Background:Identifying and addressing long-term health and societal challenges after COVID-19 is a research priority. Objectives:To create an international, multidisciplinary COVID-19 database, and synthesise long-term outcomes, predictors and costs. Design:Systematic identification of COVID-19 data sets and meta-analysis of individual participant data on long-term outcomes after COVID-19. Setting:Contributed data were collected in clinical, community and research settings. Interventions:Interventions from original studies were included as covariates in models. Data sources:MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, PsycInfo® (American Psychological Association, Washington, DC, USA), Cumulative Index to Nursing and Allied Health Literature, World Health Organization Global Index Medicus, Epistemonikos, LitCOVID; World Health Organization International Clinical Trials Registry Platform; ClinicalTrials.gov and supplementary searches for studies (November 2019-November 2021) were searched for studies on > 10 people from cohort, case-control, survey or randomised controlled trial studies, across any setting, describing validated assessment instruments, symptoms, hospitalisation, discharge destination or mortality beyond 28-days after COVID-19 onset. Data were extracted by two independent reviewers. Methods:Principal investigators contributed fully anonymised individual participant data. Demography, equity and symptoms were described. Assessment instruments were mapped to the International Classification of Functioning, Disability and Health. Factors associated with outcomes at 3-6 months, 9-12 months and beyond 12 months of index infection, for n > 500 individual participant data and > 1 data set were described using ratio of difference, point estimates, odds ratio and 95% confidence interval, as appropriate. The Mixed Methods Appraisal Tool described study quality; models were appraised using a Grading of Recommendations Assessment, Development and Evaluation-informed approach; heterogeneity was described using I2. Outcome measures:Included overall perception of health, multidomain cognitive function, anxiety, depression, stress, post-traumatic stress disorder, fatigue, strength, walking ability, mobility, coping with daily life, breathlessness, mortality, later hospitalisation and health-related quality of life. Results:PRECIOUS collated 116 data sets from 40 countries (individual participant data = 62,849), comprising 20 randomised controlled trials, 13 case-control, 60 cohort 2 longitudinal, 1 survey and 20 other study types. Participants' median age was 58 years interquartile range (45-68); 34,185 (54.4%) were female; 158 unique symptoms and 137 unique assessment instruments were captured, predominantly describing International Classification of Function, Disability and Health-body functions. Women had poorer outcomes across 30/37 models, compared with men. In 15/37 models, pre-existing lung disease and increasing age were associated with poorer outcomes; hospitalisation, diabetes and chronic kidney disease were each associated with poorer outcomes in 8/37 models. Initial hospitalisation resulted in lower health-related quality of life that did not recover for up to 2 years after initial infection. Heterogeneity was low in 34/37 models; 22/37 models were of moderate and 11/37 were of low quality. Limitations:Use of secondary data limits available covariates, outcomes and time points to those included in primary data sets; evidence was primarily based on high-income countries. There was a lack of data on longer-term healthcare resource use to estimate the costs to the healthcare system. Conclusions:PRECIOUS contributes to the overall picture of long-term COVID-19 outcomes beyond the long-COVID condition and highlights poorer long-term outcomes in women and people with pre-existing comorbidities. Future work:Evidence gaps included healthcare resource use, isolation, loneliness, societal participation and return to work outcomes. Data are needed on the role of health inequity on long-term outcomes. Study registration:This study is registered as PROSPERO (CRD42020224323, IRAS ID: 293578). Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR132895) and is published in full in Health and Social Care Delivery Research; Vol. 14, No. 29. See the NIHR Funding and Awards website for further award information.

Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder with numerous hypothesized risk factors that have not yet been thoroughly investigated in many non-Western populations, including Mongolian schoolchildren. Exploring these risk factors could yield insight on which children are more likely to be impacted and on how risk differs across locations and cultures. Objective: The aim of the study was to assess whether elevated scores reported by parents and teachers on the Conners-3 Assessment, a detailed survey tool used to assess ADHD symptoms, correspond with indicators of lower socioeconomic status. Methods: We conducted a cross-sectional analysis involving 201 schoolchildren aged 8 to 13 attending a public school in Ulaanbaatar, Mongolia. We investigated associations between factors including student age, parental education level, family income, exposure to cigarette smoke, calcium intake and vitamin D status with Conners-3 scores for inattention, hyperactivity, and defiance/aggression. Cohen’s d effect sizes and adjusted mean differences (aMD) for Conners-3 scores between groups were calculated using multivariable analysis. Results: Our findings revealed large effect sizes between different types of accommodation, a key indicator of socioeconomic status in modern Mongolia, and moderate effect sizes between different levels of parental education. Other findings included that engaging in over 2 hr of outdoor activity was independently associated with an increased inattention score (aMD 0.53, 95% CI [0.03, 1.03]) and increased hyperactivity score (aMD 0.63, 95% CI [0.10, 1.16]). A lower household income was independently associated with an increased inattention score (aMD 0.0005, 95% CI [0.000011, 0.001042]) and increased defiance/aggression score (aMD 0.0009, 95% CI [0.0004, 0.0015]). Factors such as calcium intake, Vitamin D level, exposure to cigarette smoke, and parental employment status did not yield significant associations. Conclusion: We found that Conners-3 scores indicating higher symptoms of ADHD among Mongolian schoolchildren were associated with lower household income and high outdoor activity, and should be further investigated in relation to type of accommodation.

