Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: A prospective, community-based study

Objective To assess medium-term organ impairment in symptomatic individuals following recovery from acute SARS-CoV-2 infection. Design Baseline findings from a prospective, observational cohort study. Setting Community-based individuals from two UK centres between 1 April and 14 September 2020. Participants Individuals ≥18 years with persistent symptoms following recovery from acute SARS-CoV-2 infection and age-matched healthy controls. Intervention Assessment of symptoms by standardised questionnaires (EQ-5D-5L, Dyspnoea-12) and organ-specific metrics by biochemical assessment and quantitative MRI. Main outcome measures Severe post-COVID-19 syndrome defined as ongoing respiratory symptoms and/or moderate functional impairment in activities of daily living; single-organ and multiorgan impairment (heart, lungs, kidneys, liver, pancreas, spleen) by consensus definitions at baseline investigation. Results 201 individuals (mean age 45, range 21-71 years, 71% female, 88% white, 32% healthcare workers) completed the baseline assessment (median of 141 days following SARS-CoV-2 infection, IQR 110-162). The study population was at low risk of COVID-19 mortality (obesity 20%, hypertension 7%, type 2 diabetes 2%, heart disease 5%), with only 19% hospitalised with COVID-19. 42% of individuals had 10 or more symptoms and 60% had severe post-COVID-19 syndrome. Fatigue (98%), muscle aches (87%), breathlessness (88%) and headaches (83%) were most frequently reported. Mild organ impairment was present in the heart (26%), lungs (11%), kidneys (4%), liver (28%), pancreas (40%) and spleen (4%), with single-organ and multiorgan impairment in 70% and 29%, respectively. Hospitalisation was associated with older age (p=0.001), non-white ethnicity (p=0.016), increased liver volume (

The Small GTPase RhoA Localizes to the Nucleus and Is Activated by Net1 and DNA Damage Signals

Rho GTPases control many cellular processes, including cell survival, gene expression and migration. Rho proteins reside mainly in the cytosol and are targeted to the plasma membrane (PM) upon specific activation by guanine nucleotide exchange factors (GEFs). Accordingly, most GEFs are also cytosolic or associated with the PM. However, Net1, a RhoA-specific GEF predominantly localizes to the cell nucleus at steady-state. Nuclear localization for Net1 has been seen as a mechanism for sequestering the GEF away from RhoA, effectively rendering the protein inactive. However, considering the prominence of nuclear Net1 and the fact that a biological stimulus that promotes Net1 translocation out the nucleus to the cytosol has yet to be discovered, we hypothesized that Net1 might have a previously unidentified function in the nucleus of cells.Using an affinity precipitation method to pulldown the active form of Rho GEFs from different cellular fractions, we show here that nuclear Net1 does in fact exist in an active form, contrary to previous expectations. We further demonstrate that a fraction of RhoA resides in the nucleus, and can also be found in a GTP-bound active form and that Net1 plays a role in the activation of nuclear RhoA. In addition, we show that ionizing radiation (IR) specifically promotes the activation of the nuclear pool of RhoA in a Net1-dependent manner, while the cytoplasmic activity remains unchanged. Surprisingly, irradiating isolated nuclei alone also increases nuclear RhoA activity via Net1, suggesting that all the signals required for IR-induced nuclear RhoA signaling are contained within the nucleus.These results demonstrate the existence of a functional Net1/RhoA signaling pathway within the nucleus of the cell and implicate them in the DNA damage response

The long lives of primates and the ‘invariant rate of ageing’ hypothesis

This work was supported by NIA P01AG031719 to J.W.V. and S.C.A., with additional support provided by the Max Planck Institute of Demographic Research and the Duke University Population Research Institute.Is it possible to slow the rate of ageing, or do biological constraints limit its plasticity? We test the ‘invariant rate of ageing’ hypothesis, which posits that the rate of ageing is relatively fixed within species, with a collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.Publisher PDFPeer reviewe

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Long Covid active case finding study protocol: A co-produced community-based pilot within the STIMULATE-ICP study (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways)

Background and aim Long Covid is a significant public health concern with potentially negative implications for health inequalities. We know that those who are already socially disadvantaged in society are more exposed to COVID-19, experience the worst health outcomes and are more likely to suffer economically. We also know that these groups are more likely to experience stigma and have negative healthcare experiences even before the pandemic. However, little is known about disadvantaged groups' experiences of Long Covid, and preliminary evidence suggests they may be under-represented in those who access formal care. We will conduct a pilot study in a defined geographical area in London, United Kingdom to test the feasibility of a community-based approach of identifying Long Covid cases that have not been clinically diagnosed and have not been referred to Long Covid specialist services. We will explore the barriers to accessing recognition, care, and support, as well as experiences of stigma and perceived discrimination. Methods This protocol and study materials were co-produced with a Community Advisory Board (CAB) made up primarily of people living with Long Covid. Working with voluntary organisations, a study leaflet will be distributed in the local community to highlight Long Covid symptoms and invite those experiencing them to participate in the study if they are not formally diagnosed. Potential participants will be assessed according to the study's inclusion criteria and offered the opportunity to participate if they fit them. Awareness of Long Covid and associated symptoms, experiences of trying to access care, as well as stigma and discrimination will be explored through qualitative interviews with participants. Upon completion of the interviews, participants will be offered a referral to the local social prescribing team to receive support that is personalised to them potentially including, but not restricted to, liaising with their primary care provider and the regional Long Covid clinic

