Explore the vast range of titles available.

Hazard ratios for cause-specific death were calculated according to baseline diabetes status or fasting glucose level. In addition to its association with vascular disease, diabetes was associated with premature deaths from a number of diseases and disorders, independent of several major risk factors. The presence of diabetes mellitus approximately doubles the risk of a wide range of vascular diseases. 1 Evidence is also emerging that diabetes is associated with nonvascular conditions, including positive associations with certain cancers (e.g., liver cancer) and negative associations with other cancers (e.g., prostate cancer). 2 – 4 However, a joint consensus statement of the American Diabetes Association and the American Cancer Society indicated that it is unclear whether such associations are direct (e.g., due to hyperglycemia) or indirect (e.g., due to diabetes as a marker of underlying biologic factors such as insulin resistance or hyperinsulinemia that alter the risk of cancer) . . .

Mark McCarthy, Michael Boehnke, Andrew Morris and colleagues perform large-scale association analyses using the Metabochip to gain insights into the genetic architecture of type 2 diabetes. They report several new susceptibility loci, including two that show sex-differentiated effects on disease risk. To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

Genetic influence on blood pressure Compared to other common complex diseases, it has proved remarkably difficult to establish the genetic basis of blood-pressure elevation. A multi-stage genome-wide association study involving 200,000 individuals of European descent provides some of the missing detail in the genetic picture. The study identified 16 relevant loci, of which only 6 contain genes previously known or suspected to regulate blood pressure. An association was found between hypertension, the thickness of the left ventricular wall, stroke and coronary artery disease, but not kidney disease or kidney function. Comparison with data from more than 75,000 people of East Asian, South Asian and African ancestries confirmed that many of the variants identified in European-ancestry subjects also influence blood pressure in other populations. Blood pressure is a heritable trait 1 influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure) 2 . Even small increments in blood pressure are associated with an increased risk of cardiovascular events 3 . This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure ( GUCY1A3 – GUCY1B3 , NPR3 – C5orf23 , ADM , FURIN – FES , GOSR2 , GNAS – EDN3 ); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

RationaleAdvanced fibrosing interstitial lung disease (ILD) is often progressive and associated with a high burden of symptoms and poor prognosis. Little is known about the symptom prevalence and access to palliative care services at end of life (EOL).ObjectivesCompare prevalence of symptoms and palliative treatments between patients dying with oxygen-dependent ILD and patients dying of lung cancer.MethodsNationwide registry-based cohort study of patients with oxygen-dependent ILD and patients with lung cancer who died between 1 January 2011 and 14 October 2013. Prevalence of symptoms and treatments during the last seven days of life were compared using data in Swedish Registry of Palliative Care.Measurements and main results285 patients with ILD and 10 822 with lung cancer were included. In ILD, death was more likely to be ‘unexpected’ (15% vs 4%), less likely to occur in a palliative care setting (17% vs 40%) and EOL discussions with the patients (41% vs 59%) were less common than in lung cancer. Patients with ILD suffered more from breathlessness (75% vs 42%) while patients with lung cancer had more pain (51% vs 73%) (p<0.005 for all comparisons). Patients with ILD had more unrelieved breathlessness, pain and anxiety. The survival time from initiation of oxygen therapy in ILD was a median 8.4 months (IQR 3.4–19.2 months).ConclusionsPatients with ILD receive poorer access to specialist EOL care services and experience more breathlessness than patients with lung cancer. This study highlights the need of better EOL care in oxygen-dependent ILD.

Sixteen SNPs were determined and clinical factors examined in two Scandinavian cohorts that were followed for a median of 23.5 years. Type 2 diabetes developed in 11.7% of the subjects. The inclusion of common genetic risk factors, many of which impair the capacity of beta cells to increase insulin secretion, in risk models modestly improved the prediction of future type 2 diabetes. Sixteen SNPs were determined and clinical factors examined in two Scandinavian cohorts that were followed for a median of 23.5 years. Type 2 diabetes developed in 11.7 percent of the subjects. Type 2 diabetes mellitus is a complex polygenic disorder in which common genetic variants interact with environmental factors to unmask the disease. The identification of persons at high risk for the disease may aid in disease prevention. A family history of diabetes, an increase in body-mass index (BMI, the weight in kilograms divided by the square of the height in meters), and impaired insulin secretion and action are risk factors for type 2 diabetes. 1 – 4 A challenge has been to identify genetic variants that explain the excess risk associated with a family history of diabetes. From a long list of . . .

