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Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Objective We report on: (1) the proportion of patients with known atrial fibrillation (AF); and (2) demographic, clinical or radiological differences between patients with known AF (and not treated) and patients with newly diagnosed AF, in a cohort of patients who presented with ischaemic stroke or transient ischaemic attack (TIA) not previously treated with anticoagulation.Design We reviewed cross-sectional baseline demographic and clinical data from a prospective observational cohort study, (CROMIS-2).Setting Patients were recruited from 79 hospital stroke centres throughout the UK and one centre in the Netherlands.Participants Patients were eligible if they were adults who presented with ischaemic stroke or TIA and AF and had not been previously treated with oral anticoagulation.Main outcome measures Proportion of patients with known AF before index ischaemic stroke or TIA from a cohort of patients who have not been previously treated with oral anticoagulation. Secondary analysis includes the comparison of CHA2DS2-VASc and HAS-BLED scores and other demographics and risk factors between those with newly diagnosed AF and those with previously known AF.Results Of 1470 patients included in the analysis (mean age 76 years (SD 10)), 622 (42%) were female; 999 (68%) patients had newly diagnosed AF and 471 (32%) patients had known AF. Of the 471 patients with known AF, 68% had a strong indication for anticoagulation and 89% should have been considered for anticoagulation based upon CHA2DS2-VASc score. Patients with known AF were more likely to have a prior history of dementia (4% vs 2%, p=0.02) and had higher HAS-BLED scores (median 3 vs 2). CHA2DS2-VASc, other risk factors and demographics were similar.Conclusions About 1/3 of patients who present with stroke and have AF who have not been treated with oral anticoagulation have previously known AF. Of these patients, at least 68% were not adequately treated with oral anticoagulation.Trial registration number NCT02513316.

