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Background: Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent.Methods: We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D(3). This trial is registered with ClinicalTrials.gov number NCT00419068.Findings: 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90-2·16; p=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p(interaction)=0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36-48·01; p=0·02). FokI genotype did not modify the effect of vitamin D supplementation (p(interaction)=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6-88·2; p<0·0001).Interpretation: Administration of four doses of 2·5 mg vitamin D(3) increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism.Funding: British Lung Foundation. [ABSTRACT FROM AUTHOR]

Background: Concerted efforts aim to reduce the burden of 6 months of anti-tuberculous treatment for tuberculosis (TB). Treatment cessation at 8 weeks is effective for most but incurs increased risk of disease relapse. We tested the hypothesis that blood RNA signatures or C-reactive protein (CRP) measurements discriminate 8-week sputum culture status, as a prerequisite for a biomarker to stratify risk of relapse following treatment cessation at this time-point., Methods: We identified blood RNA signatures of TB disease or cure by systematic review. We evaluated these signatures and CRP measurements in a pulmonary TB cohort, pre-treatment, at 2 and 8 weeks of treatment, and sustained cure after treatment completion. We tested biomarker discrimination of 8-week sputum culture status using area under the receiver operating characteristic curve (AUROC) analysis and, secondarily, assessed correlation of biomarker scores with time to culture positivity at 8 weeks of treatment., Results: 12 blood RNA signatures were reproduced in the dataset from 44 individuals with sputum culture-positive pulmonary TB. These normalised over time from TB treatment initiation. 11 out of 44 cases with blood RNA, CRP and sputum culture results were sputum culture-positive at 8 weeks of treatment. None of the contemporary blood RNA signatures discriminated sputum culture status at this time-point or correlated with bacterial load. CRP achieved modest discrimination with AUROC 0.69 (95% CI 0.52-0.87)., Conclusions: Selected TB blood RNA signatures and CRP do not provide biomarkers of microbiological clearance to support TB treatment cessation at 8 weeks. Resolution of blood transcriptional host responses in sputum culture-positive individuals suggests Mycobacterium tuberculosis may colonise the respiratory tract without triggering a detectable immune response., Competing Interests: Conflict of interest: C.J. Calderwood reports support for the present study from the National Institute for Health Research (Academic Clinical Fellowship), grants from the Wellcome Trust (225466/Z/22/Z), and support for attending meetings from the British Thoracic Society (Travel Award 2023). B. Oguti reports support for the present study from the National Institute for Health Research (Academic Clinical Fellowship, awarded via University College London). J.K. Roe reports patents held in relation to blood transcriptomic biomarkers of tuberculosis. R. Gupta reports support for the present study from the National Institute for Health Research (personal fellowship award). A.R. Martineau reports support for the present study from the British Lung Foundation, and patents held in relation to blood transcriptomic biomarkers of tuberculosis. M. Noursadeghi reports support for the present study from the Wellcome Trust and NIHR Biomedical Research Centre at University College London Hospitals NHS Trust, and patents held in relation to blood transcriptomic biomarkers of tuberculosis. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: Control of latent tuberculosis infection (LTBI) is a priority in the World Health Organization strategy to eliminate TB. Many high-income, low TB incidence countries have prioritised LTBI screening and treatment in recent migrants. We tested whether a novel model of care, based entirely within primary care, was effective and safe compared to secondary care., Methods: This was a pragmatic cluster-randomised, parallel group, superiority trial (ClinicalTrials.gov: NCT03069807) conducted in 34 general practices in London, UK, comparing LTBI treatment in recent migrants in primary care to secondary care. The primary outcome was treatment completion, defined as taking ≥90% of antibiotic doses. Secondary outcomes included treatment acceptance, adherence, adverse effects, patient satisfaction, TB incidence and a cost-effectiveness analysis. Analyses were performed on an intention-to-treat basis., Results: Between September 2016 and May 2019, 362 recent migrants with LTBI were offered treatment and 276 accepted. Treatment completion was similar in primary and secondary care (82.6% versus 86.0%; adjusted OR (aOR) 0.64, 95% CI 0.31-1.29). There was no difference in drug-induced liver injury between primary and secondary care (0.7% versus 2.3%; aOR 0.29, 95% CI 0.03-2.84). Treatment acceptance was lower in primary care (65.2% (146/224) versus 94.2% (130/138); aOR 0.10, 95% CI 0.03-0.30). The estimated cost per patient completing treatment was lower in primary care, with an incremental saving of GBP 315.27 (95% CI 313.47-317.07)., Conclusions: The treatment of LTBI in recent migrants within primary care does not result in higher rates of treatment completion but is safe and costs less when compared to secondary care., Competing Interests: Conflict of interest: P.J. White reports grants from the Medical Research Council and National Institute for Health and Care Research, and consulting fees from Pfizer, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: COPD is a common, preventable and treatable airway disease, and is currently the third leading cause of death worldwide. About one billion people worldwide are estimated to have vitamin D deficiency or insufficiency. Vitamin D deficiency is common among people with COPD, and has been reported to be associated with reduced lung function and increased risk of acute exacerbations of COPD. Several clinical trials of vitamin D to prevent acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and improve COPD control have been conducted, but an up-to-date meta-analysis of all double-blind, randomised, placebo-controlled trials of this intervention is lacking., Objectives: To assess the effects of vitamin D for the management of acute exacerbations and symptoms for people with COPD., Search Methods: We searched the Cochrane Airways Trials Register and reference lists of articles. We also searched trial registries directly, and contacted the authors of studies in order to identify additional trials. The date of the last search was 24 August 2022., Selection Criteria: We included double-blind, randomised, placebo-controlled trials of vitamin D or its hydroxylated metabolites, for adults with a clinical diagnosis of chronic obstructive pulmonary disease based on the presence of characteristic symptoms and irreversible airflow obstruction. We did not impose restrictions regarding disease severity or baseline vitamin D status, in order to maximise generalisability., Data Collection and Analysis: We used standard Cochrane methods. The primary outcome was the rate of moderate or severe exacerbations (requiring systemic corticosteroids, antibiotics or both). We also performed subgroup analyses to determine whether the effect of vitamin D on the rate of moderate or severe exacerbations was modified by baseline vitamin D status, COPD severity or regular inhaled corticosteroid use. The main secondary outcomes of interest were the proportion of participants experiencing one or more exacerbations (moderate or severe), the change in forced expiratory volume in one second (FEV1, % predicted) and the proportion of participants with one or more serious adverse events of any cause, mortality (all-cause) and quality of life. We used GRADE to assess the certainty of evidence for each outcome., Main Results: We included 10 double-blind, randomised, placebo-controlled trials in this review, involving a total of 1372 adults. Five studies contributed to the primary outcome analysis of the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both. The duration of studies ranged from six weeks to 40 months, and all investigated the effects of administering cholecalciferol (vitamin D 3 ). One study included two intervention arms, one where vitamin D 3 was given and one where calcitriol (1,25-dihydroxyvitamin D) was given. The majority of participants had mild to moderate COPD, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare (123 participants contributing data to subgroup analysis). Administration of vitamin D or its hydroxylated metabolites results in little to no change in the overall rate of exacerbations requiring systemic corticosteroids, antibiotics or both (rate ratio (RR) 0.98, 95% CI 0.86 to 1.11; 5 studies, 980 participants; high-certainty evidence). Vitamin D supplementation did not influence any meta-analysed secondary outcomes. These were all based on moderate- or high-certainty evidence aside from adverse events and quality of life, which were based on low-certainty evidence. We observed little to no change in the proportion of participants experiencing one or more moderate or severe exacerbations (odds ratio (OR) 0.94, 95% CI 0.72 to 1.24; 5 studies, 980 participants; high-certainty evidence). Additionally, vitamin D probably results in little to no difference in the inter-arm mean change in FEV1 (% predicted) (mean difference 2.82 higher in intervention arm, 95% CI -2.42 to 8.06; 7 studies, 1063 participants; moderate-certainty evidence). There was also probably no effect of vitamin D