Abstract
Background
Drug-resistant gram-negative (GN) pathogens are a common cause of neonatal sepsis in low- and middle-income countries. Identifying GN transmission patterns is vital to inform ...preventive efforts.
Methods
We conducted a prospective cohort study, 12 October 2018 to 31 October 2019 to describe the association of maternal and environmental GN colonization with bloodstream infection (BSI) among neonates admitted to a neonatal intensive care unit (NICU) in Western India. We assessed rectal and vaginal colonization in pregnant women presenting for delivery and colonization in neonates and the environment using culture-based methods. We also collected data on BSI for all NICU patients, including neonates born to unenrolled mothers. Organism identification, antibiotic susceptibility testing, and next-generation sequencing (NGS) were performed to compare BSI and related colonization isolates.
Results
Among 952 enrolled women who delivered, 257 neonates required NICU admission, and 24 (9.3%) developed BSI. Among mothers of neonates with GN BSI (n = 21), 10 (47.7%) had rectal, 5 (23.8%) had vaginal, and 10 (47.7%) had no colonization with resistant GN organisms. No maternal isolates matched the species and resistance pattern of associated neonatal BSI isolates. Thirty GN BSI were observed among neonates born to unenrolled mothers. Among 37 of 51 BSI with available NGS data, 21 (57%) showed a single nucleotide polymorphism distance of ≤5 to another BSI isolate.
Conclusions
Prospective assessment of maternal GN colonization did not demonstrate linkage to neonatal BSI. Organism-relatedness among neonates with BSI suggests nosocomial spread, highlighting the importance of NICU infection prevention and control practices to reduce GN BSI.
Pre-delivery maternal sampling followed by neonatal observation did not identify a maternal source for neonatal gram-negative bloodstream infection. However, most neonatal gram-negative bloodstream isolates were closely related by sequencing to at least 1 other clinical isolate, raising concern for nosocomial transmission.
The recent global pandemic associated with the highly contagious novel coronavirus (SARS-CoV-2) has led to an unpredictable loss of life and economy worldwide, and the discovery of antiviral drugs is ...an urgent necessity. For the discovery of new drug leads and for the treatment of various diseases, natural products and purified photochemical from medicinal plants are used. The RNA cap was methylated by two S-adenosyl-L-methionine (SAM)-dependent methyltransferases of SARS coronavirus (SARS-CoV-2), catalyzed by NSP16 2′-O-Mtase. Natural substrate SAM, 128 Phytocompounds retrieved from the Phytocompounds database, and 11 standard FDA-approved HIV drugs reclaimed from the PubChem database are subjected to docking analysis. The docking study was done using AutoDock Vina. Further, admetSAR and DruLiTO servers are used to analyze the drug-likeness properties. The NSP16/10 structure and natural substrate SAM, Phytocompounds Withanolide (WTL), and HIV standard drug Dolutegravir (DLT) as hit compounds were identified by molecular dynamics using the Gromacs GPU-enabled package. To examine the effectiveness of the identified drugs versus COVID-19, further in vitro and in vivo studies are required.
Communicated by Ramaswamy H. Sarma
Pediatric tuberculosis (TB) remains difficult to diagnose. The plasma kynurenine to tryptophan ratio (K/T ratio) is a potential biomarker for TB diagnosis and treatment response but has not been ...assessed in children.
We performed a targeted diagnostic accuracy analysis of four biomarkers: kynurenine abundance, tryptophan abundance, the K/T ratio, and IDO-1 gene expression. Data were obtained from transcriptome and metabolome profiling of children with confirmed tuberculosis and age- and sex-matched uninfected household contacts of pulmonary tuberculosis patients. Each biomarker was assessed as a baseline diagnostic and in response to successful TB treatment.
Despite non-significant between-group differences in unbiased analysis, the K/T ratio achieved an area under the receiver operator characteristic curve (AUC) of 0.667 and 81.5% sensitivity for TB diagnosis. Kynurenine, tryptophan, and IDO-1 demonstrated diagnostic AUCs of 0.667, 0.602, and 0.463, respectively. None of these biomarkers demonstrated high AUCs for treatment response. The AUC of the K/T ratio was lower than biomarkers identified in unbiased analysis, but improved sensitivity over existing commercial assays for pediatric TB diagnosis.
Plasma kynurenine and the K/T ratio may be useful biomarkers for pediatric TB. Ongoing studies in geographically diverse populations will determine optimal use of these biomarkers worldwide.
Transcriptomic signatures for tuberculosis (TB) have been proposed and represent a promising diagnostic tool. Data remain limited in persons with advanced HIV.
We enrolled 30 patients with advanced ...HIV (CD4 <100 cells/mm
) in India; 16 with active TB and 14 without. Whole-blood RNA sequencing was performed; these data were merged with a publicly available dataset from Uganda (
= 33; 18 with TB and 15 without). Transcriptomic profiling and machine learning algorithms identified an optimal gene signature for TB classification. Receiver operating characteristic analysis was used to assess performance.
Among 565 differentially expressed genes identified for TB, 40 were shared across India and Uganda cohorts. Common upregulated pathways reflect Toll-like receptor cascades and neutrophil degranulation. The machine-learning decision-tree algorithm selected gene expression values from
and
as most informative for TB classification. The signature accurately classified TB in discovery cohorts (India AUC 0.95 and Uganda AUC 1.0;
< 0.001); accuracy was fair in external validation cohorts.
Expression values of
and
genes in peripheral blood compose a biosignature that accurately classified TB status among patients with advanced HIV in two geographically distinct cohorts. The functional analysis suggests pathways previously reported in TB pathogenesis.
