Tuberculosis (TB) is a major source of mortality in urban India, with many structural challenges to optimal care delivery. In the government TB program in Chennai, India's fourth most populous city, ...there is a 49% gap between the official number of smear-positive TB patients diagnosed and the official number registered in TB treatment within the city in 2014. We hypothesize that this "urban registration gap" is partly due to rural patients temporarily visiting the city for diagnostic evaluation.
We collected data for one month (May 2015) from 22 government designated microscopy centers (DMCs) in Chennai where 90% of smear-positive TB patients are diagnosed and coded patient addresses by location. We also analyzed the distribution of chest symptomatics (i.e., patients screened for TB because of pulmonary symptoms) and diagnosed smear-positive TB patients for all of Chennai's 54 DMCs in 2014.
At 22 DMCs in May 2015, 565 of 3,543 (15.9%) chest symptomatics and 71 of 412 (17.2%) diagnosed smear-positive patients had an address outside of Chennai. At the city's four high patient volume DMCs, 54 of 270 (20.0%) smear-positive patients lived out-of-city. At one of these high-volume DMCs, 31 of 59 (52.5%) smear-positive patients lived out-of-city. Out of 6,135 smear-positive patients diagnosed in Chennai in 2014, 3,498 (57%) were diagnosed at the four high-volume DMCs. The 32 DMCs with the lowest patient volume diagnosed 10% of all smear-positive patients.
TB case detection in Chennai is centralized, with four high-volume DMCs making most diagnoses. One-sixth of patients are from outside the city, most of whom get evaluated at these high-volume DMCs. This calls for better coordination between high-volume city DMCs and rural TB units where many patients may take TB treatment. Patient mobility only partly explains Chennai's urban registration gap, suggesting that pretreatment loss to follow-up of patients who live within the city may also be a major problem.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Indian Council of Medical Research (ICMR) has been at the forefront in setting up the ethical guidance for the conduct of biomedical and health research in India. The latest version of National ...Guidelines for Biomedical and Health Research Involving Human Participants, 2017 was planned in order to provide a more detailed guidance to the existing topics in view of emerging ethical concerns and to add a number of newer areas in which guidance was lacking. The scope of the guidelines has been expanded to include socio-behavioural research related to health and research involving biological material and datasets. The guidelines have 12 sections which cover a wide range of topics and areas of research. The first six sections are more generic, applying to all types of biomedical and health research, while the next six sections are more subject specific. The guidelines have been revised in consultation with a large number of experts and stakeholders and went through an exhaustive process stretching over a period of two years in its drafting, review, consultation and finalisation. This commentary seeks to explain the process and key components of the Guidelines.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pediatric TB poses challenge in diagnosis due to the paucibacillary nature of the disease. We conducted a prospective diagnostic study to identify immune biomarkers of pediatric TB and controls ...(discovery cohort) and obtained a separate "validation" cohort of confirmed cases of pediatric TB and controls. Multiplex ELISA was performed to examine the plasma levels of cytokines. Discovery and validation cohorts revealed that baseline plasma levels of IFNγ, TNFα, IL-2, and IL-17A were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics (ROC) curve analysis revealed that IFNγ, IL-2, TNFα, and IL-17A (in the discovery cohort) and TNFα and IL-17A (in the validation cohort) could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 90%. In the discovery cohort, cytokines levels were significantly diminished following anti-tuberculosis treatment. In both the cohorts, combiROC models offered 100% sensitivity and 98% to 100% specificity for a three-cytokine signature of TNFα, IL-2, and IL-17A, which can distinguish confirmed or unconfirmed TB children from unlikely TB. Thus, a baseline cytokine signature of TNFα, IL-2, and IL-17A could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.
Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. ...Nevertheless, with the robust quantitative and qualitative restoration of CD4
T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4
lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8
T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR
) and profilerative (Ki-67
) CD4
T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4
T cells counts and the frequencies of Cytotoxic CD8
T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4
T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4
T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4
and CD8
T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.
