Dina Nair - Academia.edu (original) (raw)

Papers by Dina Nair

European journal of medicinal chemistry, May 1, 2024

National medical journal of India, Mar 11, 2024

Expert Review of Respiratory Medicine, 2020

Introduction: Addressing the reservoir of Latent Tuberculosis Infection (LTBI) is critical to TB ... more Introduction: Addressing the reservoir of Latent Tuberculosis Infection (LTBI) is critical to TB elimination because if left untreated LTBI can progress to active TB disease. This additional burden can prevent achieving the global targets of TB elimination. Management of LTBI has been a low priority target for National TB Elimination Programs (NTEP) due to various challenges in the field settings. Areas covered: This article reviews the most recent advances in the field of LTBI management including newer diagnostics, treatments, vaccines, programmatic challenges, and gaps and suggests a way forward that can be adopted by NTEPs for LTBI. We searched the electronic databases of PubMed, Scopus, and Web of Science for studies published between 2010 to 2020 using MeSH terms: Latent TB Diagnosis, TB preventive therapy, Vaccines, LTBI, and HIV/ COVID. Expert opinion: NTEPs of developing countries should offer a better, point-of-care diagnostic, and effective treatment for LTBI to reduce th...

Cytokine, Mar 1, 2016

Type 2 diabetes mellitus (T2DM) is recognized as major risk factor for the progress of active pul... more Type 2 diabetes mellitus (T2DM) is recognized as major risk factor for the progress of active pulmonary tuberculosis (PTB), although the mechanistic link between diabetes and tuberculosis remains poorly characterized. Moreover, the influence of poorly controlled diabetes on the baseline levels of adipocytokines in the context of tuberculosis has not been explored in detail. To characterize the influence of coexistent DM on adipocytokine levels in pulmonary or latent TB (LTB), we examined circulating levels of adipocytokines in the plasma of individuals with PTB-DM or LTB-DM and compared them with those without DM (PTB or LTB). PTB-DM or LTB-DM is characterized by diminished circulating levels of adiponectin and adipsin and/or heightened circulating levels of leptin, visfatin and PAI-1. In addition, adiponectin and adipsin exhibit a significant negative correlation, whereas with leptin, visfatin and PAI-1 display a significant positive correlation with HbA1C levels and random blood glucose levels. Therefore, our data reveal that PTB-DM or LTB-DM is characterized by alterations in the systemic levels of adipocytokines, indicating that altered adipose tissue inflammation underlying Type 2 diabetes potentially contributes to pathogenesis of TB disease.

Frontiers in Nutrition, May 30, 2023

Introduction: Low body mass index (BMI) is a major risk factor for tuberculosis (PTB). Low BMI ca... more Introduction: Low body mass index (BMI) is a major risk factor for tuberculosis (PTB). Low BMI can impair the immune system and thus might affect TB incidence. Methods: We examined the plasma levels of Type 1, Type 17, pro-inflammatory, Type 2 and regulatory cytokines and CC and CXC chemokines in PTB and latent TB (LTB) individuals with low BMI (LBMI) or normal BMI (NBMI). Results: Our data show that PTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL-17A, IL-6, IL-12, IL-4 and IL-5 cytokines but significantly higher levels of IL-10, TGFβ and GM-CSF in LBMI compared to NBMI. Similarly, PTB is also associated with significantly lower levels of CCL2, CCL3, CCL11, CXCL1, CXCL9 and CXCL10 chemokines in LBMI compared to NBMI. Our data reveals that LTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL1β, IL-12, IL-13 cytokines but significantly higher levels of IL-10, TGFβ, IL-4 and IL-22 in LBMI compared to NBMI. Similarly, LTB is also associated with significantly lower levels of CCL2, CXCL1, CXCL9 and CXCL10 and significantly higher levels of CCL1, CCL3, and CCL4 in LBMI compared to NBMI. Conclusion: Thus, LBMI has a major impact on the cytokine and chemokine milieu of both PTB and LTB and might predispose to the increased risk of tuberculosis by this immunomodulatory effect.

