Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

Ratnieks et al. Data reliability in citizen science (data sets)

Two data sets analyzed in Experiments 1 and 2, respectively, from the paper of Ratnieks et al., Data reliability in citizen science: learning curve and the effects of training method, volunteer background and experience on identification accuracy of insects visiting ivy flowers. Methods in Ecology and Evolution. Both data sets are in the form of Tab-delimited text files. The variables included are as follows: Experiment 1: (each row represents one test of one participant, where participants were tested only once) Training = training method (pamphlet only, pamphlet + slide show, pamphlet + direct training) Degree = study degree of participants, biology-related (B) or not (N) Experience = prior experience of participants (Y/N) Experiment 2: (each participant was tested three times) Participant = unique participant id TestNo = test number (first, second or third) AdMat = type of additional training material (video or stills) Both datasets: Other variables present the proportion of insects identified correctly by each participant on each test. HB - honey bees SOCW - social wasps HBMHOV - honey bee-mimicking hover flies WMHOV - wasp-mimicking hover flies OTHFLY - non-syrphid flies IVYBEE - ivy bees BB - bumble bees BF - butterflies MO - moths ALL - all insects combine

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk

Cluster randomized trial of a multilevel evidence-based quality improvement approach to tailoring VA Patient Aligned Care Teams to the needs of women Veterans

BACKGROUND: The Veterans Health Administration (VA) has undertaken a major initiative to transform care through implementation of Patient Aligned Care Teams (PACTs). Based on the patient-centered medical home (PCMH) concept, PACT aims to improve access, continuity, coordination, and comprehensiveness using team-based care that is patient-driven and patient-centered. However, how VA should adapt PACT to meet the needs of special populations, such as women Veterans (WVs), was not considered in initial implementation guidance. WVs’ numerical minority in VA healthcare settings (approximately 7–8 % of users) creates logistical challenges to delivering gender-sensitive comprehensive care. The main goal of this study is to test an evidence-based quality improvement approach (EBQI) to tailoring PACT to meet the needs of WVs, incorporating comprehensive primary care services and gender-specific care in gender-sensitive environments, thereby accelerating achievement of PACT tenets for women (Women’s Health (WH)-PACT). METHODS/DESIGN: EBQI is a systematic approach to developing a multilevel research-clinical partnership that engages senior organizational leaders and local quality improvement (QI) teams in adapting and implementing new care models in the context of prior evidence and local practice conditions, with researchers providing technical support, formative feedback, and practice facilitation. In a 12-site cluster randomized trial, we will evaluate WH-PACT model achievement using patient, provider, staff, and practice surveys, in addition to analyses of secondary administrative and chart-based data. We will explore impacts of receipt of WH-PACT care on quality of chronic disease care and prevention, health status, patient satisfaction and experience of care, provider experience, utilization, and costs. Using mixed methods, we will assess pre-post practice contexts; document EBQI activities undertaken in participating facilities and their relationship to provider/staff and team actions/attitudes; document WH-PACT implementation; and examine barriers/facilitators to EBQI-supported WH-PACT implementation through a combination of semi-structured interviews and monthly formative progress narratives and administrative data. DISCUSSION: Lack of gender-sensitive comprehensive care has demonstrated consequences for the technical quality and ratings of care among WVs and may contribute to decisions to continue use or seek care elsewhere under the US Affordable Care Act. We hypothesize that tailoring PACT implementation through EBQI may improve the experience and quality of care at many levels. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0203985