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Background The incidence of non-communicable diseases (NCDs) is increasing in rural India. The National Family Health Survey-5 (NFHS-5) provides estimates of the burden of NCDs and their risk factors in women aged 15–49 and men aged 15–54 years. The aim of this study is to estimate the prevalence of hypertension and body-mass index (BMI) in adults aged 35–70 years in rural India and to compare these estimates, where age ranges overlap, to routinely available data. Methods The Non-Communicable Disease in Rural India (NCDRI) Study was a cross-sectional household survey of 1005 women and 1025 men aged 35–70 conducted in Bihar in July 2019. Information was collected on personal characteristics, self-reported medical history and physical measurements (blood pressure, height and weight). Prevalence estimates for hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, or diagnosed and treated for hypertension), and for underweight (body-mass index 2), normal weight (18.5–25.0 kg/m2) and overweight (≥ 25.0 kg/m2) were calculated. Where age ranges overlapped, estimates from the NCDRI Study were compared to the NFHS-5 Survey. Results In the NCDRI Study, the estimated prevalence of hypertension was 27.3% (N = 274) in women and 27.6% (N = 283) in men aged 35–70, which was three-times higher in women and over two-times higher in men than in the NFHS-5 Survey. One-quarter (23.5%; N = 236) of women and one-fifth (20.2%; N = 207) of men in the NCDRI Study were overweight, which was approximately 1.5 times higher than in the NFHS-5 Survey. However, where age groups overlapped, similar age-standardized estimates were obtained for hypertension and weight in both the NCDRI Study and the NFHS-5 Survey. Conclusion The prevalence of NCDs in rural India is higher than previously reported due to the older demographic in our survey. Future routine national health surveys must widen the age range of participants to reflect the changing disease profile of rural India, and inform the planning of health services.

Rationale: The American Thoracic Society (ATS) developed a clinical practice guideline on initiating pharmacologic treatment in tobacco-dependent adults. Controller pharmacotherapies treat tobacco dependence effectively when taken as prescribed, but relapse after pharmacologic discontinuation is common. Objectives: To evaluate the effectiveness and safety of initiating controller for an extended (.12 wk) versus a standard duration (6-12 wk) in tobacco-dependent adults. Methods: We systematically searched PubMed, ExcerptaMedica Database, Cumulative Index toNursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials fromdatabase inception toDecember 2021 to identify randomized controlled trials comparing extended versus standard duration of controllers for tobacco-dependent adults. We conductedmeta-analyses using the Mantel-Haenszelmethod with random effectsmodel.Outcomes of interest include point-prevalent abstinence at 1-year follow-up or longer, relapse, adverse events, quality of life, and withdrawal symptoms. Subgroup analyses were conducted according to types of treatment and duration of extended therapy when feasible.We assessed the certainty of the estimate following the grading of recommendations, assessment, development and evaluationmethodology. Results: We included 13 randomized controlled trials including 8,695 participants that directly compared extended- (.12 wk) versus standard-duration controller therapy with varenicline, bupropion, or nicotine replacement therapy. Compared with standard-duration controller therapy, extendedduration controller therapy probably increased abstinence at 1-year follow-up, measured as 7-day point-prevalence abstinence (relative risk, 1.18; 95% confidence interval [CI], 1.05-1.33; moderate certainty). Extended-duration controller therapy probably reduced relapse compared with standardduration controller therapy, assessed at 12-18 months after initiation of therapy (hazard ratio, 0.43; 95% CI, 0.29-0.64; moderate certainty). Moderate certainty evidence also suggested that extended-duration controller therapy probably did not increase risk of serious adverse events (relative risk, 1.37; 95% CI, 0.79-2.36). Conclusions: This systematic review supported the recommendation for extended-duration therapy with controllers. Further studies on optimal extended duration are warranted.

Background Patients and clinicians can choose from several treatment options to address acute pain from non-low back, musculoskeletal injuries. Purpose To assess the comparative effectiveness of outpatient treatments for acute pain from non-low back, musculoskeletal injuries by performing a network meta-analysis of randomized clinical trials (RCTs). Data sources MEDLINE, EMBASE, CINAHL, PEDro (Physiotherapy Evidence Database), and Cochrane Central Register of Controlled Trials to 2 January 2020. Study selection Pairs of reviewers independently identified interventional RCTs that enrolled patients presenting with pain of up to 4 weeks' duration from non-low back, musculoskeletal injuries. Data extraction Pairs of reviewers independently extracted data. Certainty of evidence was evaluated by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Data synthesis The 207 eligible studies included 32 959 participants and evaluated 45 therapies. Ninety-nine trials (48%) enrolled populations with diverse musculoskeletal injuries, 59 (29%) included patients with sprains, 13 (6%) with whiplash, and 11 (5%) with muscle strains; the remaining trials included various injuries ranging from nonsurgical fractures to contusions. Topical nonsteroidal anti-inflammatory agents (NSAIDs) proved to have the greatest net benefit, followed by oral NSAIDs and acetaminophen with or without diclofenac. Effects of these agents on pain were modest (around 1 cm on a 10-cm visual analogue scale, approximating the minimal important difference). Regarding opioids, compared with placebo, acetaminophen plus an opioid improved intermediate pain (1 to 7 days) but not immediate pain (≤2 hours), tramadol was ineffective, and opioids increased the risk for gastrointestinal and neurologic harms (all moderate-certainty evidence). Limitations Only English-language studies were included. The number of head-to-head comparisons was limited. Conclusion Topical NSAIDs, followed by oral NSAIDs and acetaminophen with or without diclofenac, showed the most convincing and attractive benefit-harm ratio for patients with acute pain from non-low back, musculoskeletal injuries. No opioid achieved benefit greater than that of NSAIDs, and opioids caused the most harms. Primary funding source National Safety Council. (PROSPERO: CRD42018094412).

Heparin-induced thrombocytopenia (HIT) is a prothrombotic adverse drug reaction occurring in

Increasing evidence supports the safety and effectiveness of managing low-risk deep vein thrombosis (DVT) or pulmonary embolism (PE) in outpatient settings. We performed a systematic review to assess safety and effectiveness of managing patients with DVT or PE at home compared with the hospital. Medline, Embase, and Cochrane databases were searched up to July 2019 for relevant randomized clinical trials (RCTs), and prospective cohort studies. Two investigators independently screened titles and abstracts of identified citations and extracted data from relevant full-text papers. Risk ratios (RRs) were calculated, and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Seven RCTs (1922 patients) were included in meta-analyses on managing patients with DVT. Pooled estimates indicated decreased risk of PE (RR = 0.64; 95% confidence interval [CI], 0.44-0.93) and recurrent DVT (RR = 0.61; 95% CI, 0.42-0.90) for home management, both with moderate certainty of the evidence. Reductions in mortality and major bleeding were not significant, both with low certainty of the evidence. Two RCTs (445 patients) were included in meta-analyses on home management of low-risk patients with PE. Pooled estimates indicated no significant difference in all-cause mortality, recurrent PE, and major bleeding, all with low certainty of the evidence. Results of pooled estimates from 3 prospective cohort studies (234 patients) on home management of PE showed similar results. Our findings indicate that low-risk DVT patients had similar or lower risk of patient-important outcomes with home treatment compared with hospital treatment. In patients with low-risk PE, there was important uncertainty about a difference between home and hospital treatment.