Scientific Reports, Jul 16, 2019

Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly fro... more Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface. Tuberculosis (TB) caused an estimated 1.3 million deaths worldwide in 2016 (WHO Global Tuberculosis Report, 2017). The major challenge in the treatment of tuberculosis is the emergence of drug-resistant Mycobacterium tuberculosis 1. The drugs available for tuberculosis treatment are categorised into first-line (isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), ethambutol (EMB) and streptomycin (STR)) and second line (including fluoroquinolones, thioamides, cycloserine and the injectable aminoglycosides). Rising rates of multi-drug-resistant tuberculosis (MDR-TB, defined as resistance to INH and RIF), are of immense concern for TB control worldwide. Extended treatment is required with multiple drugs that have a higher rate of side effects but limited rate of treatment success (Gygli et al. 2). India accounts for the highest burden of tuberculosis globally and also ranks top among the countries for MDR-TB cases (WHO Global Tuberculosis Report, 2017). Drug resistance arises mainly from spontaneous mutations in the bacterial genome. Resistance to first-line anti-TB drugs has been linked to mutations in katG 3 and inhA 4 for INH resistance; rpoB for RIF resistance 5 ; embB

JAMA network open, Dec 1, 2020

IMPORTANCE Identifying biomarkers of treatment response is an urgent need in the treatment of tub... more IMPORTANCE Identifying biomarkers of treatment response is an urgent need in the treatment of tuberculosis (TB). Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are potential diagnostic biomarkers in pulmonary TB (PTB). OBJECTIVE To assess whether baseline plasma levels of MMPs and TIMPs are also prognostic biomarkers for adverse treatment outcomes in patients with PTB. DESIGN, SETTING, AND PARTICIPANTS Two different cohorts (test and validation) of individuals with PTB were recruited from 2 different sets of primary care centers in Chennai, India, and were followed up for treatment outcomes. Participants were individuals with newly diagnosed TB that was sputum smear and culture positive and drug sensitive. A total of 68 cases and 133 controls were in the test cohort and 20 cases and 40 controls were in the validation cohort. A nested case-control study was performed by matching case patients to control participants in a 1:2 ratio for age, sex, and body mass index. Data for the test cohort was taken from a study performed from 2014 to 2019, and data for the validation cohort, from a study performed from 2008 to 2012. The data analysis was performed from November 2019 to May 2020. INTERVENTIONS Individuals with PTB were treated with antituberculosis chemotherapy for 6 months and followed up for 1 year after completion of treatment. MAIN OUTCOMES AND MEASURES Individuals with PTB with adverse outcomes (treatment failure, all-cause mortality, or recurrent TB) were defined as cases and those with favorable outcomes (recurrence-free cure) were defined as controls. Plasma levels of MMPs and TIMPs were measured before treatment as potential biomarkers. RESULTS In all, 68 cases and 133 matched controls were enrolled in the study (170 [85%] males and 31 [15%] females; median age, 45 years [range, 23-73 years]) in the test cohort and 20 cases with 40 matched controls (51 [85%] males and 9 [15%] females; median age, 45 years [range, 19-61 years]) in the validation cohort. Baseline plasma levels of 5 MMPs and 2 TIMPs in the test cohort and 5 MMPs and all 4 TIMPS in the validation cohort were significantly higher in cases vs controls. In the test cohort, the geometric means (GMs), cases vs controls, were as follows: for MMP-1, 3680 vs 2484 pg/mL (P = .008); for MMP-2, 6523 vs 4762 pg/mL (P < .001); for MMP-7, 3346 vs 2100 pg/mL

International Journal of Tuberculosis and Lung Disease, 2017

BACKGROUND: Circulating angiogenic factors of the vascular endothelial growth factor family are i... more BACKGROUND: Circulating angiogenic factors of the vascular endothelial growth factor family are important biomarkers of disease severity in pulmonary tuberculosis (PTB). However, the role of angiopoietins, which are also involved in angiogenesis, in PTB is not known. OBJECTIVE AND DESIGN: To examine the association of circulating angiopoietins with TB disease or latent tuberculous infection (LTBI), we examined the systemic levels of angiopoietin (Ang) 1, Ang 2 and Tie-2 receptor in individuals with PTB (n = 44), LTBI (n = 44) or no tuberculous infection (NTBI) (n = 44). RESULTS: Circulating levels of Ang-1, Ang-2 and Tie-2 were significantly higher in PTB than in individuals with LTBI or NTBI. Moreover, Ang-1, Ang-2 and Tie-2 levels were significantly higher in PTB with bilateral disease. The levels of these factors also exhibited a significant positive relationship with bacterial burdens in PTB. Receiver operating characteristics curve analysis revealed Ang-2 as a marker distinguishing PTB from LTBI or NTBI. Finally, the circulating levels of Ang-1, Ang-2 and Tie-2 were significantly reduced following antituberculosis chemotherapy. CONCLUSIONS: Our data demonstrate that PTB is associated with elevated levels of circulating angiopoietins, possibly reflecting endothelial dysfunction. In addition, Ang-2 could prove useful as a biomarker to monitor disease severity, bacterial burden and therapeutic responses. RÉSUMÉ Les facteurs circulants angiogéniques de la famille des facteurs de croissance de l'endothélium vasculaire sont d'importants biomarqueurs de gravité de la maladie en cas de tuberculose pulmonaire (TBP). Cependant, le rôle des angiopoiétines (Ang), qui sont également impliquées dans l'angiogenése, dans la TBP n'est pas connu. Pour étudier l'association des Ang circulantes avec la maladie ou l'infection tuberculeuse latente (LTBI), nous avons examiné les niveaux systémiques des récepteurs de l'Ang-1, de l'Ang-2 et de