A Phase I HIV-1 vaccine trial sponsored by the International AIDS Vaccine Initiative (IAVI) was conducted in India in 2009 to test a subtype C prophylactic vaccine in a prime-boost regimen comprising ...of a DNA prime (ADVAX) and MVA (TBC-M4) boost. The trial demonstrated that the regimen was safe and well tolerated and resulted in enhancement of HIV-specific immune responses. Preliminary observations on vaccine-induced immune responses were limited to analysis of neutralizing antibodies and IFN-γ ELISPOT response. The present study involves a more detailed analysis of the nature of the vaccine-induced humoral immune response using specimens that were archived from the volunteers at the time of the trial. Interestingly, we found vaccine induced production of V1/V2 and V3 region-specific antibodies in a significant proportion of vaccinees. Variable region antibody levels correlated directly with the frequency of circulating T follicular helper cells (Tfh) and regulatory T cells (Treg). Our findings provide encouraging evidence to demonstrate the immunogenicity of the tested vaccine. Better insights into vaccine-induced immune responses can aid in informing future design of a successfulHIV-1 vaccine.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A systematic understanding of population-level trends in deaths due to road injuries at the subnational level over time for India's 1·4 billion people, by age, sex, and type of road user is not ...readily available; we aimed to fill this knowledge gap.
As part of the Global Burden of Diseases, Injuries, and Risk Factors Study, we estimated the rate of deaths due to road injuries in each state of India from 1990 to 2017 based on several verbal autopsy data sources. We calculated the number of deaths and death rate for road injuries by type of road user, and assessed the age and sex distribution of these deaths over time. Based on the trends of the age-standardised death rate from 1990 to 2017, we projected the age-standardised death rate to 2030 to assess if the states of India would meet the Sustainable Development Goal (SDG) target to halve the death rate for road injuries from 2015 by 2020 or 2030. We calculated 95% uncertainty intervals (UIs) for the point estimates.
In 2017, 218 876 deaths (95% UI 201 734 to 231 141) due to road injuries occurred in India, with an age-standardised death rate for road injuries of 17·2 deaths (15·7 to 18·1) per 100 000 population, which was much higher in males (25·7 deaths 23·5 to 27·4 per 100 000) than in females (8·5 deaths 7·2 to 9·1 per 100 000). The number of deaths due to road injuries in India increased by 58·7% (43·6 to 74·7) from 1990 to 2017, but the age-standardised death rate decreased slightly, by 9·2% (0·6 to 18·3). In 2017, pedestrians accounted for 76 729 (35·1%) of all deaths due to road injuries, motorcyclists accounted for 67 524 (30·9%), motor vehicle occupants accounted for 57 802 (26·4%), and cyclists accounted for 15 324 (7·0%). India had a higher age-standardised death rate for road injury among motorcyclists (4·9 deaths 3·9–5·4 per 100 000 population) and cyclists (1·2 deaths 0·9–1·4 per 100 000 population) than the global average. Road injury was the leading cause of death in males aged 15 to 39 years in India in 2017, and the second leading cause in this age group for both sexes combined. The overall age-standardised death rate for road injuries varied by up to 2·6 times between states in 2017. Wide variations were seen between the states in the percentage change in age-standardised death rate for road injuries from 1990 to 2017, ranging from a reduction of 38·2% (22·3 to 51·7) in Delhi to an increase of 17·0% (0·6 to 34·7) in Odisha. If the trends estimated up to 2017 were to continue, no state in India or India overall would achieve the SDG 2020 target in 2020 or even in 2030.
India's contribution to the global number of deaths due to road injuries is increasing, and the country is unlikely to meet the SDG targets if the trends up to 2017 continue. India needs to implement evidence-based road safety interventions, promote strong policies and traffic law enforcement, have better road and vehicle design, and improve care for road injuries at the state level to meet the SDG goal.
Bill & Melinda Gates Foundation and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.