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF

Background: Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs in ∼1 to 2 individuals per 1000 each year, corresponding to ∼300 000 to 600 000 events in the United States annually. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about treatment of VTE. Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 28 recommendations for the initial management of VTE, primary treatment, secondary prevention, and treatment of recurrent VTE events. Conclusions: Strong recommendations include the use of thrombolytic therapy for patients with PE and hemodynamic compromise, use of an international normalized ratio (INR) range of 2.0 to 3.0 over a lower INR range for patients with VTE who use a vitamin K antagonist (VKA) for secondary prevention, and use of indefinite anticoagulation for patients with recurrent unprovoked VTE. Conditional recommendations include the preference for home treatment over hospital-based treatment for uncomplicated DVT and PE at low risk for complications and a preference for direct oral anticoagulants over VKA for primary treatment of VTE.

Background Whether factor V Leiden is associated with lower bleeding risk in patients with acute coronary syndromes using (dual) antiplatelet therapy has yet to be investigated. Methods and Results We pooled data from 3 randomized clinical trials, conducted in patients with acute coronary syndromes, with adjudicated bleeding outcomes. Cox regression models were used to obtain overall and cause‐specific hazard ratios (HRs) to account for competing risk of atherothrombotic outcomes (ie, composite of ischemic stroke, myocardial infarction, and cardiovascular death) in each study. Estimates from the individual studies were pooled using fixed effect meta‐analysis. The 3 studies combined included 17 623 patients of whom 969 (5.5%) were either heterozygous or homozygous (n=23) carriers of factor V Leiden. During 1 year of follow‐up, a total of 1289 (7.3%) patients developed major (n=559) or minor bleeding. Factor V Leiden was associated with a lower risk of combined major and minor bleeding (adjusted cause‐specific HR, 0.75; 95% CI, 0.56–1.00; P =0.046; I 2 =0%) but a comparable risk of major bleeding (adjusted cause‐specific HR, 0.93; 95% CI, 0.62–1.39; P =0.73; I 2 =0%). Adjusted pooled cause‐specific HRs for the association of factor V Leiden with atherothrombotic events alone and in combination with bleeding events were 0.75 (95% CI, 0.55–1.02; P =0.06; I 2 =0%) and 0.75 (95% CI, 0.61–0.92; P =0.007; I 2 =0%), respectively. Conclusions Given that the lower risk of bleeding conferred by factor V Leiden was not counterbalanced by a higher risk of atherothrombotic events, these findings warrant future assessment for personalized medicine such as selecting patients for extended or intensive antiplatelet therapy.

Background Cardiovascular disease accounts for about one-third of all premature deaths (ie, age Methods In 1996–2002, 146,556 adults were recruited from the general population in five areas of Cuba. Participants were interviewed, measured (height, weight and blood pressure) and followed up by electronic linkage to national death registries until Jan 1, 2017; in 2006–08, 24,345 participants were resurveyed. After excluding all with missing data, cardiovascular disease at recruitment, and those who died in the first 5 years, Cox regression (adjusted for age, sex, education, smoking, alcohol and, where appropriate, BMI) was used to relate cardiovascular mortality rate ratios (RRs) at ages 35–79 years to SBP, diabetes and BMI; RR were corrected for regression dilution to give associations with long-term average (ie, ‘usual’) levels of SBP and BMI. Results After exclusions, there were 125,939 participants (mean age 53 [SD12]; 55% women). Mean SBP was 124 mmHg (SD15), 5% had diabetes, and mean BMI was 24.2 kg/m2 (SD3.6); mean SBP and diabetes prevalence at recruitment were both strongly related to BMI. During follow-up, there were 4112 cardiovascular deaths (2032 ischaemic heart disease, 832 stroke, and 1248 other). Cardiovascular mortality was positively associated with SBP (>=120 mmHg), diabetes, and BMI (>=22.5 kg/m2): 20 mmHg higher usual SBP about doubled cardiovascular mortality (RR 2.02, 95%CI 1.88–2.18]), as did diabetes (2.15, 1.95–2.37), and 10 kg/m2 higher usual BMI (1.92, 1.64–2.25). RR were similar in men and in women. The association with BMI and cardiovascular mortality was almost completely attenuated following adjustment for the mediating effect of SBP. Elevated SBP (>=120 mmHg), diabetes and raised BMI (>=22.5 kg/m2) accounted for 27%, 14%, and 16% of cardiovascular deaths, respectively. Conclusions This large prospective study provides direct evidence for the effects of these major risk factors on cardiovascular mortality in Cuba. Despite comparatively low levels of these risk factors by international standards, the strength of their association with cardiovascular death means they nevertheless exert a substantial impact on premature mortality in Cuba.

Background: Current tobacco treatment guidelines have established the efficacy of available interventions, but they do not provide detailed guidance for common implementation questions frequently faced in the clinic. An evidence-based guideline was created that addresses several pharmacotherapy-initiation questions that routinely confront treatment teams. Methods: Individuals with diverse expertise related to smoking cessation were empaneled to prioritize questions and outcomes important to clinicians. An evidence-synthesis team conducted systematic reviews, which informed recommendations to answer the questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in the estimated effects and the strength of recommendations. Results: The guideline panel formulated five strong recommendations and two conditional recommendations regarding pharmacotherapy choices. Strong recommendations include using varenicline rather than a nicotine patch, using varenicline rather than bupropion, using varenicline rather than a nicotine patch in adults with a comorbid psychiatric condition, initiating varenicline in adults even if they are unready to quit, and using controller therapy for an extended treatment duration greater than 12 weeks. Conditional recommendations include combining a nicotine patch with varenicline rather than using varenicline alone and using varenicline rather than electronic cigarettes. Conclusions: Seven recommendations are provided, which represent simple practice changes that are likely to increase the effectiveness of tobacco-dependence pharmacotherapy.

The impact of pharmacologic prophylaxis for venous thromboembolism in patients undergoing neurosurgical intervention remains uncertain. We reviewed the efficacy and safety of pharmacologic compared with nonpharmacologic thromboprophylaxis in neurosurgical patients. Three databases were searched through April 2018, including those for randomized controlled trials (RCTs) and for nonrandomized controlled studies (NRSs). Independent reviewers assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seven RCTs and 3 NRSs proved eligible. No studies reported on symptomatic proximal and distal deep vein thrombosis (DVT). Two RCTs reported on screening-detected proximal and distal DVTs. We used the findings of these 2 RCTs as the closest surrogate outcomes to inform the proximal and distal DVT outcomes. These 2 RCTs suggest that pharmacologic thromboprophylaxis may decrease the risk of developing asymptomatic proximal DVT (relative risk [RR], 0.50; 95% confidence interval [CI], 0.30-0.84; low certainty). Findings were uncertain for mortality (RR, 1.27; 95% CI, 0.57-2.86; low certainty), symptomatic pulmonary embolism (PE) (RR, 0.84; 95% CI, 0.03-27.42; very low certainty), asymptomatic distal DVT (RR, 0.54; 95% CI, 0.27-1.08; very low certainty), and reoperation (RR, 0.43; 95% CI, 0.06-2.84; very low certainty) outcomes. NRSs also reported uncertain findings for whether pharmacologic prophylaxis affects mortality (RR, 0.72; 95% CI, 0.46-1.13; low certainty) and PE (RR, 0.18; 95% CI, 0.01-3.76). For risk of bleeding, findings were uncertain in both RCTs (RR, 1.57; 95% CI, 0.70-3.50; low certainty) and NRSs (RR, 1.45; 95% CI, 0.30-7.12; very low certainty). In patients undergoing neurosurgical procedures, low certainty of evidence suggests that pharmacologic thromboprophylaxis confers benefit for preventing asymptomatic (screening-detected) proximal DVT with very low certainty regarding its impact on patient-important outcomes.

