Plasmalogen Loss in Sepsis and SARS-CoV-2 Infection.

Plasmalogens are plasma-borne antioxidant phospholipid species that provide protection as cellular lipid components during cellular oxidative stress. In this study we investigated plasma plasmalogen levels in human sepsis as well as in rodent models of infection. In humans, levels of multiple plasmenylethanolamine molecular species were decreased in septic patient plasma compared to control subject plasma as well as an age-aligned control subject cohort. Additionally, lysoplasmenylcholine levels were significantly decreased in septic patients compared to the control cohorts. In contrast, plasma diacyl phosphatidylethanolamine and phosphatidylcholine levels were elevated in septic patients. Lipid changes were also determined in rats subjected to cecal slurry sepsis. Plasma plasmenylcholine, plasmenylethanolamine, and lysoplasmenylcholine levels were decreased while diacyl phosphatidylethanolamine levels were increased in septic rats compared to control treated rats. Kidney levels of lysoplasmenylcholine as well as plasmenylethanolamine molecular species were decreased in septic rats. Interestingly, liver plasmenylcholine and plasmenylethanolamine levels were increased in septic rats. Since COVID-19 is associated with sepsis-like acute respiratory distress syndrome and oxidative stress, plasmalogen levels were also determined in a mouse model of COVID-19 (intranasal inoculation of K18 mice with SARS-CoV-2). 3 days following infection, lung infection was confirmed as well as cytokine expression in the lung. Multiple molecular species of lung plasmenylcholine and plasmenylethanolamine were decreased in infected mice. In contrast, the predominant lung phospholipid, dipalmitoyl phosphatidylcholine, was not decreased following SARS-CoV-2 infection. Additionally total plasmenylcholine levels were decreased in the plasma of SARS-CoV-2 infected mice. Collectively, these data demonstrate the loss of plasmalogens during both sepsis and SARS-CoV-2 infection. This study also indicates plasma plasmalogens should be considered in future studies as biomarkers of infection and as prognostic indicators for sepsis and COVID-19 outcomes.

Myeloperoxidase-derived hypochlorous acid targets human airway epithelial plasmalogens liberating protein modifying electrophilic 2-chlorofatty aldehydes.

Neutrophil and airway epithelial cell interactions are critical in the inflammatory response to viral infections including respiratory syncytial virus, Sendai virus, and SARS-CoV-2. Airway epithelial cell dysfunction during viral infections is likely mediated by the interaction of virus and recruited neutrophils at the airway epithelial barrier. Neutrophils are key early responders to viral infection. Neutrophil myeloperoxidase catalyzes the conversion of hydrogen peroxide to hypochlorous acid (HOCl). Previous studies have shown HOCl targets host neutrophil and endothelial cell plasmalogen lipids, resulting in the production of the chlorinated lipid, 2-chlorofatty aldehyde (2-ClFALD). We have previously shown that the oxidation product of 2-ClFALD, 2-chlorofatty acid (2-ClFA) is present in bronchoalveolar lavage fluid of Sendai virus-infected mice, which likely results from the attack of the epithelial plasmalogen by neutrophil-derived HOCl. Herein, we demonstrate small airway epithelial cells contain plasmalogens enriched with oleic acid at the sn-2 position unlike endothelial cells which contain arachidonic acid enrichment at the sn-2 position of plasmalogen. We also show neutrophil-derived HOCl targets epithelial cell plasmalogens to produce 2-ClFALD. Further, proteomics and over-representation analysis using the ω-alkyne analog of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDyA) showed cell adhesion molecule binding and cell-cell junction enriched categories similar to that observed previously in endothelial cells. However, in contrast to endothelial cells, proteins in distinct metabolic pathways were enriched with 2-ClFALD modification, particularly pyruvate metabolism was enriched in epithelial cells and mitochondrial pyruvate respiration was reduced. Collectively, these studies demonstrate, for the first time, a novel plasmalogen molecular species distribution in airway epithelial cells that are targeted by myeloperoxidase-derived hypochlorous acid resulting in electrophilic 2-ClFALD, which potentially modifies epithelial physiology by modifying proteins.

Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT).

OBJECTIVE: To determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on risk of all cause acute respiratory tract infection and covid 19. DESIGN: Phase 3 open label randomised controlled trial. SETTING: United Kingdom. PARTICIPANTS: 6200 people aged ≥16 years who were not taking vitamin D supplements at baseline. INTERVENTIONS: Offer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months. MAIN OUTCOME MEASURES: The primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat. RESULTS: Of 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63). CONCLUSIONS: Among people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04579640.

