BACKGROUND:Rates of drug-resistant tuberculosis (DR-TB) are increasing worldwide. Tuberculosis preventive treatment (TPT) for contacts of people with active TB is essential to halt infection progression and transmission. While newer TPT regimens for exposure to drug-susceptible and rifampin (R)-resistant strains (MDR-TB/RR-TB) are expanding, optimal treatment for contacts exposed to fluoroquinolone-resistant strains of TB (pre-XDR- or XDR-TB) remains unclear. In 2019-2020, Vladimir City, Russia, introduced moxifloxacin (Mfx)- and bedaquiline (Bdq)-based TPT regimens to prevent disease development in contacts exposed to MDR/RR-TB and pre-XDR-TB. METHODS:We conducted a retrospective cohort study of adult TB contacts, people experiencing homelessness, and people with HIV who received TPT in Vladimir between 2019 and 2020. Those without TB disease but with indications for TPT were offered 1 of 6 regimens, based on drug-susceptibility testing results of the index patient: rifapentine/isoniazid (3HP), isoniazid (6H), rifabutin/isoniazid (3HRb), 4R, 4Mfx, or 3Bdq. Adverse drug reactions (ADRs) were monitored with monthly lab tests and electrocardiogram (ECGs). Outcome measures included ADRs, TPT completion, and TB disease incidence during the 12-month follow-up period. RESULTS:Over 24 months, 403 people started TPT. No life-threatening ADRs or deaths occurred. The lowest ADR rate and highest completion were seen with 3Bdq (95.2%) compared to 3HP (75.9%, Mid-P exact = .03). Tuberculosis incidence per 1000 person-years was 4 times higher among eligible individuals who declined TPT versus those initiating it. CONCLUSIONS:Preventive therapy for drug-resistant TB, including fluoroquinolone-resistant strains, is acceptable, safe, and effective. Implementation of comprehensive TPT programs in high-burden DR-TB settings can protect contacts and reduce transmission.

Rates of drug-resistant tuberculosis (TB) are increasing worldwide. TB preventive treatment (TPT) for contacts of active TB patients is essential to halt infection progression and transmission. While newer TPT regimens for drug-sensitive strains are expanding, optimal treatment for contacts exposed to drug-resistant TB (DR-TB) remains unclear. In 2019-2020, Vladimir City, Russia, introduced moxifloxacin and bedaquiline-based TPT regimens to prevent disease development in contacts exposed to DR-TB. We conducted a retrospective cohort study using medical records data that included adult TB contacts, people experiencing homelessness, and persons with HIV who received TPT in Vladimir City, Russia, between 2019 and 2020. Those without TB disease but with indications for TPT were offered one of six regimens, based on drug-susceptible testing results of index patient: Rifapentine/Isoniazid (3HP), Isoniazid (6H), Rifabutin/Isoniazid (3HRb), Rifampicin (4R), Moxifloxacin (4Mfx), or Bedaquiline (3Bdq). Adverse drug reactions (ADRs) were monitored with monthly lab tests and ECGs. Over 24 months, 403 people started TPT. No life-threatening ADRs or deaths occurred. The lowest ADR rate and significantly higher completion rate was observed in 3Bdq (n=20, 95.2%) compared to 3HP (n=192, 75.9%, Mid-P exact = .03). The rate of TB disease per 1,000 person-years of observation was four times higher in individuals eligible for TPT who did not start it compared to those who initiated TPT. Treatment for the prevention of DR-TB, including forms resistant to rifampicin and fluoroquinolones, is feasible, effective and safe. This study introduces a novel paradigm for TB prevention in high-burden DR-TB settings, offering a promising strategy to protect contacts and reduce transmission. Moxifloxacin and bedaquiline are safe, effective, and feasible agents for preventive therapy among contacts of individuals with drug-resistant tuberculosis (TB) and can be used as part of the comprehensive search-treat-prevent approach for TB elimination.