Epidemiological studies have indicated that the risk of atherothrombotic coronary artery disease (CAD) is higher in patients with diabetes, but these results have not been consistently observed across clinical trials. To address this apparent discrepancy, we can apply the results of genome-wide association studies (GWAS) to provide a better understanding of the shared genetic architecture of diabetes and atherothrombotic CAD. For instance, a large GWAS has identified 16 novel loci that are associated with both diabetes and atherothrombotic CAD. These genetic variants may also be used to assess potential causal relationships reported in observational studies and clinical trials through Mendelian randomization analyses. For example, several Mendelian randomization analyses have shown that diabetes is associated with CAD independent of other risk factors (odds ratio [OR]: 1.63, 95% confidence interval [CI]: 1.23–2.07; P = 0.002). Furthermore, Mendelian randomization analyses can provide more insight into the perceived risk of diabetes among patients without diabetes receiving statin therapy. Here, genetically lower activity of HMG-CoA reductase (HMGCR) was associated with a modest increase in diabetes (OR per allele: 1.02, 95% CI: 1.00–1.05). These results highlight the biological mechanisms that link diabetes with the use of statins. In addition, this work illustrates the great potential value of genetic studies to clarify the mechanistic relationships among atherosclerotic vascular disease, dysglycemia, and diabetes. More research is needed to delineate and subsequently better understand the genetic links between diabetes and atherosclerosis.

Objective To describe and summarize equity reporting in human immunodeficiency virus (HIV) systematic reviews and explore the extent to which equity issues are addressed and reported in HIV reviews using the PROGRESS Plus framework. Study Design and Setting Application of the PROGRESS Plus framework to a bibliometric analysis of HIV reviews in the Cochrane Database of Systematic Reviews. Results The analysis included 103 reviews published as of March 2014, with a median of five studies per review (first quartile; Q1 = 2; third quartile; Q3 = 11). Reporting of PROGRESS Plus factors was as follows: Place of residence (low, middle, and high income; 55.3%), place of residence (urban or rural; 24.3%), race or ethnicity (20.4%), occupation (10.7%), gender (65.0%), religion (1.9%), education (7.8%), socioeconomic position (10.7%), social networks and capital (1.0%), age (1.9%), and sexual orientation (3.8%). Conclusion Gaps in the reporting of relevant equity indicators were identified within Cochrane HIV systematic review indicating that research is not consistently conducted through an equity lens. There is a need to incorporate PROGRESS Plus factors into both primary and secondary studies.

Background Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). Methods and findings For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D–insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. Conclusions Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects., Despoina Manousaki and co-workers investigate vitamin D levels and risk of type I diabetes., Author summary Why was this study done? Observational epidemiological studies have associated low vitamin D levels with risk of type 1 diabetes; however, these studies are susceptible to confounding and reverse causation, and thus it remains unclear whether these associations are accurate. To our knowledge, there are no randomized controlled trials published to date on this topic. If vitamin D insufficiency did cause type 1 diabetes, this would be of clinical relevance for type 1 diabetes prevention in high-risk individuals, since vitamin D insufficiency is common and safely correctable. What did researchers do and find? We applied a Mendelian randomization study design to understand if vitamin D levels are associated with a higher risk of type 1 diabetes. This approach offers an alternative analytical technique able to reduce conventional patterns of confounding and reverse causation and reestimate observations in a framework allowing causal inference. Our study did not find evidence in support of a large effect of vitamin D levels on type 1 diabetes. However, the findings do not exclude the possibility that there may be smaller effects than we could not detect. What do these findings mean? Our findings suggest that the previous epidemiological associations between vitamin D and type 1 diabetes could be due to confounding factors, such as latitude and exposure to sunlight. Our results do not support increasing vitamin D levels as a strategy to decrease the risk of type 1 diabetes.

Objective: To test whether genetically decreased vitamin D levels are associated with Alzheimer disease (AD) using mendelian randomization (MR), a method that minimizes bias due to confounding or reverse causation. Methods: We selected single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels ( p −8 ) from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) Consortium (N = 33,996) to act as instrumental variables for the MR study. We measured the effect of each of these SNPs on 25OHD levels in the Canadian Multicentre Osteoporosis Study (CaMos; N = 2,347) and obtained the corresponding effect estimates for each SNP on AD risk from the International Genomics of Alzheimer9s Project (N = 17,008 AD cases and 37,154 controls). To produce MR estimates, we weighted the effect of each SNP on AD by its effect on 25OHD and meta-analyzed these estimates using a fixed-effects model to provide a summary effect estimate. Results: The SUNLIGHT Consortium identified 4 SNPs to be genome-wide significant for 25OHD, which described 2.44% of the variance in 25OHD in CaMos. All 4 SNPs map to genes within the vitamin D metabolic pathway. MR analyses demonstrated that a 1-SD decrease in natural log–transformed 25OHD increased AD risk by 25% (odds ratio 1.25, 95% confidence interval 1.03–1.51, p = 0.021). After sensitivity analysis in which we removed SNPs possibly influenced by pleiotropy and population stratification, the results were largely unchanged. Conclusions: Our results provide evidence supporting 25OHD as a causal risk factor for AD. These findings provide further rationale to understand the effect of vitamin D supplementation on cognition and AD risk in randomized controlled trials.

Objectives To summarize the current gaps in human immunodeficiency virus (HIV) research evidence, describe the adequacy of reporting “implications for research,” and map the number of studies that inform reviews with the prevalence of HIV for each country. Study Design and Setting A bibliometric analyses of HIV reviews in the Cochrane Database of Systematic Reviews with content analysis of the “implications for research” section. Results We analyzed 103 high-quality reviews published as of March 2014. They included a median of five studies (min 0 and max 44). Almost all the reviews recommended more trials (89.3%). Limitations in trial design, duration, setting, sample size, and choice of participants were also noted. Reporting of EPICOT+ items was as follows: evidence (35.9%), population (57.3%), intervention (71.8%), comparison (20.4%), outcomes (57.3%), time stamp (34.0%), and disease burden (13.6%). The primary studies were conducted in 67 countries. Six of the top 10 countries in which primary studies were conducted had a high HIV prevalence. Conclusion Knowledge gaps were identified for research in younger participants, over longer periods, using more pragmatic interventions, conducted in resource-limited settings and incorporating economic evaluations. Implications for research are not always reported according to the EPICOT+ format. Not all countries with a high prevalence of HIV are contributing sufficiently to HIV research.