on the incidence of serious adverse events due to any cause; although we identified an anticipated absolute effect of 36 additional adverse events per 1000 people, the confidence interval included the null hypothesis of no effect (OR 1.19, 95% CI 0.82 to 1.71; 5 studies, 663 participants; moderate-certainty evidence). Vitamin D may have little to no effect on mortality (OR 1.13, 95% CI 0.57 to 2.21; 6 studies, 1019 participants; low-certainty evidence). It also may have little to no effect on quality of life as measured by validated instruments (narrative findings; 5 studies, 663 participants; low-certainty evidence). We assessed one study as being at high risk of bias in at least one domain; this did not contribute data to the meta-analysis of the primary outcome reported above. Sensitivity analysis that excluded this study from the meta-analysed outcome to which it contributed, the inter-arm mean change in FEV1, did not change the findings., Authors' Conclusions: We found that administration of vitamin D results in little to no effect on the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both or the proportion of participants experiencing one or more exacerbations (moderate or severe) (both high-certainty evidence). Further, vitamin D probably has no effect on the inter-arm difference in change in lung volumes and the proportion of participants with one or more serious adverse event of any cause (both moderate-certainty evidence), and may make little to no difference to mortality or quality of life (both low-certainty evidence). We recommend further research on the balance of benefits and harms of vitamin D supplements in COPD for those with very low or very high starting vitamin D levels, because we assessed the available evidence as low-certainty for these groups., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To determine whether vitamin D supplementation influences grip strength, explosive leg power, cardiorespiratory fitness and risk of exercise-induced bronchoconstriction (EIB) in South African schoolchildren., Methods: Substudy (n=450) in Cape Town schoolchildren aged 8-11 years nested within a phase 3 randomised placebo-controlled trial (ViDiKids). The intervention was weekly oral doses of 10 000 IU vitamin D 3 (n=228) or placebo (n=222) for 3 years. Outcome measures were serum 25-hydroxyvitamin D 3 (25(OH)D 3 ) concentrations, grip strength, standing long jump distance, peak oxygen uptake (VO 2peak , determined using 20 m multistage shuttle run tests) and the proportion of children with EIB, measured at end-study., Results: 64.7% of participants had serum 25(OH)D 3 concentrations <75 nmol/L at baseline. At 3-year follow-up, children randomised to vitamin D versus placebo had higher mean serum 25(OH)D 3 concentrations (97.6 vs 58.8 nmol/L, respectively; adjusted mean difference 39.9 nmol/L, 95% CI 36.1 to 43.6). However, this was not associated with end-study differences in grip strength, standing long jump distance, VO 2peak or risk of EIB., Conclusion: A 3-year course of weekly oral supplementation with 10 000 IU vitamin D 3 elevated serum 25(OH)D 3 concentrations in South African schoolchildren but did not influence muscle strength, exercise capacity or risk of EIB., Competing Interests: ARM declares receipt of funding in the last 36 months 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. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord, Synergy Biologics and Cytoplan; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma; receipt of consultancy fees from DSM Nutritional Products and Qiagen; 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) and unpaid work as a Programme Committee member for the Vitamin D Workshop., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine whether weekly oral vitamin D supplementation influences grip strength, explosive leg power, cardiorespiratory fitness or spirometric lung volumes in Mongolian schoolchildren., Methods: Multicentre, randomised, placebo-controlled clinical trial conducted in children aged 6-13 years at baseline attending 18 schools in Ulaanbaatar. The intervention was weekly oral doses of 14 000 IU vitamin D 3 (n=4418) or placebo (n=4433) for 3 years. Outcome measures were grip strength, standing long jump distance and serum 25-hydroxyvitamin D (25(OH)D) concentrations (determined in all participants), peak oxygen uptake (VO 2peak , determined in a subset of 632 participants using 20 m multistage shuttle run tests) and spirometric outcomes (determined in a subset of 1343 participants)., Results: 99.8% of participants had serum 25(OH)D concentrations <75 nmol/L at baseline, and mean end-study 25(OH)D concentrations in children randomised to vitamin D versus placebo were 77.4 vs 26.7 nmol/L (mean difference 50.7 nmol/L, 95% CI 49.7 to 51.4). However, vitamin D supplementation did not influence mean grip strength, standing long jump distance, VO 2peak , spirometric lung volumes or peak expiratory flow rate, either overall or within subgroups defined by sex, baseline 25(OH)D concentration <25 vs ≥25 nmol/L or calcium intake <500 vs ≥500 mg/day., Conclusion: A 3-year course of weekly oral supplementation with 14 000 IU vitamin D 3 elevated serum 25(OH)D concentrations in Mongolian schoolchildren with a high baseline prevalence of vitamin D deficiency. However, this intervention did not influence grip strength, explosive leg power, peak oxygen uptake or spirometric lung volumes, either overall or in subgroup analyses., Trial Registration Number: NCT02276755., Competing Interests: ARM declares receipt of funding in the last 36 months 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. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord, Synergy Biologics and Cytoplan; support for attending meetings from Pharma Nord and Abiogen Pharma; receipt of consultancy fees from DSM Nutritional Products and Qiagen; 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); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Vaccine development targeting SARS-CoV-2 in 2020 was of critical importance in reducing COVID-19 severity and mortality. In the U.K. during the initial roll-out most individuals either received two doses of Pfizer COVID-19 vaccine (BNT162b2) or the adenovirus-based vaccine from Oxford/AstraZeneca (ChAdOx1-nCoV-19). There are conflicting data as to the impact of age, sex and body habitus on cellular and humoral responses to vaccination, and most studies in this area have focused on determinants of mRNA vaccine immunogenicity. Here, we studied a cohort of participants in a population-based longitudinal study (COVIDENCE UK) to determine the influence of age, sex, body mass index (BMI) and pre-vaccination anti-Spike (anti-S) antibody status on vaccine-induced humoral and cellular immune responses to two doses of BNT162b2 or ChAdOx-n-CoV-19 vaccination. Younger age and pre-vaccination anti-S seropositivity were both associated with stronger antibody responses to vaccination. BNT162b2 generated higher neutralising and anti-S antibody titres to vaccination than ChAdOx1-nCoV-19, but cellular responses to the two vaccines were no different. Irrespective of vaccine type, increasing age was also associated with decreased frequency of cytokine double-positive CD4+T cells. Increasing BMI was associated with reduced frequency of SARS-CoV-2-specific TNF+CD8% T cells for both vaccines. Together, our findings demonstrate that increasing age and BMI are associated with attenuated cellular and humoral responses to SARS-CoV-2 vaccination. Whilst both vaccines induced T cell responses, BNT162b2 induced significantly elevated humoral immune response as compared to ChAdOx-n-CoV-19., (© 2024. The Author(s).)

Background: TB control requires the understanding and disruption of TB transmission. We describe prevalence, incidence and risk factors associated with childhood TB infection in Cape Town, South Africa., Methods: We report cross-sectional baseline and prospective incidence data from a large trial among primary school children living in high TB burden communities. Prevalent infection was defined as QuantiFERON™-TB Gold Plus (QFT-Plus) positivity as assessed at baseline. Subsequent conversion to QFT-Plus positivity was measured 3 years later among those QFT-Plus-negative at baseline. Multivariable logistic regression models examined factors associated with TB infection., Results: QuantiFERON-positivity at baseline (prevalence: 22.6%, 95% CI 20.9-24.4), was independently associated with increasing age (aOR 1.24 per additional year, 95% CI 1.15-1.34) and household exposure to TB during the participant's lifetime (aOR 1.87, 95% CI 1.46-2.40). QFT-Plus conversion at year 3 (12.2%, 95% CI 10.5-14.0; annual infection rate: 3.95%) was associated with household exposure to an index TB case (aOR 2.74, 95% CI 1.05-7.18)., Conclusion: Rates of QFT-diagnosed TB infection remain high in this population. The strong association with household TB exposure reinforces the importance of contact tracing, preventative treatment and early treatment of infectious disease to reduce community transmission., Competing Interests: Conflicts of interest: ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd (Vejle, Denmark), DSM Nutritional Products Ltd (Heerlen, the Netherlands, Thornton & Ross Ltd (Colne Valley, UK) and Hyphens Pharma Ltd (Singapore City, Singapore). ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd (Walsall, UK) and Cytoplan Ltd (Hanley Swan, UK); support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd (Pisa, Italy); receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd (Hilden, Germany); receipt of a speaker fee from the Linus Pauling Institute (Corvallis, OR, USA); 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); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests., (© 2024 The Authors.)

Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D3 vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6-11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D3 (25(OH)D3), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n = 1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (SD 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations <50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI, -0.94 to -0.17). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI, -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI, -1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95% CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objective: To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren., Design: Phase 3 double-blind randomised placebo-controlled trial., Setting: Socioeconomically disadvantaged peri-urban district of Cape Town, South Africa., Participants: 1682 children of black African ancestry attending government primary schools and aged 6-11 years at baseline., Interventions: Oral vitamin D 3 (10 000 IU/week) versus placebo for 3 years., Main Outcome Measures: Height-for-age and body mass index-for-age, measured in all participants; Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested substudy., Results: Mean serum 25-hydroxyvitamin D 3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D versus placebo (104.3 vs 64.7 nmol/L, respectively; mean difference (MD) 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD (aMD) -0.08, 95% CI -0.19 to 0.03) or body mass index-for-age z-score (aMD -0.04, 95% CI -0.16 to 0.07) were seen between vitamin D versus placebo groups at follow-up. Among substudy participants, allocation to vitamin D versus placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 s (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass., Conclusions: Weekly oral administration of 10 000 IU vitamin D 3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren., Trial Registration Numbers: ClinicalTrials.gov NCT02880982, South African National Clinical Trials Register DOH-27-0916-5527., Competing Interests: Competing interests: None., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To investigate whether Mycobacterium tuberculosis (Mtb) DNA is detected in peripheral blood mononuclear cells (PBMC) of subjects with tuberculosis (TB) or TB infection (TBI) living in a low-burden country., Methods: We prospectively enrolled 57 patients with TB, 41 subjects with TBI, and 39 controls in Rome, Italy. PBMC were isolated, cluster of differentiation (CD)34 + and CD34 - cells were immunomagnetic separated, DNA was extracted, and digital polymerase chain reaction for IS6110 and rpoB sequences was used to detect Mtb DNA in PBMC subsets and unfractionated PBMC., Results: We detected Mtb DNA at a low copy number in CD34 + cells in 4o f 30 (13%) patients with TB, 2 of 24 (8%) subjects with TBI, and 1 of 24 (4%) controls. Mtb DNA was detected in unfractionated PBMC in 3 of 51 (6%) patients with TB, 2 of 38 (5%) subjects with TBI, and 2 of 36 (6%) controls. In CD34 - cells, only 1 of 31 (3%) subjects with TBI tested positive for Mtb DNA., Conclusions: Mtb DNA was detected at low frequencies and levels in the PBMC of subjects with TBI and donors with TB living in a low-burden country. In particular, Mtb DNA was detected more frequently in CD34 + cells, supporting the hypothesis that these cells may represent a Mtb niche. This finding informs biological understanding of Mtb pathogenesis and may support the development of a microbial blood biomarker for Mtb infection., Competing Interests: Declarations of competing interest DG reported the following competing interest: PBD Biotech. EG reported the competing interest: research grants from Gilead Sciences and Mylan not related to the present work and speaker fees for Gilead Sciences and ViiV not related to this work. The remaining authors have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The World Health Organization's aim to end the global tuberculosis (TB) epidemic by 2050 cannot be achieved without taking measures to identify people with asymptomatic Mycobacterium tuberculosis (Mtb) infection and offer them an intervention to reduce the risk of disease progression, such as preventive antimicrobial therapy. Implementation of this strategy is limited by the fact that existing tests for Mtb infection, which use immunosensitization to Mtb-specific antigens as a proxy for infection, have low positive predictive value for progression to TB. A blood test that detects Mtb deoxyribonucleic acid (DNA) could allow preventive therapy to be targeted at individuals with microbiological evidence of persistent infection. In this review, we summarize recent advances in the development of molecular microbial blood tests for Mtb infection and discuss potential explanations for discordance between their results and those of immunodiagnostic tests in adults with recent exposure to an infectious index case. We also present a roadmap for further development of molecular microbial blood tests for Mtb infection, and highlight the potential for research in this area to provide novel insights into the biology of Mtb infection and yield new tools to support efforts to control the global TB epidemic., Competing Interests: Declarations of competing interest STR has a pending patent that is relevant to the work (WO2017207825A1). All other authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The association between air quality and risk of SARS-CoV-2 infection is poorly understood. We investigated this association using serological individual-level data adjusting for a wide range of confounders, in a large population-based cohort (COVIDENCE UK)., Methods: We assessed the associations between long-term (2015-19) nitrogen dioxide (NO 2 ) and fine particulate matter with an aerodynamic diameter of ≤2.5 μm (PM 2.5 ), exposures with SARS-CoV-2 infection, level of antibody response among those infected, and COVID-19 disease severity. We used serological data from 10,489 participants in the COVIDENCE UK cohort, and estimated annual average air pollution exposure at each participant's home postcode., Results: After controlling for potential confounders, we found a positive association between 5-year NO 2 and PM 2.5 exposures and the risk of seropositivity: 10 unit increase in NO 2 (μg/m 3 ) was associated with an increasing risk of seropositivity by 1.092 (95% CI 1.02 to 1.17; p-for-trend 0.012). For PM 2.5 , 10 unit increase (μg/m 3 ) was associated with an increasing risk of seropositivity by 1.65 (95% CI 1.015-2.68; p-for-trend 0·049). In addition, we found that NO 2 was positively associated with higher antibody titres (p-for-trend 0·013) among seropositive participants, with no evidence of an association for PM 2.5 ., Conclusion: Our findings suggest that the long-term burden of air pollution increased the risks of SARS-CoV-2 infection and has important implications for future pandemic preparedness. This evidence strengthens the case for reducing long-term air pollution exposures to reduce the vulnerability of individuals to respiratory viruses., 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 © 2024. Published by Elsevier Ltd.)

