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Background Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes. Methods Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features. Results Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11–1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59–.88) and compared with ancestral lineages was .94 (.78–1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30–.54), but no significant outcome difference by variant. Conclusions Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections.

Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented.We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes.216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown.Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid-based regimens.

Background: P7 viroporin in HCV is a cation-selective ion channel-forming protein, functional in the oligomeric form. It is considered to be a potential target for anti-HCV compounds due to its crucial role in viral entry, assembly, and release. Method: Conserved crucial residues present in HCV p7 protein were delineated from the available literature with a specific focus on the genotypes 3a and 1b prevalent in India. Using the Flex-X docking tool, a library of FDA-approved drugs was docked on the receptor sites prepared around crucial residues. In the present study, we proposed drug repurposing to target viroporin p7, which may help in the rapid development of effective anti-HCV therapies. Results: With our approach of poly-pharmacology, a variety of drugs currently identified as antibiotics, antiparasitic, antiemetic, anti-retroviral, and anti-neoplastic were found to dock successfully on the p7 viroporin. Noteworthy among these are general-purpose cephalosporin antibiotics, leucal, phthalylsulfathiazole, and granisetron, which may be useful in acute HCV infection, and anti-neoplastic sorafenib and nilotinib, which may be valuable in advanced HCV-HCC cases. Conclusion: This study could pave the way for quick repurposing of these compounds as anti-HCV therapeutics.

IntroductionOptimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal-infant health.SettingFourteen sites in 7 countries within sub-Saharan Africa and India.MethodsThe multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother-infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm.ResultsTwo thousand four hundred thirty-one mother-infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553-869), and the median mVL was 322 copies/mL (IQR 40-1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL ( P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99).ConclusionsPostpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed.Clinical trial numberClinicalTrials.gov: NCT01061151; closed to follow-up.

A new tuberculosis (TB) diagnostic cartridge assay, which detects a 3-gene TB signature in whole blood, was not diagnostic in women with maternal TB disease in India (area under the curve [AUC] = 0.72). In a cohort of pregnant women, we identified a novel gene set for TB diagnosis (AUC = 0.97) and one for TB progression (AUC = 0.96).

BACKGROUND: Household contact investigation is an important strategy to identify individuals with tuberculosis (TB) exposure, infection, and disease, including those who may benefit from tuberculosis preventive therapy (TPT). Data in children exposed to rifampin-resistant TB are limited. METHODS: In preparation for and to inform the feasibility of an interventional trial, household contacts (HHC) of adults with pulmonary rifampin-resistant TB from high TB-burden countries were evaluated in a cross-sectional study. Using interferon gamma release assay (IGRA) and study-specific and 2015 international consensus definitions of intrathoracic TB in children, we evaluated the prevalence and predictors of TB infection and disease in child (

BackgroundSeveral clinical trials of tuberculosis preventive treatment (TPT) for household contacts of patients with multidrug-resistant tuberculosis (MDR-TB) are nearing completion. The potential benefits of TPT for MDR-TB contacts extend beyond the outcomes that clinical trials can measure.MethodsWe developed an agent-based, household-structured TB and MDR-TB transmission model, calibrated to an illustrative setting in India, the country accounting for 26% of global MDR-TB burden. We simulated household contact investigation for contacts of patients with MDR-TB, comparing an MDR-TPT regimen against alternatives of isoniazid preventive treatment, household contact investigation without TPT, or no household contact intervention. We simulated outcomes of a clinical trial and estimated the patient-level and population-level effects over a longer time horizon.FindingsDuring two years of follow-up per recipient, a simulated 6-month MDR-TPT regimen with 70% efficacy against both DS- and MDR-TB infection could prevent 72% [Interquartile range (IQR): 45 – 100%] of incident MDR-TB among TPT recipients (number needed to treat (NNT) 73 [44 – 176] to prevent one MDR-TB case), compared to household contact investigation without TPT. This NNT decreased to 54 [30 – 183] when median follow-up was increased from two to 16 years, to 27 [11 – Inf] when downstream transmission effects were also considered, and to 12 [8 – 22] when these effects were compared to a scenario of no household contact intervention.InterpretationIf forthcoming trial results demonstrate efficacy, the long-term population impact of MDR-TPT implementation could be much greater than suggested by trial outcomes alone.FundingNIH K01AI138853 and K08AI127908; Johns Hopkins Catalyst Award.

BackgroundPrior observation has shown differences in COVID-19 hospitalization rates between SARS-CoV-2 variants, but limited information describes differences in hospitalization outcomes.MethodsPatients admitted to 5 hospitals with COVID-19 were included if they had hypoxia, tachypnea, tachycardia, or fever, and data to describe SARS-CoV-2 variant, either from whole genome sequencing, or inference when local surveillance showed ≥95% dominance of a single variant. The average effect of SARS-CoV-2 variant on 14-day risk of severe disease, defined by need for advanced respiratory support, or death was evaluated using models weighted on propensity scores derived from baseline clinical features.ResultsSevere disease or death within 14 days occurred for 950 of 3,365 (28%) unvaccinated patients and 178 of 808 (22%) patients with history of vaccination or prior COVID-19. Among unvaccinated patients, the relative risk of 14-day severe disease or death for Delta variant compared to ancestral lineages was 1.34 (95% confidence interval [CI] 1.13-1.55). Compared to Delta variant, this risk for Omicron patients was 0.78 (95% CI 0.62-0.97) and compared to ancestral lineages was 1.04 (95% CI 0.84-1.24). Among Omicron and Delta infections, patients with history of vaccination or prior COVID-19 had one-half the 14-day risk of severe disease or death (adjusted hazard ratio 0.46, IQR 0.34-0.62) but no significant outcome difference between Delta and Omicron infections.ConclusionsAlthough the risk of severe disease or death for unvaccinated patients with Omicron was lower than Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated patients, but there was no difference between Delta and Omicron infections.