Background:Nearly half of new tuberculosis patients in Sverdlovsk Oblast were diagnosed with multidrug-resistant tuberculosis (MDR-TB) and often exhibited fluoroquinolone resistance (FQ-R). This study aimed to (1) determine the number of MDR-TB patients who had Mycobacterium tuberculosis exhibiting the same genetic patterns (a unique combination of genotypes and mutations in genes associated with drug resistance) using the Russian microarray assay TB-TEST and (2) assess the correlation between these patterns and patient characteristics. Materials and methods:We analyzed 345 MDR-TB DNA samples from patients with pulmonary TB in Sverdlovsk Oblast between 2017 and 2020 using the TB-TEST. We assumed that isolates with unique patterns, which were seen in only one patient, indicated minimal transmission of M. tuberculosis, while the presence of more isolates with the same pattern suggested a more recent transmission. All patients were categorized into three groups to ensure that each group was approximately of the same size: Group 1 consisted of unique patterns; Group 2 (the low-frequency patterns group) included patterns shared by 2-6 patients; and Group 3, (the high-frequency patterns group, "dominant") included patterns shared by 7-18 patients. Results:In total, 174 distinct genetic patterns were identified: Group 1 included unique patterns, accounting for 36.8%; Group 2 included low-frequency patterns, accounting for 31.0%; and Group 3 included high-frequency patterns, accounting for 32.2%. The Beijing B0/W148 genotype was found in 72.4% of cases, and it was significantly less frequent in patients with unique patterns (59.1% vs. 66.4% vs. 93.7%). Mutations in gyrA/B genes were found in 50.4% of all samples; however, these mutations were significantly more common in the group with unique patterns (73% vs. 43.9% and 30.6%). This suggests that the mutations in gyrA/B genes may have developed over the years because of inadequate chemotherapy regimens. Nevertheless, these mutations have not yet spread widely, possibly due to lower transmission potential or recent emergence. Patients with M. tuberculosis-positive sputum who had undergone treatment for more than 12 months demonstrated a significantly higher proportion of unique patterns and a higher rate of fluoroquinolone resistance. Conclusion:Patients with unique patterns were found to have MDR-TB. However, a higher proportion of M. tuberculosis with mutations in gyrA/B genes in the group with unique patterns may indicate reduced transmissibility.

OBJECTIVE:A 'cluster' is an area with a higher occurrence of tuberculosis (TB) than would be expected in an average random distribution of that area. Tuberculosis clustering is commonly reported in Ethiopia, but most studies rely on registered data, which may miss patients who do not visit health facilities or those who attend but are not identified as having TB. This makes the detection of actual clusters challenging. This study analysed the clustering of pulmonary TB and associated risk factors using symptom-based population screening in Dale, Ethiopia. DESIGN:A prospective population-based cohort study. SETTING:All households in 383 enumeration areas were visited three times over a 1-year period, at 4-month intervals. PARTICIPANTS:Individuals with pulmonary TB aged ≥15 years with demographic, socioeconomic, clinical and geographical data residing in 383 enumeration areas (ie, the lowest unit/village in the kebele, each with approximately 600 residents). OUTCOME MEASURES:Pulmonary TB (ie, bacteriologically confirmed by sputum microscopy, GeneXpert or culture plus clinically diagnosed pulmonary TB) and pulmonary TB clustering. RESULTS:We identified pulmonary TB clustering in 45 out of the 383 enumeration areas. During the first round of screening, 39 enumeration areas showed pulmonary TB clustering, compared with only 3 enumeration areas in the second and third rounds. Our multilevel analysis found that enumeration areas with clusters were located farther from the health centres than other enumeration areas. No other determinants examined were associated with clustering. CONCLUSIONS:The distribution of pulmonary TB was clustered in enumeration areas distant from the health centres. Routine systematic community screening may be costly, but using existing health infrastructure with health extension workers through targeted screening, they can identify and refer persons with TB symptoms more quickly for diagnosis and treatment, thereby decreasing the duration of disease transmission and contributing to the reduction of TB burden.