Background
: Universal access to maternal new-born and child healthcare services (MNCH) is detrimental for attainment of Sustainable Development Goal (SDG) three pertaining to promotion of health at ...all ages. Incentivization in the form of cash, vouchers, and goods have been used as part of strategies to improve maternal and neonatal health outcomes around the world. However, there exists uncertainties regarding the effectiveness of various incentive-based programmes targeted for pregnant mothers in low- and middle-income countries during their antenatal period.
Methods: We will search six electronic databases, namely the Medical Literature Analysis and Retrieval System Online (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, and Embase in addition to Google Scholar. Manual searching of the reference lists of included studies will also be done. The reporting of this protocol will follow the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) 2015 statement 29. Only interventional studies that follow randomized, quasi randomized, and cluster randomized controlled study designs will be included. A three-stage screening process will be adopted to select articles. Risk of bias for the included studies will be assessed using the tools and criteria specified in the Cochrane handbook. In addition, the GRADE approach will be used to assess the quality of evidence for the maternal and neonatal health outcomes.
Conclusion: This review of trials is essential to inform the effectiveness of incentive-based programmes targeted for pregnant women in low- and middle-income countries. It will help the policy makers to utilise the resources more effectively and to integrate the evidence based public health initiatives into the health system. This can also help build the continuum of care financial packages for all pregnant women.
IntroductionThe ProSPoNS trial is a multicentre, double-blind, placebo-controlled trial to evaluate the role of probiotics in prevention of neonatal sepsis. The present protocol describes the data ...and methodology for the cost utility of the probiotic intervention alongside the controlled trial.Methods and analysisA societal perspective will be adopted in the economic evaluation. Direct medical and non-medical costs associated with neonatal sepsis and its treatment would be ascertained in both the intervention and the control arm. Intervention costs will be facilitated through primary data collection and programme budgetary records. Treatment cost for neonatal sepsis and associated conditions will be accessed from Indian national costing database estimating healthcare system costs. A cost–utility design will be employed with outcome as incremental cost per disability-adjusted life year averted. Considering a time-horizon of 6 months, trial estimates will be extrapolated to model the cost and consequences among high-risk neonatal population in India. A discount rate of 3% will be used. Impact of uncertainties present in analysis will be addressed through both deterministic and probabilistic sensitivity analysis.Ethics and disseminationHas been obtained from EC of the six participating sites (MGIMS Wardha, KEM Pune, JIPMER Puducherry, AIPH, Bhubaneswar, LHMC New Delhi, SMC Meerut) as well as from the ERC of LSTM, UK. A peer-reviewed article will be published after completion of the study. Findings will be disseminated to the community of the study sites, with academic bodies and policymakers.RegistrationThe protocol has been approved by the regulatory authority (Central Drugs Standards Control Organisation; CDSCO) in India (CT-NOC No. CT/NOC/17/2019 dated 1 March 2019). The ProSPoNS trial is registered at the Clinical Trial Registry of India (CTRI). Registered on 16 May 2019.Trial registration numberCTRI/2019/05/019197; Clinical Trial Registry.
IntroductionCurrent anaemia control programme focusing on prophylactic iron supplementation and facility-based screening with haemoglobin estimation is inadequate to reduce the high prevalence of ...anaemia in India. This study aims to examine the impact of community level ‘screen and treat’ strategy for increasing population mean haemoglobin and reducing anaemia prevalence in the rural population.Methods and analysisAn open-labelled cluster randomised controlled trial will be conducted in rural areas of Medchal district, Telangana, India. All individuals served by one Accredited Social Health Activist (ASHA) constitute one cluster and will be randomised in the ratio of 1:1 by covariate constrained randomisation. Eligible members aged between 6 months and 50 years (men, women, children and adolescents) will be included in the study. Intervention group will be screened for anaemia using a point of care haemoglobin estimation followed by treatment with iron–folic acid for 3 months. The intervention delivered by the ASHAs will be supported by an electronic decision support system and simplified medication regimen. Educational videos and interactive voice response system will be used to enhance compliance. The control group will continue to receive benefits of ongoing anaemia control programmes but there will be no active intervention by the study team. At 6 months, haemoglobin will be measured in participants from both arms. The primary outcome will be the difference in population mean haemoglobin in two arms and the secondary outcome will be the difference in the anaemia prevalence in two arms among 6–59 months old children. Multilevel models will be used for analysis accounting for data clustering.Ethics and disseminationThe study is approved by the institutional ethics committee of National Institute of Nutrition, Hyderabad. The results will be published in peer-reviewed journals and disseminated to policymakers. Findings will also be shared with study participants and community leaders.Trial registration numberCTRI/2019/01/016918.
Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the "six-week extended-dose ...nevirapine" (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.
Standard population sequencing and cloning for viral subpopulations present at > or =5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.
Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.
ClinicalTrials.gov NCT00061321.
Abstract
Background
The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood.
Methods
We enrolled a ...prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models.
Results
Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio aIRR, 1.21 95% confidence interval {CI}, 1.01–1.47) and treatment failure (aIRR, 1.16 95% CI, 1.05–1.28). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 95% CI, 1.01–1.11).
Conclusions
Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.
In a prospective cohort of patients with newly diagnosed pulmonary tuberculosis receiving standard thrice-weekly antituberculosis treatment in India, lower rifampicin concentration was associated with Human Immunodeficiency Virus coinfection and independently associated with unfavorable treatment outcomes.
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