Bi-allelic mutation of CTNNB1 causes a severe form of syndromic microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia

Background Inherited vitreoretinopathies arise as a consequence of congenital retinal vascularisation abnormalities. They represent a phenotypically and genetically heterogeneous group of disorders that can have a major impact on vision. Several genes encoding proteins and effectors of the canonical Wnt/β-catenin pathway have been associated and precise diagnosis, although difficult, is essential for proper clinical management including syndrome specific management where appropriate. This work aimed to investigate the molecular basis of disease in a single proband born to consanguineous parents, who presented with microphthalmia, persistent foetal vasculature, posterior lens vacuoles, vitreoretinal dysplasia, microcephaly, hypotelorism and global developmental delay, and was registered severely visually impaired by 5 months of age. Methods Extensive genomic pre-screening, including microarray comparative genomic hybridisation and sequencing of a 114 gene panel associated with cataract and congenital ophthalmic disorders was conducted by an accredited clinical laboratory. Whole exome sequencing (WES) was undertaken on a research basis and in vitro TOPflash transcriptional reporter assay was utilised to assess the impact of the putative causal variant. Results In the proband, WES revealed a novel, likely pathogenic homozygous mutation in the cadherin-associated protein beta-1 gene (CTNNB1), c.884C>G; p.(Ala295Gly), which encodes a co-effector molecule of the Wnt/β-catenin pathway. The proband’s parents were shown to be heterozygous carriers but ophthalmic examination did not detect any abnormalities. Functional assessment of the missense variant demonstrated significant reduction of β-catenin activity. Conclusions This is the first report of a biallelic disease-causing variation in CTNNB1. We conclude that this biallelic, transcriptional inactivating mutation of CTNNB1 causes a severe, syndromic form of microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia that results in serious visual loss in infancy

Communication style and exercise compliance in physiotherapy (CONNECT). A cluster randomized controlled trial to test a theory-based intervention to increase chronic low back pain patients’ adherence to physiotherapists’ recommendations: study rationale, design, and methods

Physical activity and exercise therapy are among the accepted clinical rehabilitation guidelines and are recommended self-management strategies for chronic low back pain. However, many back pain sufferers do not adhere to their physiotherapist’s recommendations. Poor patient adherence may decrease the effectiveness of advice and home-based rehabilitation exercises. According to self-determination theory, support from health care practitioners can promote patients’ autonomous motivation and greater long-term behavioral persistence (e.g., adherence to physiotherapists’ recommendations). The aim of this trial is to assess the effect of an intervention designed to increase physiotherapists’ autonomy-supportive communication on low back pain patients’ adherence to physical activity and exercise therapy recommendations. \ud \ud This study will be a single-blinded cluster randomized controlled trial. Outpatient physiotherapy centers (N =12) in Dublin, Ireland (population = 1.25 million) will be randomly assigned using a computer-generated algorithm to either the experimental or control arm. Physiotherapists in the experimental arm (two hospitals and four primary care clinics) will attend eight hours of communication skills training. Training will include handouts, workbooks, video examples, role-play, and discussion designed to teach physiotherapists how to communicate in a manner that promotes autonomous patient motivation. Physiotherapists in the waitlist control arm (two hospitals and four primary care clinics) will not receive this training. Participants (N = 292) with chronic low back pain will complete assessments at baseline, as well as 1 week, 4 weeks, 12 weeks, and 24 weeks after their first physiotherapy appointment. Primary outcomes will include adherence to physiotherapy recommendations, as well as low back pain, function, and well-being. Participants will be blinded to treatment allocation, as they will not be told if their physiotherapist has received the communication skills training. Outcome assessors will also be blinded. \ud \ud We will use linear mixed modeling to test between arm differences both in the mean levels and the rates of change of the outcome variables. We will employ structural equation modeling to examine the process of change, including hypothesized mediation effects. \ud \ud This trial will be the first to test the effect of a self-determination theory-based communication skills training program for physiotherapists on their low back pain patients’ adherence to rehabilitation recommendations. Current Controlled Trials ISRCTN63723433\u

Alternative patterns of sex chromosome differentiation in Aedes aegypti (L).