STIMULATE-ICP-Delphi (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways Delphi): Study protocol

Introduction As mortality rates from COVID-19 disease fall, the high prevalence of long-term sequelae (Long COVID) is becoming increasingly widespread, challenging healthcare systems globally. Traditional pathways of care for Long Term Conditions (LTCs) have tended to be managed by disease-specific specialties, an approach that has been ineffective in delivering care for patients with multi-morbidity. The multi-system nature of Long COVID and its impact on physical and psychological health demands a more effective model of holistic, integrated care. The evolution of integrated care systems (ICSs) in the UK presents an important opportunity to explore areas of mutual benefit to LTC, multi-morbidity and Long COVID care. There may be benefits in comparing and contrasting ICPs for Long COVID with ICPs for other LTCs. Methods and analysis This study aims to evaluate health services requirements for ICPs for Long COVID and their applicability to other LTCs including multi-morbidity and the overlap with medically not yet explained symptoms (MNYES). The study will follow a Delphi design and involve an expert panel of stakeholders including people with lived experience, as well as clinicians with expertise in Long COVID and other LTCs. Study processes will include expert panel and moderator panel meetings, surveys, and interviews. The Delphi process is part of the overall STIMULATE-ICP programme, aimed at improving integrated care for people with Long COVID. Ethics and dissemination Ethical approval for this Delphi study has been obtained (Research Governance Board of the University of York) as have approvals for the other STIMULATE-ICP studies. Study outcomes are likely to inform policy for ICPs across LTCs. Results will be disseminated through scientific publication, conference presentation and communications with patients and stakeholders involved in care of other LTCs and Long COVID

Triboelectric Charging and Dissipation Characteristics of the Maquet Quadrox-D Membrane Oxygenator

Triboelectric charging is commonly detected during cardiopulmonary bypass in circuits using roller pumps and PVC tubing. Dissipation of this charging is needed to prevent a spontaneous discharge from occurring. We evaluated the ability of the Quadrox-D (Maquet) to effectively remove the electrostatic charge accumulation, with and without a heater/cooler connection (H/C). A Quadrox-D oxygenator was evaluated using a Stockert SIII pump head, Cincinnati subzero H/E, and a custom adult extracorporeal membrane oxygenation tubing pack with 1/2′ PVC raceway. The circuit was primed and evaluated for triboelectric accumulation with and without H/C use. The results showed a linear relationship between increasing pump flow and static charge build-up when an H/C was not applied. The calculated r2 value was .95. Incorporation of the H/C effectively eliminated charge accumulation. Increasing pump speed increases the amount of static charge created without the use of an H/C. Incorporation of an H/C effectively eliminates charge build-up in the Quadrox-D and is recommended while priming the circuit

The Pandemic Allocation of Ventilators Model Penalizes Infants with Bronchopulmonary Dysplasia

During the COVID-19 pandemic, institutions developed ventilator allocation models. In one proposed model, neonates compete with adults for ventilators using a scoring system. Points are given for conditions that increase one- and five-year (y) mortality. For example, comparable points were added for adult conditions with mortality of 71.3% and for neonates with moderate or severe bronchopulmonary dysplasia (mod/sBPD). We hypothesized that this model overestimates mortality in neonates with BPD and would penalize these infants unfairly. There was little information available on 1 y and 5 y mortality risk for mod/sBPD. To evaluate this allocation protocol, a retrospective chart review was performed on infants born ≥22 weeks and weighing <1500 g admitted to Rainbow Babies and Children’s Hospital in 2015 to identify babies with BPD. The main outcomes were 1 and 5 y mortality. In 2015, 28 infants were diagnosed with mod/s BPD based on NIH 2001 definition; 4 infants had modBPD and 24 had sBPD. All infants (100%) with modBPD survived to 5 y; 2 infants with sBPD died by 1 y (8%) and 22 survived (92%) to 1 y; 3 died (12.5%) by 5 y; and at least 13 survived (54%) to 5 y. Infants with mod/s BPD had lower-than-predicted 1 and 5 y mortality, suggesting the points assigned in the model are too high for these conditions. We believe this model would unfairly penalize these babies