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Purpose: Chimeric antigen receptor T-cell (CART) therapy has shown clinical efficacy in refractory and relapsed large B-cell lymphomas, but is associated with serious acute and long-term toxicities. To understand the patient perspective, we measured a patient-reported outcome (PRO), specifically, health-related quality of life (HRQoL), at multiple time points over one year. Methods: This was a prospective feasibility study of a cohort of patients who were eligible for standard of care CART therapy, tisagenlecleucel. Demographic data and disease characteristics were collected. HRQoL was measured using FACT-Lym at baseline, and months 1, 3, 6 and 12. FACT-Lym includes FACT-G (physical, social, emotional and functional well-being domains), plus a lymphoma subscale. Results: Thirty-four of 35 patients approached, consented to participate. Two of them did not receive their infusion due to progressive disease. 50% were female and median age was 62 (23–77). Twenty-nine patients (91%) completed baseline FACT-Lym and 20 of 21 (95%) eligible patients completed 12-month FACT-Lym. 52% completed all 4 post-baseline FACT-Lym measures. Exploratory analyses for changes in FACT-Lym scores are reported. Conclusion: It is feasible to measure longitudinal PROs in patients who receive CART therapy. This study will inform future studies in evaluating the patient perspective on CART therapy. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic and the ensuing implementation of control measures caused widespread societal disruption. These disruptions may also have affected community transmission and seasonal circulation patterns of endemic respiratory viruses., Objective: We aimed to investigate the impact of COVID-19-related disruption on influenza-related emergency hospital admissions and deaths in Wales in the first 2 years of the pandemic., Methods: A descriptive analysis of influenza activity was conducted using anonymized pathology, hospitalization, and mortality data from the Secure Anonymised Information Linkage Databank in Wales. The annual incidence of emergency hospitalizations and deaths with influenza-specific diagnosis codes between January 1, 2015, and December 31, 2021, was estimated. Case definitions of emergency hospitalization and death required laboratory confirmation with a polymerase chain reaction test. Trends of admissions and deaths were analyzed monthly and yearly. We conducted 2 sensitivity analyses by extending case definitions to include acute respiratory illnesses with a positive influenza test and by limiting admissions to those with influenza as the primary diagnosis. We also examined yearly influenza testing trends to understand changes in testing behavior during the pandemic., Results: We studied a population of 3,235,883 Welsh residents in 2020 with a median age of 42.5 (IQR 22.9-61.0) years. Influenza testing in Wales increased notably in the last 2 months of 2020, and particularly in 2021 to 39,720 per 100,000 people, compared to the prepandemic levels (1343 in 2019). The percentage of influenza admissions matched to an influenza polymerase chain reaction test increased from 74.8% (1890/2526) in 2019 to 85.2% (98/115) in 2021. However, admissions with a positive test per 100,000 population decreased from 17.0 in 2019 to 2.7 and 0.6 in 2020 and 2021, respectively. Similarly, deaths due to influenza with a positive influenza test per 100,000 population decreased from 0.4 in 2019 to 0.0 in 2020 and 2021. Sensitivity analyses showed similar patterns of decreasing influenza admissions and deaths in the first 2 years of the COVID-19 pandemic., Conclusions: Nonpharmaceutical interventions to control COVID-19 were associated with a substantial reduction in the transmission of the influenza virus, with associated substantial reductions in hospital cases and deaths observed. Beyond the pandemic context, consideration should be given to the role of nonpharmaceutical community-driven interventions to reduce the burden of influenza., (© Mohammad Alsallakh, Davies Adeloye, Eleftheria Vasileiou, Shanya Sivakumaran, Ashley Akbari, Ronan A Lyons, Chris Robertson, Igor Rudan, Gwyneth A Davies, Aziz Sheikh. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

Cost-effectiveness analyses are required for therapies within Canada's universal healthcare system, leading to delays relative to U.S. healthcare. Patients with Hodgkin lymphoma (HL) generally have an excellent prognosis, but those who relapse after or are ineligible for transplant benefit from novel therapies, including brentuximab vedotin (BV). BV was FDA-approved in 2011 but not Canadian-funded until 2014. To assess the impact of access delays, we compared changes in survival for U.S. (by insurer) and Canadian patients in periods pre/post-U.S. approval. Patients were 16-64 years, diagnosed with HL in 2007-2010 (Period 1) and 2011-2014 (Period 2) from the U.S. SEER and Canadian Cancer Registries. Approval date (surrogate) was utilized as therapy was unavailable in registries. Kaplan-Meier survival curves and adjusted Cox regression models compared survival between periods by insurance category. Among 12,003 U.S. and 4210 Canadian patients, survival was better in U.S. patients (adjusted hazard ratio (aHR) 0.87 (95%CI 0.77-0.98)) between periods; improvement in Canadian patients (aHR 0.84 (95%CI 0.69-1.03) was similar but non-significant. Comparisons between insurers showed survival was significantly worse for U.S. uninsured and Medicaid vs. U.S. privately insured and Canadian patients. Given the increasingly complex nature of oncologic funding, this merits further investigation to ensure equity in access to therapy developments.