Women are significantly more likely to develop tuberculosis (TB) disease within the first 90 days after pregnancy than any other time in their lives. Whether pregnancy increases risk of progression from TB infection (TBI) to TB disease is unknown and is an active area of investigation. In this review, we discuss the epidemiology of TB and TBI in pregnancy, TBI diagnostics, and prevalence in pregnancy. We also review TBI treatment and highlight research priorities, such as short-course TB prevention regimens, drug-resistant TB prevention, and additional considerations for safety, tolerability, and pharmacokinetics that are unique to pregnant and postpartum people.

The microbial communities are an indispensable part of the human defense system and coexist with humans as symbionts, contributing to the metabolic functions and immune defense against pathogens. An ecologically stable vaginal microbiota is dominated by Lactobacillus species, which plays an important role in the prevention of genital infections by controlling the vaginal pH, reducing glycogen to lactic acid, and stimulating bacteriocins and hydrogen peroxide. In contrast, an abnormal vaginal microbial composition is associated with an increased risk of bacterial vaginosis, trichomoniasis, sexually transmitted diseases, preterm labor and other birth defects. This microbial diversity is affected by race, ethnicity, pregnancy, hormonal changes, sexual activities, hygiene practices and other conditions. In the present review, we discuss the changes in the microbial community of the vaginal region at different stages of a female's life cycle and its influence on her reproductive health and pathological conditions.

Tuberculosis (TB) is a leading cause of morbidity and mortality from a single infectious agent, despite being preventable and curable. Early and accurate diagnosis of active TB is critical to both enhance patient care, improve patient outcomes, and break Mycobacterium tuberculosis (Mtb) transmission cycles. In 2020 an estimated 9.9 million people fell ill from Mtb, but only a little over half (5.8 million) received an active TB diagnosis and treatment. The World Health Organization has proposed target product profiles for biomarker- or biosignature-based diagnostics using point-of-care tests from easily accessible specimens such as urine or blood. Here we review and summarize progress made in the development of pathogen- and host-based biomarkers for active TB diagnosis. We describe several unique patient populations that have posed challenges to development of a universal diagnostic TB biomarker, such as people living with HIV, extrapulmonary TB, and children. We also review additional limitations to widespread validation and utilization of published biomarkers. We conclude with proposed solutions to enhance TB diagnostic biomarker validation and uptake.

The Brief Rifapentine–Isoniazid Efficacy for TB Prevention/A5279 trial demonstrated a 1-month daily regimen of rifapentine and isoniazid was noninferior to 9 months of isoniazid alone for preventing TB in persons living with HIV (PLWH). Our objective was to evaluate rifapentine pharmacokinetics in trial participants receiving antiretroviral therapy (ART) and perform simulations to compare weight-based rifapentine dosing with a standard, fixed dose. Nonlinear mixed effect modeling was used to estimate rifapentine and 25-desacetyl rifapentine population pharmacokinetic characteristics. The pharmacokinetic model was validated using a nonparametric bootstrap and visual predictive checks. Monte Carlo simulations were performed to compare weight-based and fixed dose regimens. Rifapentine and 25-desacetyl rifapentine concentrations (347 of each; 185 participants) were each described with a one-compartment model with one-way conversion between rifapentine and 25-desacetyl rifapentine. The absorption rate was nearly doubled in fed versus fasting states. Rifapentine clearance was increased 31% in those receiving efavirenz (EFV)-based versus nevirapine-based ART. Metabolite clearance was allometrically scaled with fat-free mass. Simulations showed lower rifapentine exposures with weight-based compared with fixed dosing. With 10 mg/kg weight-based regimens, 26% and 62% of simulated exposures in

The political conditions of Kishtwar and its relations with the Mughal Emperors during the 17th century were greatly motivated by its geographical conditions and its location. Kishtwar was one of the Punjab Hill states. It was surrounded by high mountains and big rivers e.g., chanderbhaga. Kahan Sen was the first historical ruler of Kishtwar who annexed power from the Panjasasis in the 5th century A.D. The political condition of Kishtwar was also influenced by the conditions existing in its neighbouring states e.g., during the times of war of succession, rebellions, famines etc., the rebels and fugitives used to seek asylum in Kishtwar. The granting of asylum to the rebellious elements resulted in strained relations between the rulers of Kashmir and the rajas of Kishtwar because these rebels indulged in anti-Kashmir activities. The people of Kishtwar were loyal to their rajas and played a vital role in the political conditions in Kishtwar. The rajas of Kishtwar believed in the policy of imperialism which sometimes proved a source of trouble for the state of Kishtwar. The relations of the rajas of Kishtwar with the Mughal emperors played a great role in the political conditions of Kishtwar, which varied from time to time. It affected the political conditions in Kishtwar. The Mughal emperors intervened in the administration by interfering in the succession of the rajas e.g., Jagat Singh was allowed the Tika by the Mughal emperor. The political conditions of Kishtwar led to the spread of mixed cultures in Kishtwar. Due to political conditions and under the influence of Sufi saints, the rajas of Kishtwar embraced Islam but at the same time used the services of Purohits and assigned the grants to the temples.

Background Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy. Methods IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics. Results Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P Conclusions 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy. Clinical Trials Registration ClinicalTrials.gov, NCT02651259.