Mental health of people with multiple sclerosis during the COVID-19 outbreak: A prospective cohort and cross-sectional case-control study of the UK MS Register.

BACKGROUND: People with MS (pwMS) have had higher rates of anxiety and depression than the general population before the COVID-19 pandemic, placing them at higher risk of experiencing poor psychological wellbeing during the pandemic. OBJECTIVE: To assess mental health and its social/lifestyle determinants in pwMS during the first wave of the outbreak in the United Kingdom. METHODS: This is a community-based, prospective longitudinal cohort and cross-sectional case-control online questionnaire study. It includes 2010 pwMS from the UK MS Register and 380 people without MS. RESULTS: The Hospital Anxiety and Depression Scale scores of pwMS for anxiety and depression during the outbreak did not change from the previous year. PwMS were more likely to have anxiety (using General Anxiety Disorder-7) and/or depression (using Patient Health Questionnaire-9) than controls during the outbreak (OR: 2.14, 95% CI: 1.58-2.91). PwMS felt lonelier (OR: 1.37, 95% CI: 1.04-1.80) reported worse social support (OR: 1.90, 95% CI: 1.18-3.07) and reported worsened exercise habits (OR: 1.65, 95% CI: 1.18-2.32) during the outbreak than controls. CONCLUSION: Early in the pandemic, pwMS remained at higher risk of experiencing anxiety and depression than the general population. It is important that multidisciplinary teams improve their support for the wellbeing of pwMS, who are vulnerable to the negative effects of the pandemic on their lifestyle and social support.

Willingness to receive a COVID-19 vaccine in people with multiple sclerosis - UK MS Register survey.

BACKGROUND & METHODS: We conducted an online COVID-19 survey as the vaccines became available, utilising the UK MS Register, to understand people with multiple sclerosis (pwMS) views on COVID-19 vaccination and the subsequent vaccine uptake rates. RESULTS & CONCLUSION: 94.4% of 3191 pwMS surveyed indicated they would get a COVID-19 vaccine, while 5.6% would not. PwMS who have previously had an influenza vaccine, increasing age and the perception of having sufficient information about the vaccine were associated with increased likelihood of getting a vaccine. 51.7% of 3191 pwMS completed a follow-up survey indicating they received at least 1 dose of a COVID-19 vaccine. The proportion having had the vaccination based on their prior opinions was 53.2% in 'Yes' group and 27.0% in 'No' group, the latter reflecting a change based on their initial views. More information on COVID-19 vaccine safety in pwMS would be helpful for people to make informed decisions.

How a Pandemic Changes Trauma: Epidemiology and Management of Trauma Admissions in the UK during COVID-19 Lockdown.

INTRODUCTION: On June 24 in the United Kingdom, there were 277,989 cases of COVID-19 and 39,369 deaths recorded. The government enforced a complete lockdown on March 23 that resulted in cessation of all elective admissions on 24th onward, with only acute trauma cases being admitted to hospital. This study aims to characterize the changes in trauma admissions during the first 5-week lockdown period. The hypothesis states that there would be a significant reduction in overall orthopedic trauma admissions, polytrauma, and high-energy outdoor trauma during this COVID-19 period. METHODS: All trauma admissions over nearly a 5-week period from March 23, 2020, to April 26, 2020, were collated as the "COVID cohort" and compared to the "control" group of patients from the same hospitals 1 year before between March 23, 2019, and April 26, 2019. Spinal admissions and pediatrics were excluded from the study as they were managed in other regional units. RESULTS: There was a 56% reduction in trauma admissions during the COVID-19 lockdown (133 vs. 304). A majority of the COVID cohort were admitted with fractures (89 vs. 164, P = 0.017, Chi-square test) from home with low-energy falls. Overall, fewer operations were performed than the year before. However, a greater proportion of admitted patients had a surgical orthopedic intervention rather than admission and nonoperative management. CONCLUSIONS: There was a reduction in admissions as well as reductions in high energy and occupational injuries. Elderly patients continued to fall at home or in care, sustaining hip fractures. This vulnerable group requires beds, orthogeriatric management followed by surgical intervention and social care. Orthogeriatric services must be maintained to ensure the best clinical outcomes for this group.

United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH): a retrospective cohort study using linked routinely collected data, study protocol.

INTRODUCTION: COVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities. METHODS AND ANALYSIS: This study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes. ETHICS AND DISSEMINATION: Ethical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/). TRIAL REGISTRATION NUMBER: ISRCTN11811602.

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study.