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance., (© 2024. The Author(s).)

A cornerstone of asthma management is maintaining physical activity (PA), but this may lead to increased exposure to, and deeper inhalation of, pollutants. Furthermore, children and adolescents may be more susceptible to the deleterious impacts of such exposures. Despite the recent air quality campaigns and media coverage surrounding the dangers of air pollution to respiratory health, few target children and their understanding of such issues.Using semi structured interviews, understanding of PA, air pollution and their interaction was explored with 25 youth aged 7-17 years. Utilising NVIVO 12 software, an atheoretical, inductive thematic analysis was conducted to identify key themes which were subsequently presented as pen profiles with the number of common responses within a theme indicative of its strength.The majority (88%) of youth's indicated traffic-related air pollution and global manufacturing as key sources of air pollution. Whilst all youths were aware of outdoor pollution, only 52% were aware of indoor air pollutants, of which 62% had asthma. Despite some uncertainty, all youths described pollution in a negative fashion, with 52% linking air pollution to undesirable effects on health, specifically respiratory health. PA in a polluted area was thought to be more dangerous than beneficial by 44%, although 24% suggested the benefits of PA would outweigh any detriment from pollution.Youth are aware of, and potentially compensate for, the interaction between air pollution and PA. Strategies are needed to allow youth to make more informed decisions regarding how to promote PA whilst minimising exposure to air pollution., (© 2023. The Author(s).)

Purpose: The objective of this study is to investigate whether heterogeneous treatment effects occur for changes in inspiratory muscle strength, perceived dyspnea, and health-related quality of life after 8 wk of unsupervised home-based inspiratory muscle training (IMT) in adults with postacute coronavirus disease 2019 (COVID-19) syndrome., Methods: In total, 147 adults with self-reported prior COVID-19 either completed an 8-wk home-based IMT intervention ( n = 111, 92 females, 48 ± 11 yr, 9.3 ± 3.6 months postacute COVID-19 infection) or acted as "usual care" wait list controls ( n = 36, 34 females, 49 ± 12 yr, 9.4 ± 3.2 months postacute COVID-19 infection)., Results: Applying a Bayesian framework, we found clear evidence of heterogeneity of treatment response for inspiratory muscle strength: the estimated difference between standard deviations (SD) of the IMT and control groups was 22.8 cm H 2 O (75% credible interval (CrI), 4.7-37.7) for changes in maximal inspiratory pressure (MIP) and 86.8 pressure time units (75% CrI, 55.7-116.7) for sustained MIP (SMIP). Conversely, there were minimal differences in the SD between the IMT and the control group for changes in perceived dyspnea and health-related quality of life, providing no evidence of heterogeneous treatment effects. Higher cumulative power during the IMT intervention was related to changes in MIP ( β = 10.9 cm H 2 O (95% CrI, 5.3-16.8) per 1 SD) and SMIP ( β = 63.7 (32.2-95.3) pressure time units per 1 SD), clearly indicating an IMT dose response for changes in inspiratory muscle strength. Older age (>50 yr), a longer time postacute COVID-19 (>3 months), and greater severity of dyspnea at baseline were also associated with smaller improvements in inspiratory muscle strength., Conclusions: Heterogeneous individual responses occurred after an 8-wk home-based IMT program in people with postacute COVID-19 syndrome. Consistent with standard exercise theory, larger improvements in inspiratory muscle strength are strongly related to a greater cumulative dose of IMT., (Copyright © 2023 by the American College of Sports Medicine.)