Objective There are limited studies on the association of HIV infection with systemic inflammation during pregnancy. Design A cohort study (N = 220) of pregnant women with HIV (N = 70) (all on antiretroviral therapy) and without HIV (N = 150) were enrolled from an antenatal clinic in Pune, India. Methods The following systemic inflammatory markers were measured in plasma samples using immunoassays: soluble CD163 (sCD163), soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP), interferon-β (IFNβ), interferon-γ (IFNγ), interleukin (IL)-1β, IL-6, IL-13, IL-17A and tumor necrosis factor α (TNFα). Generalized estimating equation (GEE) and linear regression models were used to assess the association of HIV status with each inflammatory marker during pregnancy and by trimester, respectively. Results Pregnant women with HIV had higher levels of markers for gut barrier dysfunction (I-FABP), monocyte activation (sCD14) and markers of systemic inflammation (IL-6 and TNFα), but surprisingly lower levels of AGP, an acute phase protein, compared to pregnant women without HIV, with some trimester-specific differences. Conclusions Our data show that women with HIV had higher levels of markers of gut barrier dysfunction, monocyte activation and systemic inflammation. These markers, some of which are associated with preterm birth, might help explain the increase in adverse birth outcomes in women with HIV and could suggest targets for potential interventions.

Tuberculosis (TB) affects 2 billion people worldwide and causes 1.5 million deaths every year. There is great need for new TB vaccines that are more efficacious than the currently licensed BCG vaccine, which provides only limited protection. Our goal was to identify potential targets for new TB vaccines by characterizing the immune responses that distinguish individuals with sterilizing protection against TB (TB-resisters), defined by presence of TB-specific immune responses and absence of latent infection, from individuals with latent TB infection (LTBI-participants).Cryopreserved peripheral blood mononuclear cells (PBMC) from 13 TB-resisters and 10 LTBI-participants were analyzed by high dimensional spectral flow cytometry after overnightM. tuberculosis (Mtb)antigenic stimulation or unstimulated control. Activation of conventional and nonconventional T cells, NK cells, and antigen presenting cells (APC) was compared between the two groups. Compared with LTBI-participants, TB-resisters had significantly higher proportions of conventional and nonconventional T cells expressing granzyme B (GranzB) and PD-1, and of polyfunctional cells in unstimulated andMtb-stimulated conditions. Conversely LTBI-participants had higher expression of CD25, CD69, CD107a, IL10 and IFNγ. An unbiased cluster analysis revealed higher frequency of recently described CD8+GMM+GranzB+ T cells in unstimulated PBMC from TB-resisters than LTBI-participants. APC activation revealed very few differences between TB-resisters and LTBI-participants. An exploratory analysis of responses in 14 BCG-recipients with minimal exposure to TB showed multiple differences with TB-resisters and LTBI-participants in PBMC activation; lower polyfunctionality of T cells and APC inMtb-stimulated PBMC; and absence of CD8+GMM+GranzB+ T cells.We conclude that combined increased T cell expression of GranzB and checkpoint inhibitors may contribute to immune protection against TB and may be targeted by new vaccines.

Background The positive predictive value of tuberculin skin test and current generation interferon gamma release assays are very low leading to high numbers needed to treat. Therefore, it is critical to identify new biomarkers with high predictive accuracy to identify individuals bearing high risk of progression to active tuberculosis (TB). Methods We used stored QuantiFERON supernatants from 14 household contacts of index TB patients who developed incident active TB during a 2-year follow-up and 20 age and sex-matched non-progressors. The supernatants were tested for an expanded panel of 45 cytokines, chemokines, and growth factors using the Luminex Multiplex Array kit. Results We found significant differences in the levels of TB-antigen induced production of several analytes between progressors and non-progressors. Dominance analysis identified 15 key predictive biomarkers based on relative percentage importance. Principal component analysis revealed that these biomarkers could robustly distinguish between the 2 groups. Receiver operating characteristic analysis identified interferon-γ inducible protein (IP)-10, chemokine ligand (CCL)19, interferon (IFN)-γ, interleukin (IL)-1ra, CCL3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most promising predictive markers, with area under the curve (AUC) ≥90. IP-10/CCL19 ratio exhibited maximum sensitivity and specificity (100%) for predicting progression. Through Classification and Regression Tree analysis, a cutoff of 0.24 for IP-10/CCL19 ratio was found to be ideal for predicting short-term risk of progression to TB disease with a positive predictive value of 100 (95% confidence interval [CI] 85.8–100). Conclusions The biomarkers identified in this study will pave way for the development of a more accurate test that can identify individuals at high risk for immediate progression to TB disease for targeted intervention.