Objective: A 'Cluster' is an area with a higher occurrence of tuberculosis than would be expected in an average random distribution of that area. Tuberculosis clustering is commonly reported in Ethiopia, but most studies rely on registered data, which may miss patients who do not visit health facilities or those who attend but are not identified as having tuberculosis. This makes the detection of actual clusters challenging. This study analysed the clustering of pulmonary tuberculosis and associated risk factors using symptom-based population screening in Dale, Ethiopia. Desgign: A prospective population-based cohort study. Setting: All households in 383 enumeration areas were visited three times over 1 year period, at four-month intervals. Participants: Individuals with pulmonary tuberculosis aged ≥15 years with demographic, socioeconomic, clinical, and geographic data residing in 383 enumeration areas (i.e., the lowest unit/village in the kebele, each with approximately 600 residents). Outcome measures: Pulmonary tuberculosis (i.e., bacteriologically confirmed by sputum microscopy, GeneXpert or cluture plus clinically diagnosed pulmonary tuberculosis) and pulmonary tuberculosis clustering. Results: We identified pulmonary tuberculosis clustering in 45 out of the 383 enumeration areas. During the first round of screening, 39 enumeration areas showed pulmonary tuberculosis clustering, compared to only three enumeration areas in the second and third rounds. Our multilevel analysis found that enumeration areas with clusters were located farther from the health centres than other enumeration areas. No other determinants examined were associated with clustering. Conclusions: The distribution of pulmonary tuberculosis was clustered in enumeration areas distant from the health centres. Routine systematic community screening using existing health infrastructure with Health extension workers may be costly but through targeted screening they can identify and refer persons with TB symptoms more quickly for diagnosis and treatment, thereby decreasing the duration of disease transmission and contributing to the reduction of TB burden. Running title: Clustering of pulmonary tuberculosis from repeated population-based screening ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Norwegian Institute of Public Health and the Norwegian Health Association. ### 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: Ethics approval was obtained from the Armauer Hansen Reaserch Institute Ethics Review Committee, Ethiopia (PO12/15), National Research Ethics Committee, Ethiopia (no 104/2016), the Regional Committees for Medical and Health Research Ethics in Norway (2015/1006). 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 All data produced in the present study are available upon reasonable request to the authors

BACKGROUNDIn Pakistan, 84% of healthcare is provided by the private sector. We conducted an epidemiological and programme review for TB to document progress and guide further efforts.METHODSSurveillance and data systems were assessed before analysing epidemiological data. We reviewed the programme at federal, provincial and peripheral levels and compiled national data along with WHO estimates to describe the evolution of epidemiological and programme indicators.RESULTSIn 2021, of the estimated number of TB cases, 55% of overall cases and 18% of drug-resistant cases were diagnosed and treated respectively. The contribution of the private sector in case detection increased from 30% in 2017 to 40% by 2021. For newly diagnosed pulmonary TB cases, the overall proportion of confirmed cases was 52%. In 2021, testing for rifampicin resistance among confirmed cases was 66% for new and 84% for previously treated patients. The treatment success rate exceeded 90% for drug susceptible TB. The main challenges identified were a funding gap (60% in 2021–2023), fragmented electronic systems for data collection and suboptimal coordination among provinces.CONCLUSIONSThe main challenges prevent further progress in controlling TB. By addressing these, Pakistan could improve coverage of interventions, including diagnosis and treatment. Bacteriological confirmation using recommended diagnostics also requires further optimisation.