Although positive association between fermented vegetables intake with the risk of coronary heart disease (CHD) has increased attention nowadays, the metabolite profiling and the mechanism of action are still elusive. This study designed to investigate the secondary metabolites, hypolipidemic, and anti-atherogenic effect of mixed vegetable fermentation extract (MVFE). The metabolite screening of the MVFE was assessed using the Liquid Chromatography Tandem Mass Spectrophotometer (LC-MS/MS) method. The result of LC-MS/MS was used as ligands to inhibit the binding of oxidized LDL (oxLDL) and Cluster Differentiation 36 (CD36), Scavenger Receptor A1 (SRA1), Lectin-type oxidized LDL receptor 1 (LOX1). This work was performed with molecular docking using Discovery Studio 2021, PyRx 0.9, and Autodock Vina 4.2 followed by analyzing Network Pharmacology, Protein Protein Interaction (PPI) using Cytoscape 3.9.1 and String 2.0.0. Finally, the clinical effect of MVFE was evaluated using in vivo study. Twenty rabbits were assigned to normal, negative control, and MVFE group that were fed with standard diet, high fat diet (HFD), HFD supplemented with MVFE 100, 200 mg/kg BW, respectively. The serum level of Total Cholesterol (TC) and Low-Density Lipoprotein (LDL-c) were detected at the end of week 4. The LC-MS/MS analysis identified 17 compounds categorized as peptides, fatty acids, polysaccharides, nucleoside, flavonoids, flavanols, and phenolic compounds. Based on the docking study, more negative binding affinity was observed in the interaction between metabolites with the scavenger receptors (SR) than simvastatin. The number of nodes and edges based on Network Pharmacology analysis were 268 and 482, respectively. The PPI network showed that MVFE metabolites exerts its athero-protective effect by modulating various cellular processes including inflammation, improvement of endothelial function, and modulation of lipid metabolism. Blood TC and LDL-c concentrations in the negative control (458.82 ± 82.03; 191.87 ± 92.16 mg/dL) were higher significantly compared to the normal group (87.03 ± 29.27; 43.33 ± 5.75 mg/dL). The MVFE administration decreased the TC (100, 200 mg/kg BW MVFE: 269.96 ± 85.34; 130.17 ± 45.02 mg/dL) and LDL-c level (100, 200 mg/kg BW MVFE = 87.24 ± 22.85; 41.82 ± 11.08 mg/dL) dose-dependently (p < 0,001). The secondary metabolites derived from fermented mixed vegetables extract might be developed as a potential strategy to prevent CHD by targeting the multiple pathways in atherosclerosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: Metformin, by reducing intracellular Mycobacterium tuberculosis growth, can be considered an adjunctive therapy to anti-tuberculosis treatment (ATT). We determined whether metformin with standard ATT reduces time to sputum culture conversion and tissue inflammation in adults with pulmonary tuberculosis (PTB)., Methods: In a randomized, 8-week, clinical trial, newly diagnosed, culture-positive PTB patients were randomized to standard ATT (HREZ = control arm) or standard ATT plus daily 1000 mg metformin (MET-HREZ = Metformin with Rifampicin [METRIF] arm) for 8 weeks during 2018-2020 at 5 sites in India. The primary end point was time to sputum culture conversion by liquid culture during 8 weeks of ATT. Plasma inflammatory markers were estimated in a subset. A Cox proportional hazard model was used to estimate time and predictors of culture conversion., Results: Of the 322 patients randomized, 239 (74%) were male, and 212 (66%) had bilateral disease on chest radiograph with 54 (18%) showing cavitation. The median time to sputum culture conversion by liquid culture was 42 days in the METRIF arm and 41 days in the control arm (hazard ratio, 0.8; 95% confidence interval [CI], .624-1.019). After 8 weeks of ATT, cavitary lesions on X-ray (7, 5.3% vs 18, 12.9%; relative risk, 0.42; 95% CI, .18-.96; P = .041) and inflammatory markers were significantly lower in the METRIF arm. Higher body mass index and lower sputum smear grading were associated with faster sputum culture conversion., Conclusions: The addition of metformin to standard ATT did not hasten sputum culture conversion but diminished excess inflammation, thus reducing lung tissue damage as seen by faster clearance on X-ray and reduced inflammatory markers., Clinical Trials Registration: Clinical Trial Registry of India (CTRI/2018/01/011176)., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background & Objectives: As India and other developing countries are scaling up isoniazid preventive therapy (IPT) for people living with HIV (PLHIV) in their national programmes, we studied the feasibility and performance of IPT in terms of treatment adherence, outcome and post-treatment effect when given under programmatic settings., Methods: A multicentre, prospective pilot study was initiated among adults living with HIV on isoniazid 300 mg with pyridoxine 50 mg after ruling out active tuberculosis (TB). Symptom review and counselling were done monthly during IPT and for six-month post-IPT. The TB incidence rate was calculated and risk factors were identified., Results: Among 4528 adults living with HIV who initiated IPT, 4015 (89%) successfully completed IPT. IPT was terminated in 121 adults (3%) due to grade 2 or above adverse events. Twenty five PLHIVs developed TB while on IPT. The incidence of TB while on IPT was 1.17/100 person-years (p-y) [95% confidence interval (CI) 0.8-1.73] as compared to TB incidence of 2.42/100 p-y (95% CI 1.90-3.10) during the pre-IPT period at these centres (P=0.017). The incidence of TB post-IPT was 0.64/100 p-y (95% CI 0.04-1.12). No single factor was significantly associated with the development of TB., Interpretation & Conclusions: Under programmatic settings, completion of IPT treatment was high, adverse events minimal with good post-treatment protection. After ruling out TB, IPT should be offered to all PLHIVs, irrespective of their antiretroviral therapy (ART) status. Scaling-up of IPT services including active case finding, periodic counselling on adherence and re-training of ART staff should be prioritized to reduce the TB burden in this community., Competing Interests: None

Background & Objectives: Cardiovascular disease (CVD) risk with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides is common in the general population in India. As nevirapine (NVP)-based antiretroviral therapy (ART) tends to increase HDL-C, gene polymorphisms associated with HDL-C metabolism in HIV-infected adults on stable NVP-based ART were studied., Methods: A cross-sectional study was conducted between January 2013 and July 2014 among adults receiving NVP-based ART for 12-15 months. Blood lipids were estimated and gene polymorphisms in apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genes were analyzed by real-time polymerase chain reaction. Framingham's 10-yr CVD risk score was estimated. Logistic regression was done to show factors related to low HDL-C levels., Results: Of the 300 patients included (mean age: 38.6±8.7 yr; mean CD4 count 449±210 cell/μl), total cholesterol (TC) >200 mg/dl was observed in 116 (39%) patients. Thirty nine per cent males and 47 per cent females had HDL-C levels below normal while 32 per cent males and 37 per cent females had TC/HDL ratio of 4.5 and 4.0, respectively. Body mass index [adjusted odds ratio (aOR)=1.70, 95% confidence interval (CI) 1.01-2.84, P=0.04] and viral load (aOR=3.39, 95% CI: 1.52-7.52, P=0.003) were negatively associated with serum HDL-C levels. The 10-yr risk score of developing CVD was 11-20 per cent in 3 per cent patients. Allelic variants of APOC3 showed a trend towards low HDL-C., Interpretation & Conclusions: High-risk lipid profiles for atherosclerosis and cardiovascular disease were common among HIV-infected individuals, even after 12 months of NVP-based ART. Targeted interventions to address these factors should be recommended in the national ART programmes.