Background: Following vitamin D3 oral administration, attained serum concentrations of its metabolite 25-hydroxyvitamin D3 (25(OH)D3) are variable among children. Methods: We developed physiologically based pharmacokinetic (PBPK) modelling using annually measured serum 25(OH)D3 concentrations in 77 Cape Town schoolchildren aged 6–11 years who received weekly oral doses of 10,000 IU vitamin D3 for 3 years during a clinical trial (Δ25(OH)D = 32.2 nmol/L, 95% CI: [−3.2, 65.8] nmol/L). Simulations were performed to test the model on 463 other participants in the same trial, and in a cohort of 1756 Mongolian schoolchildren aged 6–11 years who received weekly oral doses of 14,000 IU vitamin D3 for 3 years in another trial. Results: The best model attributed most of the variability in post-supplementation 25(OH)D3 concentrations to hepatic clearance and covariates including weight (ΔAIC = −21) and ZBMI (body mass index Z-score, ΔAIC = −34). For 463 other children from the Cape Town trial (Δ25(OH)D = 25.8 nmol/L, 95% CI: [8.3, 47.2] nmol/L), mean estimation error was 5.3 nmol/L, and 76.7% of observations were within the 95% prediction intervals. Our simulation supported the previous proposal that serum 25(OH)D3 should exceed 50 nmol/L among 97.5% of European children at 24.4 μg/day vitamin D3 dosing. At a higher weekly dose (14,000 IU), the Mongolian children demonstrated a higher average increase in serum 25(OH)D3 (40.6 [−2.9, 88.9] nmol/L) but were overestimated by the model. Conclusion: We developed the first PBPK model to successfully predict the long-term serum 25(OH)D3 increases in healthy schoolchildren in Cape Town who received orally administered vitamin D3 and exhibited higher relative increases than Mongolian children.

BACKGROUND:COVID-19 booster vaccinations are offered annually to priority groups, but many people have not been vaccinated in over a year. We therefore assessed the association between time since booster vaccination and breakthrough infection characteristics. We also explored whether incident COVID-19 associates with asthma exacerbations in boosted individuals with asthma and if the risk of COVID-19-associated exacerbation is affected by time since vaccination. METHODS:COVIDENCE UK is a prospective, longitudinal, population-based study of COVID-19. We included adult participants who had received ≥1 booster vaccination. Time since vaccination was binarised at 6 or 12 months according to vaccine eligibility subgroup. We used regression models to obtain adjusted estimates for the association between time since vaccination and breakthrough infection severity (requiring bedrest vs milder symptoms), symptom duration, and impact on health-related quality of life (EQ-5D-3L Index). We then assessed the association of incident COVID-19 with asthma exacerbations using multilevel mixed models, by time since vaccination. RESULTS:7391 boosted participants reported at least one breakthrough infection. Across all eligibility subgroups, greater time since vaccination associated with increased odds of severe symptoms (ORs ranging from 1.31 (95% CI 1.06 to 1.62) to 1.61 (1.29 to 2.01)). Not receiving a booster vaccination in the previous 12 months was associated with longer time to recovery overall (HR for recovery 0.90, 95% CI 0.81 to 0.99), but evidence for vaccination subgroups was weak. Greater time since vaccination was associated with a small decrease in EQ-5D-3L Index overall (-0.02, 95% CI -0.03 to -0.00) and among participants younger than 75 years, but did not reach our estimates for a minimum clinically important difference. Among 2100 participants with asthma, incident COVID-‍19 associated with increased risk of asthma exacerbation, both within 12 months of vaccination (OR 5.11 (95% CI 4.19 to 6.24)) and later (5.60 (2.98 to 10.53)), with a greater difference in point estimates when considering severe exacerbations (6.59 (4.70 to 9.22) vs 9.20 (3.56 to 23.78)). CONCLUSION:Longer time since booster vaccination consistently associates with more severe infections and may increase the risk of severe asthma exacerbations in people with asthma. These findings highlight the importance of ensuring those currently eligible receive their boosters, and the need for research on further vaccinations in people with asthma no longer eligible for boosters.