Objective In Ethiopia, one-third of the estimated tuberculosis cases are not detected or reported. Incidence estimates are inaccurate and rarely measured directly. Assessing the ‘real’ incidence under programme conditions is useful to understand the situation. This study aimed to measure the prevalence and incidence of symptomatic pulmonary tuberculosis (PTB) during 1 year in the adult population of Dale in Ethiopia. Design A prospective population-based cohort study. Setting Every household in Dale was visited three times at 4-month intervals. Participants Individuals aged ≥15 years. Outcome measures Microscopy smear positive PTB (PTB s+), bacteriologically confirmed PTB (PTB b+) by microscopy, GeneXpert, or culture and clinically diagnosed PTB (PTB c+). Results Among 136 181 individuals, 2052 had presumptive TB (persistent cough for 14 days or more with or without haemoptysis, weight loss, fever, night sweats, chest pain or difficulty breathing ), in the first round of household visits including 93 with PTB s+, 98 with PTB b+ and 24 with PTB c+; adding those with PTB who were already on treatment, the total number of PTB was 201, and the prevalence was 147 (95% CI: 127 to 168)/100 000 population. Out of all patients with PTB, the proportion detected by symptom screening was in PTB s+ 65%, PTB b+ 67% and PTB c+44%. During 96 388 person-years follow-up, 1909 had presumptive TB, 320 had PTB and the total incidence of PTB was 332 (95% CI: 297 to 370)/100 000 person-years, while the incidence of PTB s+, PTB b+ and PTB c+ was 230 (95% CI: 201 to 262), 263 (95% CI: 232 to 297) and 68 (95% CI: 53 to 86)/100 000 person-years, respectively. Conclusion The prevalence of symptomatic sputum smear-positive TB was still high, only one-third of prevalent PTB cases notified and the incidence rate highest in the age group 25–34 years, indicating ongoing transmission. Finding missing people with TB through repeated symptom screening can contribute to reducing transmission.

Background: T cell infiltration around dying motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS). It is not known if this immune response represents a cause or a consequence of the disease. We aimed to establish whether individual variation in regulation of a T cell driven immune response is associated with long-term ALS risk.Methods: Tuberculin skin test (TST) following BCG vaccination represents a standardized measure of a secondary T cell driven immune response. During a Norwegian tuberculosis screening program (1963-1975) Norwegian citizens born from 1910 to 1955 underwent TST. In those previously BCG vaccinated (median 7 years prior to TST), we related tuberculin skin tests to later ALS disease identified through validated Norwegian health registers. We fitted Cox proportional hazard models to investigate the association between tuberculin reactivity and ALS risk.Results: Among 324,629 participants (52 % women) with median age 22 (IQR 10) years at tuberculosis screening, 496 (50 % women) later developed ALS. Hazard ratio for ALS was 0.74 (95% CI 0.57-0.95) for those who remained TST negative compared to those who mounted a positive TST. The association was strongest when time between BCG immunization and TST was short. The associations observed persisted for more than four decades after TST measurement.Conclusions: Negative TST responses after BCG vaccination is associated with decreased long-term risk for ALS development, supporting a primary role for adaptive immunity in ALS development.

BackgroundThe World Health Organization guidelines for management drug resistant tuberculosis include surgery as an additional method in selected cases. Pneumonectomies have higher risk of morbidity such as bronchial fistulas which may be prevented by bronchial stump covering. We compare two methods of bronchial stump reinforcement. Methods and materialsA retrospective single center follow-up study was done in 52 patients who underwent pneumonectomy for drug resistant pulmonary tuberculosis. Between 2000 and 2017 we performed pneumonectomies with pericardial fat reinforcement of bronchial stump in group 1 (n = 42), and between 2017 and 2021 in group 2 with pedicled muscle flap reinforcement group 2 (n = 10). ResultsBronchial fistulas occurred in 17/42 (41%) of patients group 1 and there was no fistula in group 2, and this was statistically different (Fisher's test p = 0.02). Post-operative complications were seen in 24/42 (57%) of the patients in Group 1, and 4/10 (40%) patients in Group 2 (Fischer's test p = 0.53). In group 1 positive bacteriology decreased from 74% to 24% just after surgery, and in group 2 it decreased from 90% to 10%, but this was not statistically different (Fisher's test p = 0.63). In group 1 no-one died the first month, but 8/42 (19%) died within a year; in group 2 one died within a month, and only this death (10%) within a year. This difference in case fatality was not statistically significant. ConclusionsThe use of pedicle muscle flap for bronchial stump coverage during the pneumonectomies for destructive drug resistant tuberculosis can prevent severe postoperative fistulas and improve postoperative life.