India has a high burden of drug-resistant tuberculosis (DR TB) and many cases go undetected by current drug susceptibility tests (DSTs). This study was conducted to identify rifampicin (RIF) and ...isoniazid (INH) resistance associated genetic mutations undetected by current clinical diagnostics amongst persons with DR TB in Chennai, India. Retrospectively stored 166 DR TB isolates during 2013-2016 were retrieved and cultured in Löwenstein-Jensen medium. Whole genome sequencing (WGS) and MGIT DST for RIF and INH were performed. Discordant genotypic and phenotypic sensitivity results were repeated for confirmation and the discrepant results considered final. Further, drug resistance-conferring mutations identified through WGS were analyzed for their presence as targets in current WHO-recommended molecular diagnostics. WGS detected additional mutations for rifampicin and isoniazid resistance than WHO-endorsed line probe assays. For RIF, WGS was able to identify an additional 10% (15/146) of
mutant isolates associated with borderline rifampicin resistance compared to MGIT DST. WGS could detect additional DR TB cases than commercially available and WHO-endorsed molecular DST tests. WGS results reiterate the importance of the recent WHO revised critical concentrations of current MGIT DST to detect low-level resistance to rifampicin. WGS may help inform effective treatment selection for persons at risk of, or diagnosed with, DR TB.
India accounts for one-fifth of the global TB incidence. While the exact burden of childhood TB is not known, TB remains one of the leading causes of childhood mortality in India. Bacteriological ...confirmation of TB in children is challenging due to difficulty in obtaining quality specimens, in the absence of which diagnosis is largely based on clinical judgement. While testing multiple specimens can potentially contribute to higher proportion of laboratory confirmed paediatric TB cases, lack of high sensitivity tests adds to the diagnostic challenge. We describe here our experiences in piloting upfront Xpert MTB/RIF testing, for diagnosis of TB in paediatric population in respiratory and extra pulmonary specimens, as recently recommended by WHO.
Xpert MTB/RIF testing was offered to all paediatric (0-14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities in the project areas covering 4 cities of India.
Under this pilot project, 8,370 paediatric presumptive TB & presumptive DR-TB cases were tested between April and-November 2014. Overall, 9,149 specimens were tested, of which 4,445 (48.6%) were non-sputum specimens. Xpert MTB/RIF gave 9,083 (99.2%, CI 99.0-99.4) valid results. Of the 8,143 presumptive TB cases enrolled, 517 (6.3%, CI 5.8-6.9) were bacteriologically confirmed. TB detection rates were two fold higher with Xpert MTB/RIF as compared to smear microscopy. Further, a total of 60 rifampicin resistant TB cases were detected, of which 38 were detected among 512 presumptive TB cases while 22 were detected amongst 227 presumptive DR-TB cases tested under the project.
Xpert MTB/RIF with advantages of quick turnaround testing-time, high proportion of interpretable results and feasibility of rapid rollout, substantially improved the diagnosis of bacteriologically confirmed TB in children, while simultaneously detecting rifampicin resistance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ESSENCE on Health Research initiative established a Working Group on Review of Investments in 2018 to improve coordination and collaboration among funders of health research capacity ...strengthening. The Working Group comprises more than a dozen ESSENCE members, including diverse representation by geography, country income level, the public sector, and philanthropy.
The overall goal of the Working Group is increased research on national health priorities as well as improved pandemic preparedness, and, ultimately, fewer countries with very limited research capacity.
We developed a basic set of metrics for national health research capacity, assessed different models of coordination and collaboration, took a deeper dive into eight countries to characterize their national research capacity, and began to identify opportunities to better coordinate our investments. In this article, we summarize the presentations, discussions, and outcomes of our second annual (virtual) meeting, which had more than 100 participants representing funders, researchers, and other stakeholders from higher- and lower-income countries worldwide.
Presentations on the first day included the keynote speaker, Dr. Soumya Swaminathan, chief scientist of the World Health Organization (WHO), and updates on data and metrics for research capacity, which are critical to establish targets, road maps, and budgets. The second day focused on improving collaboration and coordination among funders and other stakeholders, the potential return on investment for health research, ongoing work to increase coordination at the country level, and examples of research capacity strengthening efforts in diverse health research areas from around the world. We concluded that an intentional data- and metric-driven approach to health research capacity strengthening, emphasizing coordination among funders, local leadership, and equitable partnerships and allocation of resources, will enhance the health systems of resource-poor countries as well as the world's pandemic preparedness.
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