Introduction: Regionalization envisages a two-way ow of patients & services designated as “Referralin” and “Referral-out” cases.”Referral-in” generally means patients from Sub Center, Primary Health Center, Community Health Center & District Hospitals Referred to Tertiary Care Hospital for Specialized care.”Referred-out” Generally means patients from Tertiary Care Hospitals to Higher Centers like Apex Institutions including AIIMS (New Delhi),SKIMS(Srinagar).PGIMER(Chandigarh, SGPGI(Lucknow), etc. for Super specialized treatment. Objective: To determine the effect of Referral- in admissions on the functioning of Gynecology & Obstetrics Department in a Teaching Hospital. Methodology: An Observational study was conducted over a period of 12 months from February 2019 to January 2020 in a 750 –bedded Tertiary Care Hospital of Jammu(UT) popularly Known as Shri Maharaja Gulab Singh(SMGS) Hospital, Jammu. Observations & Results: A detailed description of academic as well as functional status of Gynae & Obs. Department including Faculty-position, OPD patients, Inpatients admitted, Deliveries conducted(LSCS & MLE), Surgical Operations(Major as well as Minor) along with Bed-Occupancy Rate(BOR) & Referred-in Admissions during the study duration was recon ciliated & put forth in Tabulated Form after collecting from the Medical Records Department of the Hospital & displayed Statistically in Bar-Charts & pie-Chart. Discussion: Excessive Referral-in admissions to Teaching Hospital from PHC,SDH,DH & AH Level results in Overcrowding/Congestion in Hospital Wards culminating in Exhaustion of Resources like Drugs, Medicines, Reagents & other logistics. Supportive Services like Sanitation, Ambulance Transportation & Dietary facilities get worsened thereby exaggerating the Sepsis as well as nasocomial infection rate. There are increased chances of Corruption, & Violence/Verbal Scufes between Hospital Staff & Attendants of patients. Conclusion & Recommendation: Instead of irrationally referring the patients to Teaching Hospitals from Lower level Health Care Facilities(HCF), they should be rst sent to Associated Medical College Hospitals established at different Districts before being referred to Provincial Tertiary care Hospital thereby reducing the extra-load over Teaching Hospitals resulting in rapid depletion of resources as well as Medico- Social and Law & Order problems.

BackgroundPersons with HIV (PWH) have an increased risk of cardiovascular disease (CVD) compared to HIV-seronegative individuals (SN). Inflammation contributes to this risk but the role of lipid mediators, with central roles in inflammation, in HIV infection remain to be established; further aspirin reduces CVD risk in the general population through production of some of these anti-inflammatory lipid mediators, but they have not been studied in PWH.MethodsWe evaluated the relationship between plasma lipid mediators (i.e. 50 lipid mediators including classic eicosanoids and specialized pro-resolving mediators (SPMs)) and HIV status; and the impact of aspirin in PWH on regulating these autacoids. Plasma samples were obtained from 110 PWH receiving antiretroviral therapy (ART) from a randomized trial of aspirin (ACTG-A5331) and 107 matched SN samples (MACS-WIHS Combined Cohort).FindingsPWH had lower levels of arachidonic acid-derived pro-inflammatory prostaglandins (PGs: PGE2 and PGD2) and thromboxanes (Tx: TxB2), and higher levels of select pro-resolving lipid mediators (e.g. RvD4 and MaR2n-3 DPA) compared to SN. At the interval tested, aspirin intervention was observed to reduced PGs and Tx, and while we did not observe an increase in aspirin triggered mediators, we observed the upregulation of other SPM in aspirin treated PWH, namely MaR2n-3 DPA.InterpretationTogether these observations demonstrate that plasma lipid mediators profiles, some with links to systemic inflammation and CVD risk, become altered in PWH. Furthermore, aspirin intervention did not increase levels of aspirin-triggered pro-resolving lipid mediators, consistent with other reports of an impaired aspirin response in PWH.FundingNIH.

BACKGROUND: Diagnosis of genital tuberculosis (TB) as a cause of infertility still remains a diagnostic dilemma for clinicians, as no standard guidelines exist. The recently proposed best practices for genital TB diagnosis have not been evaluated yet in India. OBJECTIVES: To implement best practices to diagnose and treat likely genital TB as a cause of infertility. METHODS: Between April 2016 and June 2018, consenting women seen at a tertiary hospital infertility clinic were assessed by thorough TB related clinical history, ultrasonography, tuberculin skin test (TST), and ESR. Those with suspected genital TB underwent laparohysteroscopy. Clinical and laboratory characteristics were compared between likely (microbiologically confirmed or probable TB) and unlikely (possible and no genital TB) genital TB. Fertility outcome was assessed among women initiated on anti-TB treatment (ATT). RESULTS: Of 185 women seeking infertility care, likely genital TB was identified among 29 (15.7%) women, with 6 (21%) confirmed and 23 (79%) probable genital TB. Compared to unlikely genital TB cases, the likely genital TB group were found to have past history of TB (p < 0.001); positive TST (p = 0.002) and elevated ESR (p = 0.001). Among the likely genital TB group, all 6 confirmed genital TB were started on ATT and 2 (33.3%) conceived. Of 5 probable genital TB started on ATT, 3 (60%) conceived. CONCLUSION: Approximately 1/6th of women seeking infertility care met the criteria for likely genital TB. Conception among over-half of treated probable genital TB cases provides preliminary evidence that best clinical practices can be utilized, but needs further confirmatory studies.

Background Risk factors for progression of coronavirus 2019 (COVID-19) to severe disease or death are underexplored in U.S. cohorts. Objective To determine the factors on hospital admission that are predictive of severe disease or death from COVID-19. Design Retrospective cohort analysis. Setting Five hospitals in the Maryland and Washington, DC, area. Patients 832 consecutive COVID-19 admissions from 4 March to 24 April 2020, with follow-up through 27 June 2020. Measurements Patient trajectories and outcomes, categorized by using the World Health Organization COVID-19 disease severity scale. Primary outcomes were death and a composite of severe disease or death. Results Median patient age was 64 years (range, 1 to 108 years); 47% were women, 40% were Black, 16% were Latinx, and 21% were nursing home residents. Among all patients, 131 (16%) died and 694 (83%) were discharged (523 [63%] had mild to moderate disease and 171 [20%] had severe disease). Of deaths, 66 (50%) were nursing home residents. Of 787 patients admitted with mild to moderate disease, 302 (38%) progressed to severe disease or death: 181 (60%) by day 2 and 238 (79%) by day 4. Patients had markedly different probabilities of disease progression on the basis of age, nursing home residence, comorbid conditions, obesity, respiratory symptoms, respiratory rate, fever, absolute lymphocyte count, hypoalbuminemia, troponin level, and C-reactive protein level and the interactions among these factors. Using only factors present on admission, a model to predict in-hospital disease progression had an area under the curve of 0.85, 0.79, and 0.79, at day 2, 4, and 7, respectively. Limitation The study was done in a single health care system. Conclusion A combination of demographic and clinical variables is strongly associated with severe COVID-19 disease or death and their early onset. The COVID-19 Inpatient Risk Calculator (CIRC), using factors present on admission, can inform clinical and resource allocation decisions. Primary funding source Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.