BACKGROUND: Some populations of West African Aedes aegypti, the dengue and zika vector, are reproductively incompatible; our earlier study showed that divergence and rearrangements of genes on chromosome 1, which bears the sex locus (M), may be involved. We also previously described a proposed cryptic subspecies SenAae (PK10, Senegal) that had many more high inter-sex FST genes on chromosome 1 than did Ae.aegypti aegypti (Aaa, Pai Lom, Thailand). The current work more thoroughly explores the significance of those findings. RESULTS: Intersex standardized variance (FST) of single nucleotide polymorphisms (SNPs) was characterized from genomic exome capture libraries of both sexes in representative natural populations of Aaa and SenAae. Our goal was to identify SNPs that varied in frequency between males and females, and most were expected to occur on chromosome 1. Use of the assembled AaegL4 reference alleviated the previous problem of unmapped genes. Because the M locus gene nix was not captured and not present in AaegL4, the male-determining locus, per se, was not explored. Sex-associated genes were those with FST values ≥ 0.100 and/or with increased expected heterozygosity (H exp , one-sided T-test, p < 0.05) in males. There were 85 genes common to both collections with high inter-sex FST values; all genes but one were located on chromosome 1. Aaa showed the expected cluster of high inter-sex FST genes proximal to the M locus, whereas SenAae had inter-sex FST genes along the length of chromosome 1. In addition, the Aaa M-locus proximal region showed increased H exp levels in males, whereas SenAae did not. In SenAae, chromosomal rearrangements and subsequent suppressed recombination may have accelerated X-Y differentiation. CONCLUSIONS: The evidence presented here is consistent with differential evolution of proto-Y chromosomes in Aaa and SenAae

COSMOS: COmparing Standard Maternity care with One-to-one midwifery Support: a randomised controlled trial

Background: In Australia and internationally, there is concern about the growing proportion of women giving birth by caesarean section. There is evidence of increased risk of placenta accreta and percreta in subsequent pregnancies as well as decreased fertility; and significant resource implications. Randomised controlled trials (RCTs) of continuity of midwifery care have reported reduced caesareans and other interventions in labour, as well as increased maternal satisfaction, with no statistically significant differences in perinatal morbidity or mortality. RCTs conducted in the UK and in Australia have largely measured the effect of teams of care providers (commonly 6&ndash;12 midwives) with very few testing caseload (one-to-one) midwifery care. This study aims to determine whether caseload (one-to-one) midwifery care for women at low risk of medical complications decreases the proportion of women delivering by caesarean section compared with women receiving \u27standard\u27 care. This paper presents the trial protocol in detail.Methods/design: A two-arm RCT design will be used. Women who are identified at low medical risk will be recruited from the antenatal booking clinics of a tertiary women\u27s hospital in Melbourne, Australia. Baseline data will be collected, then women randomised to caseload midwifery or standard low risk care. Women allocated to the caseload intervention will receive antenatal, intrapartum and postpartum care from a designated primary midwife with one or two antenatal visits conducted by a \u27back-up\u27 midwife. The midwives will collaborate with obstetricians and other health professionals as necessary. If the woman has an extended labour, or if the primary midwife is unavailable, care will be provided by the back-up midwife. For women allocated to standard care, options include midwifery-led care with varying levels of continuity, junior obstetric care and community based general medical practitioner care. Data will be collected at recruitment (self administered survey) and at 2 and 6 months postpartum by postal survey. Medical/obstetric outcomes will be abstracted from the medical record. The sample size of 2008 was calculated to identify a decrease in caesarean birth from 19 to 14% and detect a range of other significant clinical differences. Comprehensive process and economic evaluations will be conducted.Trial registration: Australian New Zealand Clinical Trials Registry ACTRN012607000073404.<br /

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Search for pair-produced long-lived neutral particles decaying to jets in the ATLAS hadronic calorimeter in ppcollisions at √s=8TeV

The ATLAS detector at the Large Hadron Collider at CERN is used to search for the decay of a scalar boson to a pair of long-lived particles, neutral under the Standard Model gauge group, in 20.3fb−1of data collected in proton–proton collisions at √s=8TeV. This search is sensitive to long-lived particles that decay to Standard Model particles producing jets at the outer edge of the ATLAS electromagnetic calorimeter or inside the hadronic calorimeter. No significant excess of events is observed. Limits are reported on the product of the scalar boson production cross section times branching ratio into long-lived neutral particles as a function of the proper lifetime of the particles. Limits are reported for boson masses from 100 GeVto 900 GeV, and a long-lived neutral particle mass from 10 GeVto 150 GeV

Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or τ lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, φ, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan β in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models