Background— Statins lower low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD), but they may be ineffective or not tolerated. Bile acid sequestrants (BAS) reduce LDL-C, yet their clinical efficacy on CAD remains controversial. Methods and Results— We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of cholestyramine and colesevelam. We then used Mendelian randomization to estimate the effect of BAS on reducing the risk of CAD. First, we quantified the effect of rs4299376 ( ABCG5/ABCG8 ), which affects the intestinal cholesterol absorption pathway targeted by BAS and then we used these estimates to predict the effect of BAS on CAD. Nineteen randomized controlled trials with a total of 7021 study participants were included. Cholestyramine 24 g/d was associated with a reduction in LDL-C of 23.5 mg/dL (95% confidence interval [CI] −26.8,−20.2; N=3806) and a trend toward reduced risk of CAD (odds ratio 0.81, 95% CI 0.70–1.02; P =0.07; N=3806), whereas colesevelam 3.75 g/d was associated with a reduction in LDL-C of 22.7 mg/dL (95% CI −28.3, −17.2; N=759). Based on the findings that rs4299376 was associated with a 2.75 mg/dL decrease in LDL-C and a 5% decrease in risk of CAD outcomes, we estimated that cholestyramine was associated with an odds ratio for CAD of 0.63 (95% CI 0.52–0.77; P =6.3×10 −6 ) and colesevelam with an odds ratio of 0.64 (95% CI 0.52–0.79, P =4.3×10 −5 ), which were not statistically different from BAS clinical trials ( P >0.05). Conclusions— The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD.

Introduction Type 2 diabetes is a strong risk factor for coronary artery disease (CAD). However, the absence of a clear reduction in CAD by intensive glucose lowering in randomized controlled trials has fuelled uncertainty regarding the causal role of dysglycaemia and CAD. Objective To assess whether Mendelian randomization supports a causal role of dysglycaemia and diabetes for risk of CAD. Methods Effect size estimates of common genetic variants associated with fasting glucose (FG), glycated haemoglobin (HbA1c), and diabetes were obtained from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium and Diabetes Genetics Replication and Meta-Analysis consortia. The corresponding effect estimates of these single nucleotide polymorphisms (SNPs) on the risk of CAD were then evaluated in CARDIOGRAMplusC4D. Results SNPs associated with HbA1c and diabetes were associated with an increased risk of CAD. Using information from 59 genetic variants associated with diabetes, the causal effect of diabetes on the risk of CAD was estimated at an odds ratio (OR) of 1.63 (95% Confidence Interval (CI): 1.23–2.07; P = 0.002). On the other hand, nine genetic variants associated with HbA1c were associated with an OR of 1.53 per 1% HbA1c increase (95% CI: 1.14–2.05; P = 0.023) in the risk of CAD while this effect was non-significant among 30 genetic variants associated with FG per mmol/L (OR: 1.18, 95% CI: 0.97–1.42; P = 0.102). No significant differences were observed when categorizing genetic loci according to their effect on either β-cell dysfunction or insulin resistance. Conclusions These Mendelian randomization analyses support a causal role for diabetes and its associated high glucose levels on CAD, and suggest that long-term glucose lowering may reduce CAD events.

Background— Telomeres are repetitive, gene-poor regions that cap the ends of DNA and help maintain chromosomal integrity. Their shortening is caused by inflammation and oxidative stress within the cellular environment and ultimately leads to cellular senescence. Shortened leukocyte telomere length is hypothesized to be a novel biomarker for age and age-related diseases, yet reports on its association with cardiometabolic outcomes in the literature are conflicting. Methods and Results— MEDLINE (1966 to present) and EMBASE (1980 to present) were last searched on September 9, 2013. Reference lists of retrieved citations were hand searched for relevant studies. No restrictions were placed on sample size, language, or publication type or date. Fifteen cohort and 12 case–control studies reporting the association between leukocyte telomere length and stroke, myocardial infarction, and type 2 diabetes mellitus were independently selected for inclusion by 2 reviewers. Data extraction and risk of bias assessment were completed independently by 2 reviewers using predefined criteria. Studies were pooled using the generic inverse variance method and both fixed and random effects models. A 1-SD decrease in leukocyte telomere length was significantly associated with stroke (odds ratio, 1.21; 95% confidence interval, 1.06–1.37; I 2 =61%), myocardial infarction (odds ratio, 1.24; 95% confidence interval, 1.04–1.47; I 2 =68%), and type 2 diabetes mellitus (odds ratio, 1.37; 95% confidence interval, 1.10–1.72; I 2 =91%). Stratification by measurement technique, study design, study size, and ethnicity explained heterogeneity in certain cardiometabolic outcomes. Conclusions— Shortened leukocyte telomere length demonstrates a significant association with stroke, myocardial infarction, and type 2 diabetes mellitus. Larger, well-designed studies are needed to confirm these findings and explore sources of heterogeneity.

The study investigated the stability of executive functioning (EF) measures in children and adolescents aged 8-17 years with unilateral cerebral palsy (CP). Here 44 participants with unilateral CP (mean age = 11 years, 11 months; Manual Abilities Classification Scale Level I = 6 and Level II = 37; Gross Motor Function Classification Scale Level I = 22 and Level II = 22) were randomized into the wait-list control group of a large randomized controlled trial. Participants had baseline testing with Wechsler Intelligence Scale for Children--Fourth Edition Short Form (WISC-IV-SF) and Delis-Kaplan Executive Function System (D-KEFS) subtests. Parents completed the Behavior Rating Inventory of Executive Functioning (BRIEF). Participants were re-assessed 20 ±2 weeks later with a shortened test battery including the D-KEFS subtests; Digit Span, Coding and Symbol Search (WISC-IV); and BRIEF. Pearson's test-retest reliabilities and Reliable change scores were calculated. Results indicated excellent to fair test-retest reliabilities (r = 0.91-0.74) for all measures except Digit Span Backwards (r = 0.62), Inhibition (r = 0.69), and Initiate (r = 0.68). Reliable change scores applying 90% confidence intervals for estimating reliable change while accounting for practice effects were provided for all measures. The data support the stability of EF measures in this population.

Objective: To examine the efficacy of a multi-modal web-based therapy program, Move it to improve it (Mitii™) delivered at home to improve Executive Functioning (EF) in children with an acquired brain injury (ABI). Design: Randomised Waitlist controlled trial. Setting: Home environment. Participants: Sixty children with an ABI were matched in pairs by age and intelligence quotient then randomised to either 20-weeks of Mitii™ training or 20 weeks of Care As Usual (waitlist control; n=30; 17 males; mean age=11y, 11m (±2y, 6m); Full Scale IQ=76.24±17.84). Fifty-eight children completed baseline assessments (32 males; mean age=11.87±2.47; Full Scale IQ=75.21±16.76). Main Measures: Executive functioning was assessed on four domains: attentional control, cognitive flexibility, goal setting, and information processing using subtests from the Wechsler Intelligence Scale for Children (WISC-IV), Delis-Kaplan Executive Functioning System (D-KEFS), Comprehensive Trail Making Test (CTMT), Tower of London (TOL), and Test of Everyday Attention for Children (Tea-Ch). Executive functioning performance in everyday life was assessed via parent questionnaire (Behaviour Rating Inventory of Executive Functioning; BRIEF). Results: No differences were observed at baseline measures. Groups were compared at 20-weeks using linear regression with no significant differences found between groups on all measures of EF. Out of a potential total dose of 60 hours, children in the Mitii™ group completed a mean of 17 hours of Mitii™ intervention. Conclusion: Results indicate no additional benefit to receiving Mitii™ compared to standard care. Mitii™, in its current form, was not shown to improve EF in children with ABI.