Background Despite antiretroviral therapy, chronic lung diseases remain an important source of morbidity and mortality in people with HIV (PWH). We sought to identify clinical and immunological markers of pulmonary impairment among PWH in India. Methods Two hundred ten adult PWH receiving antiretroviral therapy (ART) were prospectively evaluated for 3 years. Plasma concentrations of interleukin (IL)-6, IL-10, tumor necrosis factor alpha, D-dimer, C-reactive protein, soluble (s)CD14, and sCD163 were measured at enrollment. We used multivariable linear and logistic regression to measure the association of baseline and time-varying clinical and immunological variables with spirometry-defined chronic obstructive pulmonary disease (COPD), restrictive spirometry pattern (RSP), preserved ratio impaired spirometry (PRISm), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC) during the third year of follow-up. Results After adjusting confounders, females were 7 times more likely to have RSP (95% CI, 2.81 to 17.62; P Conclusions Female sex, higher concentrations of IL-6 and D-dimer, and lower concentrations of IL-10 were associated with pulmonary impairment in adult PWH receiving ART in India.

Many new TB vaccine candidates in the development pipeline need to be studied in people with HIV. People with HIV are at high risk of developing Mycobacterium tuberculosis (Mtb) infection and TB disease and tend to develop less robust vaccine induced immune responses. Many questions remain unanswered regarding priority vaccine indications, clinical trial design, measures of safety, immunogenicity, and efficacy considerations for people with HIV. To address these gaps, a roadmap for developing TB vaccines for people with HIV was developed through a series of symposia that posed framing questions to a panel of international experts for discussion. Framing questions specific to people with HIV included: 1) What is the use case or rationale for developing TB vaccines?; 2) What is the landscape of TB vaccines?; 3) Which vaccine candidates should be prioritized ?; 4) What are the TB vaccine trial design considerations?; 5) What is the role of immunological correlates of protection?; and 6) What are the gaps in preclinical models for studying TB vaccines? We provide a summary of our roadmap with the intention of informing TB vaccine development and the prioritization of clinical trials for inclusion of people with HIV.

ImportanceNo proven treatment is available for severely ill COVID-19. Therapeutic use of COVID-19 convalescent plasma (COPLA) is under investigation.ObjectiveTo compare the efficacy of COPLA with standard medical therapy (SMT) alone in severe COVID-19 patients.Design, setting and participantsA multicentric, open-labelled, phase-III randomised controlled trial conducted at two treatment centres with COPLA collected at the third dedicated centre in North-India, the coordinating centre during trial from June 2020 to December 2020. The study population comprised 400 participants in the ratio of 1:1 in each treatment group.InterventionOne group received COPLA with SMT (n=200), and another group received SMT only (n=200).Main outcome measuresPrimary outcome was time to clinical improvement measured by a two-point reduction in the ordinal scale. Secondary outcomes included duration of O2therapy, the proportion of patients on mechanical ventilation at day-7, mortality, SARS-CoV-2 antibody levels, cytokine levels and incidence of adverse events.ResultsThe median time to a two-point reduction in the ordinal scale in both groups was 9 days (IQR=7–13) (p=0.328). The median duration of O2therapy was 8 days (IQR=6–12) in COPLA and 10 days (IQR=6–12) in SMT group (p=0.64). The PaO2/FiO2ratio showed significant improvement at 7 days in COPLA group(p=0.036). There was no difference in mortality till 28 days in both groups (p=0.62). However, if COPLA was given within 3 days of hospital admission, a significant reduction in ordinal scale was observed (p=0.04). Neutralising antibody titres in COPLA group (80 (IQR 80–80)) were higher than SMT group (0 (IQR 0–80)) at 48 hours (p=0.001). COPLA therapy led to a significant reduction in TNF-α levels at 48 hours (p=0.048) and D-dimer at 7 days (p=0.02). Mild allergic reactions were observed in 3 (1.5%) patients in COPLA group.Conclusion and relevanceConvalescent plasma with adequate antibody titres should be transfused in COVID-19 patients along with SMT in the initial 3 days of hospitalisation for better clinical outcomes.Trial registration numberNCT04425915.

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV.

Background People with human immunodeficiency virus (HIV) and advanced immunosuppression initiating antiretroviral therapy (ART) remain vulnerable to tuberculosis (TB) and early mortality. To improve early survival, isoniazid preventive therapy (IPT) or empiric TB treatment have been evaluated; however, their benefit on longer-term outcomes warrants investigation. Methods We present a 96-week preplanned secondary analysis among 850 ART-naive outpatients (≥13 years) enrolled in a multicountry, randomized trial of efavirenz-containing ART plus either 6-month IPT (n = 426) or empiric 4-drug TB treatment (n = 424). Inclusion criteria were CD4 count Results By 96 weeks, 85 deaths and 63 TB events occurred. Kaplan-Meier estimated mortality (10.1% vs 10.5%; P = .86) and time-to-death (P = .77) did not differ by arm. Empiric had higher TB risk (6.1% vs 2.7%; risk difference, −3.4% [95% confidence interval, −6.2% to −0.6%]; P = .02) and shorter time to TB (P = .02) than IPT. Tuberculosis medication adherence lowered the hazards of death by ≥23% (P Conclusions Empiric TB treatment offered no longer-term advantage over IPT in our population with advanced immunosuppression initiating ART. High IPT adherence significantly lowered death and TB incidence through 96 weeks, emphasizing the benefit of ART plus IPT initiation and completion, in persons with advanced HIV living in high TB-burden, resource-limited settings.