BACKGROUND: The BNT162b2 mRNA (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca) COVID-19 vaccines have shown high efficacy against disease in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. Studying the real-world effects of these vaccines is an urgent requirement. The aim of our study was to investigate the association between the mass roll-out of the first doses of these COVID-19 vaccines and hospital admissions for COVID-19. METHODS: We did a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19-EAVE II-database comprising linked vaccination, primary care, real-time reverse transcription-PCR testing, and hospital admission patient records for 5·4 million people in Scotland (about 99% of the population) registered at 940 general practices. Individuals who had previously tested positive were excluded from the analysis. A time-dependent Cox model and Poisson regression models with inverse propensity weights were fitted to estimate effectiveness against COVID-19 hospital admission (defined as 1-adjusted rate ratio) following the first dose of vaccine. FINDINGS: Between Dec 8, 2020, and Feb 22, 2021, a total of 1 331 993 people were vaccinated over the study period. The mean age of those vaccinated was 65·0 years (SD 16·2). The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85-94) for reduced COVID-19 hospital admission at 28-34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 88% (95% CI 75-94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar when restricting the analysis to those aged 80 years and older (83%, 95% CI 72-89 at 28-34 days post-vaccination). INTERPRETATION: Mass roll-out of the first doses of the BNT162b2 mRNA and ChAdOx1 vaccines was associated with substantial reductions in the risk of hospital admission due to COVID-19 in Scotland. There remains the possibility that some of the observed effects might have been due to residual confounding. FUNDING: UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK.

Real-time spatial health surveillance: Mapping the UK COVID-19 epidemic.

Introduction The COVID-19 pandemic has highlighted the need for robust data linkage systems and methods for identifying outbreaks of disease in near real-time. Objectives The primary objective of this study was to develop a real-time geospatial surveillance system to monitor the spread of COVID-19 across the UK. Methods Using self-reported app data and the Secure Anonymised Information Linkage (SAIL) Databank, we demonstrate the use of sophisticated spatial modelling for near-real-time prediction of COVID-19 prevalence at small-area resolution to inform strategic government policy areas. Results We demonstrate that using a combination of crowd-sourced app data and sophisticated geo-statistical techniques it is possible to predict hot spots of COVID-19 at fine geographic scales, nationally. We are also able to produce estimates of their precision, which is an important pre-requisite to an effective control strategy to guard against over-reaction to potentially spurious features of 'best guess' predictions. Conclusion In the UK, important emerging risk-factors such as social deprivation or ethnicity vary over small distances, hence risk needs to be modelled at fine spatial resolution to avoid aggregation bias. We demonstrate that existing geospatial statistical methods originally developed for global health applications are well-suited to this task and can be used in an anonymised databank environment, thus preserving the privacy of the individuals who contribute their data.

Effect of COVID-19 on a rural orthopaedic hip fracture service.

AIMS: Our rural orthopaedic service has undergone service restructure during the COVID-19 pandemic in order to sustain hip fracture care. All adult trauma care has been centralised to the Royal Shrewsbury Hospital for assessment and medical input, before transferring those requiring operative intervention to the Robert Jones and Agnes Hunt Orthopaedic Hospital. We aim to review the impact of COVID-19 on hip fracture workload and service changes upon management of hip fractures. METHODS: We reviewed our prospectively maintained trust database and National Hip Fracture Database records for the months of March and April between the years 2016 and 2020. Our assessment included fracture pattern (intrascapular vs extracapsular hip fracture), treatment intervention, length of stay and mortality. RESULTS: We treated 288 patients during March and April between 2016 and 2020, with a breakdown of 55, 58, 53, 68, and 54 from 2016 to 2020 respectively. Fracture pattern distribution in the pre-COVID-19 years of 2016 to 2019 was 58% intracapsular and 42% extracapsular. In 2020 (COVID-19 period) the fracture patterns were 65% intracapsular and 35% extracapsular. Our mean length of stay was 13.1 days (SD 8.2) between 2016 to 2019, and 5.0 days (6.3) days in 2020 (p < 0.001). Between 2016 and 2019 we had three deaths in hip fracture patients, and one death in 2020. Hemiarthroplasty and dynamic hip screw fixation have been the mainstay of operative intervention across the five years and this has continued in the COVID-19 period. We have experienced a rise in conservatively managed patients; ten in 2020 compared to 14 over the previous four years. CONCLUSION: There has not been a reduction in the number of hip fractures during COVID-19 period compared to the same time period over previous years. In our experience, there has been an increase in conservative treatment and decreased length of stay during the COVID -19 period.Cite this article: Bone Joint Open 2020;1-8:500-507.