Burden of Typhoid and Paratyphoid Fever in India.

BACKGROUND: In 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection. METHODS: From 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community. RESULTS: A total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age. CONCLUSIONS: The incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.).

Impact of the COVID-19 pandemic on treatment of patients with acute myeloid leukaemia in India.

During the COVID-19 pandemic, our findings highlight changes in AML management strategies in India. There was a decrease in overall patient registrations, particularly at large referral centers, while smaller centers saw an increase, reflecting a shift towards more localized care. This shift was accompanied by a rise in the use of hypomethylating agents (HMAs). Despite these changes, survival outcomes remained comparable to pre-pandemic levels, likely due to improved infection control measures and maintaining treatment protocols. Our study concludes that standard AML care remained feasible during the pandemic, emphasizing the importance of continuing treatment for eligible patients even in times of crisis.

Treatment challenges and outcomes of older patients with acute myeloid leukemia from India.

Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137-234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p = .027) and baseline WBC counts (p = .006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population.

Impact of sperm DNA fragmentation in couples with unexplained recurrent pregnancy loss: A cross-sectional study.

OBJECTIVE: Recurrent pregnancy loss (RPL) has a multifactorial etiology, with a majority of cases remaining unexplained. To account for these unexplained cases, possible male factors are being explored. Conventional semen analysis lacks a qualitative assessment of sperms and information regarding sperm DNA integrity. Sperm DNA fragmentation (SDF) has diagnostic value in unexplained RPL, and it may account for a number of unexplained cases. Hence, we planned a study to explore and evaluate the impact of sperm DNA fragmentation in couples with unexplained recurrent pregnancy losses. STUDY DESIGN: Analytical cross-sectional study was conducted at a tertiary-level referral facility in India between August 2021 and July 2023. Participants (n = 70) were divided into two groups-male partners of couples with unexplained RPL (following spontaneous conceptions) (n = 35) and men with at least one previous live birth (spontaneous or following fertility treatments for female factor infertility such as ovulation induction or intrauterine insemination) as controls (n = 35). Neither of the two groups of couples recruited for this study had undergone ART as fertility treatment. Primary outcome assessed was mean DNA fragmentation index (DFI). Secondary outcomes included differences in semen parameters such as sperm concentration, progressive sperm motility and morphology, proportion of men with high (≥30%) and low DFI in the two groups, and the association between various semen parameters and DFI. RESULTS: Univariate logistic regression revealed that sperm DNA fragmentation was higher in men with unexplained RPL (30.0; IQR (interquartile range) 19.0, 46.0) as compared to controls (22.0; IQR 14.0, 30.0) although it was not statistically significant (OR, odds ratio, 1.02; 95% CI 1.0-1.1, p = 0.08). A higher proportion of men with unexplained RPL had DFI ≥30% compared to controls (54.2% vs. 25.7%; OR 3.43 (95% CI 1.2-9.4); p = 0.02). No statistically significant differences were observed in semen volume, sperm concentration, progressive motility, and morphology between the two groups. Sperm DNA fragmentation index also showed a weak but significant inverse relationship with sperm morphology (r = -0.336, p = 0.004). CONCLUSION: The current study did not show any significant difference in the mean sperm DNA fragmentation levels in male partners of couples with unexplained RPL compared to controls. However, a higher proportion of men with DFI ≥30% were observed in unexplained RPL population when compared to controls.

Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study.

BACKGROUND: Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse. METHODS: We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome. RESULTS: Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted. CONCLUSIONS: Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings.

Case-Fatality Ratio of Enteric Fever: Estimates From Multitiered Surveillance in India.

