Revisiting the association between vitamin D deficiency and active tuberculosis: A prospective case-control study in Taiwan.

BACKGROUND: To revisit the association between vitamin D deficiency (VDD, defined as serum 25(OH)D < 20 ng/ml) and incident active tuberculosis (TB), after two potentially underpowered randomized trials showed statistically non-significant 13%-22% decrease in TB incidence in vitamin D supplementation groups. METHODS: We prospectively conducted an age/sex-matched case-control study that accounting for body-mass index (BMI), smoking, and other confounding factors to examine the association between VDD and active TB among non-HIV people in Taiwan (latitude 24°N), a high-income society which continues to have moderate TB burden. RESULTS: We enrolled 62 people with incident active TB and 248 people in control group. The TB case patients had a significantly higher proportion of VDD compared to the control group (51.6% vs 29.8%, p = 0.001). The 25(OH)D level was also significantly lower in TB patients compared to control group (21.25 ± 8.93 ng/ml vs 24.45 ± 8.36 ng/ml, p = 0.008). In multivariable analysis, VDD (adjusted odds ratio [aOR]: 3.03, p = 0.002), lower BMI (aOR: 0.81, p < 0.001), liver cirrhosis (aOR: 8.99, p = 0.042), and smoking (aOR: 4.52, p = 0.001) were independent risk factors for incident active TB. CONCLUSIONS: VDD is an independent risk factor for incident active TB. Future randomized trials examining the effect of vitamin D supplementation on TB incidence should focus on people with a low BMI or other risk factors to maximize the statistical power.

Evaluating tuberculosis treatment outcomes in Haiti from 2018 to 2019: A competing risk analysis.

Objectives: This study assesses tuberculosis (TB) treatment outcomes in Haiti. Methods: Data from drug-susceptible patients with TB (2018-2019) were analyzed using the Fine & Gray model with multiple imputation. Results: Of the 16,545 patients, 14.7% had concurrent HIV coinfection, with a 66.2% success rate. The median treatment duration was 5 months, with patients averaging 30 years (with an interquartile range of 22-42 years). The estimated hazard of achieving a successful treatment outcome decreased by 2.5% and 8.1% for patients aged 45 and 60 years, respectively, compared with patients aged 30 years. Male patients had a 6.5% lower estimated hazard of success than their female counterparts. In addition, patients coinfected with HIV experienced a 35.3% reduction in the estimated hazard of achieving a successful treatment outcome compared with those with a negative HIV serologic status. Conclusions: Integrated health care approaches should be implemented, incorporating innovative solutions, such as machine learning algorithms combined with geographic information systems and non-conventional data sources (including social media), to identify TB hotspots and high-burden households.

Indole Propionic Acid Disturbs the Normal Function of Tryptophanyl-tRNA Synthetase in Mycobacterium tuberculosis.

Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis and the second-most contagious killer after COVID-19. The emergence of drug-resistant TB has caused a great need to identify and develop new anti-TB drugs with novel targets. Indole propionic acid (IPA), a structural analog of tryptophan (Trp), is active against M. tuberculosis in vitro and in vivo. It has been verified that IPA exerts its antimicrobial effect by mimicking Trp as an allosteric inhibitor of TrpE, which is the first enzyme in the Trp synthesis pathway of M. tuberculosis. However, other Trp structural analogs, such as indolmycin, also target tryptophanyl-tRNA synthetase (TrpRS), which has two functions in bacteria: synthesis of tryptophanyl-AMP by catalyzing ATP + Trp and producing Trp-tRNATrp by transferring Trp to tRNATrp. So, we speculate that IPA may also target TrpRS. In this study, we found that IPA can dock into the Trp binding pocket of M. tuberculosis TrpRS (TrpRSMtb), which was further confirmed by isothermal titration calorimetry (ITC) assay. The biochemical analysis proved that TrpRS can catalyze the reaction between IPA and ATP to generate pyrophosphate (PPi) without Trp as a substrate. Overexpression of wild-type trpS in M. tuberculosis increased the MIC of IPA to 32-fold, and knock-down trpS in Mycolicibacterium smegmatis made it more sensitive to IPA. The supplementation of Trp in the medium abrogated the inhibition of M. tuberculosis by IPA. We demonstrated that IPA can interfere with the function of TrpRS by mimicking Trp, thereby impeding protein synthesis and exerting its anti-TB effect.