We have previously shown that high-dose vitamin D 3 improved weight gain and neurodevelopmental indices in children receiving standard therapy for uncomplicated severe acute malnutrition (SAM). Here we present results of a randomised placebo-controlled trial in Lahore, Pakistan, to determine whether two oral doses of 200,000 international units (IU) vitamin D 3 (the first administered on or before the day of hospital discharge and the second administered 14 days later) would benefit children aged 6-59 months during the convalescent phase of complicated SAM. Eligible participants were individually randomised to intervention vs. control arms with a one-to-one allocation ratio and stratification by hospital of recruitment using computer-generated random sequences. Double-blinding to treatment allocation was maintained by concealing allocation from participants’ parents or guardians, their medical care providers, and all trial staff. The primary outcome was mean weight-for-height or -length z-score (WHZ) at 2-month follow-up. Secondary efficacy outcomes included mean WHZ at 6-month follow-up and mean lean mass index, Malawi Development Assessment Tool (MDAT) scores and serum 25-hydroxyvitamin D (25[OH]D) concentrations at 2- and 6-month follow-up. The trial has now completed. 259 children were randomised (128 to vitamin D, 131 to placebo), of whom 251 (96.9%) contributed data to analysis of the primary outcome (123 allocated to vitamin D, 128 to placebo). At 2-month follow-up, participants allocated to vitamin D had significantly higher mean serum 25(OH)D concentrations than those allocated to placebo (adjusted mean difference [aMD] 100.0 nmol/L, 95% confidence interval [CI] 72.2–127.8 nmol/L). This was not associated with an inter-arm difference in mean WHZ at 2-month follow-up (aMD 0.02, 95% CI −0.20 to 0.23), or in any anthropometric or neurodevelopmental secondary outcome assessed at 2- or 6-month follow-up. The intervention was safe. In conclusion, high-dose vitamin D 3 elevated mean serum 25(OH)D concentrations in children receiving standard therapy for complicated SAM in Pakistan, but did not influence any anthropometric or neurodevelopmental outcome studied. The trial was registered at ClinicalTrials.gov with the identifier NCT04270643.

BACKGROUND:A 2021 meta-analysis of 37 randomised controlled trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARIs) revealed a statistically significant protective effect of the intervention (odds ratio [OR] 0·92 [95% CI 0·86 to 0·99]). Since then, six eligible RCTs have been completed, including one large trial (n=15 804). We aimed to re-examine the link between vitamin D supplementation and prevention of ARIs. METHODS:Updated systematic review and meta-analysis of data from RCTs of vitamin D for ARI prevention using a random effects model. Subgroup analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, dosing regimen, or age. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov between May 1, 2020 (end-date of search of our previous meta-analysis) and April 30, 2024. No language restrictions were imposed. Double-blind RCTs supplementing vitamin D for any duration, with placebo or lower-dose vitamin D control, were eligible if approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. The study was registered with PROSPERO (no. CRD42024527191). FINDINGS:We identified six new RCTs (19 337 participants). Data were obtained for 16 085 (83·2%) participants in three new RCTs and combined with data from 48 488 participants in 43 RCTs identified in our previous meta-analysis. For the primary comparison of any vitamin D versus placebo, the intervention did not statistically significantly affect overall ARI risk (OR 0·94 [95% CI 0·88-1·00], p=0·057; 40 studies; 61 589 participants; I2=26·4%). Pre-specified subgroup analysis did not reveal evidence of effect modification by age, baseline vitamin D status, dosing frequency, or dose size. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0·96 [95% CI 0·90-1·04]; 38 studies; I2=0·0%). A funnel plot showed left-sided asymmetry (p=0·0020, Egger's test). INTERPRETATION:This updated meta-analysis yielded a similar point estimate for the overall effect of vitamin D supplementation on ARI risk to that obtained previously, but the 95% CI for this effect estimate now includes 1·00, indicating no statistically significant protection. FUNDING:None.

Summary Background Studies into the bidirectional relationship between sleep and long COVID have been limited by retrospective pre-infection sleep data and infrequent post-infection follow-up. We therefore used prospectively collected monthly data to evaluate how pre-infection sleep characteristics affect risk of long COVID, and to track changes in sleep duration during the year after SARS-CoV-2 infection. Methods COVIDENCE UK is a prospective, population-based UK study of COVID-19 in adults. We included non-hospitalised participants with evidence of SARS-CoV-2 infection, and estimated odds ratios (ORs) for the association between pre-infection sleep characteristics and long COVID using logistic regression, adjusting for potential confounders. We assessed changes in sleep duration after infection using multilevel mixed models. We defined long COVID as unresolved symptoms at least 12 weeks after infection. We defined sleep quality according to age-dependent combinations of sleep duration and efficiency. COVIDENCE UK is registered with ClinicalTrials.gov, NCT04330599 . Findings We included 3994 participants in our long COVID risk analysis, of whom 327 (8.2%) reported long COVID. We found an inverse relationship between pre-infection sleep quality and risk of long COVID (medium vs good quality: OR 1.37 [95% CI 1.04–1.81]; medium–low vs good: 1.55 [1.12–2.16]; low vs good: 1.94 [1.11–3.38]). Greater variability in pre-infection sleep efficiency was also associated with long COVID (OR per percentage-point increase 1.06 [1.01–1.11]). We assessed post-infection sleep duration in 6860 participants, observing a 0.11 h (95% CI 0.08–0.13) increase in the first month after infection compared with pre-infection, with larger increases for more severe infections. After 1 month, sleep duration largely returned to pre-infection levels, although fluctuations in duration lasted up to 6 months after infection among people reporting long COVID. Interpretation Our findings highlight the bidirectional relationship between sleep and long COVID. While poor-quality sleep before SARS-CoV-2 infection associates with increased risk of long COVID thereafter, changes in sleep duration after infection in these non-hospitalised cases were modest and generally quick to resolve. Funding Barts Charity.