The aim of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is to develop a tool to identify problematic RCTs in systematic reviews. In stage 1 of the project, a list of potential trustworthiness checks was created. The checks on this list must be evaluated to determine which should be included in the INSPECT-SR tool. We attempted to apply 72 trustworthiness checks to randomized controlled trials (RCTs) in 50 Cochrane reviews. For each, we recorded whether the check was passed, failed, or possibly failed or whether it was not feasible to complete the check. Following application of the checks, we recorded whether we had concerns about the authenticity of each RCT. We repeated each meta-analysis after removing RCTs flagged by each check and again after removing RCTs where we had concerns about authenticity to estimate the impact of trustworthiness assessment. Trustworthiness assessments were compared to Risk of Bias and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments in the reviews. Ninety-five RCTs were assessed. Following application of the checks, assessors had some or serious concerns about the authenticity of 25% and 6% of the RCTs, respectively. Removing RCTs with either some or serious concerns resulted in 22% of meta-analyses having no remaining RCTs. However, many checks proved difficult to understand or implement, which may have led to unwarranted skepticism in some instances. Furthermore, we restricted assessment to meta-analyses with no more than five RCTs (54% contained only 1 RCT), which will distort the impact on results. No relationship was identified between trustworthiness assessment and Risk of Bias or GRADE. This study supports the case for routine trustworthiness assessment in systematic reviews, as problematic studies do not appear to be flagged by Risk of Bias assessment. The study produced evidence on the feasibility and impact of trustworthiness checks. These results will be used, in conjunction with those from a subsequent Delphi process, to determine which checks should be included in the INSPECT-SR tool. Systematic reviews collate evidence from randomized controlled trials (RCTs) to find out whether health interventions are safe and effective. However, it is now recognized that the findings of some RCTs are not genuine, and some of these studies appear to have been fabricated. Various checks for these “problematic” RCTs have been proposed, but it is necessary to evaluate these checks to find out which are useful and which are feasible. We applied a comprehensive list of “trustworthiness checks” to 95 RCTs in 50 systematic reviews to learn more about them and to see how often performing the checks would lead us to classify RCTs as being potentially inauthentic. We found that applying the checks led to concerns about the authenticity of around 1 in three RCTs. However, we found that many of the checks were difficult to perform and could have been misinterpreted. This might have led us to be overly skeptical in some cases. The findings from this study will be used, alongside other evidence, to decide which of these checks should be performed routinely to try to identify problematic RCTs, to stop them from being mistaken for genuine studies and potentially being used to inform health care decisions. •An extensive list of potential checks for assessing study trustworthiness was assessed via an application to 95 randomized controlled trials (RCTs) in 50 Cochrane Reviews.•Following application of the checks, assessors had concerns about the authenticity of 32% of the RCTs.•If these RCTs were excluded, 22% of meta-analyses would have no remaining RCTs.•However, the study showed that some checks were frequently infeasible, and others could be easily misunderstood or misinterpreted.•The study restricted assessment to meta-analyses, including five or fewer RCTs, which might distort the impact of applying the checks.

Christopher Newton-Cheh and colleagues report a genome-wide association study for blood pressure traits as part of the Global BPgen consortium. They report eight loci with replicated association to systolic and/or diastolic blood pressure, with each also showing association to hypertension. Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping ( N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 ( P = 7 × 10 −24 ), CYP1A2 ( P = 1 × 10 −23 ), FGF5 ( P = 1 × 10 −21 ), SH2B3 ( P = 3 × 10 −18 ), MTHFR ( P = 2 × 10 −13 ), c10orf107 ( P = 1 × 10 −9 ), ZNF652 ( P = 5 × 10 −9 ) and PLCD3 ( P = 1 × 10 −8 ) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Agricultural pesticides are extensively used for weed- and pest control, resulting in residues of these compounds in food. The general population is mainly exposed through dietary intake. Exposure to certain pesticides has been associated with adverse human health outcomes. Our aim was to assess urinary concentrations and temporal trends in the biomarkers of commonly used pesticides. Samples were collected from adolescents (n = 1060) in Scania, Sweden, from 2000 to 2017. Concentrations of 14 pesticide biomarkers were analyzed in urine using LC–MS/MS. Temporal trends in biomarker concentrations (ln-transformed) were evaluated using linear regression. Biomarkers of pyrethroids (3-PBA and DCCA), chlorpyrifos (TCPy), chlormequat (CCC), thiabendazole (OH-TBZ), and mancozeb (ETU) were detected in >90% of the population all sampling years. The biomarkers CCC and TCPy had the highest median concentrations (>0.8 µg/L), whereas the biomarkers of cyfluthrin (4F-3-PBA) and two pyrethroids (CFCA) had the lowest median concentrations (<0.02 µg/L). Increasing temporal trends were found for the biomarkers 3-PBA (3.7%/year), TCPy (1.7%/year) and biomarkers of pyrimethanil (11.9%/year) and tebuconazole (12.2%/year). Decreasing trends were found for CCC (–5.5%/year), OH-TBZ (−5.5%/year), and ETU (−3.9%/year). Our results suggest that Swedish adolescents are commonly exposed to pesticides in low concentrations (median concentrations <3.88 µg/L).

Richard Watanabe and colleagues of the MAGIC consortium report meta-analyses of genome-wide association studies to glucose levels two hours after an oral glucose challenge. They identify variants in GIPR associated with glucose and insulin responses. Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies ( n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci ( n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10 −15 ). The GIPR A-allele carriers also showed decreased insulin secretion ( n = 22,492; insulinogenic index, P = 1.0 × 10 −17 ; ratio of insulin to glucose area under the curve, P = 1.3 × 10 −16 ) and diminished incretin effect ( n = 804; P = 4.3 × 10 −4 ). We also identified variants at ADCY5 ( rs2877716, P = 4.2 × 10 −16 ), VPS13C (rs17271305, P = 4.1 × 10 −8 ), GCKR (rs1260326, P = 7.1 × 10 −11 ) and TCF7L2 (rs7903146, P = 4.2 × 10 −10 ) associated with 2-h glucose. Of the three newly implicated loci ( GIPR , ADCY5 and VPS13C ), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies ( n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10 −18 ).

PurposeHigh plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon.MethodsThirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water.ResultsAfter acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34–45) (p < 0.001) and remained low the entire test period (4 h). One week of increased water intake led to a 15% reduction (95 CI 5–25) (p = 0.003) of copeptin compared to control week. The greatest reduction occurred among subjects with habitually high copeptin and concentrated urine (“water-responders”). Water-responders had significant water-induced reduction of glucagon, but glucose and insulin were unaffected.ConclusionsBoth acute and 1 week extra water intake potently reduced copeptin concentration. In those with the greatest decline (water-responders), who are typically low drinkers with high baseline copeptin, water induced a reduction in fasting glucagon. Long-term trials assessing the effect of water on glucometabolic traits should focus on low-water drinkers with high copeptin concentration.