73 research outputs found
Genetic predisposition to mosaic Y chromosome loss in blood.
Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.This research has been conducted using the UK Biobank Resource under application 9905 and 19808. This work was supported by the Medical Research Council [Unit Programme number MC_UU_12015/2]. Full study-specific and individual acknowledgements can be found in the supplementary information
Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study
Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk
ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals
Common Fund of the Office of the Director of the
National Institutes of Health. Additional funds were provided by
the National Cancer Institute (NCI), National Human Genome
Research Institute (NHGRI), National Heart, Lung, and Blood Institute
(NHLBI), National Institute on Drug Abuse (NIDA), National
Institute of Mental Health (NIMH), and National Institute of Neurological
Disorders and Stroke (NINDS)
Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
The electrocardiographic PR interval reflects atrioventricular
conduction, and is associated with conduction abnormalities, pacemaker
implantation, atrial fibrillation (AF), and cardiovascular mortality.
Here we report a multi-ancestry (N = 293,051) genome-wide association
meta-analysis for the PR interval, discovering 202 loci of which 141
have not previously been reported. Variants at identified loci increase
the percentage of heritability explained, from 33.5% to 62.6%. We
observe enrichment for cardiac muscle developmental/contractile and
cytoskeletal genes, highlighting key regulation processes for
atrioventricular conduction. Additionally, 8 loci not previously
reported harbor genes underlying inherited arrhythmic syndromes and/or
cardiomyopathies suggesting a role for these genes in cardiovascular
pathology in the general population. We show that polygenic
predisposition to PR interval duration is an endophenotype for
cardiovascular disease, including distal conduction disease, AF, and
atrioventricular pre-excitation. These findings advance our
understanding of the polygenic basis of cardiac conduction, and the
genetic relationship between PR interval duration and cardiovascular
disease.
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MAGNETOLUMINESCENCE OF THE 2-DIMENSIONAL ELECTRON-HOLE FLUID
Band-gap renormalization due to the presence of a dense electron-hole plasma in GaAs quantum wells is studied by time-resolved luminescence and magnetoluminescence spectroscopy. We show that heterostructures with long carrier lifetimes exhibit saturation of the band-gap renormalization in a magnetic field, in accord with previous results. However, the usual carrier-density-dependent gap shrinkage in a magnetic field is observed in multiple quantum wells with short carrier lifetimes. The strong dependence of the magneto-optical properties on the carrier lifetimes indicates that two different phases can be formed in the plasma at high magnetic field: a highly correlated phase, analogous to the condensed electronic or excitonic state at the equilibrium density, in quantum wells with sufficiently long carrier lifetimes; and a free-carrier gas in heterostructures with short lifetimes. In the former state, the band gap is found to renormalize by an amount equal to twice the exciton binding energy, independent of the actual photogeneration rate. On the other hand, condensation processes are prevented in the short-lived phase, thus resulting in the expected density-dependent band-gap renormalization
Correlated electron states at level crossings of bilayer two-dimensional electron systems in tilted magnetic fields
We have measured the energy-level structure of high mobility, strongly coupled bilayer two-dimensional electron systems in tilted magnetic fields by means of magnetotransport experiments. At tilt angles where single-particle levels with opposite spin and symmetry cross, we observe a surprising sudden broadening of the quantum Hall plateaus and a deepening of the Shubnikov-de Haas minima. This observation is explained by an interaction-induced rearrangement of the energy level structure which strongly increases the energetic splitting of two (anti-)crossing levels
Observation of charge transport by negatively charged excitons.
We report transport of electron-hole complexes in semiconductor quantum wells under applied electric fields. Negatively charged excitons (X-), created by laser excitation of a high electron mobility transistor, are observed to drift upon applying a voltage between the source and drain. In contrast, neutral excitons do not drift under similar conditions. The X- mobility is found to be as high as 6.5 x 10(4) cm2 V-1 s-1. The results demonstrate that X- exists as a free particle in the best-quality samples and suggest that light emission from opto-electronic devices can be manipulated through exciton drift under applied electric fields
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