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.

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.

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.

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.

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.

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.

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.

Antidepressant class, age, and the risk of deliberate self-harm: a propensity score matched cohort study of SSRI and SNRI users in the USA.

BACKGROUND: The US Food and Drug Administration's meta-analyses of placebo-controlled antidepressant trials found approximately twice the rate of suicidal behaviors among children and adults aged 24 years and younger who were randomized to receive antidepressant medication than among those who were randomized to placebo. Rates of suicidal behavior were similar for subjects aged 25-64 years whether they received antidepressants or placebo, and subjects aged 65 years or older randomized to antidepressants were found to have lower rates of suicidal behavior. The age-stratified FDA meta-analyses did not have adequate power to investigate rates of suicidal behaviors by antidepressant drug class. OBJECTIVE: Our objective was to assess the risk of deliberate self-harm associated with the two most commonly prescribed classes of antidepressant agents. DESIGN: Propensity score matched cohort study of incident users of antidepressant agents. SETTING: Population-based healthcare utilization data of US residents. PATIENTS: US residents aged 10-64 years with a recorded diagnosis of depression who initiated use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) between 1 January 1998 and 31 December 2010. MAIN OUTCOME MEASURES: ICD-9 external cause of injury codes E950.x-E958.x (deliberate self-harm). RESULTS: A total of 102,647 patients aged between 10 and 24 years, and 338,021 aged between 25 and 64 years, initiated therapy with antidepressants. Among 10-24 year olds, prior to propensity score matching, 75,675 initiated therapy with SSRIs and 5,344 initiated SNRIs. After matching, there were 5,344 SNRI users and 10,688 SSRI users. Among the older cohort, 36,037 SNRI users were matched to 72,028 SSRI users (from an unmatched cohort of 225,952 SSRI initiators). Regardless of age cohort, patients initiating SSRIs and patients initiating SNRIs had similar rates of deliberate self-harm. Restriction to patients with no antidepressant use in the past 3 years did not alter our findings. CONCLUSIONS: Our findings of similar rates of deliberate self-harm for depressed patients who initiate treatment with either an SSRI or an SNRI suggests that physicians who have decided that their patients would benefit from initiating antidepressant therapy need not weigh differential suicide risk when deciding which class of antidepressant to prescribe.

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.

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.

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.

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.

Prevalence of antibiotic resistance in Escherichia coli: overview of geographical, temporal, and methodological variations.

The increase in bacterial antibiotic resistance is of major concern worldwide, but pertinent epidemiologic studies have used strongly divergent approaches and are widely scattered in the literature. The aim of this study was to conduct a systematic review of studies reporting on the prevalence of antibiotic resistance in Escherichia coli in different parts of the world. Studies published from 1970 to 2006 on the prevalence of E. coli resistance were identified by a systematic Medline research and reviewed with respect to characteristics of the study design and study population, the method of resistance detection, and the prevalence of resistance. The prevalence of resistance to specific antibiotics was highly variable in different populations and in different countries and ranged from 0 to 100%. The prevalence of resistance reported in studies from Middle and South America, Spain, and Turkey was higher than that reported in the USA and Central Europe. Moreover, a tendency towards higher prevalence rates of resistance in recent years was observed. The findings indicate a need for regular monitoring of antimicrobial susceptibility rates in different human and animal populations by standardized sampling and measurement procedures. Such monitoring would help identify relevant factors that contribute to the spread of resistant pathogens and would support the prudent use of antibiotics.

Does a negative screening colonoscopy ever need to be repeated?

BACKGROUND AND AIMS: Screening colonoscopy is thought to be a powerful and cost-effective tool to reduce colorectal cancer incidence and mortality. Whether and when colonoscopy with negative findings has to be repeated is not well defined. The aim of this study was to assess the long term risk of clinically manifest colorectal cancer among subjects with negative findings at colonoscopy. PATIENTS: 380 cases and 485 controls participating in a population based case-control study in Germany. METHODS: Detailed history and results of previous colonoscopies were obtained by interview and from medical records. Adjusted relative risks of colorectal cancer among subjects with a previous negative colonoscopy compared with those without previous colonoscopy were estimated according to time since colonoscopy. RESULTS: Subjects with previous negative colonoscopy had a 74% lower risk of colorectal cancer than those without previous colonoscopy (adjusted odds ratio (aOR) = 0.26 (95% confidence interval, 0.16 to 0.40)). This low risk was seen even if the colonoscopy had been done up to 20 or more years previously. Particularly low risks were seen for sigma cancer (aOR = 0.13 (0.04 to 0.43)) and for rectal cancer (aOR = 0.19 (0.09 to 0.39)), and after a negative screening colonoscopy at ages 55 to 64 (aOR = 0.17 (0.08 to 0.39)) and older (aOR = 0.21 (0.10 to 0.41)). CONCLUSIONS: Subjects with negative findings at colonoscopy are at very low risk of colorectal cancer and might not need to undergo repeat colonoscopy for 20 years or more, if at all. The possibility of extending screening intervals to 20 years or more might reduce complications and increase the feasibility and cost-effectiveness of colonoscopy based screening programmes.

