UNASSIGNED: Tuberculosis (TB) remains endemic in Singapore. Singapore\'s clinical practice guidelines for the management of tuberculosis were first published in 2016. Since then, there have been major new advances in the clinical management of TB, ranging from diagnostics to new drugs and treatment regimens. The National TB Programme convened a multidisciplinary panel to update guidelines for the clinical management of drug-susceptible TB infection and disease in Singapore, contextualising current evidence for local practice.
UNASSIGNED: Following the ADAPTE framework, the panel systematically reviewed, scored and synthesised English-language national and international TB clinical guidelines published from 2016, adapting recommendations for a prioritised list of clinical decisions. For questions related to more recent advances, an additional primary literature review was conducted via a targeted search approach. A 2-round modified Delphi process was implemented to achieve consensus for each recommendation, with a final round of edits after consultation with external stakeholders.
UNASSIGNED: Recommendations for 25 clinical questions spanning screening, diagnosis, selection of drug regimen, monitoring and follow-up of TB infection and disease were formulated. The availability of results from recent clinical trials led to the inclusion of shorter treatment regimens for TB infection and disease, as well as consensus positions on the role of newer technologies, such as computer-aided detection-artificial intelligence products for radiological screening of TB disease, next-generation sequencing for drug-susceptibility testing, and video observation of treatment.
UNASSIGNED: The panel updated recommendations on the management of drug-susceptible TB infection and disease in Singapore.

Data harmonization involves combining data from multiple independent sources and processing the data to produce one uniform dataset. Merging separate genotypes or whole-genome sequencing datasets has been proposed as a strategy to increase the statistical power of association tests by increasing the effective sample size. However, data harmonization is not a widely adopted strategy due to the difficulties with merging data (including confounding produced by batch effects and population stratification). Detailed data harmonization protocols are scarce and are often conflicting. Moreover, data harmonization protocols that accommodate samples of admixed ancestry are practically non-existent. Existing data harmonization procedures must be modified to ensure the heterogeneous ancestry of admixed individuals is incorporated into additional downstream analyses without confounding results. Here, we propose a set of guidelines for merging multi-platform genetic data from admixed samples that can be adopted by any investigator with elementary bioinformatics experience. We have applied these guidelines to aggregate 1544 tuberculosis (TB) case-control samples from six separate in-house datasets and conducted a genome-wide association study (GWAS) of TB susceptibility. The GWAS performed on the merged dataset had improved power over analyzing the datasets individually and produced summary statistics free from bias introduced by batch effects and population stratification. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Processing separate datasets comprising array genotype data Alternate Protocol 1: Processing separate datasets comprising array genotype and whole-genome sequencing data Alternate Protocol 2: Performing imputation using a local reference panel Basic Protocol 2: Merging separate datasets Basic Protocol 3: Ancestry inference using ADMIXTURE and RFMix Basic Protocol 4: Batch effect correction using pseudo-case-control comparisons.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches. In this context, computational techniques were used to elucidate the potential molecular target underlying the inhibitory action of LQM495. Then, a consensus reverse docking (CRD) protocol was used to investigate the interactions between this compound and several Mtb targets. Out of 98 Mtb targets investigated, the enhanced intracellular survival (Eis) protein emerged as a target for LQM495. To gain insights into the stability of the LQM495-Eis complex, molecular dynamics (MD) simulations were conducted over a 400 ns trajectory. Further insights into its binding modes within the Eis binding site were obtained through a Quantum mechanics (QM) approach, using density functional theory (DFT), with B3LYP/D3 basis set. These calculations shed light on the electronic properties and reactivity of LQM495. Subsequently, inhibition assays and kinetic studies of the Eis activity were used to investigate the activity of LQM495. Then, an IC50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its Vmax, Km, and Ki parameters indicated that it is a competitive inhibitor. Lastly, this study presents LQM495 as a promising inhibitor of Mtb Eis protein, which could be further explored for developing novel anti-TB drugs in the future.

BACKGROUND: Tuberculosis (TB) preventive treatment (TPT) is recommended by the World Health Organization (WHO) for persons living with HIV, including pregnant and breastfeeding women. Given the President\'s Emergency Plan for AIDS Relief (PEPFAR)\'s investment in TPT services for persons living with HIV as a strategy to prevent TB as well as uncertainty in guidelines and policy regarding use of TPT during pregnancy and the postpartum period, we conducted a review of current relevant national guidelines among PEPFAR-supported countries.
METHODS: Our review included 44/49 PEPFAR-supported countries to determine if TB screening and TPT are recommended specifically for pregnant and breastfeeding women living with HIV (WLHIV). National guidelines reviewed and abstracted included TB, HIV, prevention of vertical HIV transmission, TPT, and any other relevant guidelines. We abstracted information regarding TB screening, including screening tools and frequency; and TPT, including timing, regimen, frequency, and laboratory monitoring.
RESULTS: Of 44 PEPFAR-supported countries for which guidelines were reviewed, 66% were high TB incidence countries; 41% were classified by WHO as high TB burden countries, and 43% as high HIV-associated TB burden countries. We found that 64% (n = 28) of countries included TB screening recommendations for pregnant WLHIV in their national guidelines, and most (n = 35, 80%) countries recommend TPT for pregnant WLHIV. Fewer countries included recommendations for breastfeeding as compared to pregnant WLHIV, with only 32% (n = 14) mentioning TB screening and 45% (n = 20) specifically recommending TPT for this population; most of these recommend isoniazid-based TPT regimens for pregnant and breastfeeding WLHIV. However, several countries also recommend isoniazid combined with rifampicin (3RH) or rifapentine (3HP).
CONCLUSIONS: Despite progress in the number of PEPFAR-supported countries that specifically include TB screening and TPT recommendations for pregnant and breastfeeding WLHIV in their national guidelines, many PEPFAR-supported countries still do not include specific screening and TPT recommendations for pregnant and breastfeeding WLHIV.

