GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic ...understanding is lacking
. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high
, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.
Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments ...are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy.
We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18–65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2–4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing.
Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 SE 0·61) and placebo (0·40 0·65) groups (difference 0·43 SE 0·56; 95% CI –1·04 to 1·89; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study.
Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy.
Fulcrum Therapeutics.
Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium ...conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
Physician profiling is widely used by many health care systems, but little is known about the reliability of commonly used profiling systems.
To determine the reliability of a set of physician ...performance measures for diabetes care, one of the most common conditions in medical practice, and to examine whether physicians could substantially improve their profiles by preferential patient selection.
Cohort study performed from 1990 to 1993 at 3 geographically and organizationally diverse sites, including a large staff-model health maintenance organization, an urban university teaching clinic, and a group of private-practice physicians in an urban area.
A total of 3642 patients with type 2 diabetes cared for by 232 different physicians.
Physician profiles for their patients' hospitalization and clinic visit rates, total laboratory resource utilization rate and level of glycemic control by average hemoglobin A1c level with and without detailed case-mix adjustment.
For profiles based on hospitalization rates, visit rates, laboratory utilization rates, and glycemic control, 4% or less of the overall variance was attributable to differences in physician practice and the reliability of the median physician's case-mix-adjusted profile was never better than 0.40. At this low level of physician effect, a physician would need to have more than 100 patients with diabetes in a panel for profiles to have a reliability of 0.80 or better (while more than 90% of all primary care physicians at the health maintenance organization had fewer than 60 patients with diabetes). For profiles of glycemic control, high outlier physicians could dramatically improve their physician profile simply by pruning from their panel the 1 to 3 patients with the highest hemoglobin A1c levels during the prior year. This advantage from gaming could not be prevented by even detailed case-mix adjustment.
Physician "report cards" for diabetes, one of the highest-prevalence conditions in medical practice, were unable to detect reliably true practice differences within the 3 sites studied. Use of individual physician profiles may foster an environment in which physicians can most easily avoid being penalized by avoiding or deselecting patients with high prior cost, poor adherence, or response to treatments.
The Electron Ion Collider (EIC) is the next generation of precision QCD facility to be built at Brookhaven National Laboratory in conjunction with Thomas Jefferson National Laboratory. There are a ...significant number of software and computing challenges that need to be overcome at the EIC. During the EIC detector proposal development period, the ECCE consortium began identifying and addressing these challenges in the process of producing a complete detector proposal based upon detailed detector and physics simulations. In this document, the software and computing efforts to produce this proposal are discussed; furthermore, the computing and software model and resources required for the future of ECCE are described.
We present the first measurement of the timelike Compton scattering process, γp→p^{'}γ^{*}(γ^{*}→e^{+}e^{-}), obtained with the CLAS12 detector at Jefferson Lab. The photon beam polarization and the ...decay lepton angular asymmetries are reported in the range of timelike photon virtualities 2.25<Q^{'2}<9 GeV^{2}, squared momentum transferred 0.1<-t<0.8 GeV^{2}, and average total center-of-mass energy squared s=14.5 GeV^{2}. The photon beam polarization asymmetry, similar to the beam-spin asymmetry in deep virtual Compton scattering, is sensitive to the imaginary part of the Compton form factors and provides a way to test the universality of the generalized parton distributions. The angular asymmetry of the decay leptons accesses the real part of the Compton form factors and thus the D-term in the parametrization of the generalized parton distributions.
Strange matter is believed to exist in the cores of neutron stars based on simple kinematics. If this is true, then hyperon-nucleon interactions will play a significant part in the neutron star ...equation of state. Yet, compared to other elastic scattering processes, there is very little data on Λ-N scattering. This experiment utilized the CEBAF Large Acceptance Spectrometer (CLAS) detector to study the Λp→Λp elastic scattering cross section in the incident Λ momentum range 0.9-2.0 GeV/c. These are the first data on this reaction since the 1970s. The new cross sections have significantly better accuracy and precision than the existing world data, and the techniques developed here can also be used in future experiments.
This article presents a collection of simulation studies using the ECCE detector concept in the context of the EIC’s exclusive, diffractive, and tagging physics program, which aims to further explore ...the rich quark–gluon structure of nucleons and nuclei. To successfully execute the program, ECCE proposed to utilize the detector system close to the beamline to ensure exclusivity and tag ion beam/fragments for a particular reaction of interest. Preliminary studies confirm the proposed technology and design satisfy the requirements. The projected physics impact results are based on the projected detector performance from the simulation at 10 or 100 fb−1 of integrated luminosity. Additionally, insights related to a potential second EIC detector are documented, which could serve as a guidepost for future development.
In the past two decades, deeply virtual Compton scattering of electrons has been successfully used to advance our knowledge of the partonic structure of the free proton and investigate correlations ...between the transverse position and the longitudinal momentum of quarks inside the nucleon. Meanwhile, the structure of bound nucleons in nuclei has been studied in inclusive deep-inelastic lepton scattering experiments off nuclear targets, showing a significant difference in longitudinal momentum distribution of quarks inside the bound nucleon, known as the EMC effect. In this Letter, we report the first beam spin asymmetry (BSA) measurement of exclusive deeply virtual Compton scattering off a proton bound in ^{4}He. The data used here were accumulated using a 6 GeV longitudinally polarized electron beam incident on a pressurized ^{4}He gaseous target placed within the CLAS spectrometer in Hall-B at the Thomas Jefferson National Accelerator Facility. The azimuthal angle (ϕ) dependence of the BSA was studied in a wide range of virtual photon and scattered proton kinematics. The Q^{2}, x_{B}, and t dependencies of the BSA on the bound proton are compared with those on the free proton. In the whole kinematical region of our measurements, the BSA on the bound proton is smaller by 20% to 40%, indicating possible medium modification of its partonic structure.
We describe the design and performance the calorimeter systems used in the ECCE detector to achieve the overall performance specifications cost-effectively with careful consideration of appropriate ...technical and schedule risks. The calorimeter systems consist of three electromagnetic calorimeters, covering the combined pseudorapidity range from −3.7 to 3.8 and two hadronic calorimeters covering a combined range of −1.1<η<3.8. Key calorimeter performances which include energy and position resolutions, reconstruction efficiency, and particle identification will be presented.
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