Background: WHO recommends the use of a simplified symptom-based algorithm for screening for tuberculosis (TB) among people living with HIV (PLHIV). We assessed the feasibility and effectiveness of this algorithm and determined the prevalence and incidence of TB among PLHIV attending antiretroviral treatment (ART) centres in India., Methods: We did a prospective multicentric implementation research study in four states of India. To rule out TB, we administered the WHO symptom-screen algorithm to all PLHIV every month for 6 months. If they were found to be symptomatic any time during this period, they were referred for investigations for TB. A case of TB diagnosed during the first month of screening was taken as a prevalent case while those detected TB in the subsequent 5 months were considered cases of incident TB. We calculated the incidence rate using the person-years method. Results . Between May 2012 and October 2013, a total of 6099 adults and 1662 children living with HIV were screened for TB at the ART centres of four states. Of the 6099 adult PLHIV, 1815 (30%) had at least one symptom suggestive of TB, of whom only 634 (35%) were referred for investigations of TB. Of those referred, 97 (15%) PLHIV were diagnosed with TB. Overall, the prevalence of undiagnosed TB was 0.84 person-years and in the subsequent period, the incidence of TB was 2.4/100 person-years (95% CI 1.90-3.10). Among 1662 children, 434 (26%) had at least one symptom suggestive of TB. But only 57 (13%) children were referred for investigations of TB and 13 (23%) of them were diagnosed with TB. The prevalence of TB among children was 0.5% and its incidence among them was 2.7/100 person-years (95% CI 1.60-4.30)., Conclusion: Prevalence and incidence of TB is high among PLHIV attending ART centres. This emphasizes the need to strengthen regular screening for symptoms of TB and further referral of those symptomatic for diagnosis of TB.

We compared the pharmacokinetics of rifampicin (RMP) during daily and intermittent (thrice weekly) anti-tuberculosis treatment in human immunodeficiency virus infected tuberculosis patients. Patients treated with a thrice-weekly regimen had significantly lower plasma peak concentration, area under the time concentration curve from 0 to 24 h and higher oral clearance of RMP than those treated with the daily regimen. The median values were respectively 3.7 and 6.4 μg/ml (P < 0.001), 20.7 and 29.4 μg/ml.h (P = 0.03) and 21.7 and 15.3 ml/min (P = 0.03).

The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (Cmax) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median Cmax and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC0-8]) of INH (Cmax, 2.5 versus 5.1 μg/ml, respectively [P=0.016]; AUC0-8, 11.1 versus 22.0 μg/ml·h, respectively [P=0.047[) and PZA (Cmax, 34.1 versus 42.3 μg/ml, respectively [P=0.055]; AUC0-8, 177.9 versus 221.7 μg/ml·h, respectively [P=0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median Cmax of RMP (1.0 versus 2.8 μg/ml, respectively; P=0.002) and PZA (31.9 versus 44.4 μg/ml, respectively; P=0.045) were significantly lower. Among all factors studied, the PZA Cmax influenced TB treatment outcome (P=0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP Cmax. The PZA Cmax significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Risk factors for acquired rifampicin resistance (ARR) in human immunodeficiency virus (HIV)/tuberculosis coinfection, in the highly active antiretroviral therapy (HAART) era, needs evaluation. We studied the impact of HIV and HAART on ARR among patients taking thrice-weekly antituberculosis therapy., Methods: This cross-protocol analysis included patients with newly diagnosed, rifampicin-susceptible pulmonary tuberculosis, with and without HIV, enrolled in clinical trials (who took >80% of medication) at the National Institute for Research in Tuberculosis between 1999 and 2013. All patients received rifampicin and isoniazid for 6 months reinforced with pyrazinamide and ethambutol in the first 2 months, given thrice-weekly throughout the study along with HAART in one of the groups. Outcomes were categorized and multivariate logistic regression analysis performed to identify risk factors for ARR., Results: The per-protocol results included patients with tuberculosis: 246 HIV-uninfected patients (HIV(-)TB(+)), 212 HIV patients not on HAART (non-HAART), and 116 HIV-infected patients on HAART. Median CD4 counts of the latter 2 groups were 150 and 93 cells/µL, respectively, and the median viral loads were 147 000 and 266 000 copies/mL, respectively. Compared with HIV(-)TB(+), the relative risks (RRs) for an unfavorable response in the coinfected, non-HAART and HAART groups were 2.1 (95% confidence interval [CI], 1.7-14.8; P<.0001) and 2.1 (95% CI, .9-5.2; P=.3), whereas for ARR, the RRs were 21.1 (95% CI, 2.6-184; P<.001) and 8.2 (95% CI, .6-104; P=.07), respectively., Conclusions: HIV-infected patients with tuberculosis treated with a thrice-weekly antituberculosis regimen are at a higher risk of ARR, compared with HIV-uninfected patients, in the presence of baseline isoniazid resistance. HAART reduces but does not eliminate the risk of ARR., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The Revised National TB Control Program bases diagnosis of tuberculosis (TB) on sputum smear examination and response to a course of antibiotics, whereas World Health Organization recommends early chest radiography [chest x-ray (CXR)] for HIV-infected symptomatic patients. We evaluated the utility of initial CXR in the diagnostic algorithm for symptomatic HIV-infected patients with negative sputum smears., Methods: HIV-infected ambulatory patients with cough or fever of ≥2 weeks and 3 sputum smears negative for acid-fast bacilli were enrolled in Chennai and Pune, India, between 2007 and 2009. After a CXR and 2 sputum cultures, a course of broad-spectrum antibiotics was given and patients were reviewed after 14 days. Sensitivity, specificity, positive and negative predictive values of symptoms, CXR, and various combinations for diagnosing pulmonary tuberculosis (PTB) were determined, using sputum culture as gold standard., Results: Five hundred four patients (330 males; mean age: 35 years; median CD4: 175 cells per cubic millimeter) were enrolled. CXR had a sensitivity and specificity of 72% and 57%, respectively, with positive predictive value (PPV) of 21% and negative predictive value (NPV) of 93% to diagnose PTB. TB culture was positive in 49 of 235 patients (21%) with an abnormal initial CXR and 19 of 269 patients (7%) with a normal CXR (P < 0.001). Sensitivity and specificity of cough ≥2 weeks for predicting PTB was 97% and 6%, with PPV and NPV of 14% and 94%, respectively., Conclusions: Although moderately sensitive, basing a diagnosis of TB on initial CXR leads to overdiagnosis. An absence of weight loss had a high NPV, whereas none of the combinations had a good PPV. A rapid and accurate diagnostic test is required for HIV-infected chest symptomatic.