Indian Journal of Medical Microbiology, Oct 1, 2016

susceptibility study of 148 M. kansasii strains isolated from clinical specimens, moxifloxacin fo... more susceptibility study of 148 M. kansasii strains isolated from clinical specimens, moxifloxacin followed by levofloxacin, clarithromycin and linezolid showed a good therapeutic alternative. [2] Here, we report a series of patients treated with a short-course regimen for M. kansasii pulmonary disease, with favourable response at the end of 2-year of follow-up. Case Reports Patients reported here were enrolled in a randomised controlled clinical trial that assessed the efficacy of moxifloxacin in shortening the duration of TB treatment in new sputum smear positive, non-HIV-infected patients. As per the trial protocol, based on sputum smear status and CXR findings, they were randomised to either a 3-or 4-month regimen of daily moxifloxacin [M], isoniazid [H], rifampicin [R], ethambutol [E] and pyrazinamide [Z] (3MHREZ 7 or 2MHREZ 7 /2MHR 7 or 2MHREZ 7 /2MHR 3) or 6-month of thrice-weekly regimen (2EHRZ 3 /4RH 3). After starting treatment under direct observation, sputum samples were subjected to Lowenstein-Jensen solid culture for acid-fast bacilli. Following the growth of mycobacteria, species were identified using high-performance liquid chromatography technique. Patients, who grew M. tuberculosis in their sputum, were retained in the clinical trial while those showing NTM were considered as pre-treatment exclusions. However, by

International Journal of Tuberculosis and Lung Disease, Oct 1, 2011

Ten extensively drug-resistant tuberculosis (XDR-TB) patients were identifi ed among 104 human im... more Ten extensively drug-resistant tuberculosis (XDR-TB) patients were identifi ed among 104 human immunodeficiency virus negative multidrug-resistant tuberculosis (MDR-TB) patients treated at the Tuberculosis Research Centre, Chennai, India, in two different cohorts between 1999-2003 and 2006-2007. They were managed with individualised treatment regimens. At the time of diagnosis of MDR-TB, one patient had XDR-TB and three had initial ofl oxacin resistance. One patient who had had a lobectomy in addition to chemotherapy became bacteriologically negative, three died, three defaulted and the remaining three, who are bacteriologically positive, are still continuing treatment. Although based on a small number of patients, our results have not been encouraging.

