telopeptide (CTX-II) and N-terminal telopeptide (NTX-I)). (2) To explore interactions with race, gender and low back symptoms. DESIGN: Cross-sectional analysis of 547 participants enrolled in the Johnston County (JoCo) Osteoarthritis Project from 2003 to 2004. Mean biomarker levels were estimated with linear regression. Proportional and partial-proportional odds models were used to estimate associations. Interactions were tested with likelihood ratio tests at a P-value < 0.10. Biomarkers were natural log (ln) transformed. RESULTS: Significant differences in mean biomarker levels were found across severity of DSN for lnHA and lnC2C and lnCTX-II across severity of both DSN and OST. Moderate-to-strong associations were found between biomarkers of type II collagen and DSN, whereas associations with OST were weak. An association between lnHA and DSN was seen in women (adjusted odds ratio [aOR] = 1.34 (95% confidence intervals (CI) 1.08, 1.65)) but no association among men (aOR = 0.90 (95% CI 0.63, 1.26)). In Caucasians there was a decreased association with NTX-I and OST (aOR = 0.67 (95% CI 0.49, 0.91)) and no association in African Americans (AAs) (aOR = 1.06 (95% CI 0.76, 1.47)). There was a positive association of lnCOMP with DSN among those with low back symptoms (aOR = 1.82 (95% CI 1.02, 3.27)), but no association in those without low back symptoms (aOR = 0.65 (95% CI 0.35, 1.20)). CONCLUSION: Joint metabolism biomarkers suggest biological differences in the pathologic process involved in DSN and OST that may be gender (HA) and ethnicity (NTX-I) specific.

Work-related stress, inability to relax after work and risk of adult asthma: a population-based cohort study.

BACKGROUND: There is an extensive literature linking stressful work conditions to adverse health outcomes. Notwithstanding, the relationship with asthma has not been examined, although various other measures of psychological stress have been associated with asthma. Therefore, we aimed to investigate the relation between work stress and asthma prevalence and incidence. METHODS: We used data from a population-based cohort study (n = 5114 at baseline in 1992-1995 and n = 4010 at follow-up in 2002/2003). Asthma was measured by self-reports. Two scales that assessed psychologically adverse work conditions were extracted from a list of work-condition items by factor analysis (these scales were termed 'work stress' and 'inability to relax after work'). For each scale, the derived score was employed both as continuous z-score and as categorized variable in analyses. Associations with asthma were estimated by prevalence ratios (PRs) and risk ratios (RRs) using Poisson regression with a log-link function adjusting for demographics, health-related lifestyles, body mass index and family history of asthma. Analyses were restricted to those in employment (n = 3341). RESULTS: Work stress and inability to relax z-scores were positively associated with asthma prevalence (PR = 1.15, 95%CI = 0.97, 1.36 and PR = 1.43, 95%CI = 1.12, 1.83, respectively). Prospective analyses using z-scores showed that for each 1 standard deviation increase in work stress and inability to relax, the risk of asthma increased by approximately 40% (RR for work stress = 1.46, 95%CI = 1.06, 2.00; RR for inability to relax = 1.39, 95%CI = 1.01, 1.91). Similar patterns of associations were observed in analyses of categorized exposures. CONCLUSIONS: This is the first study to show a cross-sectional and longitudinal association of work stress with asthma.

Comparative gastrointestinal safety of weekly oral bisphosphonates.

SUMMARY: Weekly bisphosphonates are the primary agents used to treat osteoporosis. Although these agents are generally well tolerated, serious gastrointestinal adverse events, including hospitalization for gastrointestinal bleed, may arise. We compared the gastrointestinal safety between weekly alendronate and weekly risedronate and found no important difference between new users of these agents. INTRODUCTION: Weekly bisphosphonates are the primary agents prescribed for osteoporosis. We examined the comparative gastrointestinal safety between weekly bisphosphonates. METHODS: We studied new users of weekly alendronate and weekly risedronate from June 2002 to August 2005 among enrollees in a state-wide pharmaceutical benefit program for seniors. Our primary outcome was hospitalization for upper gastrointestinal bleed. Secondary outcomes included outpatient diagnoses for upper gastrointestinal disease, symptoms, endoscopic procedures, use of gastroprotective agents, and switching between therapies. We used Cox proportional hazard models to compare outcomes between agents within 120 days of treatment initiation, adjusting for propensity score quintiles. We also examined composite safety outcomes and stratified results by age and prior gastrointestinal history. RESULTS: A total of 10,420 new users were studied, mean age = 79 years (SD, 6.9), and 95% women. We observed 31 hospitalizations for upper gastrointestinal bleed (0.91 per 100 person-years) within 120 days of treatment initiation. Adjusting for covariates, there was no difference in hospitalization for upper gastrointestinal bleed among those treated with risedronate compared with alendronate (HR, 1.12; 95%CI, 0.55 to 2.28). Risedronate switching rates were lower; otherwise, no differences were observed for secondary or composite outcomes. CONCLUSIONS: We found no important difference in gastrointestinal safety between weekly oral bisphosphonates.