Setting: The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children., Objective: To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes., Methods: Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes., Results and Conclusions: Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.

Background: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively., Methods: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS., Results: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14-47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7-16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9-23). Two patients died due to CNS TB-IRIS. Lower CD4(+) T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis., Conclusion: Paradoxical TB-IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions.

We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.

The absorption of rifampin, isoniazid, and D-xylose in patients with human immunodeficiency virus (HIV) infection and diarrhea, in patients with HIV infection and tuberculosis (TB), in patients with pulmonary TB alone, and in healthy subjects was studied. Percentage of dose of the drugs, their metabolites, and D-xylose excreted in urine were calculated. A significant reduction in the absorption of drugs and D-xylose in both the HIV infection/diarrhea and HIV infection/TB groups was observed (P<.05), and the correlation between them was significant. Our results indicate that patients with HIV infection and diarrhea and those with HIV infection and TB have malabsorption of rifampin and isoniazid.

In most settings in India, private pharmacies dispense prescriptions for anti-tuberculosis drugs made out by private practitioners. In a cross-sectional study, we assessed the dispensing practices for tuberculosis and knowledge about the national tuberculosis programme of 300 pharmacies. In all, 2800 prescriptions were dispensed monthly by the pharmacies. Doctors' prescriptions were for durations of several months, but half of the patients bought drugs one dose at a time for self-administration. This practice might promote drug resistance. Although 95% of pharmacists were not aware of the existence of the tuberculosis programme, the majority (97%) were willing to learn and contribute towards tuberculosis control. The need and the potential of private pharmacies for participation in tuberculosis control are highlighted.

Among 155 patients who were initiated on continuous ambulatory peritoneal dialysis (CAPD), 4 patients (2 men, 2 women) developed tuberculous peritonitis. They had been on PD for between 2 months and 84 months when they developed the peritonitis. The Mantoux test was negative in all of them. The diagnosis was made by a variety of means in the various cases: demonstration of Mycobacterium tuberculosis in the peritoneal cavity; presence of caseating granuloma in a peritoneal biopsy; Mycobacterium tuberculosis in a cold abscess adjacent to the peritoneal cavity; and demonstration of IS6110 and MPB64 genes of Mycobacterium tuberculosis by polymerase chain reaction (PCR) technique. Two of the patients developed ultrafiltration failure. Among 3 patients who were switched to hemodialysis, 2 died and 1 continues on maintenance dialysis. The last patient, whose catheter was removed, was reimplanted with a new catheter and continues on PD without ultrafiltration failure. Any patient with peritonitis unresponsive to conventional therapy should be investigated for tuberculous peritonitis. Institution of chemotherapy without delay will preserve peritoneal membrane integrity.