YY1 Contributes to the Inflammatory Responses of Mycobacterium tuberculosis-Infected Macrophages Through Transcription Activation-Mediated Upregulation TLR4.

Tuberculosis (TB) is a chronic respiratory infectious disease and is induced by Mycobacterium tuberculosis (M.tb) infection. Macrophages serve as the cellular home in immunoreaction against M.tb infection, which is tightly regulated through Toll-like receptor 4 (TLR4) expression. Therefore, this study is designed to explore the role and mechanism of TLR4 in mycobacterial injury in human macrophages (THP-1 cells) after M.tb infection. Cell proliferation and apoptosis were assessed using MTT, EdU, and flow cytometry assays. ELISA kits were utilized to assess the levels of Interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor α (TNF-α). The binding between Yin-Yang-1 (YY1) and TLR4 promoter was predicted by JASPAR and verified using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. M.tb infection might repress THP-1 cell proliferation, and induce cell apoptosis and inflammatory response in a multiplicity of infection (MOI)-dependent manner. Moreover, M.tb infection increased the expression of TLR4 in HTP-1 cells in an MOI-dependent way, and its downregulation might overturn M.tb infection-mediated HTP-1 cell damage and inflammatory response. At the molecular level, YY1 was a transcription factor of TLR4 and promoted TLR4 transcription via binding to its promoter region. Besides, YY1 might activate the NF-kB signaling pathway via regulating TLR4. Meanwhile, TLR4 inhibitor BAY11-7082 might overturn the repression effect of TLR4 on M.tb-infected HTP-1 cell damage. YY1-activated TLR4 might aggravate mycobacterial injury in human macrophages after M.tb infection by the NF-kB pathway, providing a promising therapeutic target for TB treatment.

Development of a self-microemulsifying drug delivery system to deliver delamanid via a pressurized metered dose inhaler for treatment of multi-drug resistant pulmonary tuberculosis.

Tuberculosis (TB) is a serious health issue that contributes to millions of deaths throughout the world and increases the threat of serious pulmonary infections in patients with respiratory illness. Delamanid is a novel drug approved in 2014 to deal with multi-drug resistant TB (MDR-TB). Despite its high efficiency in TB treatment, delamanid poses delivery challenges due to poor water solubility leading to inadequate absorption upon oral administration. This study involves the development of novel formulation-based pressurized metered dose inhalers (pMDIs) containing self-microemulsifying mixtures of delamanid for efficient delivery to the lungs. To identify the appropriate self-microemulsifying formulations, ternary diagrams were plotted using different combinations of surfactant to co-surfactant ratios (1:1, 2:1, and 3:1). The combinations used Cremophor RH40, Poly Ethylene Glycol 400 (PEG 400), and peppermint oil, and those that showed the maximum microemulsion region and rapid and stable emulsification were selected for further characterization. The diluted self-microemulsifying mixtures underwent evaluation of dose uniformity, droplet size, zeta potential, and transmission electron microscopy. The selected formulations exhibited uniform delivery of the dose throughout the canister life, along with droplet sizes and zeta potentials that ranged from 24.74 to 88.99 nm and - 19.27 to - 10.00 mV, respectively. The aerosol performance of each self-microemulsifying drug delivery system (SMEDDS)-pMDI was assessed using the Next Generation Impactor, which indicated their capability to deliver the drug to the deeper areas of the lungs. In vitro cytotoxicity testing on A549 and NCI-H358 cells revealed no significant signs of toxicity up to a concentration of 1.56 µg/mL. The antimycobacterial activity of the formulations was evaluated against Mycobacterium bovis using flow cytometry analysis, which showed complete inhibition by day 5 with a minimum bactericidal concentration of 0.313 µg/mL. Moreover, the cellular uptake studies showed efficient delivery of the formulations inside macrophage cells, which indicated the potential for intracellular antimycobacterial activity. These findings demonstrated the potential of the Delamanid-SMEDDS-pMDI for efficient pulmonary delivery of delamanid to improve its effectiveness in the treatment of multi-drug resistant pulmonary TB.

Prevalence of co-infection of human immunodeficiency virus in diagnosed tuberculosis cases: Meta-analysis.