In 1837 Guillaume von Dupuytren (1777-1835) wrote that the innovative method of reducing an ankle fracture by relaxing the calf muscles was due to both William Sharp (1729-1810) and Percivall Pott (1714-1788). While history records the many surgical achievements of Percivall Pott, little is known of William Sharp's contribution. He is probably best known as one of a remarkable family portrayed by Johan Zoffany (1733-1810) and exhibited at the Royal Academy in 1781. We review William Sharp's career and contribution as a surgeon to the treatment of fracture/dislocations of the ankle and ask why his concept is not better known today.

Objectives: To characterise microbiology testing and results associated with emergency admissions for acute exacerbation of COPD (AECOPD), and determine the accuracy of ICD-10 codes in retrospectively identifying laboratory-confirmed respiratory pathogens in this setting., Methods: Using person-level data from the Secure Anonymised Information Linkage Databank in Wales, we extracted emergency admissions for COPD from 1/12/2016 to 30/11/2018 and undertook linkage of admissions data to microbiology data to identify laboratory-confirmed infection. We further used these data to assess the accuracy of pathogen-specific ICD-10 codes., Results: We analysed data from 15,950 people who had 25,715 emergency admissions for COPD over the two-year period. 99.5% of admissions could be linked to a laboratory test within 7 days of admission date. Sputum was collected in 5,013 (19.5%) of admissions, and respiratory virus testing in 1,219 (4.7%). Where respiratory virus testing was undertaken, 46.7% returned any positive result. Influenza was the virus most frequently detected, in 21.5% of admissions where testing was conducted. ICD-10 codes exhibited low sensitivity in detecting laboratory-confirmed respiratory pathogens., Conclusions: In people admitted to hospital with AECOPD, increased testing for respiratory viruses could enable more effective antibiotic stewardship and isolation of cases. Linkage with microbiology data achieves more accurate and reliable case definitions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prospective population-based studies investigating associations between reactive symptoms following SARS-CoV-2 vaccination and serologic responses to vaccination are lacking. We therefore conducted a study in 9003 adults from the UK general population receiving SARS-CoV-2 vaccines as part of the national vaccination programme. Titres of combined IgG/IgA/IgM responses to SARS-CoV-2 spike (S) glycoprotein were determined in eluates of dried blood spots collected from all participants before and after vaccination. 4262 (47.3%) participants experienced systemic reactive symptoms after a first vaccine dose. Factors associating with lower risk of such symptoms included older age (aOR per additional 10 years of age 0.85, 95% CI: 0.81-0.90), male vs. female sex (0.59, 0.53-0.65) and receipt of an mRNA vaccine vs. ChAdOx1 nCoV-19 (0.29, 0.26-0.32 for BNT162b2; 0.06, 0.01-0.26 for mRNA-1273). Higher risk of such symptoms was associated with SARS-CoV-2 seropositivity and COVID-19 symptoms prior to vaccination (2.23, 1.78-2.81), but not with SARS-CoV-2 seropositivity in the absence of COVID-19 symptoms (0.94, 0.81-1.09). Presence vs. absence of self-reported anxiety or depression at enrolment associated with higher risk of such symptoms (1.24, 1.12-1.39). Post-vaccination anti-S titres were higher among participants who experienced reactive symptoms after vaccination vs. those who did not (P < 0.001). We conclude that factors influencing risk of systemic symptoms after SARS-CoV-2 vaccination include demographic characteristics, pre-vaccination SARS-CoV-2 serostatus and vaccine type. Participants experiencing reactive symptoms following SARS-CoV-2 vaccination had higher post-vaccination titres of IgG/A/M anti-S antibodies. Improved public understanding of the frequency of reactogenic symptoms and their positive association with vaccine immunogenicity could potentially increase vaccine uptake., (© 2023. The Author(s).)

