Acute compartment syndrome of the thigh in a body builder following open reduction and internal fixation for proximal femur fracture.

Acute compartment syndrome (ACS) of the thigh following femoral fracture has been rarely reported in previous literature. This condition must be diagnosed quickly to prevent the affected limb becoming ischaemic. We document the management of ACS of the thigh in a healthy male patient who suffered a proximal femur fracture following a high-speed road traffic accident.

Do probiotics prevent antibiotic-associated diarrhoea? Results of a multicentre randomized placebo-controlled trial.

Background: Antibiotic-associated diarrhoea (AAD) is a side-effect of antibiotic consumption and probiotics have been shown to reduce AAD.

Methods: A multicentre, double-blind, placebo-controlled, randomized trial was conducted to evaluate the role of Lactobacillus casei DN114001 (combined as a drink with two regular yoghurt bacterial strains) in reducing AAD and Clostridioides difficile infection in patients aged over 55 years. The primary outcome was the incidence of AAD during 2 weeks of follow-up.

Intussusception of a large circumferential caecal adenoma with ileocaecal valve consumption.

We present a case of an unusually large, circumferential tubulovillous adenoma involving the terminal ileum and the caecum with ileocaecal valve consumption, presenting as intussusception in an otherwise healthy 90-year-old woman. The patient presented with several months of chronic symptoms of weight loss and diarrhoea. Clinical examination revealed a right-sided mass.

Platypnoea-orthodeoxia syndrome: beware of investigations undertaken supine.

Platypnoea-orthodeoxia syndrome (POS) is a rare disorder, manifesting as deoxygenation occurring when the patient is in the upright position. Four broad mechanisms for the condition have been described: intracardiac shunts, intrapulmonary shunts, hepatopulmonary syndrome and pulmonary ventilation-perfusion mismatch. Here, we present the first case of POS in a patient with a proven right to left intracardiac shunt occurring in the context of postural hypotension and normal right heart pressures.

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.

Disentangling the genetics of lean mass.

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Proof of concept for quantitative urine NMR metabolomics pipeline for large-scale epidemiology and genetics.

Background: Quantitative molecular data from urine are rare in epidemiology and genetics. NMR spectroscopy could provide these data in high throughput, and it has already been applied in epidemiological settings to analyse urine samples. However, quantitative protocols for large-scale applications are not available.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.

Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

A correction to this article has been published and is linked from the HTML version of this article.

Exome-wide association study of plasma lipids in >300,000 individuals.

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits).

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29).

Translational Perspective on Epigenetics in Cardiovascular Disease.

A plethora of environmental and behavioral factors interact, resulting in changes in gene expression and providing a basis for the development and progression of cardiovascular diseases. Heterogeneity in gene expression responses among cells and individuals involves epigenetic mechanisms. Advancing technology allowing genome-scale interrogation of epigenetic marks provides a rapidly expanding view of the complexity and diversity of the epigenome.

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10) or suggestively genome wide (p < 2.

Loss of Cardioprotective Effects at the Locus as a Result of Gene-Smoking Interactions.

Background: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify.

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci.

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype.

Training a model for estimating leukocyte composition using whole-blood DNA methylation and cell counts as reference.

Aim: Whole-blood DNA methylation depends on the underlying leukocyte composition and confounding hereby is a major concern in epigenome-wide association studies. Cell counts are often missing or may not be feasible. Computational approaches estimate leukocyte composition from DNA methylation based on reference datasets of purified leukocytes.