Background. The paucibacillary nature of spinal tuberculosis (STB) makes diagnosis challenging, particularly in people living with HIV-1 (PLWH). It is suggested that HIV-1 and Mycobacterium tuberculosis ( Mtb ) co-infection in tissues favours reciprocal replication, infection and reservoir expansion. Yet, confirmation of this detrimental synergism in diseased tissues is scant. Methods In a prospective study of 25 adults (13 (52%) people living with HIV-1 (PLWH) on antiretroviral treatment (ART)) undergoing spinal biopsy investigation for STB in South Africa, droplet digital PCR (ddPCR) was used to detect and quantify Mtb complex (MTBC) DNA ( rpoB and IS6110 ) in 93 biopsy segments, and HIV-1 DNA ( pol and gag ) in 41 segments from PLWH. ddPCR sensitivity for Mtb was validated against Xpert-Ultra and culture. Relationships between pathogen DNA abundance, co-detection, human cellularity, HIV status, and peripheral viral load (VL) were evaluated. Findings ddPCR detected MTBC DNA in 19/25 (76%) patients (range: 8- 59,144 rpoB copies/biopsy), with increased detection in those with confirmed STB and a history of TB. MTBC rpoB copies/million cells were higher in biopsies from PLWH (p=0.0096) and positively correlated with matched biopsy segment HIV-1 pol copies/million cells (r=0.40; p=0.0003), but not peripheral VL. HIV-1 DNA was detected in all biopsies from PLWH, four with undetectable VL. HIV-1 pol copies/million cells were higher in biopsy segments with MTBC DNA co-detected (p=0.011) and strongly correlated with VL (r=0.91; p=0.0003). Interpretation ddPCR has high sensitivity for Mtb and HIV-1 DNA quantification in STB biopsies. Mtb tissue abundance correlated with localised but not systemic HIV-1 abundance. Increased HIV-1 DNA detection at sites co-localised with Mtb supports further investigating the TB microenvironment as a site for HIV-1 reservoir persistence and expansion in PLWH on ART. Funding Wellcome (203135Z/16/Z); Academy of Science of SA (ASSAf); ORU, UCT; UCT Merit Award. Contacts Anna Coussens, Walter and Eliza Hall Institute of Medical Research (WEHI), 1G Royal Parade, Parkville, 3052, Australia; Tel: +61 3 39452699; Email: coussens.a{at}wehi.edu.au Robyn Waters, Division of Orthopaedic Surgery, University of Cape Town, Anzio Rd, Observatory, 7925, South Africa; Email: robyn.waters{at}uct.ac.za ### Competing Interest Statement The authors have declared no competing interest.

