Complex Structure in Class 0 Protostellar Envelopes II: Kinematic Structure from Single-Dish and Interferometric Molecular Line Mapping

We present a study of dense molecular gas kinematics in seventeen nearby protostellar systems using single-dish and interferometric molecular line observations. The non-axisymmetric envelopes around a sample of Class 0/I protostars were mapped in the N2H+ (J=1-0) tracer with the IRAM 30m, CARMA and PdBI as well as NH3 (1,1) with the VLA. The molecular line emission is used to construct line-center velocity and linewidth maps for all sources to examine the kinematic structure in the envelopes on spatial scales from 0.1 pc to ~1000 AU. The direction of the large-scale velocity gradients from single-dish mapping is within 45 degrees of normal to the outflow axis in more than half the sample. Furthermore, the velocity gradients are often quite substantial, the average being ~2.3 km\s\pc. The interferometric data often reveal small-scale velocity structure, departing from the more gradual large-scale velocity gradients. In some cases, this likely indicates accelerating infall and/or rotational spin-up in the inner envelope; the median velocity gradient from the interferometric data is ~10.7 km/s/pc. In two systems, we detect high-velocity HCO+ (J=1-0) emission inside the highest-velocity \nthp\ emission. This enables us to study the infall and rotation close to the disk and estimate the central object masses. The velocity fields observed on large and small-scales are more complex than would be expected from rotation alone, suggesting that complex envelope structure enables other dynamical processes (i.e. infall) to affect the velocity field.Comment: 85 Pages, 31 Figures, 11 Tables, Accepted to ApJ

UV-driven Chemistry as a Signpost for Late-stage Planet Formation

The chemical reservoir within protoplanetary disks has a direct impact on planetary compositions and the potential for life. A long-lived carbon-and nitrogen-rich chemistry at cold temperatures (<=50K) is observed within cold and evolved planet-forming disks. This is evidenced by bright emission from small organic radicals in 1-10 Myr aged systems that would otherwise have frozen out onto grains within 1 Myr. We explain how the chemistry of a planet-forming disk evolves from a cosmic-ray/X-ray-dominated regime to an ultraviolet-dominated chemical equilibrium. This, in turn, will bring about a temporal transition in the chemical reservoir from which planets will accrete. This photochemical dominated gas phase chemistry develops as dust evolves via growth, settling and drift, and the small grain population is depleted from the disk atmosphere. A higher gas-to-dust mass ratio allows for deeper penetration of ultraviolet photons is coupled with a carbon-rich gas (C/O > 1) to form carbon-bearing radicals and ions. This further results in gas phase formation of organic molecules, which then would be accreted by any actively forming planets present in the evolved disk.Comment: Accepted to Nature Astronomy, Published Dec 8th 202

‘Scrutinised, judged and sabotaged’: A qualitative video diary study of first-time breastfeeding mothers

Objective To explore how support impacted on mothers’ breastfeeding experiences in the first few weeks following birth. Design A qualitative approach explored real-time experiences of breastfeeding captured by five first-time mothers in the South of England on camcorder as video diaries. A multi-dimensional approach involving thematic analysis ensured both the audio and visual elements of the data were analysed. Findings Mothers felt ‘under surveillance’ by the biomedical approach to support from the healthcare team. At best mothers felt reassured that they were ‘on the right track’. When mothers felt their breastfeeding was constantly being examined, criticised and threatened they felt ‘scrutinised, judged and sabotaged’. When they found it difficult to access healthcare support, or they avoided it altogether to circumvent further scrutiny, they felt ‘abandoned and alone’. Key conclusions Collecting audio-visual data in real-time adds fresh insights into how support impacts mothers’ experiences of breastfeeding. The biomedical approach to support for breastfeeding is not effective. Scrutinising, judging and/or sabotaging mothers’ attempts to breastfeed can have long-lasting effects on maternal emotional wellbeing. Implications for practice Breastfeeding support might be improved by adopting a more social model of care. Future research needs to explore how relationship-based support can be provided by the health service

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.</p

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.</p

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.</p

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Background Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. Findings The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtyp

High rates of viral suppression in adults and children with high CD4+ counts using a streamlined ART delivery model in the SEARCH trial in rural Uganda and Kenya.

INTRODUCTION: The 2015 WHO recommendation of antiretroviral therapy (ART) for all HIV-positive persons calls for treatment initiation in millions of persons newly eligible with high CD4+ counts. Efficient and effective care models are urgently needed for this population. We evaluated clinical outcomes of asymptomatic HIV-positive adults and children starting ART with high CD4+ counts using a novel streamlined care model in rural Uganda and Kenya. METHODS: In the 16 intervention communities of the HIV test-and-treat Sustainable East Africa Research for Community Health Study (NCT01864603), all HIV-positive individuals irrespective of CD4 were offered ART (efavirenz [EFV]/tenofovir disoproxil fumarate + emtricitabine (FTC) or lamivudine (3TC). We studied adults (≥fifteen years) with CD4 ≥ 350/μL and children (two to fourteen years) with CD4 > 500/μL otherwise ineligible for ART by country guidelines. Clinics implemented a patient-centred streamlined care model designed to reduce patient-level barriers and maximize health system efficiency. It included (1) nurse-conducted visits with physician referral of complex cases, (2) multi-disease chronic care (including for hypertension/diabetes), (3) patient-centred, friendly staff, (4) viral load (VL) testing and counselling, (5) three-month return visits and ART refills, (6) appointment reminders, (7) tiered tracking for missed appointments, (8) flexible clinic hours (outside routine schedule) and (9) telephone access to clinicians. Primary outcomes were 48-week retention in care, viral suppression (% with measured week 48 VL ≤ 500 copies/mL) and adverse events. Results Overall, 972 HIV-positive adults with CD4+ ≥ 350/μL initiated ART with streamlined care. Patients were 66% female and had median age thirty-four years (IQR, 28-42), CD4+ 608/μL (IQR, 487-788/μL) and VL 6775 copies/mL (IQR, <500-37,003 c/mL). At week 48, retention was 92% (897/972; 2 died/40 moved/8 withdrew/4 transferred care/21/964 [2%] were lost to follow-up). Viral suppression occurred in 778/838 (93%) and 800/972 (82%) in intention-to-treat analysis. Grade III/IV clinical/laboratory adverse events were rare: 95 occurred in 74/972 patients (7.6%). Only 8/972 adults (0.8%) switched ART from EFV to lopinavir (LPV) (n = 2 for dizziness, n = 2 for gynaecomastia, n = 4 for other reasons). Among 83 children, week 48 retention was 89% (74/83), viral suppression was 92% (65/71) and grade III/IV adverse events occurred in 4/83 (4.8%). CONCLUSIONS: Using a streamlined care model, viral suppression, retention and ART safety were high among asymptomatic East African adults and children with high CD4+ counts initiating treatment. CLINICAL TRIAL NUMBER: NCT01864603