Coronavirus disease 2019 (COVID-19) has rapidly affected mortality worldwide
. There is unprecedented urgency to understand who is most at risk of severe outcomes, and this requires new approaches ...for the timely analysis of large datasets. Working on behalf of NHS England, we created OpenSAFELY-a secure health analytics platform that covers 40% of all patients in England and holds patient data within the existing data centre of a major vendor of primary care electronic health records. Here we used OpenSAFELY to examine factors associated with COVID-19-related death. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19-related deaths. COVID-19-related death was associated with: being male (hazard ratio (HR) 1.59 (95% confidence interval 1.53-1.65)); greater age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared with people of white ethnicity, Black and South Asian people were at higher risk, even after adjustment for other factors (HR 1.48 (1.29-1.69) and 1.45 (1.32-1.58), respectively). We have quantified a range of clinical factors associated with COVID-19-related death in one of the largest cohort studies on this topic so far. More patient records are rapidly being added to OpenSAFELY, we will update and extend our results regularly.
Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results ...from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.
The diagnosis of malignant lymphoma is a recognized difficult area in histopathology. Therefore, detection of clonality in a suspected lymphoproliferation is a valuable diagnostic criterion. We have ...developed primer sets for the detection of rearrangements in the B- and T-cell receptor genes as reliable tools for clonality assessment in lymphoproliferations suspected for lymphoma. In this issue of Leukemia, the participants of the BIOMED-2 Concerted Action CT98-3936 report on the validation of the newly developed clonality assays in various disease entities. Clonality was detected in 99% of all B-cell malignancies and in 94% of all T-cell malignancies, whereas the great majority of reactive lesions showed polyclonality. The combined BIOMED-2 results are summarized in a guideline, which can now be implemented in routine lymphoma diagnostics. The use of this standardized approach in patients with a suspect lymphoproliferation will result in improved diagnosis of malignant lymphoma.
ABSTRACT
We present the first asteroseismic results for δ Scuti and γ Doradus stars observed in Sectors 1 and 2 of the TESS mission. We utilize the 2-min cadence TESS data for a sample of 117 stars ...to classify their behaviour regarding variability and place them in the Hertzsprung–Russell diagram using Gaia DR2 data. Included within our sample are the eponymous members of two pulsator classes, γ Doradus and SX Phoenicis. Our sample of pulsating intermediate-mass stars observed by TESS also allows us to confront theoretical models of pulsation driving in the classical instability strip for the first time and show that mixing processes in the outer envelope play an important role. We derive an empirical estimate of 74 per cent for the relative amplitude suppression factor as a result of the redder TESS passband compared to the Kepler mission using a pulsating eclipsing binary system. Furthermore, our sample contains many high-frequency pulsators, allowing us to probe the frequency variability of hot young δ Scuti stars, which were lacking in the Kepler mission data set, and identify promising targets for future asteroseismic modelling. The TESS data also allow us to refine the stellar parameters of SX Phoenicis, which is believed to be a blue straggler.
Detection of the IceCube-170922A neutrino coincident with the flaring blazar TXS 0506+056, the first and only ∼3 high-energy neutrino source association to date, offers a potential breakthrough in ...our understanding of high-energy cosmic particles and blazar physics. We present a comprehensive analysis of TXS 0506+056 during its flaring state, using newly collected Swift, NuSTAR, and X-shooter data with Fermi observations and numerical models to constrain the blazar's particle acceleration processes and multimessenger (electromagnetic (EM) and high-energy neutrino) emissions. Accounting properly for EM cascades in the emission region, we find a physically consistent picture only within a hybrid leptonic scenario, with γ-rays produced by external inverse-Compton processes and high-energy neutrinos via a radiatively subdominant hadronic component. We derive robust constraints on the blazar's neutrino and cosmic-ray emissions and demonstrate that, because of cascade effects, the 0.1-100 keV emissions of TXS 0506+056 serve as a better probe of its hadronic acceleration and high-energy neutrino production processes than its GeV-TeV emissions. If the IceCube neutrino association holds, physical conditions in the TXS 0506+056 jet must be close to optimal for high-energy neutrino production, and are not favorable for ultrahigh-energy cosmic-ray acceleration. Alternatively, the challenges we identify in generating a significant rate of IceCube neutrino detections from TXS 0506+056 may disfavor single-zone models, in which γ-rays and high-energy neutrinos are produced in a single emission region. In concert with continued operations of the high-energy neutrino observatories, we advocate regular X-ray monitoring of TXS 0506+056 and other blazars in order to test single-zone blazar emission models, clarify the nature and extent of their hadronic acceleration processes, and carry out the most sensitive possible search for additional multimessenger sources.