Public health action, Mar 21, 2017

G lobal efforts to control tuberculosis (TB) are being hampered by the emergence of drug-resistan... more G lobal efforts to control tuberculosis (TB) are being hampered by the emergence of drug-resistant disease, which is a major concern for TB control programmes worldwide. Globally, in 2014 an estimated 3.3% of new cases and 20% of previously treated cases were multidrug-resistant TB (MDR-TB, defined as TB resistant to at least isoniazid [INH] and rifampicin [RMP]), resulting in an estimated total of 480 000 new cases of MDR-TB associated with 190 000 deaths worldwide for the year. 1 The standard treatment for MDR-TB is a 24-month regimen largely comprising second-line drugs that are less effective, more costly and associated with a high number of adverse events. 2 Not surprisingly, treatment outcomes in MDR-TB are significantly worse than for standard first-line therapy. Globally, the proportion of MDR-TB patients in the 2012 cohort who successfully completed treatment (i.e., were cured or completed treatment) was 50%, due largely to high rates of mortality and loss to follow-up (LTFU). 1 Under study conditions, treatment outcomes are marginally better. A systematic review of 36 studies reported that 62% of patients with MDR-TB achieved successful outcomes, with 11% deaths, 8% failures, 13% LTFU and 2% transferred out. Data were not available for the remaining 4%. 3 In another review of 29 studies of individualised treatment regimens for MDR-TB, the reported treatment success rate was 64%. 4 India has one of the highest burdens of MDR-TB, with 71 000 estimated MDR-TB cases among 300 000 TB cases notified in 2014. 1,5 India's Revised National Tuberculosis Control Programme (RNTCP) introduced the programmatic management of drug-resistant TB (PMDT) services in 2007 to address the needs of this growing patient population, and services have been rapidly scaled up across the country to achieve universal access. 6 Cumulative outcomes have been reported in 31 365 MDR-TB patients; of these, 14 632 (47%) were successfully treated, 6811 (22%) died and 6229 (20%) were lost to follow-up. 5 Although a few studies in India have reported on treatment outcomes, there is insufficient knowledge about the sociodemographic and clinical factors associated with unfavourable treatment outcomes. A better understanding of these risk factors is necessary to design effective interventions that might help reduce morbidity and mortality and thereby improve treatment success. The objectives of this study were therefore 1) to describe the demographic and clinical characteristics of MDR-TB patients enrolled in three states of India during the period 2009-2011, 2) to describe programme-defined treatment outcomes, and 3) to describe factors associated with unfavourable treatment outcomes. METHODS Study design This was a retrospective cohort study involving a review of the records of MDR-TB patients registered under India's RNTCP.

Background Government of India is committed to eliminate tuberculosis by 2025 under National Tube... more Background Government of India is committed to eliminate tuberculosis by 2025 under National Tuberculosis Elimination Program which provides free investigations and treatment as well as incentives for nutritional support during their treatment course.Many tuberculosis patients prefer to seek treatment fromthe private sector which sometimes leads tofinancial constraints for the patients. Our study aims to find the burden of tuberculosis patients in the private sector and the expenses borne by them for their treatment.Methodology :Sales data of Rifampicin-containing formulations drug consumption in the private sector of six districts of Jharkhand was collected from Clearing and Forwarding (C & F) agencies and drug controller office during the SNC activities in the state. Based on the drug sales data total incurring costs of the drugs, total private patient months, total number of patients and cost per patient seeking treatment from private sector were calculated for the year 2015–2021...

The International Journal of Tuberculosis and Lung Disease, 2016

Sputum culture conversion in pulmonary multidrug-resistant tuberculosis (MDR-TB) is important to ... more Sputum culture conversion in pulmonary multidrug-resistant tuberculosis (MDR-TB) is important to make treatment-related decisions and prevent transmission of disease. O B J E C T I V E : To identify factors associated with sputum culture conversion, and to determine time to culture conversion and the impact of culture conversion on successful treatment outcomes in MDR-/rifampicin (RMP) resistant TB. M E T H O D : Retrospective analysis of data from treatment cards and registers of MDR-/RMP-resistant patients initiated on treatment under India's Revised National TB Control Programme in Delhi, West Bengal and Kerala from January 2009 to December 2011. Proportions were calculated and logistic regression analysis was performed.

Indian Journal of Community Medicine

PLOS ONE, 2020

Background Household contacts (HHC) of tuberculosis (TB) patients are at risk of TB infection and... more Background Household contacts (HHC) of tuberculosis (TB) patients are at risk of TB infection and disease. The study assessed the utility of "Household contact card and register" for screening of HHC of pulmonary TB (PTB) patients for TB and explored the reasons for HHC not being screened and followed-up.

IL-27 and TGFb mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correla... more IL-27 and TGFb mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial

Clinical Infectious Diseases, 2020

Background Plasma chemokines are biomarkers of greater disease severity, higher bacterial burden,... more Background Plasma chemokines are biomarkers of greater disease severity, higher bacterial burden, and delayed sputum culture conversion in pulmonary tuberculosis (PTB). Whether plasma chemokines could also serve as biomarkers of unfavorable treatment outcomes in PTB is not known. Methods A cohort of newly diagnosed, sputum smear- and culture-positive adults with drug-sensitive PTB were recruited under the Effect of Diabetes on Tuberculosis Severity study in Chennai, India. Plasma chemokine levels measured before treatment initiation were compared between 68 cases with unfavorable outcomes (treatment failure, death, or recurrence) and 136 control individuals who had recurrence-free cure. A second validation cohort comprising newly diagnosed, culture-positive adults with drug-sensitive TB was used to measure plasma chemokine levels in 20 cases and 40 controls. Results Six chemokines (CCL2, CCL3, CCL4, CXCL8, CXCL10, and CX3CL1) were associated with increased risk, while CXCL1 was asso...