Introduction: Asthma is one of the commonest chronic conditions in the world. Subtypes of asthma have been defined, typically from clinical datasets on small, well-characterised subpopulations of asthma patients. We sought to define asthma subtypes from large longitudinal primary care electronic health records (EHRs) using cluster analysis., Methods: In this retrospective cohort study, we extracted asthma subpopulations from the Optimum Patient Care Research Database (OPCRD) to robustly train and test algorithms, and externally validated findings in the Secure Anonymised Information Linkage (SAIL) Databank. In both databases, we identified adults with an asthma diagnosis code recorded in the three years prior to an index date. Train and test datasets were selected from OPCRD using an index date of Jan 1, 2016. Two internal validation datasets were selected from OPCRD using index dates of Jan 1, 2017 and 2018. Three external validation datasets were selected from SAIL using index dates of Jan 1, 2016, 2017 and 2018. Each dataset comprised 50,000 randomly selected non-overlapping patients. Subtypes were defined by applying multiple correspondence analysis and k-means cluster analysis to the train dataset, and were validated in the internal and external validation datasets., Results: We defined six asthma subtypes with clear clinical interpretability: low inhaled corticosteroid (ICS) use and low healthcare utilisation (30% of patients); low-to-medium ICS use (36%); low-to-medium ICS use and comorbidities (12%); varied ICS use and comorbid chronic obstructive pulmonary disease (4%); high (10%) and very high ICS use (7%). The subtypes were replicated with high accuracy in internal (91-92%) and external (84-86%) datasets., Conclusion: Asthma subtypes derived and validated in large independent EHR databases were primarily defined by level of ICS use, level of healthcare use, and presence of comorbidities. This has important clinical implications towards defining asthma subtypes, facilitating patient stratification, and developing more personalised monitoring and treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings ltd, FIECON ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; stock/stock options from AKL Research and Development ltd which produces phytopharmaceuticals; owns 74 % of the social enterprise Optimum Patient Care ltd (Australia and UK) and 92.61 % of Observational and Pragmatic Research Institute Pte ltd (Singapore); 5 % shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. All other authors have no conflict of interest to declare., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To better understand the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among healthcare workers, leading to recommendations for the prioritisation of personal protective equipment, testing, training and vaccination., Design: Observational, longitudinal, national cohort study., Setting: Our cohort were secondary care (hospital-based) healthcare workers employed by NHS Wales (United Kingdom) organisations from 1 April 2020 to 30 November 2020., Participants: We included 577,756 monthly observations among 77,587 healthcare workers. Using linked anonymised datasets, participants were grouped into 20 staff roles. Additionally, each role was deemed either patient-facing, non-patient-facing or undetermined. This was linked to individual demographic details and dates of positive SARS-CoV-2 PCR tests., Main Outcome Measures: We used univariable and multivariable logistic regression models to determine odds ratios (ORs) for the risk of a positive SARS-CoV-2 PCR test., Results: Patient-facing healthcare workers were at the highest risk of SARS-CoV-2 infection with an adjusted OR (95% confidence interval [CI]) of 2.28 (95% CI 2.10-2.47). We found that after adjustment, foundation year doctors (OR 1.83 [95% CI 1.47-2.27]), healthcare support workers [OR 1.36 [95% CI 1.20-1.54]) and hospital nurses (OR 1.27 [95% CI 1.12-1.44]) were at the highest risk of infection among all staff groups. Younger healthcare workers and those living in more deprived areas were at a higher risk of infection. We also observed that infection rates varied over time and by organisation., Conclusions: These findings have important policy implications for the prioritisation of vaccination, testing, training and personal protective equipment provision for patient-facing roles and the higher risk staff groups.