Background Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk–benefit of interventions. Methods A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated. Results The composite outcome scoring/ranking system categorized mother–infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4–26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, −3.2–6.2; P = .53). Conclusions For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT. Clinical Trials Registration. NCT01494038 (IMPAACT P1078).

Background International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1078, a randomized noninferiority study designed to compare the safety of starting isoniazid preventive therapy (IPT) in women living with human immunodeficiency virus (HIV) either during pregnancy or after delivery, showed that IPT during pregnancy increased the risk of composite adverse pregnancy outcomes, but not individual outcomes. Many known factors are associated with adverse pregnancy outcomes: these factors’ associations and effect modifications with IPT and pregnancy outcomes were examined. Methods Pregnant women living with HIV from 8 countries with tuberculosis incidences >60/100 000 were randomly assigned to initiate 28 weeks of IPT either during pregnancy or at 12 weeks after delivery. Using univariable and multivariable logistic regression and adjusting for factors associated with pregnancy outcomes, composite and individual adverse pregnancy outcome measures were analyzed. Results This secondary analysis included 925 mother-infant pairs. All mothers were receiving antiretrovirals. The adjusted odds of fetal demise, preterm delivery (PTD), low birth weight (LBW), or a congenital anomaly (composite outcome 1) were 1.63 times higher among women on immediate compared to deferred IPT (95% confidence interval [CI], 1.15–2.31). The odds of fetal demise, PTD, LBW, or neonatal death within 28 days (composite outcome 2) were 1.62 times higher among women on immediate IPT (95% CI, 1.14–2.30). The odds of early neonatal death within 7 days, fetal demise, PTD, or LBW (composite outcome 3) were 1.74 times higher among women on immediate IPT (95% CI, 1.22–2.49). Conclusions We confirmed higher risks of adverse pregnancy outcomes associated with the initiation of IPT during pregnancy, after adjusting for known risk factors for adverse pregnancy outcomes., After adjusting for known risk factors, we compared composite and individual adverse pregnancy outcomes in women with human immunodeficiency virus initiating isoniazid preventive therapy during or after pregnancy, and found higher risks of adverse pregnancy outcomes with initiation during pregnancy.

OBJECTIVE: The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine. METHODS: A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid and rifapentine pharmacokinetics were assessed. RESULTS: Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (p = 2.6 × 10(−3)) and 25-desacetyl rifapentine (p = 7.0 × 10(−5)) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks, and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics. CONCLUSIONS: Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

BackgroundPregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity.Methods944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations.ResultsFrom entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum.ConclusionsDecreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.

Mosquitoborne diseases (e.g., malaria, dengue, and chikungunya) are endemic to India and pose diagnostic challenges during pregnancy. We evaluated an intensified short symptom screening program in India to diagnose dengue during pregnancy. During October 2017–January 2018, we screened pregnant women during antenatal surveillance for symptoms of mosquitoborne diseases (fever only, fever with conjunctivitis, fever with rash, or all 3 symptoms) within the previous 15 days. Of 5,843 pregnant women screened, 52 were enrolled and tested for dengue, chikungunya, and Zika viruses by using a Trioplex real-time reverse transcription PCR. Of 49 who had complete results, 7 (14%) were dengue positive. Of these ocular pain was seen in 4 (57%) and conjunctivitis in 7 (100%). Intensified symptom screening using conjunctivitis, in addition to rash, in pregnant women with fever might improve dengue case detection and can be included in routine symptom screening during pregnancy.

Background Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens. Methods In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/μL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation. Results Among 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0–2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI, .06–.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06–1.70]). Conclusions Severe hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age.

Macrolide antibiotics, such as erythromycin and josamycin, are natural polyketide products harboring 14- to 16-membered macrocyclic lactone rings to which various sugars are attached. These antibiotics are used extensively in the clinic because of their ability to inhibit bacterial protein synthesis. More recently, some macrolides have been shown to also possess anti-inflammatory and other therapeutic activities in mammalian cells. To better understand the targets and effects of this drug class in mammalian cells, we used a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate cellular sensitivity to josamycin. Among the most sensitizing hits were proteins involved in mitochondrial translation and the mitochondrial unfolded protein response, glycolysis, and the mitogen-activated protein kinase signaling cascade. Further analysis revealed that cells treated with josamycin or other antibacterial agents exhibited impaired oxidative phosphorylation and metabolic shifts to glycolysis. Interestingly, we observed that knockdown of the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene, which contributes to p38 mitogen-activated protein kinase signaling, sensitized cells only to josamycin but not to other antibacterial agents. There is a growing interest in better characterizing the therapeutic effects and toxicities of antibiotics in mammalian cells to guide new applications in both cellular and clinical studies. To our knowledge, this is the first report of an unbiased genome-wide screen to investigate the effects of a clinically used antibiotic on human cells.

This article draws from a series of qualitative inquiries conducted with early childhood teachers in some Asian countries (primarily India) and interrogates the sustainability of applying E...