Dear Editor, Modelling studies suggest that ~30,000 children develop multidrug-resistant TB (MDR-TB) each year.1,2 However, most remain undiagnosed, with high associated mortality.3 Children exposed to MDR-TB in their household are at high risk of developing MDR-TB,4 and TB preventive therapy is increasingly advised following exposure. While several clinical trials are currently underway to evaluate MDR-TB preventive therapy, evidence for safety and efficacy is currently limited.5 The aim of this study was to assess the feasibility and safety of a 9-month fluoroquinolone (FQ) based preventive therapy regimen in children exposed to MDR-TB in their households. We conducted a prospective cohort study of children aged ,18 years identified through a systematic MDR-TB contact investigation in the Arkhangelsk Region, Russian Federation, which has a high prevalence of MDR-TB. In 2020, MDR-TB accounted for 31% of new TB cases and 78% of retreatment cases in adults. All children consecutively identified as household contacts of confirmed pulmonary MDRTB cases, with no FQ resistance, were invited to join the study between January 2011 to March 2014. Children were followed up for at least 1 year after completion of their preventive treatment, or for 2 years if they did not receive preventive treatment. Latent TB infection (LTBI) was diagnosed based on a positive tuberculin skin test (2 tuberculin units of purified protein derivative; cut-off 10 mm induration) or positive Diaskintest (Generium, Moscow, Russia; culture filtrate protein 10-early secreted antigenic target 6 [CFP10-ESAT6] produced by Escherichia coli BL21[DE3]/pCFP-ESAT; induration of any size) in the absence of TB disease.6 All exposed children were offered preventive therapy with FQs irrespective of LTBI status. As per national TB guidance, all children undergoing preventive TB treatment were offered treatment in sanatoria. Children whose parents opted out from treatment in sanatoria were offered outpatient treatment. For young children, powder formulations were prepared individually for each child (using mg/kg dose) and given with food or juice. All children received either directlyor video-observed treatment by medical staff. Safety monitoring on preventive therapy included 1–4 weekly clinical reviews with medical history and 4-weekly evaluation of full blood count, alanine and aspartate aminotransferases, total bilirubin, urine analysis and ECG (with measured QT interval). Adverse drug reactions were assessed and graded according to Division of AIDS grading tables.7 Parents of all eligible children were invited to give informed consent for the study; parents who refused preventive treatment provided consent for the collection of routine data. Ethics approval was provided by the Northern State Medical University Ethics Committee, Arkhangelsk (no. 1; 12 January 2011). Of 74 children identified as household contacts of MDR-TB cases, two were exposed to index cases with FQ resistance, and were therefore not eligible. Seventy-two children were included, with a median age of 7.0 years (interquartile range [IQR] 4.0–12.3; 20 (28%) were aged ,5 years). All index cases were bacteriologically confirmed using culture or molecular testing (Xpertw MTB/RIF, [Cepheid, Sunnyvale, CA, USA]; GenoTypeMTBDRplus, GenoTypeMTBDRsl [Hain Lifesciences, Nehren, Germany]). Sixty-three (82.9%) were sputum smear-positive for acid-fast bacilli. In total, there were 79 index cases, with four children having household exposure to more than one MDR-TB index case. LTBI was diagnosed in 51 (71%) children (38 children had both positive TST and Diaskintest, 12 children were TST-positive only and one child was Diaskintest-positive only). There were no significant differences in children who received preventive treatment and those who did not receive treatment in terms of age at registration at TB dispensary, size of positive TB skin test reactions and duration of follow-up (Table). Fifty-eight children (81%) received preventive therapy and 52 (90%) completed the prescribed 9-month course of treatment (Table). The first three children to be treated received ofloxacin (10 mg/kg, once daily), the rest were treated with moxifloxacin (10 mg/kg, once daily), once it became available. Six children had adverse events considered to be related to the study drug. All were mild (Grade 1 or 2) and only one adverse reaction led to treatment discontinuation (allergic reaction with urticarial rash and dry cough). Fourteen children (19%) did not receive preventive therapy due to parental preference. Median follow-up TG and AT are joint first authors.