Neuroticism, extraversion, stressful life events and asthma: a cohort study of middle-aged adults.

BACKGROUND: Stressful life events can trigger asthma exacerbations, but could also contribute to the development of incident asthma. However, only few studies have investigated the association between stressful life events and adult asthma prospectively. Likewise, stress-related personality traits (e.g. neuroticism and extraversion) may increase asthma risk, but this has been examined in only one prospective study. We therefore aimed to investigate the association between neuroticism, extraversion, stressful life events and incident asthma. METHODS: A population-based sample of 5114 middle-aged adults completed questionnaires between 1992 and 1995. Among those alive in 2002/2003, 4010 (83%) were followed-up by questionnaires. Exposures of interest included neuroticism, extraversion and three stressful life events (unemployment, having broken off a life partnership and death of a close person). Associations with incident asthma were estimated by multivariable risk ratios (RR) and 95% confidence intervals (95% CI) using Poisson regression. RESULTS: High vs low neuroticism predisposed to developing asthma (RR = 3.07, 95% CI = 1.71-5.48), but high extraversion did not (RR = 1.30, 95% CI = 0.79-2.15). Having broken off a life partnership significantly increased asthma risk (RR = 2.24, 95% CI = 1.20-4.21) in contrast to death of a close person (RR = 1.06, 95% CI = 0.64-1.75) or unemployment (RR = 1.65, 95% CI = 0.72-3.78). CONCLUSIONS: High levels of neuroticism may increase the risk of asthma in middle-aged adults. Having broken off a life partnership was the only stressful event, which was associated with incident asthma. Synthesized with evidence from earlier studies, this could reflect that interpersonal conflicts may increase asthma risk, possibly along an immunological pathway.

Osteoarthritis-patterns, cardio-metabolic risk factors and risk of all-cause mortality: 20 years follow-up in patients after hip or knee replacement.

Osteoarthritis (OA) is a common musculoskeletal disorder and occur in different patterns. However, its impact on long-term all-cause-mortality is inconclusive. STUDY AIMS: Investigate 20-year all-cause-mortality in patients with hip/knee arthroplasty (recruited 1995/1996, N = 809) from the Ulm Osteoarthritis Study-cohort, in comparison to general population. Furthermore, to enlighten the triangle between baseline life-style and cardio-metabolic risk factors, phenotypic OA-patterns (laterality, generalization, cause) and all-cause-mortality. Mortality was assessed during 20 years follow-up. Standardized mortality ratios (SMR), adjusted odds ratios and hazard ratios (aHR) were calculated. After five years cohort-mortality was reduced compared to the general population, however 20 years later assimilated (SMR = 1.11; 95%-CI 0.73-1.49). OA-patterns were associated with age, cholesterol, and overweight/obesity. In comparison to primary OA decreased mortality was observed for patients with secondary OA (aHR = 0.76; 95%-CI 0.61-0.95) adjusted for age, smoking, overweight/obesity, diabetes, hypertension, cardiac insufficiency, uric acid, and lower cholesterol. There was no increased mortality in patients after 20 years follow-up compared to general population. Significantly decreased mortality in secondary compared to primary OA suggests a subtype-specific involvement of systemic co-factors in determination of all-cause-mortality. Because cardio-metabolic risk factors were associated with increased risk of bilateral OA and lower long-term survival, those risk factors should be consequently targeted in OA-patients.

Reduction of clinically manifest colorectal cancer by endoscopic screening: empirical evaluation and comparison of screening at various ages.