Purpose state: Determine the efficacy of Move-it-to-improve-it (Mitii™), a multi-modal web-based program, in improving Executive Function (EF) in children with unilateral cerebral palsy (UCP).Participants (n = 102) were matched in pairs then randomized to: intervention (Mitii™ for 20 weeks; n = 51; 26 males; mean age = 11 years 8 months (SD = 2 years 4 months); Full Scale IQ = 84.65 (SD = 15.19); 28 left UCP; GMFCS-ER (I = 20, II = 31) or waitlist control (n = 50; 25 males; mean age = 11 years 10 months (SD = 2 years 5 months); Full Scale IQ = 80.75 (SD = 19.81); 20 left UCP; GMFCS-ER (I = 25, II = 25). Mitii™ targeted working memory (WM), visual processing (VP), upper limb co-ordination and physical activity. EF capacity was assessed: attentional control (DSB; WISC-IV); cognitive flexibility (inhibition and number-letter sequencing DKEFS); goal setting (D-KEFs Tower Test); and information processing (WISC-IV Symbol Search and Coding). EF performance was assessed via parent report (BRIEF). Groups were compared at 20 weeks using linear regression (SPSS 21).There were no significant between group differences in attentional control (DSB; p = 0.20;CI= -0.40,1.87); cognitive flexibility (Inhibition, p = 0.34; CI= -0.73,2.11; number/letter sequencing, p = 0.17; CI= -0.55,2.94); problem solving (Tower; p = 0.28; CI= -0.61,2.09), information processing (Symbol; p = 0.08; CI= -0.16, 2.75; Coding; p = 0.07; CI= -0.12,2.52) or EF performance (p = 0.13; CI= -10.04,1.38).In a large RCT, Mitii

BACKGROUND: Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS. METHODS AND FINDINGS: Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely. CONCLUSION: Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

We performed a systematic review and meta-analysis of cervical cancer risk in indigenous women in Australia, Canada, New Zealand, and the United States, in order to identify whether risks of cervical dysplasia, cervical cancer, and cervical cancer-related mortality are higher in indigenous relative to non-indigenous populations. We identified 35 studies published in 1969-2008. In our findings, indigenous populations did not have an elevated risk of cervical dysplasia or carcinoma in situ relative to non-indigenous populations, but had elevated risks of invasive cervical cancer (pooled RR=1.72) and cervical cancer-related mortality (pooled RR=3.45). There was a log-linear relationship between relative risk and disease stage. In conclusion, the indigenous women have a markedly higher risk of cervical cancer morbidity and mortality than non-indigenous women, but no increased risk of early-stage disease, suggesting that structural, social, or individual barriers to screening, rather than baseline risk factors, are influencing poor health outcomes.

We examined the course of major depressive disorder (MDD) and predictors of MDD recovery and relapse in a longitudinal sample of women with eating disorders (ED).246 Boston-area women with DSM-IV anorexia nervosa-restricting (ANR; n=51), AN-binge/purge (ANBP; n=85), and bulimia nervosa (BN; n=110) were recruited between 1987 and 1991 and interviewed using the Eating Disorders Longitudinal Interval Follow-up Evaluation (LIFE-EAT-II) every 6-12 months for up to 12 years. 100 participants had MDD at study intake and 45 developed MDD during the study. Psychological functioning and treatment were assessed.Times to MDD onset (1 week-4.3 years), recovery (8 weeks-8.7 years), and relapse (1 week-5.2 years) varied. 70% recovered from MDD, but 65% subsequently relapsed. ANR patients were significantly less likely to recover from MDD than ANBP patients (p=0.029). Better psychological functioning and history of MDD were associated with higher chance of MDD recovery. Higher baseline depressive severity and full recovery from ED were associated with greater likelihood of MDD relapse; increased weight loss was somewhat protective. Adequate antidepressant treatment was given to 72% of patients with MDD and generally continued after MDD recovery. Time on antidepressants did not predict MDD recovery (p=0.27) or relapse (p=0.26).Small ED diagnostic subgroups; lack of non-ED control group.The course of MDD in EDs is protracted; MDD recovery may depend on ED type. Antidepressants did not impact likelihood of MDD recovery, nor protect against relapse, which may impact on treatment strategies for comorbid MDD and EDs.

Objective To investigate whether, at study entry, (a) weight suppression (WS), the difference between highest past adult weight and current weight, prospectively predicts time to first full remission from bulimia nervosa (BN) over a follow-up period of 8 years, and (b) weight change over time mediates the relationship between WS and time to first full remission. Method A well-characterized sample of women with BN (N = 110; M age = 25.58 years, SD = 6.48) from the Massachusetts General Hospital Longitudinal Study of Eating Disorders was interviewed at 6-12 month intervals over 8 years. The main outcome measure, a "time to first full remission" variable, was based on psychiatric status ratings generated from the Eating Disorders Longitudinal Interval Follow-up Evaluation. Results WS was significantly associated with time to first full remission (p = .01; hazard ratio = .89; 95% confidence interval [0.82, 0.97]), indicating that women who were more weight suppressed at study entry took longer to recover. Weight change did not mediate the relationship between WS and time to remission. Conclusions Results add to a growing body of evidence that WS predicts maintenance of BN symptoms and extend previous short-term findings by demonstrating, over a period of approximately 8 years, that WS predicts longer time to first full remission. Beyond absolute weight status, WS level may significantly inform the treatment of BN.

This paper outlines the development of an algorithm to determine appropriate levels of care (LOC) for individuals with a serious mental illness (SMI). The algorithm, drew on several domains of the Resident Assessment Instrument-Mental Health (RAI-MH) to support a statistical model that would explain a maximum of variance with the gold standard, a consensus-based global rating of required LOC. The RAI-MH model explained 67.5% of the variance. The validity of the model was further examined by determining how the discrepancy between the current and predicted levels of care related to psychiatric outcomes. The results demonstrated that undersupported clients experienced significant negative psychiatric outcomes compared to clients receiving adequate care. Although the model based on the RAI-MH is not perfect, the results warrant further research to determine its usefulness in predicting required LOC.

Summary There is considerable interindividual variation in the response to antiplatelet and anticoagulant therapies. It has been proposed that this variability in drug response may be attributable to genetic variants. Thus, pharmacogenetics may help to accurately predict response to cardiovascular disease (CVD) therapies in order to maximize drug efficacy, minimize drug toxicity, and to tailor personalized care for these patients. Although the clinical utility of pharmacogenetics is promising, its adoption in clinical practice has been slow. This resistance may stem from sometimes conflicting findings among pharmacogenetic studies. Thus, this review focuses on the genetic determinants of commonly used platelet antagonists and anticoagulants including aspirin, clopidogrel, dabigatran, and warfarin. We also explore the clinical translation of pharmacogenetics in the management of patients with CVD.

Background— Observational studies support a possible association between decreased vitamin D levels and risk of coronary artery disease (CAD); however, it remains unclear whether this relationship is causal. We aimed to evaluate whether genetically lowered vitamin D levels influence the risk of CAD using a Mendelian randomization approach. Methods and Results— In this 2-stage Mendelian randomization study, we first identified single-nucleotide polymorphisms associated with 25-hydroxyvitamin D (25OHD) levels in the SUNLIGHT consortium (n=33 996), then tested them for possible violation of Mendelian randomization assumptions. A count of risk alleles was tested for association with 25OHD levels in a separate cohort (n=2347). Alleles were weighted by their relative effect on 25OHD and tested for their combined effect on CAD in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study (22 233 cases/64 762 controls). Four single-nucleotide polymorphisms were identified to be associated with 25OHD levels, all in or near genes implicated in 25OHD synthesis, transport or metabolism. A count of these risk alleles was strongly associated with 25OHD (n=2347, F -test statistic=49.7, P =2×10 −12 ). None of the single-nucleotide polymorphisms associated with 25OHD levels were associated with CAD (all P values >0.6). The Mendelian randomization odds ratio (OR) for CAD was 0.99 (95% confidence interval, 0.84–1.17; P =0.93; I 2 =0) per SD decrease in log-transformed 25OHD levels. These results persisted after sensitivity analyses for population stratification and pleiotropy. Conclusions— Genetically lowered 25OHD levels were not associated with increased risk of CAD in a large, well-powered study, suggesting that previous associations between circulating 25OHD levels and CAD are possibly confounded or due to reverse causation.

