Community seroprevalence of SARS-CoV-2 in children and adolescents in England, 2019-2021.

OBJECTIVE: To understand community seroprevalence of SARS-CoV-2 in children and adolescents. This is vital to understanding the susceptibility of this cohort to COVID-19 and to inform public health policy for disease control such as immunisation. DESIGN: We conducted a community-based cross-sectional seroprevalence study in participants aged 0-18 years old recruiting from seven regions in England between October 2019 and June 2021 and collecting extensive demographic and symptom data. Serum samples were tested for antibodies against SARS-CoV-2 spike and nucleocapsid proteins using Roche assays processed at UK Health Security Agency laboratories. Prevalence estimates were calculated for six time periods and were standardised by age group, ethnicity and National Health Service region. RESULTS: Post-first wave (June-August 2020), the (anti-spike IgG) adjusted seroprevalence was 5.2%, varying from 0.9% (participants 10-14 years old) to 9.5% (participants 5-9 years old). By April-June 2021, this had increased to 19.9%, varying from 13.9% (participants 0-4 years old) to 32.7% (participants 15-18 years old). Minority ethnic groups had higher risk of SARS-CoV-2 seropositivity than white participants (OR 1.4, 95% CI 1.0 to 2.0), after adjusting for sex, age, region, time period, deprivation and urban/rural geography. In children <10 years, there were no symptoms or symptom clusters that reliably predicted seropositivity. Overall, 48% of seropositive participants with complete questionnaire data recalled no symptoms between February 2020 and their study visit. CONCLUSIONS: Approximately one-third of participants aged 15-18 years old had evidence of antibodies against SARS-CoV-2 prior to the introduction of widespread vaccination. These data demonstrate that ethnic background is independently associated with risk of SARS-CoV-2 infection in children. TRIAL REGISTRATION NUMBER: NCT04061382.

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.

Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.

Anti-platelet factor 4 immunoglobulin G levels in vaccine-induced immune thrombocytopenia and thrombosis: Persistent positivity through 7 months.

Background: Anti-platelet factor 4 (PF4) antibodies that activate platelets via FcγRIIA drive the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT). Evolution of these antibodies and their ability to activate platelets after initial treatment remains unknown. Objectives: To assess how clinical and platelet parameters, anti-PF4 antibody levels, and patient serum reactivity changes during follow-up after VITT presentation. Methods: We describe cases of seven discharged VITT patients that were followed from diagnosis up to 280 days (range 199-280) after vaccination. We measured anti-PF4 antibodies and PF4 levels in patient serum during follow-up and tested the ability of patient serum to activate healthy donor platelets and patient platelets over time. Results: Anti-PF4 immunoglobulin G antibody levels are very high at diagnosis (0.9-2.6 OD) and remain relatively high (>1.0 OD) in all patients, except one treated with rituximab, at 7 months post vaccination. All patients were on direct oral anticoagulants throughout follow-up and no patients had recurrent thrombosis. Patients' platelets during follow-up have normal FcγRIIA levels and responsiveness to platelet agonists. Patient diagnostic serum strongly activated control platelets, either alone or with PF4. Most follow-up serum alone was weaker at stimulating donor and patient platelets. However, follow-up serum beyond 150 days still strongly activated platelets with PF4 addition in three patients. Patient serum PF4 levels were lower than controls at diagnosis but returned within normal range by day 50. Conclusions: Explanations for reduced platelet activation during follow-up, despite similar total anti-PF4 antibody levels, remains unclear. Clinical implications of persistent anti-PF4 antibodies in VITT require further study.

'Virtually Pen Green': developing a synchronous teaching response for adult learners studying early childhood degree programmes during COVID-19

This article explores an idea the researchers are calling Andragogical Isomorphism. The idea being that adults who are motivated to learn become academic when in non-linear relationships with other learners and their tutors. When all are able to be curious, vulnerable and confident shifts in academic capabilities occur. The global pandemic COVID-19 in 2020 brought with it exceptional challenges in education across the globe. Adaptations to teach virtually were expected almost immediately, educators needed to facilitate learning experiences in an unfamiliar, virtual world with little or no previous training. Research was conducted to gather feedback to capture how the recreation of face-to-face teaching online impacted female, undergraduate early years students. The researchers spent time reflecting on the principles that underpin their practice of working with mature learners. Essential elements of social constructivism alongside the critical nature of highly effective andragogical practice and the importance of practice wisdom/life experiences are explored. The benefits of reflection and gaining academic recognition are considered, as are the implications of these within the sector. The results suggest a principled synchronous teaching approach that attends to emotional and cognitive needs, could lead to internalising an altered sense of self in academia - Andragogical Isomorphism.

EPICENTRE - Delivery of high quality acute medical care without transfer to hospital

The NHS Five Year Forward View focuses on expansion and development of community services and out-of-hospital care. Hospital at Home is a concept that provides acute active treatment that would traditionally be provided in an inpatient setting, involving nursing staff and therapists. As well as being financially favourable, it is important to acknowledge that often, for a multitude of reasons, people prefer to remain at home rather than be admitted to hospital for treatment. The COVID-19 pandemic has further reiterated that patients are at risk of nosocomial infection. More importantly Hospital at Home care has consistently been associated with greater satisfaction compared to acute hospital care for both patients and their family members.