UNASSIGNED: To determine alignment between national and World Health Organization (WHO) treatment recommendations, medicines prioritisation in country\'s essential medicines list (EML), and medicines availability in National drug register.
UNASSIGNED: An audit of medicines for malaria, tuberculosis, hypertension and type 2 diabetes mellitus listed in the national standard treatment guidelines (STGs) of Kenya, Tanzania and Uganda, as of March 2021, against WHO treatment guidelines, and respective country EML and National drug register.
UNASSIGNED: Not applicable.
UNASSIGNED: None.
UNASSIGNED: Proportion of medicine in country\'s STGs that align with WHO treatment recommendations, country\'s EML and country\'s drug register.
UNASSIGNED: Some disease areas had two sets of treatment guidelines - national STGs and disease-specific treatment guidelines (DSGs) developed at different times with different recommended medicines. Both STGs and DSGs included medicines not recommended by the WHO or not listed on the country EML and drug register. Non-WHO-recommended medicines accounted for 17/68 (25%), 10/57 (18%) and 3/30 (10%) of all STG medicines in Kenya, Tanzania and Uganda, respectively. For tuberculosis, the numbers and proportion of STG medicines listed on the respective national EMLs were 2/6 (33%), 15/19 (79%) and 4/5 (80%) in Kenya, Tanzania and Uganda. All tuberculosis medicines included in Kenya\'s and Uganda\'s STGs were registered compared with only 12/19 (63%) tuberculosis medicines in Tanzania\'s STG.
UNASSIGNED: Alignment between treatment guidelines, EMLs and drug registers is crucial for effective national pharmaceutical policy. Research is needed to understand the inclusion of medicines on STGs and DSGs which fall outside WHO treatment guidelines; the non-alignment of some STGs and DSGs, and STGs and DSGs including medicines which are not on country EML and drug register.

BACKGROUND: The suboptimal case notification rates for tuberculosis (TB) globally could partly be due to the poor implementation of TB testing guidelines or policies. We identified, appraised and synthesized qualitative evidence exploring the barriers and facilitators to implementing TB testing guidelines.
METHODS: We searched electronic databases and grey literature and included studies based on predefined inclusion criteria (PROSPERO registered protocol CRD42016039790) until 9th February 2023. We used the Critical Appraisal Skills Programme tool to assess the methodological quality of the included studies. Two authors reviewed the search output, extracted data and assessed methodological quality independently, resolving disagreements by consensus. We used the Supporting the Use of Research Evidence framework to identify themes and analyse and synthesize our data. We applied the Confidence in the Evidence from Reviews of Qualitative Research approach to assess the confidence of the review findings.
RESULTS: Our search output was 6976 articles, from which we included 25 qualitative studies, mostly from low- and middle-income countries (n=19) and about national guidelines (n=22). All studies were from healthcare settings. Most barriers revolved around health system constraints involving the guidelines (low trust and adherence, ambiguous and poorly developed or adapted guidelines) and poorly resourced and organized health facilities to enable the implementation of the guidelines. Individual-level barriers included low trust and low awareness among recipients and providers of care. Donor dependence was the main socio-political constraint. These barriers were similar across all income settings except poorly resourced health facilities and social and political constraints which were only reported in low- and middle-income settings. The reported facilitators were improved trust and knowledge of guidelines, national leadership support and availability of training tools and opportunities for guidelines across all income settings. We had high confidence in most of the review findings.
CONCLUSIONS: Limited guideline knowledge, trust and adherence related to poorly developed and disseminated guidelines in all income settings and poorly resourced facilities in low- and middle-income countries hinder the implementation of TB testing guidelines. This could be improved by better guideline training and adaptation and resourcing of health facilities.
BACKGROUND: The protocol of this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42016039790, and published in a peer-reviewed journal.

The current active-latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.

Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care.

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.

OBJECTIVE: Review of the scientific medical literature dedicated to clinical data, diagnosis and treatment for laryngeal tuberculosis published since the turn of the 21st century.
METHODS: Search of the Medline, Cochrane and Embase databases for the period 2000-2022. Selection of cohorts and case reports documenting clinical data, diagnosis and treatment for laryngeal tuberculosis.
RESULTS: In total, 119 articles were analyzed. Immunodepression, HIV infection, history of lung tuberculosis, general symptoms suggesting tuberculosis, smoking and associated laryngeal cancer were noted in 18%, 3%, 20% and 41% of cases, respectively. No pathognomonic symptoms or signs emerged. Voice impairment, of various types and severity, isolated and/or associated with other signs, was the most frequent laryngeal symptom, in 86% of cases. All laryngeal sites were involved, with numerous and various associations. Impaired laryngeal motion and tracheotomy were noted in 6% and 1% of cases, respectively. Time to diagnosis varied from less than 1month to 36months, for a median 3months, in case reports. Laryngeal tuberculosis was diagnosed bacteriologically with certainty in 28% of cases while diagnosis was based on indirect criteria and/or involvement of another site in the other 72%, with lung involvement in 54%. Treatment duration ranged from 6 to 24months (median, 6months), using 3 to 5 (median: 4) antitubercular antibiotics, with 4 used in 80% of cohorts and 77% of case reports. Overall rates of cure, death, treatment resistance, adverse events, and laryngeal sequelae were 99%, 0.5%, 0.5%, 6% and 5%, respectively.
CONCLUSIONS: The clinical presentation and diagnostic difficulty in laryngeal tuberculosis did not change since the end of the 20th century. Quadritherapy is highly effective, with a low resistance rate and few adverse effects or laryngeal sequelae.