Objective: The objective of the study was to find pooled prevalence and risk factors of co-infection of human immunodeficiency virus (HIV) in diagnosed tuberculosis (TB) cases. Methods: Search engines including PubMed and Google Scholar were used to find literature using search terms such as "co-infection," "HIV," "Acquired Immunodeficiency Syndrome," TB and "Prevalence" among others. All original studies conducted on the prevalence of HIV co-infection among diagnosed TB patients that were freely available in full length had a clear methodology and relevant results were included in the study. Result: From 1021 initial studies, a total of 18 studies were selected for analysis. A total of 18 studies were included with a total sample size of 44943. The minimum prevalence of HIV-TB was reported in a study from Pakistan as 0.29% and the maximum prevalence of HIV-TB was found in Nigeria, that is, 44.20%. The pooled prevalence of HIV/TB co-infection was 16.291% (95%; 9.57-24.38) using the random effect method. As per Begg's test, there was no publication bias. As I2 is 99.74% so, there is high heterogeneity among studies; hence, random effect model is preferred. Conclusion: The study concludes that the pooled prevalence of HIV/TB co-infection was found to be 16.291% (95%; 9.57-24.38). The risk of mortality will be substantially raised by the co-existence of HIV-TB co-infection, so early screening and emphasizing the urgent need for integrated health-care interventions can cope with the situation.

The Indiscriminate Chemical Makeup of Secondary Metabolites Derived from Endophytes Harvested from Aloe barbadensis Miller in South Africa's Limpopo Region.

The efficacy of 23 bacterial isolates obtained from surface-sterilized stems and leaves of three medicinal plants (Aloe barbadensis Miller, Artemisia afra, and Moringa oleifera) was investigated in an endeavour to prevent the growth of Mycobacterium bovis using the cross-streak method. Endophytes were isolated by incubating sterile plant materials on nutrient agar at 30 °C for 5 days. Two isolates showing activity were subsequently utilized to produce the extracts. Whole-genome sequencing (WGC) was used to identify the isolates. Secondary metabolites produced after 7 days of growth in nutrient broth were harvested through extraction with ethyl acetate. The extracts were chemically profiled using gas chromatography-high resolution time-of-flight mass spectrometry (GC-HRTOF-MS). NCBI BLAST search results revealed that the isolated endophytes belonged to the Pseudomonas and Enterobacter genera, based on WGC. Two endophytes, Aloe I4 and Aloe I3-I5 from Aloe barbadensis, exhibited potency based on the cross-streak method. The metabolite profiling of the selected endophytes identified 34 metabolites from Aloe I4, including ergotamine, octadecane, L-proline and 143 other metabolites including quinoline and valeramide, which inhibit microbial quorum sensing. These findings suggest that bacterial endophytes from medicinal plants, particularly Aloe barbadensis, hold promise as sources of antimycobacterial agents for human health applications.

Identification of Novel Antimicrobial Compounds Targeting Mycobacterium tuberculosis S-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening.

The emergence of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (M. tuberculosis) has become a major medical problem. S-adenosyl-L-homocysteine hydrolase (MtSAHH) was selected as the target protein for the identification of novel anti-TB drugs. Dual hierarchical in silico Structure-Based Drug Screening was performed using a 3D compound structure library (with over 150 thousand synthetic chemicals) to identify compounds that bind to MtSAHH's active site. In vitro experiments were conducted to verify whether the nine compounds selected as new drug candidates exhibited growth-inhibitory effects against mycobacteria. Eight of the nine compounds that were predicted by dual hierarchical screening showed growth-inhibitory effects against Mycobacterium smegmatis (M. smegmatis), a model organism for M. tuberculosis. Compound 7 showed the strongest antibacterial activity, with an IC50 value of 30.2 µM. Compound 7 did not inhibit the growth of Gram-negative bacteria or exert toxic effects on human cells. Molecular dynamics simulations of 40 ns using the MtSAHH-Compound 7 complex structure suggested that Compound 7 interacts stably with the MtSAHH active site. These in silico and in vitro results suggested that Compound 7 is a promising lead compound for the development of new anti-TB drugs.

Interventions to prevent post-tuberculosis sequelae: a systematic review and meta-analysis.