Background: Vitamin D supplementation has been shown to increase total hip areal bone mineral density in healthy children and adolescents. We aimed to investigate whether supplementing schoolchildren living in Mongolia with weekly vitamin D 3 for 3 years affected fracture risk., Methods: We did a multicentre, double-blind, randomised, placebo-controlled trial across 18 public schools in Ulaanbaatar, Mongolia. Schoolchildren were eligible if they were aged 6-13 years at screening, had a negative QuantiFERON-TB Gold In-tube assay (QFT) result, were not hypersensitive to vitamin D or immunocompromised, did not use vitamin D supplements, did not have clinical signs of rickets, and had no intention of leaving Ulaanbaatar within 3 years. Participants were randomly assigned (1:1) to receive either vitamin D (oral dose of 14 000 international units [IU] vitamin D 3 , once per week) or placebo for 3 years using permuted block randomisation stratified by school of attendance. Participants, care providers, and all trial staff were masked to group assignment during the intervention. Prespecified secondary outcomes were incidence of fractures and adverse events, ascertained using questionnaires. The fracture and safety analyses included participants who completed at least one follow-up fracture questionnaire. We estimated adjusted risk ratios (RRs) and 95% CIs using generalised linear models with binomial distribution and a log link function with adjustment for school of attendance. The trial is registered with ClinicalTrials.gov, NCT02276755, and the intervention ended in May, 2019., Findings: Between Sept 2, 2015, and March 20, 2017, 11 475 children were invited to participate in the study and 8851 were recruited and randomly assigned to receive either vitamin D (n=4418) or placebo (n=4433). 8348 participants were included in the fracture and safety analyses (4176 [94·5%] in the vitamin D group and 4172 [94·1%] in the placebo group). Of these, 4125 (49·4%) were female, 4223 (50·6%) were male, and 7701 (92·2%) were of Khalkh ancestry. Median age was 9·2 years (IQR 8·0-10·7) and 7975 (95·5%) participants had baseline serum 25-hydroxyvitamin D concentrations less than 50 nmol/L. During a median follow-up of 3·0 years (IQR 2·9-3·1), 268 (6·4%) participants in the vitamin D group and 253 (6·1%) in the placebo group reported one or more fractures (adjusted RR 1·10, 95% CI 0·93-1·29; p=0·27). Incidence of adverse events did not differ between study groups., Interpretation: Oral vitamin D supplementation at a dose of 14 000 IU/week for 3 years was safe, but did not influence fracture risk in schoolchildren living in Mongolia who had a high baseline prevalence of vitamin D deficiency., Funding: US National Institutes of Health., Competing Interests: Declaration of interests ARM declares receipt of funding to support vitamin D research from Pharma Nord, DSM Nutritional Products, Thornton & Ross, and Hyphens Pharma. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord, Synergy Biologics, and Cytoplan; support for attending meetings from Pharma Nord and Abiogen Pharma; receipt of consultancy fees from DSM Nutritional Products and Qiagen; receipt of a speaker fee from the Linus Pauling Institute (Corvallis, OR, USA); participation on data and safety monitoring boards for the VITALITY trial (PACTR20200989766029) and the trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (NCT04641195); and unpaid work as a programme committee member for the Vitamin D Workshop. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Long COVID is a well recognised, if heterogeneous, entity. Acute respiratory infections (ARIs) due to other pathogens may cause long-term symptoms, but few studies compare post-acute sequelae between SARS-CoV-2 and other ARIs. We aimed to compare symptom profiles between people with previous SARS-CoV-2 infection, people with previous non-COVID-19 ARIs, and contemporaneous controls, and to identify clusters of long-term symptoms., Methods: COVIDENCE UK is a prospective, population-based UK study of ARIs in adults. We analysed data for 16 potential long COVID symptoms and health-related quality of life (HRQoL), reported between January 21 and February 15, 2021, by participants unvaccinated against SARS-CoV-2. We classified participants as having previous SARS-CoV-2 infection or previous non-COVID-19 ARI (≥4 weeks prior) or no reported ARI. We compared symptoms by infection status using logistic and fractional regression, and identified symptom clusters using latent class analysis (LCA). This study is registered with