Objective Many individuals with persistent cough and smear microscopy-negative sputum test for tuberculosis (TB) remain at risk of developing the disease. This study estimates the incidence of pulmonary TB (PTB) among initially smear-negative persistent coughers and its risk factors. Design A prospective population-based follow-up study. Setting Health extension workers visited all households in Dale woreda three times at 4-month intervals in 2016-2017 to identify individuals with symptoms compatible with TB (presumptive TB) using pretested and semistructured questionnaires. Participants We followed 3484 presumptive TB cases (>= 15 years) with an initial smear-negative TB (PTB) test. Outcome measures Bacteriologically confirmed PTB (PTB b+) and clinically diagnosed PTB (PTB c+). Results 3484 persons with initially smear-negative presumptive PTB were followed for 2155 person-years (median 0.8 years); 90 individuals had PTB b+ and 90 had PTB c+. The incidence rates for PTB b+ and PTB c+ were both 4176 (95% CI 3378 to 5109) per 100 000 person-years. We used penalised (lasso) and non-penalised proportional hazards Cox regression models containing all exposures and outcomes to explore associations between exposures and outcomes. In lasso regression, the risk of development of PTB b+ was 63% (HR 0.37) lower for people aged 35-64 years and 77% (HR 0.23) lower for those aged >= 65 years compared with 15-34 year-olds. Men had a 62% (HR 1.62) greater risk of PTB b+ development than women. The risk of PTB c+ was 39% (HR 0.61) lower for people aged 35-54 years than for those aged 15-34 years. Men had a 56% (HR 1.56) greater risk of PTB c+ development than women. Conclusions PTB incidence rate among persistent coughers was high, especially among men and young adults, the latter signifying sustained transmission. Awareness about this among healthcare workers may improve identification of more new TB cases.

Abstract Background Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette–Guérin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk. Methods Using data from a Norwegian tuberculosis screening programme (1963–1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship. Results Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76–0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST. Conclusion A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades.

Background: Pakistan implemented initiatives to detect tuberculosis (TB) patients through extended contact screening (ECS); it improved case detection but treatment outcomes need assessment. Objectives: To compare treatment outcomes of pulmonary TB (PTB) patients detected by ECS with those detected by routine passive case finding (PCF). Methods: A cohort study using secondary program data conducted in Lahore, Faisalabad and Rawalpindi districts and Islamabad in 2013–15. We used log binomial regression models to assess if ECS was associated with unfavorable treatment outcomes (death, loss-to-follow-up, failure, not evaluated) after adjusting for potential confounders. Results: We included 79,431 people with PTB; 4604 (5.8%) were detected by ECS with 4052 (88%) bacteriologically confirmed. In all PTB patients the proportion with unfavorable outcomes was not significantly different in ECS group (9.6%) compared to PCF (9.9%), however, among bacteriologically confirmed patients unfavorable outcomes were significantly lower in ECS (9.9%) than PCF group (11.6%, P = 0.001). ECS was associated with a lower risk of unfavorable outcomes (adjusted relative risk (aRR) 0.90; 95% CI 0.82–0.99) among ‘all PTB’ patients and bacteriologically confirmed PTB patients (aRR 0.91; 95% CI 0.82–1.00). Conclusion: In PTB patients detected by ECS the treatment outcomes were not inferior to those detected by PCF.

The management of tuberculosis (TB) is complicated. TB management requires a concerted and coordinated effort from different medical disciplines, sectors in society, and all government levels in a country. The management of TB includes preventive measures such as vaccination and addressing social problems such as overcrowding and malnutrition. TB management involves the treatment of latent or active TB and addressing the side effects of medications and the interaction with other medicines taken for comorbid conditions. Treatment of TB also includes the non-pharmacologic management of the infection or its complications. Challenges in the management of TB include the emergence of drug-resistant TB, non-adherence by patients due to the long duration of treatment, the HIV pandemic, which fuels TB and extra-pulmonary TB. Internationally, heads of state under the World Health Organization are making efforts to eliminate TB. This effort would require the use of every available resource and technology to achieve. Positron emission tomography integrated with computed tomography could address some of the challenges in the management of TB.

Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.44) and 24% (HR = 1.24, 95% CI 1.03-1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).