Background: Tuberculosis (TB) remains a global public health challenge, causing substantial mortality and morbidity. While TB treatment has made significant progress, it often leaves survivors with post-TB sequelae, resulting in long-term health issues. Current healthcare systems and guidelines lack comprehensive strategies to address post-TB sequelae, primarily due to insufficient evidence. This systematic review and meta-analysis aimed to identify effective interventions for preventing post-TB sequelae. Methods: A systematic search was conducted across four databases including PubMed, SCOPUS, Web of Science, and Cochrane Central Register of Controlled Trials from inception to September 22, 2023. Eligible studies reported interventions designed to prevent post-TB sequelae were included. A random effect meta-analysis was conducted where applicable, and heterogeneity between studies was evaluated visually using forest plots and quantitatively using an index of heterogeneity (I2). This study is registered with PROSPERO (CRD42023464392). Findings: From the 2525 unique records screened, 25 studies involving 10,592 participants were included. Different interventions were evaluated for different outcomes. However, only a few interventions were effective in preventing post-TB sequelae. Rehabilitation programs significantly improved lung function (Hedges's g = 0.21; 95% confidence interval (CI): 0.03, 0.39) and prevented neurological sequelae (relative risk (RR) = 0.10; 95% CI: 0.02, 0.42). Comprehensive interventions and cognitive-behavioural therapy significantly reduced the risk of mental health disorders among TB survivors (Hedges's g = -1.89; 95% CI: -3.77, -0.01). In contrast, interventions targeting post-TB liver sequelae, such as vitamin A and vitamin D supplementation and hepatoprotective agents, did not show significant reductions in sequelae (RR = 0.90; 95% CI: 0.52, 1.57). Moreover, adjunctive therapies did not show a significant effect in preventing post-TB neurological sequelae (RR = 0.62, 95% CI: 0.31, 1.24). Interpretation: Rehabilitation programs prevented post-TB lung, neurologic and mental health sequelae, while adjuvant therapies and other interventions require further investigation. Funding: Healy Medical Research Raine Foundation, Curtin School of Population Health and the Australian National Health and Medical Research Council.

Prevalence and Spatial Autocorrelation of Tuberculosis in Indigenous People in Brazil, 2002-2022.

Tuberculosis (TB) among indigenous populations in Brazil poses a multifaceted public health challenge influenced by geographical, social, institutional, economic, and cultural factors. This study scrutinized the prevalence and spatial distribution of TB among Brazilian indigenous communities from 2002 to 2022. Employing a cross-sectional and descriptive approach, we analyzed data from the Notifiable Diseases Information System (SINAN) and conducted spatial autocorrelation tests to identify clusters and outliers. The findings uncovered substantial disparities in TB prevalence between the North and Central-West regions, in contrast to the South and Southeast, mirroring social, economic, and cultural inequalities in Brazil. It is concluded that public health strategies should not only consider the epidemiological aspects of TB but also encompass social and environmental determinants, notably the impact of climate change. Holistic and context-sensitive approaches are imperative for addressing TB within indigenous communities, underscoring the need for adaptive and culturally sensitive interventions in the public health landscape.

Why do patients with DR-TB do not complete their treatment? Findings of a qualitative study from Pakistan.

BACKGROUND: One of the major reasons for unsuccessful treatment outcomes among patients with drug-resistant tuberculosis (DR-TB) is the high rate of loss to follow-up (LTFU). However, in Pakistan, no qualitative study has been conducted to explore the perceptions of LTFU patients with regard to DR-TB treatment, the problems they face and the reasons for LTFU in detail. METHODS: This was a qualitative study that involved semistructured, indepth, face-to-face interviews of 39 LTFU patients with DR-TB. All interviews were carried out in Pakistan's national language 'Urdu' using an interview guide in two phases: the first phase was from December 2020 to February 2021 among patients with extensively drug-resistant tuberculosis and the second phase from July 2021 to September 2021 among patients with multidrug-resistant tuberculosis. RESULTS: The inductive thematic analysis of audio-recorded interviews generated the following four key themes, which were the major reasons reported by the participants of the current study to have led to LTFU: (1) patient-related factors, such as lack of awareness about the total duration of DR-TB treatment, fatigue from previous multiple failed episodes, lack of belief in treatment efficacy and perception of DR-TB as a non-curable disease; (2) medication-related factors, such as use of injectables, high pill burden, longer duration and adverse events; (3) socioeconomic factors, such as gender discrimination, poor socioeconomic conditions, non-supportive family members, social isolation and unemployment; and (4) service provider-related factors, such as distant treatment centres, non-availability of a qualified person, lack of adequate counselling and poor attitude of healthcare professionals. CONCLUSION: In the current study, patients' perceptions about DR-TB treatment, socioeconomic condition, medication and service provider-related factors emerged as barriers to the successful completion of DR-TB treatment. Increasing patients' awareness about the duration of DR-TB treatment, interacting sessions with successfully treated patients, availability of rapid drug susceptibility testing facilities at treatment centres, decentralising treatment and using the recently recommended all-oral regimen may further decrease the rate of LTFU.