ClinicalTrials.gov, NCT04330599., Findings: We included 10,171 participants (1311 [12.9%] with SARS-CoV-2 infection, 472 [4.6%] with non-COVID-19 ARI). Both types of infection were associated with increased prevalence/severity of most symptoms and decreased HRQoL compared with no infection. Participants with SARS-CoV-2 infection had increased odds of problems with taste/smell (odds ratio 19.74, 95% CI 10.53-37.00) and lightheadedness or dizziness (1.74, 1.18-2.56) compared with participants with non-COVID-19 ARIs. Separate LCA models identified three symptom severity groups for each infection type. In the most severe groups (representing 22% of participants for both SARS-CoV-2 and non-COVID-19 ARI), SARS-CoV-2 infection presented with a higher probability of problems with taste/smell (probability 0.41 vs 0.04), hair loss (0.25 vs 0.16), unusual sweating (0.38 vs 0.25), unusual racing of the heart (0.43 vs 0.33), and memory problems (0.70 vs 0.55) than non-COVID-19 ARI., Interpretation: Both SARS-CoV-2 and non-COVID-19 ARIs are associated with a wide range of symptoms more than 4 weeks after the acute infection. Research on post-acute sequelae of ARIs should extend from SARS-CoV-2 to include other pathogens., Funding: Barts Charity., Competing Interests: PEP declares grants paid to their institution from the National Institute for Health and Care Research (NIHR) and UK Research and Innovation (UKRI). The remaining authors declare no competing interests., (© 2023 The Author(s).)

Background: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors., Method: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third ( n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change., Results: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status., Conclusions: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Objectives: To determine whether weekly oral supplementation with 10,000 IU vitamin D 3  for 3 years reduces the risk of sensitization to M. tuberculosis in South African schoolchildren aged 6-11 years with negative QuantiFERON-tuberculosis (TB) Gold Plus (QFT-Plus) assay results at baseline., Methods: We conducted a phase 3 randomized placebo-controlled trial in 1682 children attending 23 primary schools in Cape Town. The primary outcome was a positive end-trial QFT-Plus result, analyzed using a mixed effects logistic regression model with the school of attendance included as a random effect., Results: 829 vs. 853 QFT-Plus-negative children were randomized to receive vitamin D 3 vs. placebo, respectively. Mean end-study 25(OH)D concentrations in participants randomized to vitamin D vs. placebo were 104.3 vs 64.7 nmol/l, respectively (95% confidence interval for difference, 37.6 to 41.9 nmol/l). A total of 76/667 (11.4%) participants allocated to vitamin D vs. 89/687 (13.0%) participants allocated to placebo tested QFT-Plus positive at 3-year follow-up (adjusted odds ratio 0.86, 95% confidence interval 0.62-1.19, P = 0.35)., Conclusion: Weekly oral supplementation with 10,000 IU vitamin D 3 for 3 years elevated serum 25(OH)D concentrations among QFT-Plus-negative Cape Town schoolchildren but did not reduce their risk of QFT-Plus conversion., Competing Interests: Declarations of Competing Interest ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; 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); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The imposition of restrictions on social mixing early in the COVID-19 pandemic was followed by a reduction in asthma exacerbations in multiple settings internationally. Temporal trends in social mixing, incident acute respiratory infections (ARI) and asthma exacerbations following relaxation of COVID-19 restrictions have not yet been described., Methods: We conducted a population-based longitudinal study in 2312 UK adults with asthma between November 2020 and April 2022. Details of face covering use, social mixing, incident ARI and severe asthma exacerbations were collected via monthly online questionnaires. Temporal changes in these parameters were visualised using Poisson generalised additive models. Multilevel logistic regression was used to test for associations between incident ARI and risk of asthma exacerbations, adjusting for potential confounders., Results: Relaxation of COVID-19 restrictions from April 2021 coincided with reduced face covering use (p<0.001), increased frequency of indoor visits to public places and other households (p<0.001) and rising incidence of COVID-19 (p<0.001), non-COVID-19 ARI (p<0.001) and severe asthma exacerbations (p=0.007). Incident non-COVID-19 ARI associated independently with increased risk of asthma exacerbation (adjusted OR 5.75, 95% CI 4.75 to 6.97) as did incident COVID-19, both prior to emergence of the omicron variant of SARS-CoV-2 (5.89, 3.45 to 10.04) and subsequently (5.69, 3.89 to 8.31)., Conclusions: Relaxation of COVID-19 restrictions coincided with decreased face covering use, increased social mixing and a rebound in ARI and asthma exacerbations. Associations between incident ARI and risk of severe asthma exacerbation were similar for non-COVID-19 ARI and COVID-19, both before and after emergence of the SARS-CoV-2 omicron variant., Study Registration Number: NCT04330599., Competing Interests: Competing interests: RAL declares membership of the Welsh Government COVID19 Technical Advisory Group. 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. All other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

This review summarises evidence relating to a potential role for vitamin D supplementation in the prevention or treatment of coronavirus disease 2019 (COVID-19). Laboratory studies show that the active vitamin D metabolite 1,25-dihydroxyvitamin D induces innate antiviral responses and regulates immunopathological inflammation with potentially favourable implications for the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Meta-analyses of cross-sectional, case-control and longitudinal studies report consistent protective associations between higher circulating 25-hydroxyvitamin D [25(OH)D] concentrations or vitamin D supplement use and reduced risk and severity of COVID-19. However, Mendelian randomisation studies testing for associations between genetically predicted circulating 25(OH)D concentrations and COVID-19 outcomes have yielded consistently null results. Positive findings from observational epidemiological studies may therefore have arisen as a result of residual or unmeasured confounding or reverse causality. Randomised controlled trials of prophylactic or therapeutic vitamin D supplementation to reduce risk or severity of COVID-19 reporting to date have yielded inconsistent findings. Results of further intervention studies are pending, but current evidence is insufficient to support routine use of vitamin D supplements as a therapeutic or prophylactic agent for COVID-19, or as an adjunct to augment immunogenicity of SARS-CoV-2 vaccination. Accordingly, national and international bodies have not made any recommendations regarding a role for vitamin D in the prevention or treatment of COVID-19.

Background: The tuberculin skin test is commonly used to diagnose latent tuberculosis infection (LTBI) in resource-limited settings, but its specificity is limited by factors including cross-reactivity with BCG vaccine and environmental mycobacteria. Interferon-gamma release assays (IGRA) overcome this problem by detecting M. tuberculosis complex-specific responses, but studies to determine risk factors for IGRA-positivity in high TB burden settings are lacking., Methods: We conducted a cross-sectional study to determine factors associated with a positive IGRA by employing the QuantiFERON-TB® Gold-plus (QFT Plus) assay in a cohort of asymptomatic adult TB contacts in Kampala, Uganda. Multivariate logistic regression analysis with forward stepwise logit function was employed to identify independent correlates of QFT Plus-positivity., Results: Of the 202 participants enrolled, 129/202 (64%) were female, 173/202 (86%) had a BCG scar, and 67/202 (33%) were HIV-infected. Overall, 105/192 (54%, 95% CI 0.48-0.62) participants had a positive QFT Plus result. Increased risk of QFT-Plus positivity was independently associated with casual employment/unemployment vs. non-casual employment (adjusted odds ratio (aOR) 2.18, 95% CI 1.01-4.72), a family vs. non-family relation to the index patient (aOR 2.87, 95% CI 1.33-6.18), living in the same vs. a different house as the index (aOR 3.05, 95% CI 1.28-7.29), a higher body mass index (BMI) (aOR per additional kg/m2 1.09, 95% CI 1.00-1.18) and tobacco smoking vs. not (aOR 2.94, 95% CI 1.00-8.60). HIV infection was not associated with QFT-Plus positivity (aOR 0.91, 95% CI 0.42-1.96)., Conclusion: Interferon Gamma Release Assay positivity in this study population was lower than previously estimated. Tobacco smoking and BMI were determinants of IGRA positivity that were previously unappreciated., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mayito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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).)