Anti-PF4 levels of patients with VITT do not reduce 4 months following AZD1222 vaccination (preprint)

BackgroundAnti-Platelet Factor 4 (PF4) IgG antibodies that activate platelets via Fc{gamma}RIIa have been shown to be an important part of the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT). There is now extensive literature on its presentation and initial management. There is no literature however on what happens to these patients following discharge. MethodsWe collected clinical data and samples from seven patients presenting with VITT and followed them up for 82-145 days. We also collected clinical samples from them at last follow-up. Testing for anti-PF4/heparin antibodies was done using an anti-PF4/heparin enzymatic immunoassay. Flow Cytometry was used to look at Fc{gamma}RIIa levels on patient platelets. Light Transmission Aggregometry with patient serum and healthy donor / patient platelets was used to analyse platelet responsiveness, in the presence and absence of PF4. FindingsAll patients were discharged on direct oral anticoagulants. Two patients remain completely symptom free, three have ongoing headaches, two have residual neurological deficits. Two patients developed mild thrombocytopenia and worsening headache (but without cerebral venous sinus thrombosis) and were retreated, one of these with rituximab. All patients, except the one treated with rituximab, had similar anti-PF4 antibody titres at 80-120 days to their levels at diagnosis. Platelets from patients at follow-up had normal levels of Fc{gamma}RIIa and had normal responses to thrombin and collagen-related-peptide. Patient serum from diagnosis strongly activated healthy donor platelets in the presence of PF4. Serum from follow-up was much weaker at stimulating platelets, even in the presence of PF4. InterpretationThis study shows that despite similar PF4 antibody titres at diagnosis and during follow-up, there are further differences in patient serum, that are not apparent from currently used testing, that result in lower levels of platelet activation during the follow-up period. Further understanding of these factors are important in order to assess duration of anticoagulation for these patients. FundingThis work was supported by an Accelerator Grant (AA/18/2/34218) from the British Heart Foundation (BHF) and by a National Institute for Health Research (NIHR) grant. Key pointsO_LIPF4 antibody titres do not reduce up to 4-months post ChAdOx1 nCoV-19 in patients with VITT C_LIO_LIDespite similar PF4 antibody titres, diagnostic serum is more potent at activating platelets in the presence of PF4 than follow-up serum. C_LI

Diagnosing Asthma with and without Aerosol-Generating Procedures.

BACKGROUND: Asthma diagnostic guidelines require procedures with aerosol-generating potential (aerosol-generating procedures [AGPs]) to guide decision making. Restricted access to AGPs poses significant challenges in primary care and resource-poor countries, further amplified during the coronavirus disease 2019 pandemic. OBJECTIVE: To establish an approach to asthma diagnosis that does not require AGPs. METHOD: Symptomatic yet untreated (beyond as-required bronchodilator use) adults with clinician-suspected asthma and maximum 10 pack year smoking history were recruited. Clinical history, physical examination, spirometry with bronchodilator reversibility, home peak flow monitoring, and bronchial challenges were performed, and fractional exhaled nitric oxide and serum eosinophils measured. Tests were then repeated following treatment with inhaled corticosteroids before an asthma diagnosis was confirmed or refuted by an expert panel. RESULTS: A total of 65 adults (mean age, 34.8 ± 12.2 years) were recruited. Five were excluded as "unclassifiable," because of borderline results or missing data. Of the remainder, 36 were diagnosed with asthma and 24 were not. Using data from non-AGPs only (wheeze on auscultation and blood eosinophilia) and home peak flow variability, a "rule-in" diagnostic model provided comparable discriminative ability to the application of established guidelines. Clinical suspicion of asthma together with at least 1 positive non-AGP test result provided a sensitivity of 55%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 60%. Application of this model reduced the need for spirometry-based tests by one-third. CONCLUSIONS: The proposed diagnostic algorithm may be clinically useful in "ruling-in" asthma in adults when access to AGPs is limited. This algorithm is not suitable for those with low clinical probability, with a significant smoking history, or where alternative diagnoses are more likely. This pragmatic approach to asthma diagnosis merits prospective validation.

Point-of-care lung ultrasound in the assessment of suspected COVID-19: a retrospective service evaluation with a severity score.

INTRODUCTION: Point-of-care lung ultrasound (POCUS) has been advocated as a tool to assess the severity of COVID19 and thereby aid risk stratification. METHODS: We conducted a retrospective service evaluation between the 3rd March and the 5th May 2020 to describe and characterise the use of POCUS within an acute care pathway designed specifically for the assessment of suspected or confirmed COVID-19. A novel POCUS severity scale was formulated by assessing pleural and interstitial abnormalities within six anatomical zones (three for each lung). An aggregated score was calculated for each patient and evaluated as a marker of disease severity using standard metrics of discriminatory performance. RESULTS: POCUS was performed in the assessment of 100 patients presenting with suspected COVID-19. POCUS was consistent with COVID-19 infection in 92% (n = 92) of the patients assessed. Severity, as assessed by POCUS, showed good discriminatory performance to predict all-cause inpatient mortality, death or critical care admission, and escalated oxygen requirements (AUC .80, .80, 82). The risk of all-cause mortality in patients with scores in lowest quartile was 2.5% (95%CI 0.12- 12.95) compared with 42.9% (95CI 15.8 - 75.0%) in the highest quartile. POCUS assessed severity correlated with length of stay and duration of supplemental oxygen therapy. CONCLUSION: A simple aggregated score formed by the summating the degree of pleural and interstitial change within six anatomical lung zones showed good discriminatory performance in predicting a range of adverse outcomes in patients with suspected COVID-19.