Post COVID-19 condition can occur following infection with SARS-CoV-2 and is characterised by persistent symptoms, including fatigue, breathlessness and cognitive dysfunction, impacting everyday functioning. This study explored how people living with post COVID-19 experienced an eight-week inspiratory muscle training (IMT) rehabilitation programme. Individualised semi-structured interviews with 33 adults (29 female; 49 ± 10 years; 6-11 months post-infection) explored expectations of IMT prior to the intervention, and post intervention interviews explored perceptions of IMT and its impact on recovery. Inductive thematic analysis was used to analyse the data. IMT helped many to feel proactive in managing their symptoms and was associated with perceived improvements in respiratory symptoms, exercise and work capacity, and daily functioning. IMT was well perceived and offers significant potential for use as part of a holistic recovery programme, although it is important to consider the complex, varied symptoms of post COVID-19, necessitating an individually tailored rehabilitation approach., Competing Interests: The authors have declared that no competing interests exist.

Background: Many people recovering from coronavirus disease 2019 (COVID-19) experience prolonged symptoms, particularly breathlessness. We urgently need to identify safe and effective COVID-19 rehabilitative strategies. The aim of the current study was to investigate the potential rehabilitative role of inspiratory muscle training (IMT)., Methods: 281 adults (age 46.6±12.2 years; 88% female) recovering from self-reported COVID-19 (9.0±4.2 months post-acute infection) were randomised 4:1 to an 8-week IMT or a "usual care" waitlist control arm. Health-related quality-of-life and breathlessness questionnaires (King's Brief Interstitial Lung Disease (K-BILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength, and fitness (Chester Step Test) were assessed pre- and post-intervention. The primary end-point was K-BILD total score, with the K-BILD domains and TDI being key secondary outcomes., Results: According to intention to treat, there was no difference between groups in K-BILD total score post-intervention (control: 59.5±12.4; IMT: 58.2±12.3; p<0.05) but IMT elicited clinically meaningful improvements in the K-BILD domains for breathlessness (control: 59.8±12.6; IMT: 62.2±16.2; p<0.05) and chest symptoms (control: 59.2±18.7; IMT: 64.5±18.2; p<0.05), along with clinically meaningful improvements in breathlessness according to TDI (control: 0.9±1.7 versus 2.0±2.0; p<0.05). IMT also improved respiratory muscle strength and estimated aerobic fitness., Conclusions: IMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies. Given the diverse nature of long COVID, further research is warranted on the individual responses to rehabilitation; the withdrawal rate herein highlights that no one strategy is likely to be appropriate for all., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare., (Copyright ©The authors 2022.)

Background: Little is known about how demographic, behavioural, and vaccine-related factors affect risk of post-vaccination SARS-CoV-2 infection. We aimed to identify risk factors for SARS-CoV-2 infection after primary and booster vaccinations., Methods: This prospective, population-based, UK study in adults (≥16 years) vaccinated against SARS-CoV-2 assessed risk of breakthrough SARS-CoV-2 infection up to February, 2022, for participants who completed a primary vaccination course (ChAdOx1 nCoV-19 or BNT162b2) and those who received a booster dose (BNT162b2 or mRNA-1273). Cox regression models explored associations between sociodemographic, behavioural, clinical, pharmacological, and nutritional factors and test-positive breakthrough infection, adjusted for local weekly SARS-CoV-2 incidence., Findings: 1051 (7·1%) of 14 713 post-primary participants and 1009 (9·5%) of 10 665 post-booster participants reported breakthrough infection, over a median follow-up of 203 days (IQR 195-216) and 85 days (66-103), respectively. Primary vaccination with ChAdOx1 ( vs BNT162b2) was associated with higher risk of infection in both post-primary analysis (adjusted hazard ratio 1·63, 95% CI 1·41-1·88) and after an mRNA-1273 booster (1·26 [1·00-1·57] vs BNT162b2 primary and booster). Lower risk of infection was associated with older age (post-primary: 0·97 [0·96-0·97] per year; post-booster: 0·97 [0·97-0·98]), whereas higher risk of infection was associated with lower educational attainment (post-primary: 1·78 [1·44-2·20] for primary/secondary vs postgraduate; post-booster: 1·46 [1·16-1·83]) and at least three weekly visits to indoor public places (post-primary: 1·36 [1·13-1·63] vs none; post-booster: 1·29 [1·07-1·56])., Interpretation: Vaccine type, socioeconomic status, age, and behaviours affect risk of breakthrough