BackgroundMultidrug-resistant tuberculosis (MDR-TB) represents a significant clinical and public health challenge worldwide. Out of concern for possible resistance, some providers prescribe first- and second-line tuberculosis treatment together before completing drug susceptibility testing (DST), which may increase emergent resistance.MethodsMDR-TB patients at an Indian referral center were enrolled in an observational cohort. Participants with drug susceptibility test (DST) results were categorized as prescribed fluoroquinolones, streptomycin, both, or neither with first-line treatment before DST. Odds of additional resistance to fluoroquinolones and aminoglycosides (XDR-TB) were calculated in association with empiric combined first- and second-line treatment before DST.ResultsOf 494 participants, 130 (26.3%) received a fluoroquinolone or streptomycin with first-line drugs before DST. Odds of XDR-TB were associated with fluoroquinolone prescription before DST [odds ratio (OR): 2.19, 95% confidence interval (CI): 1.26–3.76). The association with XDR-TB persisted in multivariable analysis (adjusted OR: 2.43, 95% CI: 1.19-4.91). Combined empiric first- and second-line treatment before DST was not associated with eventual outcomes.ConclusionMany participants received empiric combined first- and second-line drugs before DST, which was associated with XDR-TB. To minimize emerging resistance, treatment-associated side effects, and provide the best possible care, this approach should be discouraged in favor of early DST and DST-guided TB treatment.

A new tuberculosis diagnostic cartridge assay, which detects a 3-gene tuberculosis signature in whole blood, was not diagnostic in women with maternal tuberculosis disease in India (AUC = 0.72). In a cohort of pregnant women, we identified a novel gene set for TB diagnosis (AUC = 0.97) and one for TB progression (AUC = 0.96).

Objective: To implement the Comprehensive Unit-based Safety Program (CUSP) in four neonatal intensive care units (NICUs) in Pune, India, to improve infection prevention and control (IPC) practices.Design: In this quasi-experimental study, we implemented CUSP in four NICUs in Pune, India, to improve IPC practices in three focus areas: hand hygiene, aseptic technique for invasive procedures, and medication and intravenous fluid preparation and administration. Sites received training in CUSP methodology, formed multidisciplinary teams, and selected interventions for each focus area. Process measures included fidelity to CUSP, hand hygiene compliance, and central line insertion checklist completion. Outcome measures included the rate of healthcare-associated bloodstream infection (HA-BSI), all-cause mortality, patient safety culture, and workload.Results: A total of 144 healthcare workers and administrators completed CUSP training. All sites conducted at least 75% of monthly meetings. Hand hygiene compliance odds increased 6% per month [odds ratio (OR) 1.06 (95% CI 1.03–1.10)]. Providers completed insertion checklists for 68% of neonates with a central line; 83% of checklists were fully completed. All-cause mortality and HA-BSI rate did not change significantly after CUSP implementation. Patient safety culture domains with greatest improvement were management support for patient safety (+7.6%), teamwork within units (+5.3%), and organizational learning—continuous improvement (+4.7%). Overall workload increased from a mean score of 46.28 ± 16.97 at baseline to 65.07 ± 19.05 at follow-up (p < 0.0001).Conclusion: CUSP implementation increased hand hygiene compliance, successful implementation of a central line insertion checklist, and improvements in safety culture in four Indian NICUs. This multimodal strategy is a promising framework for low- and middle-income country healthcare facilities to reduce HAI risk in neonates.

BackgroundMycobacterium tuberculosis (Mtb) transmissibility may vary between lineages (or variants) and this may contribute to the slow decline of tuberculosis (TB) incidence. The objective of our study was to compare transmissibility across four major lineages (L1-4) of Mtb among participants from two cohort studies in Pune, India.MethodsWe performed whole-genome sequencing (WGS) of Mtb sputum culture-positive isolates from participants in two prospective cohort studies of adults with pulmonary TB seeking care at public treatment centers in Pune, Maharashtra. We performed genotypic susceptibility prediction for both first- and second-line drugs using a previously validated random forest model. We used single nucleotide substitutions (SNS) and maximum likelihood estimation to build isolate phylogenies by lineage. We used Bayesian molecular dating to estimate ancestral node ages and compared tree characteristics using a two-sample Kolmogorov-Smirnov (KS) test.ResultsOf the 642 isolates from distinct study participants that underwent WGS, 612 met sequence quality criteria. The median age of the 612 participants was 31 years (IQR 24.4-44.2), the majority were male (64.7%) and sputum smear-positive (83.3%), and 6.7% had co-infection with HIV. Most isolates belonged to L3 (44.6%). The majority (61.1%) of multidrug-resistant isolates (MDR, resistant to isoniazid and rifampin) belonged to L2 (P < 0.001 [Fisher’s Exact]). There was no significant difference in host characteristics between participants infected with the four major lineages. In phylogenetic analysis, we measured shorter terminal branch lengths in the L2 tree compared to L1 and L3 trees indicating less time elapsing between transmission and sampling and higher transmissibility (median branch lengths: L2 - 3.3, L3 - 7.8, p ConclusionModern Mtb lineages (L2 and L4) were more recently introduced in western India, compared to older lineages (L1 and L3). L2 shows a higher frequency of drug-resistance and higher transmissibility. Our findings highlight the need for contact tracing around cases of TB due to L2, and heightened surveillance of TB antibiotic resistance in India.

IntroductionHost lipids play important roles in tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well characterised. We used unbiased lipidomics to study the prospective association of host lipids with TB treatment failure.MethodsA case–control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least-square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls.ResultsBaseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two cholesteryl ester lipids combined in a unique classifier model provided an AUC of 0.79 (95% CI 0.65–0.93) in the test dataset for prediction of TB treatment failure.ConclusionsWe identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. In addition, a lipid signature with prognostic accuracy for TB treatment failure was identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.