Endoscopic screening (sigmoidoscopy, colonoscopy) with removal of precancerous lesions can prevent a large proportion of colorectal cancers (CRCs). However, there is lack of data regarding optimal age, time intervals and numbers of screening examinations. We developed and applied modified techniques of epidemiological analysis to evaluate the impact of various endoscopy-based screening strategies on prevention of clinically manifest CRCs between the ages of 50 and 79 in a population-based case-control study (294 cases, 254 controls) conducted in Saarland, Germany. We found a strong potential for reduction of CRC occurrence even with a single screening endoscopy. The optimal age for a single screening endoscopy appears to be around 55 (estimated potential for prevention of cases between the ages of 55 and 79 in case of 100% compliance: 77% (95% confidence interval (CI) 46-90%)). A single screening endoscopy at age 50 would have a lower impact due to failure to prevent CRC at higher ages. Similarly, screening at ages 60 or older would have a lower impact because it would fail to prevent CRC at lower ages. Repeated offers of screening examinations could provide substantial additional benefit with the levels of compliance to be expected in practice, but they would have to be weighed against the increased risks and costs.

Differences in the views of orthopaedic surgeons and referring practitioners on the determinants of outcome after total hip replacement.

In order to assess current opinions on the long-term outcome after primary total hip replacement, we performed a multicentre, cross-sectional survey in 22 centres from 12 European countries. Different patient characteristics were categorised into 'decreases chances', 'does not affect chances', and 'increases chances' of a favourable long-term outcome, by 304 orthopaedic surgeons and 314 referring practitioners. The latter were less likely to associate age older than 80 years and obesity with a favourable outcome than orthopaedic surgeons (p < 0.001 and p = 0.006, respectively) and more likely to associate age younger than 50 years with a favourable outcome (p = 0.006). Comorbidity, rheumatoid arthritis, and poor bone quality were thought to be associated with a decreased chance of a favourable outcome. We found important differences in the opinions regarding long-term outcome after total hip replacement within and between referring practitioners and orthopaedic surgeons. These are likely to affect access to and the provision of total hip replacement.

A computer program to estimate power and relative efficiency of flexibly matched case-control studies.

OBJECTIVES: We recently introduced the concept of flexible matching strategies with varying proportions of a dichotomous matching factor among controls to increase power and efficiency of case-control studies. We now present a method and a computer program to calculate power and relative efficiency compared to an unmatched design varying the proportion of the matching factor in controls over all possible values from 0 to 100 percent. METHODS: For all these values, the program calculates the expected variance of the combined Mantel-Haenszel odds ratio and determines the power using the standard error of the expected combined Mantel-Haenszel odds ratio under the null hypothesis as derived from the Mantel-Haenszel test statistic without continuity correction. RESULTS: Thereby, the program allows estimating the optimal prevalence of the matching factor in selected controls for a given scenario which often differs from the prevalence in cases. It furthermore allows to estimate loss in power and efficiency compared to optimal matching by suboptimal matching. CONCLUSIONS: Estimations like these are helpful with respect to the decision when to stop efforts to optimize the degree of matching during the recruitment of controls. Our program will strongly facilitate assessing the benefits of flexible matching strategies.

Age-specific detriments to quality of life among breast cancer patients one year after diagnosis.

The aim of our study was to identify any differences in the quality of life (QOL) of breast cancer survivors one year after diagnosis when the acute treatment effects should not longer be apparent. QOL was assessed in a population-based cohort of 387 women with breast cancer from Saarland (Germany) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLC30). Functional and symptom QOL-scores were compared with published reference data from the general population. Breast cancer survivors and women from the general population reported similar scores of global health/QOL. However, major deficits among women with breast cancer were found, for emotional, social, role and cognitive functioning. Age-specific comparisons between breast cancer patients and the reference population revealed that these deficits are predominantly found in younger age groups. The overall QOL of life of breast cancer survivors one year after diagnosis is comparable to women from the general population. However, some differences exist that seem to predominantly affect younger women who show a poorer QOL in certain domains.