Background Acquired brain injury (ABI) refers to multiple disabilities arising from damage to the brain acquired after birth. Children with an ABI may experience physical, cognitive, social and emotional-behavioural impairments which can impact their ability to participate in activities of daily living (ADL). Recent developments in technology have led to the emergence of internet-delivered therapy programs. “Move it to improve it” (Mitii™) is a web-based multi-modal therapy that comprises upper limb (UL) and cognitive training within the context of meaningful physical activity. The proposed study aims to compare the efficacy of Mitii™ to usual care to improve ADL motor and processing skills, gross motor capacity, UL and executive functioning in a randomised waitlist controlled trial. Methods/Design Sixty independently ambulant children (30 in each group) at least 12 months post ABI will be recruited to participate in this trial. Children will be matched in pairs at baseline and randomly allocated to receive either 20 weeks of Mitii™ training (30 min per day, six days a week, with a potential total dose of 60 h) immediately, or be waitlisted for 20 weeks. Outcomes will be assessed at baseline, immediately post-intervention and at 20 weeks post-intervention. The primary outcomes will be the Assessment of Motor and Process Skills and 30 s repetition maximum of functional strength exercises (sit-to-stand, step-ups and half kneel to stand). Measures of body structure and functions, activity, participation and quality of life will assess the efficacy of Mitii™ across all domains of the International Classification of Functioning, Disability and Health framework. A subset of children will undertake three tesla (3T) magnetic resonance imaging scans to evaluate functional neurovascular changes, structural imaging, diffusion imaging and resting state functional connectivity before and after intervention. Discussion Mitii™ provides an alternative approach to deliver intensive therapy for children with an ABI in the convenience of the home environment. If Mitii™ is found to be effective, it may offer an accessible and inexpensive intervention option to increase therapy dose. Trial Registration ANZCTR12613000403730 Electronic supplementary material The online version of this article (doi:10.1186/s12883-015-0381-6) contains supplementary material, which is available to authorized users.

This study examined interest in and barriers to participation in a multiple family group intervention (MFG) for adult cancer survivors and their family caregivers. The intervention was developed to assist families in coping with the persistent challenges of cancer diagnosis, treatment, and rehabilitation. Eighty eligible families having a member diagnosed and treated for cancers of the head and neck region completed a baseline quality of life survey consisting of standardized psychosocial measures, and then all patients and their families were invited to participate in a day-long multiple family group program. However, despite extensive recruitment efforts and accommodations to address anticipated barriers for nonparticipation, only 15 of the 80 (19%) eligible families agreed to attend the MFG workshop. Post-MFG, participating families reported high levels of program satisfaction and usefulness. These findings are discussed in the context of increasing the use of family-focused interventions in cancer care settings.

A genetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial.The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 × 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 × 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers.The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.

Human carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are serine esterases responsible for the hydrolysis of ester and amide bonds present in a number of pharmaceutical products. Several common genetic variants of the CES1 and CES2 genes have been shown to influence drug metabolism and clinical outcomes. Polymorphisms of the CES1 gene have been reported to affect the metabolism of dabigatran etexilate, methylphenidate, oseltamivir, imidapril, and clopidogrel, whereas variants of the CES2 gene have been found to affect aspirin and irinotecan. Although the findings of these studies may be preliminary, they demonstrate the potential clinical utility of CES polymorphisms; however, more research is required, especially with respect to CES2. In this review, we outline the functional, molecular, and genetic properties of CES1 and CES2, and highlight recent studies that have shown relations between CES1 and CES2 variants and contemporary pharmacotherapy.

Importance Because of the similarity in clinical outcomes after elective open and endovascular repair of abdominal aortic aneurysm (AAA), cost may be an important factor in choosing a procedure. Objective To compare total and AAA-related use of health care services, costs, and cost-effectiveness between groups randomized to open or endovascular repair. Design, Setting, and Participants This unblinded randomized clinical trial enrolled 881 patients undergoing planned elective repair of AAA who were candidates for open and endovascular repair procedures. Patients were randomized from October 15, 2002, to April 15, 2008, at 42 Veterans Affairs medical centers. Follow-up was completed on October 15, 2011, and data were analyzed from April 15, 2013, to April 15, 2016, based on intention to treat. Main Outcomes and Measures Mean total and AAA-related health care cost per life-year and per quality-adjusted life-year (QALY). Results A total of 881 patients (876 men [99.4%]; 5 women [0.6%]; mean [SD] age, 70 [7.8] years) were included in the analysis. After a mean of 5.2 years of follow-up, mean life-years were 4.89 in the endovascular group and 4.84 in the open repair group ( P = .68), and mean QALYs were 3.72 in the endovascular group and 3.70 in the open repair group ( P = .82). Total mean health care costs did not differ significantly between the 2 groups (endovascular group, $142 745; open repair group, $153 533; difference, −$10 788; 95% CI, −$29 796 to $5825; P = .25). Costs related to AAA, including the initial repair, constituted nearly 40% of total costs and did not differ significantly between the 2 groups (endovascular group, $57 501; open repair group, $57 893; difference, −$393; 95% CI, −$12 071 to $7928; P = .94). Lower costs due to shorter hospitalization for initial endovascular repair were offset by increased costs from AAA-related secondary procedures and imaging studies. The probability of endovascular repair being less costly and more effective was 56.8% when effectiveness was measured in life-years and 55.4% when effectiveness was measured in QALYs for total costs and 31.3% and 34.3%, respectively, for AAA-related costs. Conclusions and Relevance In this multicenter randomized clinical trial with follow-up to 9 years, survival, quality of life, costs, and cost-effectiveness did not differ between elective open and endovascular repair of AAA. Trial Registration clinicaltrials.gov Identifier:NCT00094575

To determine if a relationship exists between blood glucose control and variability in nutrient intake from day-to-day in subjects with type 1 diabetes.Two three-day diet records and one measurement of glycated hemoglobin (HbA1c) were obtained from 272 subjects with type 1 diabetes treated with a mixture of regular and NPH insulins before breakfast and supper and using a standardized algorithm to adjust insulin dose according to the results of self-monitoring of blood glucose two to four times daily. Day-to-day variation in nutrient intake was expressed as the coefficient of variation (CV = SDx100/mean).Nutrient intakes in the study population (mean +/- SD) were energy 8.35+/-2.43 MJ, fat 81+/-30 g, protein 94+/-28 g, carbohydrate 227+/-68 g, starch 126+/-38 g and dietary fiber 20+/-6 g with diet glycemic index being 84.2+/-7.4. Neither energy, nutrient intakes nor insulin dose was significantly related to HbA1c. Day-to-day variation of carbohydrate (p = 0.0097) and starch (p = 0.0016) intakes and diet glycemic index (p = 0.033) was positively related to HbA1c, and the associations remained significant when adjusted for age, sex, duration of diabetes and BMI. Day-to-day variation in energy, protein or fat intakes was not related to HbA1c.Consistency in the amount and source of carbohydrate intake from day-to-day is associated with improved blood glucose control in people with type 1 diabetes, a result which supports continued educational efforts to achieve adherence to a diabetes diet plan. This conclusion may not apply to people on intensified insulin therapy who adjust their insulin dose based on their actual carbohydrate intake at each meal.