infection after primary and booster vaccinations., Funding: Barts Charity, UK Research and Innovation Industrial Strategy Challenge Fund., Competing Interests: R.A.L. has received grants from UKRI Medical Research Council, UKRI Economic and Social Research Council, Health Data Research UK, and Health and Care Research Wales. R.A.L. is a member of the Welsh Government COVID-19 Technical Advisory group, in an unremunerated role. A.S. is a member of the Scottish Government's Standing Committee on Pandemics, the Scottish Science Advisory Council, the UK Government's New and Emerging Respiratory Virus Threats Risk Stratification Subgroup and the Department of Health and Social Care's COVID-19 Therapeutics Modelling Group. He was a member of the Scottish Government Chief Medical Officer's COVID-19 Advisory Group and AstraZeneca's Thrombotic Thrombocytopenic Taskforce. All of A.S.’ roles are unremunerated. A.R.M. declares receipt of funding to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord DSM Nutritional Products, Thornton & Ross, and Hyphens Pharma. A.R.M. also declares support for attending meetings from the following companies who manufacture or sell vitamin D supplements: Pharma Nord and Abiogen Pharma. A.R.M. also declares participation on the Data and Safety Monitoring Board for the Chair, DSMB, VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology). A.R.M. also declares unpaid work as a Programme Committee member for the Vitamin D Workshop. A.R.M. also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord, Synergy Biologics, and Cytoplan. All other authors declare no competing interests., (© 2022 The Authors.)

Antibody responses to SARS-CoV-2 vaccines vary for reasons that remain poorly understood. A range of sociodemographic, behavioural, clinical, pharmacologic and nutritional factors could explain these differences. To investigate this hypothesis, we tested for presence of combined IgG, IgA and IgM (IgGAM) anti-Spike antibodies before and after 2 doses of ChAdOx1 nCoV-19 (ChAdOx1, AstraZeneca) or BNT162b2 (Pfizer-BioNTech) in UK adults participating in a population-based longitudinal study who received their first dose of vaccine between December 2020 and July 2021. Information on sixty-six potential sociodemographic, behavioural, clinical, pharmacologic and nutritional determinants of serological response to vaccination was captured using serial online questionnaires. We used logistic regression to estimate multivariable-adjusted odds ratios (aORs) for associations between independent variables and risk of seronegativity following two vaccine doses. Additionally, percentage differences in antibody titres between groups were estimated in the sub-set of participants who were seropositive post-vaccination using linear regression. Anti-spike antibodies were undetectable in 378/9101 (4.2%) participants at a median of 8.6 weeks post second vaccine dose. Increased risk of post-vaccination seronegativity associated with administration of ChAdOx1 vs. BNT162b2 (adjusted odds ratio (aOR) 6.6, 95% CI 4.2−10.4), shorter interval between vaccine doses (aOR 1.6, 1.2−2.1, 6−10 vs. >10 weeks), poor vs. excellent general health (aOR 3.1, 1.4−7.0), immunodeficiency (aOR 6.5, 2.5−16.6) and immunosuppressant use (aOR 3.7, 2.4−5.7). Odds of seronegativity were lower for participants who were SARS-CoV-2 seropositive pre-vaccination (aOR 0.2, 0.0−0.6) and for those taking vitamin D supplements (aOR 0.7, 0.5−0.9). Serologic responses to vaccination did not associate with time of day of vaccine administration, lifestyle factors including tobacco smoking, alcohol intake and sleep, or use of anti-pyretics for management of reactive symptoms after vaccination. In a sub-set of 8727 individuals who were seropositive post-vaccination, lower antibody titres associated with administration of ChAdOx1 vs. BNT162b2 (43.4% lower, 41.8−44.8), longer duration between second vaccine dose and sampling (12.7% lower, 8.2−16.9, for 9−16 weeks vs. 2−4 weeks), shorter interval between vaccine doses (10.4% lower, 3.7−16.7, for <6 weeks vs. >10 weeks), receiving a second vaccine dose in October−December vs. April−June (47.7% lower, 11.4−69.1), older age (3.3% lower per 10-year increase in age, 2.1−4.6), and hypertension (4.1% lower, 1.1−6.9). Higher antibody titres associated with South Asian ethnicity (16.2% higher, 3.0−31.1, vs. White ethnicity) or Mixed/Multiple/Other ethnicity (11.8% higher, 2.9−21.6, vs. White ethnicity), higher body mass index (BMI; 2.9% higher, 0.2−5.7, for BMI 25−30 vs. <25 kg/m2) and pre-vaccination seropositivity for SARS-CoV-2 (105.1% higher, 94.1−116.6, for those seropositive and experienced COVID-19 symptoms vs. those who were seronegative pre-vaccination). In conclusion, we identify multiple determinants of antibody responses to SARS-CoV-2 vaccines, many of which are modifiable.