Every year, World Tuberculosis (TB) Day is commemorated on March 24 and is targeted at raising public and political awareness of TB, a preventable and treatable disease. World TB Day commemorates the day in 1882 when Professor Robert Koch announced his discovery of the microbial cause of TB, the TB bacillus, Mycobacterium tuberculosis. Despite effective TB treatment being available for over 65 years, TB today causes 1.3 million deaths yearly, mostly in low- and middle-income countries. Drug-resistant TB is the leading cause of death owing to antimicrobial resistant disease in the world today and is a growing global health security threat, with hundreds of thousands of people affected every year [1World Health Organization. Global tuberculosis report 2023, https://www.who.int/publications-detail-redirect/9789240083851; 2023 [accessed 27 February 2024].Google Scholar]. It is in this dismal global situation that "Yes! We can end TB!" is the World Health Organization (WHO) and STOP TB Partnership's theme for World TB Day [1World Health Organization. Global tuberculosis report 2023, https://www.who.int/publications-detail-redirect/9789240083851; 2023 [accessed 27 February 2024].Google Scholar]. This theme remains the same as that of World TB Day 2023 to emphasize and deliver a message of hope to those who continue to be affected. Critical to highlight on this day will be the provision of the required global funding to enable faster uptake of new WHO management recommendations for finding, diagnosing, and effectively treating infections and all cases of clinical TB using new and updated WHO recommendations and guidelines [2World Health Organization. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment 2020, https://www.who.int/publications-detail-redirect/9789240001503; 2020 [accessed 27 February 2024].Google Scholar, 3World Health Organization. WHO consolidated guidelines on tuberculosis: module 2: screening: systematic screening for tuberculosis disease 2021, https://www.who.int/publications-detail-redirect/9789240022676; 2021 [accessed 27 February 2024].Google Scholar, 4World Health Organization. WHO consolidated guidelines on tuberculosis: module 3: diagnosis: rapid diagnostics for tuberculosis detection, 2021 update 2021, https://www.who.int/publications-detail-redirect/9789240029415; 2021 [accessed 27 February 2024].Google Scholar, 5World Health Organization. WHO consolidated guidelines on tuberculosis: module 4: treatment: drug-resistant tuberculosis treatment 2020, https://www.who.int/publications-detail-redirect/9789240007048; 2020 [accessed 27 February 2024].Google Scholar]. Although global efforts to combat TB have saved an estimated 75 million lives since 2000, the COVID-19 pandemic, coupled with conflicts across Europe, Africa, and the Middle East [6Casco N Jorge AL Palmero DJ Alffenaar JW Fox GJ et al.Global Tuberculosis Network and TB/COVID-19 Global Study GroupLong-term outcomes of the global tuberculosis and COVID-19 co-infection cohort.Eur Respir J. 2023; 622300925https://doi.org/10.1183/13993003.00925-2023Crossref Scopus (7) Google Scholar,7TB/COVID-19 Global Study GroupTuberculosis and COVID-19 co-infection: description of the global cohort.Eur Respir J. 2022; 592102538https://doi.org/10.1183/13993003.02538-2021Crossref Scopus (64) Google Scholar] and poor socioeconomic conditions, have reversed years of progress that was being made by global efforts to control and eventually end TB. The deteriorating global economic situation, with rising cost of living and reduction of budgets for national health programs, has disproportionately affected the poorest and disadvantaged, the very populations who are most affected by TB. Moreover, access to available WHO-recommended TB diagnostics and treatment regimens remains a major challenge, especially in low- and middle-income countries, where 80% of the annual TB caseload occurs. The United Nations General Assembly (UNGA) convened its second High-Level Meeting (HLM) on the fight against TB on September 22, 2023 to revisit the global targets established for 2018-2022 during the first meeting and to develop new targets up to 2027. Member states at the meeting endorsed a political declaration that reaffirms global commitments to end TB by 2030. The targets of the first United Nations HLM sought to treat at least 40 million individuals with TB worldwide from 2018 to 2022, addressing the TB needs of 3.5 million children, providing treatment for 1.5 million individuals with drug-resistant TB, and initiating TB preventive treatment (TPT) for at least 30 million people. The new global targets for 2023-2027 are more ambitious [1World Health Organization. Global tuberculosis report 2023, https://www.who.int/publications-detail-redirect/9789240083851; 2023 [accessed 27 February 2024].Google Scholar]. These include achieving 90% of patients having access to quality-assured diagnosis and treatment, 90% of individuals at risk of developing disease having access to TPT, 100% of people with TB having access to health and social benefits packages, raising 22 billion US$ for research, and developing a new vaccine against TB. In this special International Journal of Infectious Diseases issue to commemorate World TB Day, we present nine reports covering several of these aspects. We discuss several prevention issues. Prevention starts with vaccines [8da Costa C Benn CS Nyirenda T Mpabalwani E Grewal HMS Ahmed R et al.Perspectives on development and advancement of new tuberculosis vaccines.Int J Infect Dis. 2024; https://doi.org/10.1016/j.ijid.2024.106987Abstract Full Text Full Text PDF Scopus (2) Google Scholar]. There have been no new TB vaccines available since the introduction of the bacille Calmette–Guerin vaccine over a century ago. Encouragingly, several promising TB vaccine candidates are currently being evaluated in phase II and III clinical trials [8da Costa C Benn CS Nyirenda T Mpabalwani E Grewal HMS Ahmed R et al.Perspectives on development and advancement of new tuberculosis vaccines.Int J Infect Dis. 2024; https://doi.org/10.1016/j.ijid.2024.106987Abstract Full Text Full Text PDF Scopus (2) Google Scholar]. In parallel, we describe the immunology approaches to design vaccines and immune diagnostic tests for TB [9Panda S Kearns K Cheng C Arlehamn CSL. From antigens to immune responses: shaping the future of TB detection and prevention.Int J Infect Dis. 2024; https://doi.org/10.1016/j.ijid.2024.106983Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. The screening strategies are reported in terms of political commitments, as the Prevention and Systematic Screening Initiative, which is a new approach to technical assistance, focused on prevention and systematic screening, to end TB in the WHO European Region by 2030 [10Dadu A Yedilbayev A Migliori GB Ahmedov S Falzon D den Boon S et al.PASS to End TB in Europe: accelerated efforts on prevention and systematic screening to end tuberculosis in the WHO European Region by 2030.Int J Infect Dis. 2024; https://doi.org/10.1016/j.ijid.2024.02.023Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,11World Health Organization. Gearing up towards ending TB in Europe: regional workshop on prevention and systematic screening (PASS-to-EndTB), https://www.who.int/europe/news-room/events/item/2023/10/30/default-calendar/gearing-up-towards-ending-tb-in-europe–regional-workshop-on-prevention-And-systematic-screening-(pass-to-endtb); 2023 [accessed 27 February 2024].Google Scholar]. Screening procedures and TPT are also discussed, with a focus on persons moving from high- to low-TB endemic countries [12Petersen E Al-Abri S Al Jardani A Memish ZA Aklillu E Ntoumi F et al.Screening for latent tuberculosis in migrants – status quo and future challenges.Int J Infect Dis. 2024; 107002Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. This highlights the importance of identifying persons with TB infection and ensuring they receive TPT to prevent the re-activation of latent TB infection (LTBI) toward TB disease, leading to further transmission. In addition to screening migrants, South Korea developed a highly successful program for LTBI screening. This intervention has contributed to an annual 5.2% reduction in TB incidence between 2011 and 2016 through the screening of community workers, including daycare centers for children, kindergarten, and schools [13Go U Park M Kim UN Lee S Han S Lee J et