Determinants of impaired renal function with use of nonsteroidal anti-inflammatory drugs: the importance of half-life and other medications.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with renal function, but little is known about the effects of the half-life of these agents, or the use of other medications, on renal function. SUBJECTS AND METHODS: Medication use was assessed during a standardized interview in a cross-sectional study of 802 patients undergoing total joint replacement because of osteoarthritis. Preoperative blood samples were used to estimate creatinine clearance using a standard formula that takes age, sex, and weight into account. Impaired renal function was defined as an estimated creatinine clearance less than 60 mL/min (fifteenth percentile). Multivariable logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between NSAID use (alone or in combination with diuretics or angiotensin-converting enzyme [ACE] inhibitors) and impaired renal function. RESULTS: NSAID use per se was only marginally associated with impaired renal function (OR = 1.4; 95% CI, 0.9 to 2.2). This association was almost exclusively the result of the use of NSAIDs with a half-life of 4 or more hours (OR = 2.6; 95% CI: 1.2 to 5.7). Patients who used diuretics with NSAIDs (OR = 3.7; 95% CI: 1.7 to 8.3) or without NSAIDs (OR = 3.5; 95% CI: 1.6 to 7.6) had a higher risk of impaired renal function than did patients using NSAIDs alone (OR = 1.6) or none of these drugs (reference). A similar but less pronounced pattern was observed for ACE inhibitors. CONCLUSION: NSAID-associated impaired renal function seems to be mainly the result of compounds with intermediate-long half-life. We found no evidence that the adverse effects of diuretics and ACE inhibitors on renal function were greater in those who also used NSAIDs.

A prospective study of blood pressure and risk of cataract in men.

PURPOSE: Cataract is the leading cause of blindness worldwide. Blood pressure has been identified as a risk factor in some, but not all, previous studies. We aimed to test prospectively the hypothesis that high blood pressure increases risk of age-related cataract. METHODS: Participants in the Physicians' Health Study of 22,071 men aged 40 to 84 years in 1982 completed annual questionnaires that provided medical history including self-reported blood pressure, treatment for hypertension, and cataract. Over 12 years, 1392 cataracts were confirmed by medical record review among 17,762 physicians with complete data and no reported cataract at baseline. We used proportional hazards regression models to examine relations of systolic blood pressure (SBP), diastolic blood pressure (DBP), hypertension, as well as antihypertensive medications with cataract, after control for potential confounding factors. RESULTS: In models adjusting for age and randomized treatment assignment, there was a significant relationship of SBP, but not DBP, hypertension, or antihypertensive medications (each p > or = 0.23) with incident cataract. Estimates were attenuated after adjusting for multiple potential confounders, although the relationship of SBP with incident cataract remained significant. The multivariate adjusted rate ratio (95% confidence interval) of cataract for SBP > or = 150 versus < 120 mm Hg was 1.31 (1.04-1.66), p for trend = 0.04. For DBP > or = 90 versus < 70 mm Hg, the estimate was 1.11 (0.84-1.45), p for trend = 0.33. CONCLUSIONS: Overall, these data suggest that the relationship of blood pressure with cataract is not strong, and is subject to confounding by other risk factors. The modest magnitude of the association with SBP and lack of significant relationships with DBP and hypertension may suggest a non-causal relationship of blood pressure with cataract.

Obesity, overweight and patterns of osteoarthritis: the Ulm Osteoarthritis Study.

The objective of this study was to assess the association between obesity and osteoarthritis (OA) of the knee, hip, and hand. OA patterns were studied in 809 patients with knee or hip joint replacement due to OA. Patients with OA were categorized as having bilateral or generalized OA according to the presence of radiographic OA in the contralateral joint or different finger joints, and as normal weight, overweight, or obese according to their body mass index (BMI). Odds ratios (OR) and 95% confidence intervals (CI) for relative weight and OA patterns were estimated with multivariable logistic regression. Eighty-five percent of participants had bilateral OA, 26% had generalized OA, and 31% were obese. Obesity (BMI >/= 30 kg/m(2); OR = 8.1; 95% CI: 2.4-28) and overweight (BMI >/= 25 kg/m(2); OR = 5.9; 95% CI: 2.0-18) were strongly associated with bilateral knee OA. No association between obesity and bilateral hip OA (OR = 0.7; 95% CI: 0.3-1.7) nor generalized OA (OR = 1.1; 95% CI: 0.6-2.1) was observed. Obesity seems to be a mechanical rather than a systemic risk factor for OA with the knee joint being especially susceptible.