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., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: funding from Barts Charity, Pharma Nord, Fischer Family Foundation, DSM Nutritional Products, Exilarch’s Foundation, Karl R Pfleger Foundation, AIM Foundation, Synergy Biologics, Cytoplan, UK National Institute for Health and Care Research Clinical Research Network, the HDR UK BREATHE Hub, the UK Research and Innovation Industrial Strategy Challenge Fund, Thornton & Ross, Warburtons, Matthew Isaacs (a philanthropist without financial interests constituting a potential conflict), and Hyphens Pharma. JS receives payments from Reach for news stories written about recruitment to, and findings of, the COVIDENCE UK study. RAL is a member of the Welsh government COVID-19 Technical Advisory Group. AS and JN declare research infrastructure support to the University of Edinburgh from the Industrial Strategy Challenge Fund (ISCF) and Health Data Research United Kingdom (HDR UK). AS is a member of the Scottish government chief medical officer’s COVID-19 Advisory Group and its Standing Committee on Pandemics. He is also a member of the UK Government’s NERVTAG’s Risk Stratification Subgroup. ARM declares receiving funding in the past three years to support vitamin D research from several companies that manufacture or sell vitamin D supplements: Pharma Nord, DSM Nutritional Products, Thornton & Ross, and Hyphens Pharma. ARM also declares support for attending meetings from companies that manufacture or sell vitamin D supplements (Pharma Nord and Abiogen Pharma); receipt of a consultancy fee from DSM Nutritional Products; receipt of a speaker fee from the Linus Pauling Institute; participation on data and safety monitoring boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref NCT04641195); unpaid work as a programme committee member for the Vitamin D Workshop; and receipt of vitamin D capsules for clinical trial use from Pharma Nord, Synergy Biologics, and Cytoplan., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Prospective population-based studies investigating multiple determinants of pre-vaccination antibody responses to SARS-CoV-2 are lacking., Methods: We did a prospective population-based study in SARS-CoV-2 vaccine-naive UK adults recruited between May 1 and November 2, 2020, without a positive swab test result for SARS-CoV-2 prior to enrolment. Information on 88 potential sociodemographic, behavioural, nutritional, clinical and pharmacological risk factors was obtained through online questionnaires, and combined IgG/IgA/IgM responses to SARS-CoV-2 spike glycoprotein were determined in dried blood spots obtained between November 6, 2020, and April 18, 2021. We used logistic and linear regression to estimate adjusted odds ratios (aORs) and adjusted geometric mean ratios (aGMRs) for potential determinants of SARS-CoV-2 seropositivity (all participants) and antibody titres (seropositive participants only), respectively., Results: Of 11,130 participants, 1696 (15.2%) were seropositive. Factors independently associated with  higher risk of SARS-CoV-2 seropositivity included frontline health/care occupation (aOR 1.86, 95% CI 1.48-2.33), international travel (1.20, 1.07-1.35), number of visits to shops and other indoor public places (≥ 5 vs. 0/week: 1.29, 1.06-1.57, P-trend = 0.01), body mass index (BMI) ≥ 25 vs. < 25 kg/m 2 (1.24, 1.11-1.39), South Asian vs. White ethnicity (1.65, 1.10-2.49) and alcohol consumption ≥15 vs. 0 units/week (1.23, 1.04-1.46). Light physical exercise associated with  lower risk (0.80, 0.70-0.93, for ≥ 10 vs. 0-4 h/week). Among seropositive participants, higher titres of anti-Spike antibodies associated with factors including BMI ≥ 30 vs. < 25 kg/m 2 (aGMR 1.10, 1.02-1.19), South Asian vs. White ethnicity (1.22, 1.04-1.44), frontline health/care occupation (1.24, 95% CI 1.11-1.39), international travel (1.11, 1.05-1.16) and number of visits to shops and other indoor public places (≥ 5 vs. 0/week: 1.12, 1.02-1.23, P-trend = 0.01); these associations were not substantially attenuated by adjustment for COVID-19 disease severity., Conclusions: Higher alcohol consumption and lower light physical exercise represent new modifiable risk factors for SARS-CoV-2 infection. Recognised associations between South Asian ethnic origin and obesity and higher risk of SARS-CoV-2 seropositivity were independent of other sociodemographic, behavioural, nutritional, clinical, and pharmacological factors investigated. Among seropositive participants, higher titres of anti-Spike antibodies in people of South Asian ancestry and in obese people were not explained by greater COVID-19 disease severity in these groups., (© 2022. The Author(s).)