al.Tuberculosis prevention and care in Korea: evolution of policy and practice.J Clin Tuberc Other Mycobact Dis. 2018; 11: 28-36https://doi.org/10.1016/j.jctube.2018.04.006Crossref PubMed Scopus (69) Google Scholar]. Although TB mainly affects the lungs, it can also affect other organs. When people with pulmonary TB cough, sneeze, or spit, TB bacilli are propelled and spread through the air and respiratory droplets. A person in close contact needs to inhale only a few mycobacteria to become infected. About a quarter of the global population (around 2 billion people) is estimated to have an immune response against TB and are likely to have TB infection. Most people with LTBI will not go on to develop TB disease and some will clear the infection. People showing an immune response against TB bacteria have a 5-10% lifetime risk of falling ill with TB disease during their whole life span. Those with compromised immune systems, such as people living with HIV, malnutrition, or diabetes, or using tumor necrosis factor inhibitor therapies or tobacco, have a higher risk of falling ill [14Cantini F Niccoli L Capone A Petrone L Goletti D. Risk of tuberculosis reactivation associated with traditional disease modifying anti-rheumatic drugs and non-anti-tumor necrosis factor biologics in patients with rheumatic disorders and suggestion for clinical practice.Expert Opin Drug Saf. 2019; 18: 415-425https://doi.org/10.1080/14740338.2019.1612872Crossref PubMed Scopus (44) Google Scholar,15Goletti D Pisapia R Fusco FM Aiello A Van Crevel R. Epidemiology, pathogenesis, clinical presentation and management of TB in patients with HIV and diabetes.Int J Tuberc Lung Dis. 2023; 27: 284-290https://doi.org/10.5588/ijtld.22.0685Crossref PubMed Scopus (12) Google Scholar]. Screening is done by standardized interferon-γ release assays and skin tests [16Alonzi T Repele F Goletti D. Research tests for the diagnosis of tuberculosis infection.Expert Rev Mol Diagn. 2023; 23: 783-795https://doi.org/10.1080/14737159.2023.2240230Crossref PubMed Scopus (9) Google Scholar, 17Kontsevaya I Cabibbe AM Cirillo DM DiNardo AR Frahm N Gillespie SH et al.Update on the diagnosis of tuberculosis.Clin Microbiol Infect. 2023; https://doi.org/10.1016/j.cmi.2023.07.014Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 18Goletti D Delogu G Matteelli A Migliori GB. The role of IGRA in the diagnosis of tuberculosis infection, differentiating from active tuberculosis, and decision making for initiating treatment or preventive therapy of tuberculosis infection.Int J Infect Dis. 2022; 124: S12-S19https://doi.org/10.1016/j.ijid.2022.02.047Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar], the new one based on the intradermal inoculation of ESAT-6 and CFP-10, which are M. tuberculosis-specific antigens compared with those included in the tuberculin skin test [16Alonzi T Repele F Goletti D. Research tests for the diagnosis of tuberculosis infection.Expert Rev Mol Diagn. 2023; 23: 783-795https://doi.org/10.1080/14737159.2023.2240230Crossref PubMed Scopus (9) Google Scholar, 17Kontsevaya I Cabibbe AM Cirillo DM DiNardo AR Frahm N Gillespie SH et al.Update on the diagnosis of tuberculosis.Clin Microbiol Infect. 2023; https://doi.org/10.1016/j.cmi.2023.07.014Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 18Goletti D Delogu G Matteelli A Migliori GB. The role of IGRA in the diagnosis of tuberculosis infection, differentiating from active tuberculosis, and decision making for initiating treatment or preventive therapy of tuberculosis infection.Int J Infect Dis. 2022; 124: S12-S19https://doi.org/10.1016/j.ijid.2022.02.047Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. The challenges of these new skin tests are also covered here [19To KW Rui Z Lee SS. Is the new TB antigen-based skin test ready for use as an alternative to TST/IGRA for TB diagnosis? A narrative review.Int J Infect Dis. 2024; Abstract Full Text Full Text PDF Google Scholar]. Finally, we report an overview of experimental non-sputum diagnostic and biomarkers assays for TB disease detection and progression to disease. Non-sputum tests can be very important for diagnosing extra-pulmonary TB or pulmonary TB in those unable to expectorate, such as children, or in immunocompromised subjects where the sputum M. tuberculosis load can be very low. A test based on the Actiphage technology to detect M. tuberculosis DNA in the blood is described [20Rees C Swift B Haldar P. State of art of the detection of M. tuberculosis during TB infection by blood tests using the phage technology.Int J Infect Dis. 2024; https://doi.org/10.1016/j.ijid.2024.106991Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] as useful for TB diagnosis and identifying those with TB infection that may progress to TB disease [21Verma R Swift BMC Handley-Hartill W Lee JK Woltmann G Rees CED et al.A novel, high-sensitivity, bacteriophage-based assay identifies low-level Mycobacterium tuberculosis bacteremia in immunocompetent patients with active and incipient tuberculosis.Clin Infect Dis. 2020; 70: 933-936https://doi.org/10.1093/cid/ciz548Crossref PubMed Scopus (28) Google Scholar,22Kim JW Bowman K Nazareth J Lee J Woltmann G Verma R et al.PET-CT-guided characterisation of progressive, preclinical tuberculosis infection and its association with low-level circulating Mycobacterium tuberculosis DNA in household contacts in Leicester, UK: a prospective cohort study.Lancet Microbe. 2024; 5: e119-e130https://doi.org/10.1016/S2666-5247(23)00289-6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. An alternative and potentially complementary approach for the detection of progressors to TB disease is by measuring host inflammation [23Källenius G Correia-Neves M Sundling C. Diagnostic markers reflecting dysregulation of the host response in the transition to TB disease.Int J Infect Dis. 2024; https://doi.org/10.1016/j.ijid.2024.106984Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Host immune responses can be measured by a proteomic and transcriptomic assessment that can detect increasing immune activation associated with TB disease progression several months before the onset of clinical disease [24Tabone O Verma R Singhania A Chakravarty P Branchett WJ Graham CM et al.Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis.J Exp Med. 2021; 218e20210915https://doi.org/10.1084/jem.20210915Crossref PubMed Scopus (32) Google Scholar,25Scriba TJ Penn-Nicholson A Shankar S Hraha T Thompson EG Sterling D et al.Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease.PLoS Pathog. 2017; 13e1006687https://doi.org/10.1371/journal.ppat.1006687Crossref PubMed Scopus (149) Google Scholar]. The potential importance of new methodologies for defining the latency stage of TB infection based on the detection of M. tuberculosis DNA in CD34+ cells in the blood of subjects with TB infection is discussed [26Martineau AR Chandran S Palukani W Garrido P Mayito J Reece ST et al.Towards a molecular microbial blood test for tuberculosis infection.Int J Infect Dis. 2024; https://doi.org/10.1016/j.ijid.2024.106988Abstract Full Text Full Text PDF Scopus (2) Google Scholar,27Repele F Alonzi T Navarra A Farroni C Salmi A Cuzzi G et al.Detection of Mycobacterium tuberculosis DNA in CD34+ peripheral blood mononuclear cells of adults with tuberculosis infection and disease.Int J Infect Dis. 2024; 106999Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. These methodologies could help to better understand TB pathogenesis and may allow specific targeting of the patients who require TPT. To achieve global TB control and eventually elimination, we need several actions: increased investments to accelerate the promising new TB vaccines pipeline, implementation of new immune strategies for better vaccine design, new therapies and/or therapy regimens, new diagnostic tests, implementation of prevention through screening using standardized old and new diagnostic tests for TB infection detection [28Migliori GB Wu SJ Matteelli A Zenner D Goletti D Ahmedov S et al.Clinical standards for the diagnosis, treatment and prevention of TB infection.Int J Tuberc Lung Dis. 2022; 26: 190-205https://doi.org/10.5588/ijtld.21.0753Crossref PubMed Scopus (44) Google Scholar], implementation of the non-sputum diagnostic tests for TB disease, and implementation of tests for the identification of those progressing toward TB disease to better target those needing therapy.