Self-driven solutions and resilience adapted by people with drug-resistant tuberculosis and their caregivers in Bengaluru and Hyderabad, India: a qualitative study.

Background: One-fifth of people with drug-resistance tuberculosis (DR-TB) who were initiated on newer shorter treatment regimen (with injection) had unfavourable treatment outcomes in India as on 2020. Evidence on self-driven solutions and resilience adapted by people with DR-TB (PwDR-TB) towards their multi-dimensional disease and treatment challenges are scarce globally, which we aimed to understand. Methods: In this qualitative study using positive deviance framework, we conducted semi-structured in-depth interviews among consenting adult PwDR-TB (7 women, 13 men) who completed shorter treatment regimen (including injections) with maximum treatment adherence. The study was conducted in the southern districts of Bengaluru and Hyderabad, India between June 2020 and December 2022. Caregivers (14 women, 6 men) and health providers (8 men, 2 women) of PwDR-TB were also interviewed. Interviews were conducted in local language (Kannada, Tamil, Telugu, Urdu and Hindi) and inquired about practices, behaviours, experiences, perceptions and attributes which enabled maximum adherence and resilience of PwDR-TB. Interviews were audio recorded, transcribed, and translated to English and coded for thematic analysis using inductive approach. Findings: Distinctive themes explanatory of the self-driven solutions and resilience exhibited by PwDR-TB and their caregivers were identified: (i) Self-adaptation towards the biological consequences of drugs, by personalised nutritional and adjuvant practices, which helped to improve drug ingestion and therapeutic effects. Also home remedies and self-plans for ameliorating injection pain. (ii) Perceptual adaptation towards drugs aversion and fatigue, by their mind diversion practices, routinisation and normalisation of drug intake process. and constant reinforcement and re-interpretation of bodily signs of disease recovery (iii) Family caregivers intense and participatory care for PwDR-TB, by aiding their essential life activities and ensuring survival, learning and fulfilling special nutritional needs and goal oriented actions to aid drug intake (iv) Health care providers care, marked by swift and timely risk mitigation of side-effects and crisis response (v) Acquired self-efficacy of PwDR-TB, by their decisive family concerns resulting in attitudinal change. Also being sensitised on the detrimental consequences of disease and being motivated through positive examples. Interpretation: Synthesised findings on self-driven solutions and resilience towards the multi-dimensional DR-TB challenges provides opportunity for developing and testing new interventions for its effectiveness in DR-TB care settings globally. Designing and testing personalised cognitive interventions for PwDR-TB: to inculcate attitudinal change and self-efficacy towards medication, developing cognitive reinforcements to address the perception burden of treatment, skill building and mainstreaming the role of family caregivers as therapeutic partners of PwDR-TB, curating self-adaptive behaviours and practices of PwDR-TB to normalise their drug consumptions experiences could be the way forward in building resilience towards DR-TB. Funding: United States Agency for International Development (USAID) through Karnataka Health Promotion Trust (KHPT), Bengaluru, India.