Public Health Action, 2015

Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculo... more Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem. Objective: To systematically identify and rank research priorities in childhood drug-resistant TB. Design: Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey. Results: A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery. Conclusion: This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children. MCB and SS contributed equally to this work. Public Health Action Research priorities in childhood DR-TB 223 list of questions. The finalised questions were pilot-tested among 10 other clinicians to achieve better clarity in framing and wording. The two groups of respondents included in the formal ranking process were not involved in finalising the questions, nor were they involved in pilot testing the questions. The questions were then organised using the CHNRI framework for listing research priorities. The final list used for scoring consisted of questions of three different research types: descriptive, development and discovery. These were systematically listed among four research areas, namely epidemiology, diagnostics, treatment and prevention (Table 1). TABLE 1 Methodology used for development and categorisation of research Research area Research type Research avenue Research options Research questions Epidemiology Diagnosis Treatment Prevention Research on disease burden and determinants (descriptive) Measuring the disease burden Understanding risk factors Evaluating existing strategies Research options were identified within the research avenue Specific research questions were framed based on consensus among the experts A total of 79 research questions were initially identified which were subsequently reduced to 53 questions Research for improving performance of existing strategies (development) Public Health Action Research priorities in childhood DR-TB 232 TABLE A.2 Final ranking of all 53 research questions with RPS and AEA Rank Question number Research question Research area Research type Answerability Feasibility Effectiveness Deliverability Equitability RPS AEA Public Health Action Research priorities in childhood DR-TB 233 TABLE A.2 (continued) Rank Question number Research question Research area Research type Answerability Feasibility Effectiveness Deliverability Equitability RPS AEA q5 What are the clinical and epidemiological risk factors for the development and transmission of DR-TB? Public Health Action Research priorities in childhood DR-TB 234 TABLE A.2 (continued) Rank Question number Research question Research area Research type Answerability Feasibility Effectiveness Deliverability Equitability RPS AEA Public Health Action Research priorities in childhood DR-TB 235 TABLE A.2 (continued) Rank Question number Research question Research area Research type Answerability Feasibility Effectiveness Deliverability Equitability RPS AEA q9 Can mathematical modelling of dynamics and transmission of DR-TB in children be computed in settings with high and low rates of DR-TB?

Journal of the American College of Cardiology, 2010

Background: Matrix metalloproteinase-9 (MMP-9) is a vascular protease thought to serve as a bioma... more Background: Matrix metalloproteinase-9 (MMP-9) is a vascular protease thought to serve as a biomarker of vascular remodeling. Plasma MMP-9 is decreased in hypertensive subjects with increased vascular stiffness. We tested the hypothesis that plasma MMP-9 would correlate with vascular health. Methods: In a cross-sectional study of 99 healthy adults (age 41-69 years, mean 52.0±7.5) without hypertension, hypercholesterolemia, diabetes, or tobacco use were compared with 117 subjects (age 43-79, mean 60.7±8.4) with subclinical atherosclerosis and elevated cardiac risk (mean Framingham Risk Score = 7.6±8.7%). Carotid intima media thickness (IMT) by ultrasound, arterial stiffness by tonometry, and plasma MMP-9 were measured. Results: Healthy subjects had lower carotid artery IMT (0.66±0.11 versus 0.79±0.14 mm, p<0.001) and lower arterial stiffness (augmentation index of 13.1±14.5 versus 25.5±11.0, p=0.002) than in at-risk subjects. Plasma MMP-9 was higher in healthy subjects than in the cardiovascular risk cohort (82.4±40.6 versus 33.5±17.6 ng/mL, p<0.001), even after controlling for age (Figure 1) and sex. While age in healthy subjects correlated with IMT (r=0.541, p<0.001) and augmentation index (0.238, p=0.025), there was no correlation with MMP-9 levels. Conclusions: MMP-9 is an age-independent marker associated with reduced subclinical atherosclerosis and preserved arterial compliance, suggesting a contribution of MMP-9 in maintenance of vascular health.