Objective To determine whether vitamin D supplementation influences grip strength, explosive leg power, cardiorespiratory fitness and risk of exercise-induced bronchoconstriciton (EIB) in South African schoolchildren. Methods Sub-study (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 D3 (n=228) or placebo (n=222) for 3 years. Outcome measures were serum 25-hydroxyvitamin D3 (25[OH]D3) concentrations, grip strength, standing long jump distance, peak oxygen uptake (VO2peak, determined using 20-metre multi-stage shuttle run tests) and the proportion of children with EIB, all measured at end-study. Results 64.7% of participants had serum 25(OH)D3 concentrations <75 nmol/L at baseline. At 3-year follow-up, children randomised to vitamin D vs. placebo had higher mean serum 25(OH)D3 concentrations (97.6 vs. 58.8 nmol/L respectively; adjusted mean difference [aMD] 39.9 nmol/L, 95% CI 36.1 to 43.6) and long jump distance (128.3 vs. 122.1 cm; aMD 3.6 cm, 95% CI 0.0 to 7.2). No end-study differences in grip strength, VO2peak, or spirometric lung volumes were seen, but administration of vitamin D vs. placebo was associated with a borderline-significant increased risk of EIB (14.5% vs. 8.6%; adjusted odds ratio 1.92, 95% CI 0.99 to 3.73). Conclusion A 3-year course of weekly oral supplementation with 10,000 IU vitamin D3 elevated serum 25(OH)D3 concentrations in South African schoolchildren and induced a small increase in long jump distance, but had no effect on grip strength or VO2 peak. Potential effects of vitamin D on risk of EIB require further research. What is already known on this topic? Observational studies have reported that vitamin D deficiency associates with reduced muscle strength and peak oxygen uptake and increased risk of exercise-induced bronchoconstriction (EIB) in children. Randomised controlled trials (RCT) of vitamin D supplementation to improve children’s muscle strength and cardiorespiratory fitness have yielded conflicting results. What this study adds This RCT, conducted in South African schoolchildren aged 8-11 years at baseline, found that a 3-year course of weekly oral supplementation with 10,000 IU vitamin D3 improved vitamin D status and resulted in a small (3.6 cm), borderline-significant increase in long jump distance, but had no effect on grip strength or peak oxygen uptake. Administration of vitamin D was associated with a borderline-significant increased risk of EIB. How this study might affect research, practice or policy Taken together with null results from another Phase 3 randomised controlled trial of vitamin D supplementation conducted in Mongolian children, our findings do not suggest that weekly oral vitamin D supplementation exerts clinically significant effects on muscle strength or peak oxygen uptake in schoolchildren in whom rickets has been excluded. Further research into potential effects of vitamin D supplementation on risk of EIB is needed. ### Competing Interest Statement 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][1]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. ### Clinical Trial NCT02880982 ### Funding Statement This research was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). RJW was supported by Wellcome (104803, 203135). He also received support from the Francis Crick Institute which is funded by Cancer Research UK (FC2112), the UK Medical Research Council (FC2112) and Wellcome (FC2112). NCH and CC are supported by the UK Medical Research Council [MC\_PC\_21003; MC\_PC\_21001]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2). Participants and their parents/guardians provided written informed assent and consent, respectively, to take part in the trial before any study procedures were conducted. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04641195&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F27%2F2024.03.26.24304912.atom