Plan de implementación de la red nacional de apoyo para el diagnóstico y tratamiento de la tuberculosis pediátrica / Implementation plan for the national support network for the diagnosis and treatment of paediatric tuberculosis

La tuberculosis en la edad pediátrica está íntimamente ligada a la enfermedad del adulto y se considera que los casos pediátricos son centinelas de lo que sucede en la comunidad en que la niña y el niño vive. Por lo antes expuesto, el Sistema Nacional Integrado de Salud (SNIS) debe sumar esfuerzos bajo el enfoque de la Ley Crecer Juntos, para garantizar el bienestar de la niñez y adolescencia, y alcanzar el Objetivo de Desarrollo Sostenible (ODS) "Salud y Bienestar", ya que considera fundamental crear un "Plan de implementación de la red nacional de apoyo para el diagnóstico 10 y tratamiento de la tuberculosis pediátrica en El Salvador: RedNaTBPediátrica-ES", que contribuya a cumplir con los documentos regulatorios como la "Guía clínica para la atención pediátrica de la Tuberculosis y la coinfección TB/VIH" y demás normativas relacionadas al control de la tuberculosis en esta edad

Tuberculosis in paediatric age is closely linked to adult disease and paediatric cases are considered to be sentinels of what happens in the community in which the child lives. In view of the foregoing, the National Integrated Health System (NIS) must join forces under the Grow Together Act to guarantee the well-being of children and adolescents and achieve the Sustainable Development Goal (SDG) "Health and Well-being"considers it essential to create a "Plan for the implementation of the national network of support for the diagnosis and treatment of pediatric tuberculosis in El Salvador: RedNaTBPediátrica-ES", which contributes to comply with regulatory documents such as the Clinical Guide for Pediatric Care of TB and TB/HIV Co-infection" and other regulations related to tuberculosis control at this age

Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

An Updated Trial Sequential Meta-analysis of Vitamin D Receptor Gene Polymorphism (Fok1, Bsm1, Taq1 and Apa1) and Risk to Tuberculosis.

Vitamin D receptor (VDR) is one of the most widely studied genes for the Tuberculosis (TB) susceptibility. Several studies have been conducted to establish some association between them but most of the time they are contradictory and underpowered. So, a trial sequential meta-analysis between VDR gene polymorphisms and TB susceptibility can provide a better understanding of the relationship. A meta-analysis was carried out using a total of 17 case-control studies which includes Fok1 (14 Studies), Bsm1 (8 Studies), Apa1 (8 Studies) and Taq1 (12 Studies) polymorphisms in the VDR gene searched from Pubmed and Google Scholar. Pooled Odds Ratio (OR) and 95% Confidence Interval (CI) were calculated using StatsDirect Version 3, using random effects model. Trial sequential analysis (TSA) was also performed to assess if the statistical significance of the meta-analysis was within monitoring boundaries. It was found that the individuals with BB genotype of Bsm1 polymorphism with OR = 0.713 (95%CI = 0.521, 0.974; p value < 0.05) and FF genotype of Fok1 polymorphism with pooled OR = 0.716 (95%CI = 0.523, 0.979; p value < 0.05) had decreased incidence of TB. Also, the aa genotype of Apa1 gene polymorphism increases susceptibility to TB with pooled OR = 1.997 (95%CI = 1.121, 3.558; p value < 0.05). All these analyses reached the required information size through TSA analysis. No statistically significant result was found for Taq1 polymorphisms and TB susceptibility. VDR polymorphisms in Fok1 and Bsm1 played protective roles against development of TB infection, while Apa1 appeared to have a significant association to TB susceptibility. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01091-3.

Bilateral hand dactylitis: An unusual presentation of the great imitator: Tuberculosis.

The incidence of tuberculosis in developed countries has decreased over the years due to the use of effective tuberculosis drugs and improvements in socio-economic conditions. However, with the ease of global transport and increased travel to countries with high tuberculosis prevalence, the reduction in extrapulmonary tuberculosis cases has been less significant compared with the overall decrease in tuberculosis cases. Extrapulmonary tuberculosis can manifest in a variety of ways. Tuberculous dactylitis, a rare form of tuberculous osteomyelitis, was first described by Rankin in 1886. It mainly affects the short tubular bones in the hands and feet of children and is sometimes called 'spina ventosa'. A 42-year-old male patient initially presented to an external centre reporting swelling and pain in the hand joints of one year's duration. Despite one year of treatment with leflunomide and methylprednisolone (16 mg) and a history of methotrexate use during this period, he experienced no improvement. The patient's condition worsened after the start of sulfasalazine. Dermatological examination was performed due to the presence of haemorrhagic crusted papules and plaques on the ventral surface of both hands. A wound culture was taken, but no bacterial growth was observed. One week after the initial evaluation, the patient complained of persistent foul-smelling nasal discharge, which led to an evaluation by the infectious disease department. At this time, the Quantiferon test was positive. Mycobacterial culture on Days 1 and 3 showed growth of the Mycobacterium tuberculosis complex.