Abstract
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant (B.1.1.7) is associated with higher transmissibility than wild-type virus, becoming the dominant ...variant in England by January 2021. We aimed to describe the severity of the alpha variant in terms of the pathway of disease from testing positive to hospital admission and death.
Methods
With the approval of NHS England, we linked individual-level data from primary care with SARS-CoV-2 community testing, hospital admission, and Office for National Statistics all-cause death data. We used testing data with S-gene target failure as a proxy for distinguishing alpha and wild-type cases, and stratified Cox proportional hazards regression to compare the relative severity of alpha cases with wild-type diagnosed from 16 November 2020 to 11 January 2021.
Results
Using data from 185 234 people who tested positive for SARS-CoV-2 in the community (alpha = 93 153; wild-type = 92 081), in fully adjusted analysis accounting for individual-level demographics and comorbidities as well as regional variation in infection incidence, we found alpha associated with 73% higher hazards of all-cause death (adjusted hazard ratio aHR: 1.73; 95% confidence interval CI: 1.41–2.13; P < .0001) and 62% higher hazards of hospital admission (1.62; 1.48–1.78; P < .0001) compared with wild-type virus. Among patients already admitted to the intensive care unit, the association between alpha and increased all-cause mortality was smaller and the CI included the null (aHR: 1.20; 95% CI: .74–1.95; P = .45).
Conclusions
The SARS-CoV-2 alpha variant is associated with an increased risk of both hospitalization and mortality than wild-type virus.
The SARS-CoV-2 alpha variant is associated with a 62% increased risk of hospitalization and a 73% increased risk of death, compared with the originally circulating wild-type virus in England between 16 November 2020 and 21 April 2021.
The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of ...COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes.
The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107).
We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity.
We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care.
UK Research and Innovation and National Institute for Health Research.
Summary
A systematic review and meta‐analyses were conducted to evaluate the effects of interventions to reduce sugar‐sweetened beverages (SSB) or increase water intakes and to examine the impact of ...behaviour change techniques (BCTs) in consumption patterns. Randomized and nonrandomized controlled trials published after January 1990 and until December 2016 reporting daily changes in intakes of SSB or water in volumetric measurements (mL d−1) were included. References were retrieved through searches of electronic databases and quality appraisal followed Cochrane principles. We calculated mean differences (MD) and synthesized data with random‐effects models. Forty studies with 16 505 participants were meta‐analysed. Interventions significantly decreased consumption of SSB in children by 76 mL d−1 (95% confidence interval CI −105 to −46; 23 studies, P < 0.01), and in adolescents (−66 mL d−1, 95% CI −130 to −2; 5 studies, P = 0.04) but not in adults (−13 mL d−1, 95% CI −44 to 18; 12 studies, P = 0.16). Pooled estimates of water intakes were only possible for interventions in children, and results were indicative of increases in water intake (MD +67 mL d−1, 95% CI 6 to 128; 7 studies, P = 0.04). For children, there was evidence to suggest that modelling/demonstrating the behaviour helped to reduce SSB intake and that interventions within the home environment had greater effects than school‐based interventions. In conclusion, public health interventions – mainly via nutritional education/counselling – are moderately successful at reducing intakes of SSB and increasing water intakes in children. However, on average, only small reductions in SSBs have been achieved by interventions targeting adolescents and adults. Complementary measures may be needed to achieve greater improvements in both dietary behaviours across all age groups.
Selecting test populations by age and/or family history, failure to apply reference standard tests consistently, and poor conversion to definitive testing are all potential sources of bias 13. Most ...previous studies involve insurance-based healthcare systems; this is fraught with difficulty because fear of lack of reimbursement by services 17 and increased insurance premiums in individuals 18 influences testing decisions. ...the aims of this prospective study were to (1) establish the prevalence of LS and (2) evaluate the diagnostic accuracy of common LS testing strategies in an unselected EC population within a non–insurance-based healthcare system. All women gave written, informed consent to participate, providing blood-DNA, tumour, and clinical data (age, body mass index BMI, self-reported ethnicity) including detailed family histories (pedigrees). Diagnostic accuracy measures were conducted to establish the utility of clinical parameters and tumour triage strategies for risk stratifying women with EC for MMR germline sequencing, including age, family history, histological subtype, density of TILs, MMR deficiency by IHC, MSI status, and MLH1-methylation status.
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