Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Imaging of Intimate Partner Violence, From the AJR Special Series on Emergency Radiology.

Intimate partner violence (IPV) is a highly prevalent public health issue with multiple adverse health effects for affected persons. Radiologists are well suited to assess a patient's likelihood of IPV. Recognition of common IPV injury mechanisms and resulting target and defensive injury patterns on imaging, as well as understanding differences in imaging utilization between patients with and without IPV, will aid radiologists in accurate IPV diagnosis. Target injuries often involve the face and neck as a result of blunt trauma or strangulation, whereas defensive injuries often involve the extremity. Awareness of differences in injury patterns resulting from IPV-related and accidental trauma can aid radiologists in detecting a mismatch between the provided clinical history and imaging findings, to support suspicion for IPV. Radiologists should consider all available current and prior imaging in assessing the likelihood of IPV; this process may be aided by machine learning methods. Even if correctly suspecting IPV based on imaging, radiologists face challenges in acting upon that suspicion, including appropriately documenting the findings, without compromising the patient's confidentiality and safety. However, through a multidisciplinary approach with appropriate support mechanisms, radiologists may serve as effective frontline physicians for raising suspicion for IPV.

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors in two UK longitudinal studies.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. Higher levels of SARS-CoV-2 anti-Spike antibodies are known to be associated with increased protection against future SARS-CoV-2 infection. However, variation in antibody levels and risk factors for lower antibody levels following each round of SARS-CoV-2 vaccination have not been explored across a wide range of socio-demographic, SARS-CoV-2 infection and vaccination, and health factors within population-based cohorts. Methods: Samples were collected from 9361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies and tested for SARS-CoV-2 antibodies. Cross-sectional sampling was undertaken jointly in April-May 2021 (TwinsUK, N=4256; ALSPAC, N=4622), and in TwinsUK only in November 2021-January 2022 (N=3575). Variation in antibody levels after first, second, and third SARS-CoV-2 vaccination with health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables were analysed. Using multivariable logistic regression models, we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables. Results: Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had threefold greater odds of SARS-CoV-2 infection over the next 6-9 months (OR = 2.9, 95% CI: 1.4, 6.0), compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK 'Shielded Patient List' had consistently greater odds (two- to fourfold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. Conclusions: These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies. Funding: Antibody testing was funded by UK Health Security Agency. The National Core Studies program is funded by COVID-19 Longitudinal Health and Wellbeing - National Core Study (LHW-NCS) HMT/UKRI/MRC ([MC_PC_20030] and [MC_PC_20059]). Related funding was also provided by the NIHR 606 (CONVALESCENCE grant [COV-LT-0009]). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The UK Medical Research Council and Wellcome (Grant ref: [217065/Z/19/Z]) and the University of Bristol provide core support for ALSPAC.

Vaccination against the virus that causes COVID-19 triggers the body to produce antibodies that help fight future infections. But some people generate more antibodies after vaccination than others. People with lower levels of antibodies are more likely to get COVID-19 in the future. Identifying people with low antibody levels after COVID-19 vaccination is important. It could help decide who receives priority for future vaccination. Previous studies show that people with certain health conditions produce fewer antibodies after one or two doses of a COVID-19 vaccine. For example, people with weakened immune systems. Now that third booster doses are available, it is vital to determine if they increase antibody levels for those most at risk of severe COVID-19. Cheetham et al. show that a third booster dose of a COVID-19 vaccine boosts antibodies to high levels in 90% of individuals, including those at increased risk. In the experiments, Cheetham et al. measured antibodies against the virus that causes COVID-19 in 9,361 individuals participating in two large long-term health studies in the United Kingdom. The experiments found that UK individuals advised to shield from the virus because they were at increased risk of complications had lower levels of antibodies after one or two vaccine doses than individuals without such risk factors. This difference was also seen after a third booster dose, but overall antibody levels had large increases. People who received the Oxford/AstraZeneca vaccine as their first dose also had lower antibody levels after one or two doses than those who received the Pfizer/BioNTech vaccine first. Positively, this difference in antibody levels was no longer seen after a third booster dose. Individuals with lower antibody levels after their first dose were also more likely to have a case of COVID-19 in the following months. Antibody levels were high in most individuals after the third dose. The results may help governments and public health officials identify individuals who may need extra protection after the first two vaccine doses. They also support current policies promoting booster doses of the vaccine and may support prioritizing booster doses for those at the highest risk from COVID-19 in future vaccination campaigns.