Genetic polymorphisms are thought to contribute to the wide intraindividual variability in antiplatelet and anticoagulant drug response. Pharmacogenetics is the study of how genetic variants influence drug response and how the adoption of a more personalized approach in antiplatelet and anticoagulant therapy may help to minimize harmful drug effects and optimize care for individual patients. However, due to sometimes conflicting evidence, the uptake of pharmacogenetics in the clinical setting has been slow. In this article, we review the genetic mechanisms contributing to the variability in response to three commonly used and emerging antiplatelet and anticoagulant drug therapies, namely clopidogrel, warfarin and dabigatran. We will focus on common genetic variants that influence the absorption, metabolism and/or action of these agents, including CYP2C19 (*2, *3 and *17), CYP3A4, CYP3A5, CYP2C9, ABCB1, P2RY12, CYP2C9 (*2/*3), VKORC1 and CESI.

The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P10) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans.Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.

Atherosclerosis and associated cardiovascular diseases (CVD) are multifaceted disorders, influenced by environmental and heritable risk factors. Inflammation plays a significant role in each stage of atherosclerosis and as such, discovery and characterization of inflammatory biomarkers associated with risk of CVD is an active area of research. Because of the strong predicted genetic components of both CVD and inflammatory biomarkers, there is interest in identifying genetic determinants of inflammatory markers and characterizing their role in CVD. Recent developments in the methodological approaches of genetic epidemiology, especially genome-wide association studies and Mendelian randomization studies, have been effective in identifying novel gene associations and determining the causality of these genes with CVD. In this review, we will summarize the current understanding of the genetic architecture of inflammatory markers. The markers selected for this review include C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6, and P-selectin.

A recent report suggested that carriers of the Q allele of the PON1 Q192R polymorphism had decreased biotransformation of clopidogrel into its active metabolite and decreased efficacy of clopidogrel in preventing cardiovascular events. Furthermore, PON1 has been reported to have a central role in the antioxidant function of high-density lipoprotein, and the Q192R polymorphism has been previously associated with cardiovascular risk in patients not treated with clopidogrel.Patients (n=5059) from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) randomized trial that demonstrated benefits of clopidogrel versus placebo in preventing cardiovascular events in acute coronary syndromes were genotyped for the PON1 Q192R polymorphism. Clopidogrel compared with placebo significantly reduced the first primary efficacy outcome, irrespective of PON1 Q192R genotype (P=0.07 for heterogeneity). No association was observed between the Q192R polymorphism and cardiovascular events in the overall sample (hazard ratio [HR], 1.09 per allele; 95% confidence interval [CI], 0.95-1.24; P=0.23). However, an association was observed between the Q allele and increased cardiovascular events in the placebo group (HR, 1.23 per allele; 95% CI, 1.03-1.47; P=0.03) but not in the clopidogrel group (HR, 0.93 per allele; 95% CI, 0.76-1.13; P=0.46). In 1156 atrial fibrillation patients from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events, there was no evidence of interaction between PON1 genotype and clopidogrel for any outcome or for an association between genotype and cardiovascular events.In conclusion, our study shows that PON1 Q192R genotype does not modify the efficacy and safety of clopidogrel in patients with acute coronary syndromes. Further studies are needed to confirm or refute the association of the Q allele with adverse cardiovascular events independent of clopidogrel in secondary prevention patients.

OBJECTIVE To estimate the prevalence and examine the extent that pain, urinary symptoms, depression and pain catastrophizing predict the quality of life (QoL) in Canadian male adolescents, as the prevalence and impact of chronic prostatitis (CP)-like symptoms in adolescents is unknown. SUBJECTS AND METHODS Participants completed the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the Patient Health Questionnaire-depression screen (PHQ-D), and the Pain Catastrophizing Scale (PCS). CP-like case identification was based on NIH-CPSI report of pain/discomfort in perineum and/or with ejaculation and NIH-CPSI total pain score (0–20) of ≥4 (mild) and ≥8 (moderate-severe). The point prevalence was estimated and regressions used to examine predictors of diminished QoL gathered from the NIH-CPSI. RESULTS The prevalence of at least mild CP-like symptoms in 264 Canadian adolescents aged 16–19 years (mean age 17.5, sd 1.1) was 8.3%, with 3% reporting moderate-severe CP-like symptoms. Pain, urinary symptoms, depression and catastrophizing were correlated with diminished QoL. Additionally, catastrophizing predicted diminished QoL when the variance of pain, urinary symptoms and depression were simultaneously considered in the analysis. CONCLUSIONS Similar to that reported by older cohorts, these data provide the first point-prevalence estimate of CP-like symptoms in adolescents. These findings suggest increased vigilance to a potential diagnosis of adolescent CP syndrome and indicate that psychological features (i.e. catastrophizing) are significant in diminished QoL. Adolescent male chronic pelvic pain is an important and understudied area for future investigations.