Background Undernutrition is the leading risk factor for tuberculosis (TB) globally. Its impact on treatment outcomes is poorly defined. Methods We conducted a prospective cohort analysis of adults with drug-sensitive pulmonary TB at 5 sites from 2015–2019. Using multivariable Poisson regression, we assessed associations between unfavorable outcomes and nutritional status based on body mass index (BMI) nutritional status at treatment initiation, BMI prior to TB disease, stunting, and stagnant or declining BMI after 2 months of TB treatment. Unfavorable outcome was defined as a composite of treatment failure, death, or relapse within 6 months of treatment completion. Results Severe undernutrition (BMI Conclusions Premorbid undernutrition, undernutrition at treatment initiation, lack of BMI increase after intensive therapy, and severe stunting are associated with unfavorable TB treatment outcomes. These data highlight the need to address this widely prevalent TB comorbidity. Nutritional assessment should be integrated into standard TB care.

INTRODUCTION: Preoperative assessment of various anatomic and clinical features helps in identifying potentially difficult laryngoscopy and intubation in advance allowing the anesthetist to be prepared for such a scenario. Though “ Short Neck” is a commonly used term in airway assessment indicating the possibility of a difficult airway. there is a lack of clarity regrading the cut off value and the association of different neck lengths (Anterior, Posterior and Lateral) to the laryngoscopic view. AIM : Evaluation of anterior, posterior and lateral neck length in neutral and extended positions and correlate each measurement with prediction of difficult laryngoscopic view. MATERIALS AND METHODS : This prospective observational study was conducted on 150 patients belonging to American Society of Anesthesiologists (ASA) grade 1/11 , aged 18-65 years with body mass index (BMI) 18 to 35 kg/m2,scheduled to undergo elective surgeries under general anaesthesia with endotracheal intubation. Each subject’s anterior,lateral and posterior neck lengths (ANL,LNL,PNL) were measured pre operatively. Direct laryngoscopy was done to achieve the best Cormack Lehane(CL) grade using manoeuvres (Backward upward rightward manoeuvre(BURP)/OELM/Change of Blade/Change of pillow height/RAMP positioning) when indicated and the same compared to the measured neck lengths. RESULT : The incidence of difficult laryngoscopy was found to be 18 per cent in our study population. Anterior neck length in neutral position was found to be the best predictor of difficult laryngoscopy, with a threshold of less than or equal to 9 cms. No particular neck length correlated with BMI and age. All the neck lengths showed positive correlation with the height of the subject CONCLUSION : ANL with a cut off criterion of less than or equal to 9 cm in neutral position can used objectively when measuring neck length. All neck lengths showed significant change with neck mobility. Rate of change of both PNL and LNL with head extension position showed significant change in difficult laryngoscopy subjects.

Background Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available. Methods We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes. Results Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6–2.4]) or adjusted (HR, 0.8 [95% CI, .5–1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2–8.8]). Conclusions In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test–based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB., In a large observational cohort, adding high-dose moxifloxacin at 600 mg daily to a susceptibility testing–based regimen for multidrug-resistant tuberculosis (MDR-TB) with low-level moxifloxacin resistance did not improve overall outcomes and should be avoided for treatment of moxifloxacin-resistant MDR-TB.

BACKGROUND Unhealthy alcohol use is associated with increased morbidity and mortality among persons with HIV and tuberculosis (TB). Computer-based interventions (CBIs) can reduce unhealthy alcohol use, are scalable, and may improve outcomes among patients with HIV or TB. OBJECTIVE We assessed the acceptability, adaptability, and feasibility of a novel CBI for alcohol reduction in HIV and TB clinical settings in Pune, India. METHODS We conducted 10 in-depth interviews with persons with alcohol use disorder (AUD): TB (6/10), HIV (2/10), or HIV-TB co-infected (1/10) selected using convenience sampling method, no HIV or TB disease (1/10), 1 focus group with members of Alcoholics Anonymous (AA; n=12), and 2 focus groups with health care providers (HCPs) from a tertiary care hospital (n=22). All participants reviewed and provided feedback on a CBI for AUD delivered by a 3D virtual counselor. Qualitative data were analyzed using structured framework analysis. RESULTS The majority (9/10) of in-depth interview respondents were male, with median age 42 (IQR 38-45) years. AA focus group participants were all male (12/12), and HCP focus group participants were predominantly female (n=15). Feedback was organized into 3 domains: (1) virtual counselor acceptability, (2) intervention adaptability, and (3) feasibility of the CBI intervention in clinic settings. Overall, in-depth interview participants found the virtual counselor to be acceptable and felt comfortable honestly answering alcohol-related questions. All focus group participants preferred a human virtual counselor to an animal virtual counselor so as to potentially increase CBI engagement. Additionally, interaction with a live human counselor would further enhance the program’s effectiveness by providing more flexible interaction. HCP focus group participants noted the importance of adding information on the effects of alcohol on HIV and TB outcomes because patients were not viewed as appreciating these linkages. For local adaptation, more information on types of alcoholic drinks, additional drinking triggers, motivators, and activities to substitute for drinking alcohol were suggested by all focus group participants. Intervention duration (about 20 minutes) and pace were deemed appropriate. HCPs reported that the CBI provides systematic, standardized counseling. All focus group and in-depth interview participants reported that the CBI could be implemented in Indian clinical settings with assistance from HIV or TB program staff. CONCLUSIONS With cultural tailoring to patients with HIV and TB in Indian clinical care settings, a virtual counselor–delivered alcohol intervention is acceptable and appears feasible to implement, particularly if coupled with person-delivered counseling.