Occupational health screening during Gurkha Central Selection: a retrospective cohort study

ObjectiveThe selection process to the British Army’s Brigade of Gurkhas is rigorous, demanding and competitive. The ethos of recruitment to the Gurkhas is grounded in an overarching tenant: that selection is free, fair and transparent. The aim of this study was to retrospectively review reasons for potential recruits (PRs) to be deemed medically unsuitable or deferred suitability on medical grounds for selection to the Brigade of Gurkhas.MethodsA retrospective review was conducted by extracted data from published post-exercise reports for the past four years to ascertain numbers of PRs deemed medically fit, medically unsuitable or deferred suitability on medical grounds. The International Classification of Disease version 11 (ICD-11) codes were retrospectively assigned to code medical reasons for non-progression. Rates of medical non-progression were compared by year.ResultsA total of 3154 PRs were analysed between 2018 and 2021. There was no significant difference between PRs deemed medically fit and those deemed medically suitable or deferred on medical grounds over the study period (p=0.351). There was a significant difference in the ratio of PRs deferred on medical grounds and those deemed medically unsuitable over the study period (p<0.05).ConclusionSelection to the Gurkhas is extremely competitive. These data demonstrate that, overall, reasons for medical deferral or unsuitability have remained constant despite the impact of a global pandemic. These data reinforce the central tenant of Gurkha selection;that it continues to be free, fair, and transparent.

Impact of the first wave of COVID-19 on stroke admissions across three tertiary hospitals in Brisbane.

BACKGROUND: COVID-19 has caused a global shift in healthcare-seeking behaviour; however, presentation rates with serious conditions, such as stroke in low COVID-19-prevalence cities, has received less attention. AIMS: To determine if there was a significant reduction in stroke admissions, delivery of acute reperfusion therapies, or increased delays to presentation during the first wave of the COVID-19 pandemic. METHODS: A multicentre, retrospective, observational cohort study was performed across three tertiary hospitals in Brisbane, Australia. Cases were identified using ICD-10 codes and then individually reviewed for eligibility using prespecified inclusion and exclusion criteria. All metrics were compared over 3 months from 1 March to 31 May 2020 with two corresponding 3-month periods in 2018 and 2019. RESULTS: There was a mean of 2.15 (95% CI 1.87-2.48) stroke admissions per day in the examined pandemic months compared with 2.13 (95% CI 1.85-2.45) and 2.26 (95% CI 1.97-2.59) in March to May 2018 and 2019 respectively, with no significant difference found (P = 0.81). There was also no difference in rates of intravenous thrombolysis (P = 0.82), endovascular thrombectomy (P = 0.93) and time from last known well to presentation (P = 0.54). Conversely, daily emergency department presentations (including non-stroke presentations) significantly reduced (P < 0.0001). CONCLUSIONS: During the early months of the COVID-19 pandemic there was no significant reduction in stroke presentations, use of acute reperfusion therapies or delays to presentation, despite a reduction in ED presentations for any cause. Our results differ from the global experience, with possible explanations, including differences in public health messaging and healthcare infrastructure.

Broad auto-reactive IgM responses are common in critically ill patients, including those with COVID-19.

The pathogenesis of severe coronavirus disease 2019 (COVID-19) remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (93%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM) and less frequently auto-reactive IgG or IgA. Importantly, these auto-IgMs preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, analytical proteome microarray technology, and lactose dehydrogenase (LDH)-release cytotoxicity assays, we identify high-affinity, complement-fixing, auto-reactive IgM directed against 260 candidate autoantigens, including numerous molecules preferentially expressed on the cellular membranes of pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for therapeutic interventions.