Quinoline Derivatives as Promising Scaffolds for Antitubercular Activity: A Comprehensive Review.

BACKGROUND: Heterocyclic compounds and their derivatives play a significant role in the design and development of novel quinoline drugs. Among the various pharmacologically active heterocyclic compounds, quinolines stand out as the most significant rings due to their broad pharmacological roles, specifically antitubercular activity, and their presence in plant-based compounds. Quinoline is also known as benzpyridine, benzopyridine, and 1-azanaphthalene. It has a benzene ring fused with a pyridine ring, and both rings share two carbon atoms. The importance of quinoline lies in its incorporation as a key component in various natural compounds found in medicinal plant families like Fumariaceae, Berberidaceae, Rutaceae, Papavaraceae, and others. OBJECTIVE: This article is expected to have a significant impact on the advancement of effective antitubercular drugs. Through harnessing the potent activity of quinoline derivatives, the research aims to make valuable contributions to combating tuberculosis more efficiently and ultimately reducing the global burden of this infectious disease. METHODS: Numerous nitrogen-containing heterocyclic compounds exhibit significant potential as antitubercular agents. These chemicals have fused aromatic nitrogen-heterocyclic nuclei that can change the number of electrons they have, which can change their chemical, physical, and biological properties. This versatility comes from their ability to bind with the receptors in multiple modes, a critical aspect of drug pharmacological screening. Among these compounds, quinoline stands out as it incorporates a stable fusion of a benzene ring with a pyridine nucleus. Quinolines have demonstrated a diverse range of pharmacological activities, including but not limited to anti-tubercular, anti-tumor, anticoagulant, anti-inflammatory, antioxidant, antiviral, antimalarial, anti-HIV, and antimicrobial effects. RESULTS: Some molecules, such as lone-paired nitrogen species, include pyrrole, pyrazole, and quinoline. These molecules contain nitrogen and take part in metabolic reactions with other molecules inside the cell. However, an excessive accumulation of reactive nitrogen species can lead to cytotoxicity, resulting in damage to essential biological macromolecules. Among these compounds, quinoline stands out as the oldest and most effective one, exhibiting a wide range of significant properties such as antitubercular, antimicrobial, anti-inflammatory, antioxidant, analgesic, and anticonvulsant activities. Notably, naturally occurring quinoline compounds, such as quinine, have proven to be potent antimalarial drugs. CONCLUSION: This review highlights quinoline derivatives' antitubercular potential, emphasizing recent research advancements. Utilizing IC50 values, the study emphasizes the efficacy of various quinoline substitutions, hybrids, and electron-withdrawing groups against MTB H37Rv. Continued research is essential for developing potent, low-toxicity quinoline derivatives to combat tuberculosis.

Latent Tuberculosis Infection Testing Practices in a Large US Integrated Healthcare System.

BACKGROUND: Tuberculosis (TB) is a public health threat, with >80% of active TB in the United States occurring due to reactivation of latent TB infection (LTBI). We may be underscreening those with high risk for LTBI and overtesting those at lower risk. A better understanding of gaps in current LTBI testing practices in relation to LTBI test positivity is needed. METHODS: This study, conducted between 1 January 2008 and 31 December 2019 at Kaiser Permanente Southern California, included individuals aged ≥18 years without a history of active TB. We examined factors associated with LTBI testing and LTBI positivity. RESULTS: Among 3 816 884 adults (52% female, 37% White, 37% Hispanic, mean age 43.5 years [standard deviation, 16.1]), 706 367 (19%) were tested for LTBI, among whom 60 393 (9%) had ≥1 positive result. Among 1 211 971 individuals who met ≥1 screening criteria for LTBI, 210 025 (17%) were tested for LTBI. Factors associated with higher adjusted odds of testing positive included male sex (1.32; 95% confidence interval, 1.30-1.35), Asian/Pacific Islander (2.78, 2.68-2.88), current smoking (1.24, 1.20-1.28), diabetes (1.13, 1.09-1.16), hepatitis B (1.45, 1.34-1.57), hepatitis C (1.54, 1.44-1.66), and birth in a country with an elevated TB rate (3.40, 3.31-3.49). Despite being risk factors for testing positive for LTBI, none of these factors were associated with higher odds of LTBI testing. CONCLUSIONS: Current LTBI testing practices may be missing individuals at high risk of LTBI. Additional work is needed to refine and implement screening guidelines that appropriately target testing for those at highest risk for LTBI.