The majority of women do not meet the recommended levels of exercise during their pregnancies, frequently due to a lack of time. High-intensity interval training offers a potential solution, providing an effective, time-efficient exercise modality. This exercise modality has not been studied in pregnancy therefore, the objective of this study was to evaluate fetal response to a high-intensity interval training resistance circuit in the late second and early third trimesters of pregnancy. Fourteen active, healthy women with uncomplicated, singleton pregnancies participated in a high-intensity interval training resistance circuit between 28 + 0/7 and 32 + 0/7 weeks. A Borg rating of perceived exertion of 15-17/20 and an estimated heart rate of 80%-90% of maternal heart-rate maximum was targeted. Fetal well-being was evaluated continuously with fetal heart-rate tracings and umbilical artery Doppler velocimetry conducted pre-and post-exercise. Fetal heart rate tracings were normal throughout the exercise circuit. Post-exercise, umbilical artery end-diastolic flow was normal and significant decreases were observed in the mean systolic/diastolic ratios, pulsatility indexes and resistance indexes. Therefore, in a small cohort of active pregnant women, a high-intensity interval training resistance circuit in the late second and early third trimesters of pregnancy appears to be a safe exercise modality with no acute, adverse fetal effects but further study is required. Novelty: High-intensity interval training, at an intensity in excess of current recommendations, does not appear to be associated with any adverse fetal effects in previously active pregnant women. High-intensity interval training is an enjoyable and effective exercise modality in previously active pregnant women.

Background: There is no published algorithm predicting asthma crisis events (accident and emergency [A&E] attendance, hospitalisation, or death) using routinely available electronic health record (EHR) data., Aim: To develop an algorithm to identify individuals at high risk of an asthma crisis event., Design and Setting: Database analysis from primary care EHRs of people with asthma across England and Scotland., Method: Multivariable logistic regression was applied to a dataset of 61 861 people with asthma from England and Scotland using the Clinical Practice Research Datalink. External validation was performed using the Secure Anonymised Information Linkage Databank of 174 240 patients from Wales. Outcomes were ≥1 hospitalisation (development dataset) and asthma-related hospitalisation, A&E attendance, or death (validation dataset) within a 12-month period., Results: Risk factors for asthma-related crisis events included previous hospitalisation, older age, underweight, smoking, and blood eosinophilia. The prediction algorithm had acceptable predictive ability with a receiver operating characteristic of 0.71 (95% confidence interval [CI] = 0.70 to 0.72) in the validation dataset. Using a cut-point based on the 7% of the population at greatest risk results in a positive predictive value of 5.7% (95% CI = 5.3% to 6.1%) and a negative predictive value of 98.9% (95% CI = 98.9% to 99.0%), with sensitivity of 28.5% (95% CI = 26.7% to 30.3%) and specificity of 93.3% (95% CI = 93.2% to 93.4%); those individuals had an event risk of 6.0% compared with 1.1% for the remaining population. In total, 18 people would need to be followed to identify one admission., Conclusion: This externally validated algorithm has acceptable predictive ability for identifying patients at high risk of asthma-related crisis events and excluding those not at high risk., (© The Authors.)