Indications for total hip replacement: comparison of assessments of orthopaedic surgeons and referring physicians.

OBJECTIVES: To analyse differences of opinions on indications for primary total hip replacements (THRs) within and between groups of orthopaedic surgeons and the physicians who refer patients to them. METHODS: 22 orthopaedic centres in 12 European countries took part, resulting in a postal survey of 304 orthopaedic surgeons and 314 referring physicians. Each participant was asked to state what importance different domains (pain, functional impairment, physical examination and radiographs) have on their decision to recommend THR and to select the most appropriate level of severity of each symptom or sign for recommending THR. In addition, the participants were asked to prioritise other personal or environmental factors that affect their decision to undertake a THR. RESULTS: Rest pain, pain with activity and functional limitations were the most important criteria for THR, although range of motion and radiographic changes were of least importance. Both similarities and differences were observed within and between groups of surgeons and referring physicians in the overall approach to indications and the most appropriate level of severity of disease for recommending THR. Most surgeons agreed on severity levels in only 4 of 11 items and most referring physicians in only one. Between the groups, major differences occurred with regard to the importance of activities of daily living and the appropriate level of symptoms for THR. In general, compared with surgeons, referring physicians reported that the disease needed to be more advanced to warrant surgery. CONCLUSION: Currently, no consensus exists on objective indication criteria for THR. The observed differences between the gatekeepers (referring physicians) and surgeons can lead to variations and perhaps inequities in the provision of care.

Assessment of cognitive status in the elderly using telephone interviews.

OBJECTIVE: To examine the feasibility to assess cognitive status in the elderly using telephone interviews. RESEARCH DESIGN AND METHODS: From January to December 2003, 740 participants of the ongoing Heidelberg longitudinal study (HeiDE) aged 70 years or more were eligible for a telephone interview on cognitive status. Validated instruments to assess cognitive status, including the Telephone Interview of Cognitive Status (TICS) and the East Boston Memory Test (EBMT, immediate and delayed recall), the Verbal Fluency Test, the HAWIE-"Vocabulary Test" and the HAWIE-"General Knowledge", a prospective memory test, and a digit span backwards-test were translated into German, if applicable. RESULTS: Out of 740 participants at the age of 70 or older, 473 participants were interviewed (64.9%). The total score of the TICS (maximum=best: 41) ranged from 21 to 40 (mean 33.5, SD 3.1; median 34.0). The EBMT scores (immediate recall; maximum=best: 12) ranged from 4 to 12 (mean 9.2, SD 1.7; median 9.0). CONCLUSIONS: Cognitive status could be successfully assessed by telephone interview in elderly participants of an ongoing population-based cohort study. Specifically, some of the tests showed pronounced variability allowing cross-sectional analyses whereas others seem more valuable for longitudinal assessment.

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.

Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain.

BACKGROUND: The severity of pain from musculoskeletal disorders might be associated with high sensitivity C reactive protein (hsCRP), a sensitive marker of low grade systemic inflammation. OBJECTIVE: To study the association between pain as assessed by a visual analogue scale (VAS) and hsCRP in patients with chronic low back pain and acute sciatic pain. METHODS: Information on pain severity, determinants of hsCRP, and hsCRP values were obtained prospectively at up to 10 time points during six months in 72 consecutive patients (mean age 43.3 years; 59.7% female): 41 with chronic low back pain and 31 with acute sciatic pain. The association between severity of pain and raised (highest quartile) hsCRP values at any time point was estimated by multivariable logistic regression using generalised estimating equations to adjust odds ratios (OR) and their confidence intervals (CI) for intraindividual dependence of measurements. RESULTS: Mean intensity of pain (VAS 0-10) at baseline was 4.9 and 5.5 in patients with chronic low back and acute sciatic pain, respectively. Highest v lowest tertile of average intensity of pain during the last 24 hours was associated with increased hsCRP levels among patients with acute sciatic pain (adjusted OR = 3.4 (95% CI, 1.1 to 10), but not in patients with chronic low back pain (adjusted OR = 0.87 (0.25 to 3.0)). CONCLUSIONS: Mean intensity of pain during the previous 24 hours as assessed by VAS was independently associated with high levels of hsCRP in patients with acute sciatic pain but not in those with chronic low back pain.