Background Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS. Methods and Findings We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10−10 to 2 × 10−109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10−12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7–2.5; p = 7.7 × 10−12; I 2 = 63%, 95% CI: 0%–88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3–2.2; p = 2.3 × 10−5; I 2 = 47%, 95% CI: 0%–85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6–2.6, p = 1 × 10−9; ORmetabolism = 1.9, 95% CI: 1.3–2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely. Conclusions A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials., J. Brent Richards and colleagues assess whether genetically predicted vitamin D levels associate with risk of multiple sclerosis., Editors' Summary Background Multiple sclerosis (MS) is a debilitating neurological disorder that affects the nerves in the brain and spinal cord and that usually presents between the ages of 20 and 40 years. It is an autoimmune disease—a disease in which the body’s immune system attacks healthy tissues. In the case of MS, the immune system attacks myelin, the fatty tissue that forms an insulating sheath around nerves fibers. Multiple areas of scarring (sclerosis) in the myelin are produced by immune attack, and the damage slows down or blocks the transmission of electrical signals along the nerves to and from the brain and causes symptoms such as loss of vision, muscle stiffness, and daytime fatigue. For most affected individuals, MS initially follows a relapsing–remitting course characterized by periods lasting days or weeks during which symptoms flare up, followed by periods during which symptoms becomes milder or disappear. Half of people with relapsing–remitting MS eventually develop secondary progressive MS, in which their symptoms inexorably worsen. There is currently no cure for MS, but some treatments can relieve its symptoms or reduce the number of relapses. Why Was This Study Done? Why the immune system attacks myelin to cause MS is unclear but probably involves both genetic and environmental risk factors. One potential environmental risk factor is reduced levels of vitamin D. Circulating levels of 25-hydroxyvitamin D (25OHD; the clinical determinant of vitamin D status) are determined in part by exposure to sunlight, and MS is more common at higher latitudes, where exposure to sunlight is decreased. Other epidemiological studies (investigations that examine disease patterns in populations) also suggest an association between lower vitamin D level and an increased risk of MS but cannot prove that a decreased vitamin D level actually causes MS. Individuals who develop MS might share another unknown characteristic that increases their risk of MS (confounding), or individuals who have MS might spend less time outdoors and, as a result, have lower circulating vitamin D levels (reverse causation). It is important to know whether a decreased vitamin D level increases the risk of MS because vitamin D insufficiency is becoming increasingly common. Here, the researchers undertake a Mendelian randomization study to determine whether circulating vitamin D level has a causal effect on MS susceptibility. Because gene variants are inherited randomly, they are not prone to confounding. Reverse causation is also prevented since MS does not change genetic variants. So, if vitamin D level actually affects MS risk, genetic variants that affect vitamin D level should be associated with altered susceptibility to MS. What Did the Researchers Do and Find? The researchers first ascertained the effect on 25OHD level among participants in the Canadian Multicentre Osteoporosis Study of four single nucleotide polymorphisms (SNPs, a type of genetic variant) that were associated with 25OHD level in a genome-wide association study (SUNLIGHT). Each of the SNPs explained an important proportion of the population-level variance in 25OHD level in the Canadian Multicentre Osteoporosis Study. The researchers then used the SNPs to examine whether there was an association between genetically reduced 25OHD level and susceptibility to MS among participants in the International Multiple Sclerosis Genetics Consortium study, a genome-wide association study involving up to 14,498 people with MS and 24,091 healthy controls. They found that a genetic decrease in the natural-log-transformed 25OHD level by one standard deviation was associated with a 2-fold increased risk of MS. In practical terms, this finding means that increasing an individual’s circulating 25OHD level by approximately 1.5-fold decreases their odds of developing MS by 50%. What Do These Findings Mean? These findings show that, among the participants of the International Multiple Sclerosis Genetics Consortium study, all of whom were of European ancestry, genetically lowered 25OHD level was strongly associated with increased susceptibility to MS. Although the Mendelian randomization approach used here largely avoids the possibility of confounding or reverse causation, the reliability of these findings may be limited by some of the assumptions made by the researchers during their analysis. Moreover, although these findings support a role for vitamin D in MS susceptibility, they provide no information about whether vitamin D modulates the course of MS after its onset, and they may not apply to people of non-European ancestry. Nevertheless, these findings provide a strong rationale for undertaking randomized controlled trials to investigate whether vitamin D supplementation can prevent the onset and/or progression of MS. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001866. The UK National Health Service Choices website provides information about multiple sclerosis, including personal stories, and information about vitamin D and how to get vitamin D from sunlight; A “Behind the Headlines” article examines health claims made for vitamin D The US National Institute of Neurological Disorders and Stroke provides information about multiple sclerosis and links to MS societies The National Multiple Sclerosis Society, a US not-for-profit organization, provides information about all aspects of MS, including information about vitamin D and MS and personal stories about MS The Multiple Sclerosis Society, a UK not-for-profit organization, also provides information about MS for patients, carers, and professionals in several languages, including news about the latest research, personal blogs, and forums The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish) MedlinePlus has links to further information about multiple sclerosis and vitamin D (in English and Spanish) Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Objective Prior analysis in the Open vs Endovascular Repair Veterans Affairs (VA) Cooperative Study (CSP #498) demonstrated that survival, quality of life, and total health care costs are not significantly different between the open and endovascular methods of repair of abdominal aortic aneurysm. The device is a major cost of this method of repair, and the objective of this study was to evaluate the costs of the device, abdominal aortic aneurysm repair, and total health care costs when different endograft systems are selected for the endovascular repair (EVR). Within each selected system, EVR costs are compared with open repair costs. Methods The study randomized 881 patients to open (n = 437) or EVR (n = 444). Device selection was recorded before randomization; therefore, open repair controls were matched to each device cohort. Data were excluded for two low-volume devices, implanted in only 13 individuals, leaving 423 control and 431 endovascular patients: 166 Zenith (Cook Medical, Bloomington, Ind), 177 Excluder (W. L. Gore & Associates, Flagstaff, Ariz), and 88 AneuRx (Medtronic, Minneapolis, Minn). Mean device, hospitalization, and total health care costs from randomization to 2 years were compared. Health care utilization data were obtained from patients and national VA and Medicare data sources. VA costs were determined using methods previously developed by the VA Health Economics Resource Center. Non-VA costs were obtained from Medicare claims data and billing data from the patient's health care providers. Results Implant costs were 38% of initial hospitalization costs. Mean device (range, $13,600-$14,400), initial hospitalization (range, $34,800-$38,900), and total health care costs at 2 years in the endovascular (range, $72,400-$78,200) and open repair groups (range, $75,600-$82,100) were not significantly different among device systems. Differences between endovascular and corresponding open repair cohorts showed lower mean costs for EVR (range, $3200-$8300), but these were not statistically different. Conclusions The implant costs of endovascular aneurysm repair are substantial. When evaluating total health care system expenditures, there is large individual variability in costs, and there is no significant difference at 2 years among systems or when an individual system is compared with open repair.

This study examined the efficacy of a couple-focused group intervention on psychological adaptation of women with early stage breast cancer and evaluated whether perceived partner unsupportive behavior or patient functional impairment moderated intervention effects. Two hundred thirty-eight women were randomly assigned to receive either 6 sessions of a couple-focused group intervention or usual care. Intent-to-treat growth curve analyses indicated that participants assigned to the couples' group reported lower depressive symptoms. Women rating their partners as more unsupportive benefited more from the intervention than did women with less unsupportive partners, and women with more physical impairment benefited more from the intervention group than did women with less impairment. Subgroup analyses comparing women attending the couple-focused group intervention with women not attending groups and with usual care participants indicated that women attending sessions reported significantly less distress than did women receiving usual care and women who dropped out of the intervention.

This study examined associations between couple communication about cancer and psychological distress and relationship satisfaction of women diagnosed with early stage breast cancer. One hundred forty-eight couples completed a videotaped discussion of a cancer-related issue and a general issue. Patients completed measures of psychological distress and relationship satisfaction. Videotapes were coded with the Rapid Marital Interaction Coding System. Analyses focused on partner responses to patient self-disclosures. During cancer-issue discussions, patients reported less distress when partners responded to disclosures with reciprocal self-disclosure and humor and when partners were less likely to propose solutions. Fewer links between partner responses to patient self-disclosures and distress were found in general-issue discussions. Results suggest partner responses play a role in women's adaptation to breast cancer.

Aims: To study the effect of acarbose, an α-glucosidase inhibitor, on glycemic control in elderly patients with type 2 diabetes. Methods: Elderly patients with type 2 diabetes treated with diet alone were randomly treated in a double-blind fashion with placebo ( n =99) or acarbose ( n =93) for 12 months. Results: After 12 months of therapy, there was a statistically significant difference in the change in glycated haemoglobin (HbA 1c ) (−0.6%) in the acarbose group versus placebo, as well as in the incremental post-prandial glucose values (−2.1 mmol h/l) and mean fasting plasma glucose (−0.7 mmol/l). Although there was no effect of acarbose on insulin release, there was a clear effect of acarbose to decrease relative insulin resistance (−0.8) (HOMA method). In addition, acarbose was generally well tolerated and safe in the elderly; most discontinuations were due to gastrointestinal side effects such as flatulence and diarrhea. There were no cases of hypoglycemia reported, and no clinically relevant changes in laboratory abnormalities or vital signs during the study. Conclusions: Acarbose improves the glycemic profile and insulin sensitivity in elderly patients with type 2 diabetes who are inadequately controlled on diet alone.