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 D3 (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 (VO2peak, 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, VO2peak, 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 D3 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.

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.

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 D3 (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 D3 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 D3 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.

ABSTRACT Background We have previously reported detection of genomic DNA of Mycobacterium tuberculosis (Mtb) in peripheral blood mononuclear cells (PBMC) of asymptomatic adults with recent household exposure to an index case of infectious pulmonary tuberculosis (TB). It is not known whether this phenomenon indicates quiescent Mtb infection or incipient TB disease. Methods We did a cross-sectional study with a nested prospective component, utilizing blood samples collected from a previously studied cohort of TB contacts recruited in Ethiopia to detect eight different blood RNA signatures for incipient TB. Gene expression analysis was performed on baseline blood samples from 24 HIV-uninfected Mtb DNA-negative individuals, 24 HIV-uninfected Mtb DNA-positive individuals, and 24 HIV-infected Mtb DNA-positive participants. Analysis was also performed on follow-up blood samples of 24 HIV-infected participants following completion of isoniazid preventive therapy (IPT), of whom 17 were classified as ‘responders’ to IPT (Mtb DNA undetectable at follow-up) and 7 were classified as ‘non-responders’ to IPT (Mtb DNA detectable at follow-up). Results Cross-sectional analysis of baseline gene expression data from HIV-uninfected participants revealed no differences in Z-scores between Mtb DNA-positive vs. Mtb DNA-negative participants for any of the eight gene expression signatures investigated. Prospective analyses comparing expression of the same eight signatures in HIV-infected participants before vs. after administration of IPT showed no change in gene expression Z-scores over the course of treatment, either for ‘responders’ or ‘non-responders’ to treatment. Conclusions Lack of any association between detection of Mtb DNA in PBMC of asymptomatic TB contacts and presence of gene expression signatures investigated suggests that detection of this bacillary biomarker is more likely to represent quiescent Mtb infection than incipient TB disease. Funding United Kingdom Medical Research Council (Ref. MR/P024548/1) RESEARCH IN CONTEXT Evidence before this study□ We searched PubMed from database inception to Sept 30, 2023, for studies published in any language evaluating associations between blood RNA signatures for tuberculosis (TB) and biomarkers of Mycobacterium tuberculosis (Mtb) infection using comprehensive terms for “tuberculosis infection”, “latent tuberculosis”, “transcriptional” and “biomarker”. Several reports have described whole blood transcriptional signatures associating with positive Interferon-Gamma Release Assay results in individuals without clinical or radiological evidence of active tuberculosis, but we did not find studies investigating transcriptional correlates of microbial biomarkers of Mtb infection. Added value of this study□ To our knowledge, this is the first study to investigate whether detection of Mtb DNA in blood of individuals with asymptomatic tuberculosis infection associates with blood RNA signatures for incipient tuberculosis. Cross-sectional analysis of samples from HIV-uninfected TB contacts in Ethiopia revealed no differences in any of eight whole blood gene expression signatures compared between Mtb DNA-positive vs. Mtb DNA-negative participants. Prospective analyses comparing expression of the same eight signatures in HIV-infected participants before vs. after administration of isoniazid preventive therapy showed no change in gene expression signatures over the course of treatment. Implications of all the available evidence□ Lack of any association between detection of Mtb DNA in the blood of asymptomatic TB contacts vs. presence of gene expression signatures for incipient TB provides the best available evidence for bona fide latent Mtb infection.

Vitamin D is precursor of the steroid hormone calcitriol and has important functions throughout the body, including increasing intestinal absorption of calcium, magnesium and phosphate. Vitamin D deficiency has been linked with a range of disorders, including several bone diseases. However, large trials of vitamin D supplementation have produced mixed results. Here, experts from around the world discuss several key questions in the vitamin D research and clinical fields.

ObjectivesTo 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 TB burden country.MethodsWe prospectively enrolled 57 TB-patients, 41 TBI-subjects and 39 controls in Rome, Italy. PBMC were isolated, CD34+ and CD34− cells were immunomagnetic separated, DNA was extracted and digital PCR for IS6110 and rpoB sequences was used to detect Mtb DNA in PBMC subsets and unfractionated PBMC.ResultsWe detected Mtb DNA at low copy number in CD34+ cells in 4/30 (13%) TB-patients, 2/24 (8%) TBI-subjects and 1/24 (4%) controls. Mtb DNA was detected in unfractionated PBMC in 3/51 (6%) TB-patients, 2/38 (5%) TBI-subjects and 2/36 (6%) controls. In CD34− cells only 1/31 (3%) TBI-subject was Mtb DNA positive.ConclusionsMtb DNA was detected at low frequency and levels in PBMC of TBI-subjects and TB-donors living in a low TB 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 development of a microbial blood biomarker for Mtb infection.

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.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.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).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.

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.