Impact of lockdown on key workers: findings from the COVID-19 survey in four UK national longitudinal studies.

BACKGROUND: Key workers played a pivotal role during the national lockdown in the UK's response to the COVID-19 pandemic. Although protective measures have been taken, the impact of the pandemic on key workers is yet to be fully elucidated. METHODS: Participants were from four longitudinal age-homogeneous British cohorts (born in 2001, 1990, 1970 and 1958). A web-based survey provided outcome data during the first UK national lockdown (May 2020) on COVID-19 infection status, changes in financial situation, trust in government, conflict with people around, household composition, psychological distress, alcohol consumption, smoking and sleep duration. Generalised linear models with logit link assessed the association between being a key worker and the above outcomes. Adjustment was made for cohort design, non-response, sex, ethnicity, adult socioeconomic position (SEP), childhood SEP, the presence of a chronic illness and receipt of a shielding letter. Meta-analyses were performed across the cohorts. FINDINGS: 13 736 participants were included. During lockdown, being a key worker was associated with increased chances of being infected with COVID-19 (OR 1.43, 95% CI 1.22 to 1.68) and experiencing conflict with people around (OR 1.19, 95% CI 1.03 to 1.37). However, key workers were less likely to be worse off financially (OR 0.32, 95% CI 0.24 to 0.65), to consume more alcohol (OR 0.88, 95% CI 0.79 to 0.98) or to smoke more (OR 0.60, 95% CI 0.44 to 0.80) during lockdown. Interestingly, being a key worker was not associated with psychological distress (OR 0.95, 95% CI 0.85 to 1.05). INTERPRETATION: Being a key worker during the first UK COVID-19 lockdown was a double-edged sword, with both benefits and downsides. The UK government had the basic duty to protect its key workers from SARS-CoV-2 infection, but it may have failed to do so, and there is an urgent need to rectify this in light of the ongoing third wave.

Evaluating access to health and care services during lockdown by the COVID-19 survey in five UK national longitudinal studies.

OBJECTIVE: Access to health services and adequate care is influenced by sex, ethnicity, socioeconomic position (SEP) and the burden of comorbidities. Our study aimed to assess whether the COVID-19 pandemic further deepened these already existing health inequalities. DESIGN: Cross-sectional study. SETTING: Data were collected from five longitudinal age-homogenous British cohorts (born in 2000-2002, 1989-1990, 1970, 1958 and 1946). PARTICIPANTS: A web survey was sent to the cohorts. Anybody who responded to the survey was included, resulting in 14 891 eligible participants. MAIN OUTCOMES MEASURED: The survey provided data on cancelled surgical or medical appointments, and the number of care hours received in a week during the first UK COVID-19 national lockdown. INTERVENTIONS: Using binary or ordered logistic regression, we evaluated whether these outcomes differed by sex, ethnicity, SEP and having a chronic illness. Adjustment was made for study design, non-response weights, psychological distress, presence of children or adolescents in the household, COVID-19 infection, key worker status, and whether participants had received a shielding letter. Meta-analyses were performed across the cohorts, and meta-regression was used to evaluate the effect of age as a moderator. RESULTS: Women (OR 1.40, 95% CI 1.27 to 1.55) and those with a chronic illness (OR 1.84, 95% CI 1.65 to 2.05) experienced significantly more cancellations during lockdown (all p<0.0001). Ethnic minorities and those with a chronic illness required a higher number of care hours during the lockdown (both OR≈2.00, all p<0.002). SEP was not associated with cancellation or care hours. Age was not independently associated with either outcome in the meta-regression. CONCLUSION: The UK government's lockdown approach during the COVID-19 pandemic appears to have deepened existing health inequalities, impacting predominantly women, ethnic minorities and those with chronic illnesses. Public health authorities need to implement urgent policies to ensure equitable access to health and care for all in preparation for a fourthwave.