A descriptive study on isoniazid resistance-associated mutations, clustering and treatment outcomes of drug-resistant tuberculosis in a high burden country.

PURPOSE: To describe katG and inhA mutations, clinical characteristics, treatment outcomes and clustering of drug-resistant tuberculosis (TB) in the State of São Paulo, southeast Brazil. METHODS: Mycobacterium tuberculosis isolates from patients diagnosed with drug-resistant TB were screened for mutations in katG and inhA genes by line probe assay and Sanger sequencing, and typed by IS6110-restriction fragment-length polymorphism for clustering assessment. Clinical, epidemiological and demographic data were obtained from surveillance information systems for TB. RESULTS: Among the 298 isolates studied, 127 (42.6%) were isoniazid-monoresistant, 36 (12.1%) polydrug-resistant, 93 (31.2%) MDR, 16 (5.4%) pre-extensively drug-resistant (pre-XDR), 9 (3%) extensively drug-resistant (XDR) and 17 (5.7%) susceptible after isoniazid retesting. The frequency of katG 315 mutations alone was higher in MDR isolates, while inhA promoter mutations alone were more common in isoniazid-monoresistant isolates. Twenty-six isolates phenotypically resistant to isoniazid had no mutations either in katG or inhA genes. The isolates with inhA mutations were found more frequently in clusters (75%) when compared to the isolates with katG 315 mutations (59.8%, p = 0.04). In our population, being 35-64 years old, presenting MDR-, pre-XDR- or XDR-TB and being a retreatment case were associated with unfavourable TB treatment outcomes. CONCLUSION: We found that katG and inhA mutations were not equally distributed between isoniazid-monoresistant and MDR isolates. In our population, clustering was higher for isolates with inhA mutations. Finally, unfavourable TB outcomes were associated with specific factors.

Screening Practices and Risk Factors for Co-Infection with Latent Tuberculosis and Hepatitis B Virus in an Integrated Healthcare System - California, 2008-2019.

BACKGROUND: Hepatitis B virus (HBV) and latent tuberculosis infection are associated with a significant global burden, but both are underdiagnosed and undertreated. We described the screening patterns and risk factors for co-infection with latent tuberculosis and HBV within a large healthcare system. METHODS: Using data from Kaiser Permanente Southern California during 2008-2019, we described HBV infections, defined as a positive HBV surface antigen, e-antigen, or DNA test, and latent tuberculosis, defined as a positive Mantoux tuberculin skin test or interferon-gamma release assay test. We estimated adjusted odds ratios (aOR) for co-infection among screened adults with either infection. RESULTS: Among 1997 HBV patients screened for latent tuberculosis, 23.1% were co-infected, and among 35,820 patients with latent tuberculosis screened for HBV, 1.3% were co-infected. Among HBV patients, co-infection risk was highest among Asians compared with White race/ethnicity (29.4% vs 5.7%, aOR 4.78; 95% confidence interval [CI], 2.75-8.31), and persons born in a high-incidence country compared with low-incidence countries (31.0% vs 6.6%; aOR 4.19; 95% CI, 2.61-6.73). For patients with latent tuberculosis, risk of co-infection was higher among Asian (aOR 9.99; 95% CI, 5.79-17.20), or Black race/ethnicity (aOR 3.33; 95% CI, 1.78-6.23) compared with White race/ethnicity. Persons born in high-incidence countries had elevated risk of co-infection compared with persons born in low-incidence countries (aOR 2.23; 95% CI, 1.42-3.50). However, Asians or persons born in high-incidence countries were screened at similar rates to other ethnicities or persons born in low-incidence countries. CONCLUSIONS: Latent tuberculosis risk is elevated among HBV patients, and vice versa. Risk of co-infection was highest among persons born in high-incidence countries and Asians. These findings support recent guidelines to increase HBV and tuberculosis screening, particularly among persons with either infection.