BACKGROUND: The case-fatality ratio (CFR) for enteric fever is essential for estimating disease burden and calibrating measures that balance the likely health gains from interventions against social and economic costs. METHODS: We aimed to estimate the CFR for enteric fever using multiple data sources within the National Surveillance System for Enteric Fever in India. This surveillance (2017-2020) was established as a multitiered surveillance system including community cohorts (tier 1), facility-based (tier 2), and tertiary care surveillance (tier 3) for estimating the burden of enteric fever in India. The CFR was calculated after accounting for healthcare-seeking behavior for enteric fever and deaths occurring outside the hospital. RESULTS: A total of 1236 hospitalized patients with blood culture-confirmed enteric fever were enrolled, of which 9 fatal cases were identified, for an estimated hospitalized CFR of 0.73% (95% confidence interval [CI], .33%-1.38%). After adjusting for severity, healthcare-seeking behavior, and deaths occurring out-of-hospital, the CFR was estimated to be 0.16% (95% CI, .07%-.29%) for all enteric fevers. CONCLUSIONS: Our estimates of the CFR are relatively lower than previously estimated, accounting for care-seeking behavior and deaths outside the hospital.

Healthcare Utilization Survey in the Hybrid Model of the Surveillance for Enteric Fever in India (SEFI) Study: Processes, Monitoring, Results, and Challenges.

BACKGROUND: Lack of reliable data in India drove the "Surveillance of Enteric Fever in India" (SEFI) concept. Hybrid surveillance, combining facility-based surveillance for the crude incidence, and a community-based healthcare utilization survey (HCUS) to calculate the factor needed to arrive at the adjusted incidence, was used in 6 sites. The HCUS aimed to determine the percentage of utilization of study facilities by the catchment population for hospitalizations due to febrile illness. METHODS: Population proportional to size sampling and systematic random sampling, in 2 stages, were used to survey 5000 households per site. Healthcare utilization was assessed. RESULTS: Febrile illness accounted for 20% of admissions among 137 990 individuals from 30 308 households. Only 9.6%-38.3% of those admitted with febrile illness sought care in the study hospitals. The rate of rural utilization of the private sector for hospitalization was 67.6%. The rate of hospitalization for febrile illness, per 1000 population, ranged from 2.6 in Manali to 9.6 in Anantapur; for 25.8% of the deaths associated with febrile illness, no facility was used before death. CONCLUSIONS: One in 5 hospitalizations were associated with fever. Rural utilization of the private sector for hospitalization due to febrile illness was more than that of the public sector. Healthcare utilization patterns for hospital admissions due to febrile illness varied across sites. A meticulously performed HCUS is pivotal for accurate incidence estimation in a hybrid surveillance. CLINICAL TRIALS REGISTRATION: ISRCTN72938224.

Antibiotics for Fever Among Children: Findings From the Surveillance for Enteric Fever in India Cohorts.

BACKGROUND: Acute febrile illness in children is frequently treated with antibiotics. However, the inappropriate use of antibiotics has led to the emergence of multidrug-resistant pathogens. METHODS: We measured use of antibiotics for fever in 4 pediatric cohorts that were part of the Surveillance for Enteric Fever in India (SEFI) network. In this network, 24 062 children were followed up weekly, capturing information on fever and other morbidity between October 2017 and December 2019. RESULTS: An antibiotic was given in 27 183 of the 76 027 (35.8%) episodes of fever. The incidence of fever-related antibiotic use was 58.0 (95% confidence interval [CI], 57.2-58.6) per 100 child-years. The median time to initiation of antibiotics was 4 days, and in 65% of those who received an antibiotic it was initiated by the second day. Antibiotics were continued for <3 days in 24% of the episodes. Higher temperature, younger age, male sex, joint family, higher education, internet access, and availability of personal conveyance were associated with antibiotic treatment for fever. CONCLUSIONS: In developing countries where antibiotic use is not regulated, broad-spectrum antibiotics are initiated early, and often inappropriately, in febrile illness. Frequent and inappropriate use of antibiotics may increase risk of antimicrobial resistance.

Heterogeneous susceptibility to rotavirus infection and gastroenteritis in two birth cohort studies: Parameter estimation and epidemiological implications.

Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis (RVGE) in low- and middle-income countries. While susceptibility of children to rotavirus is known to vary within and between settings, implications for estimation of immune protection are not well understood. We sought to re-estimate naturally-acquired protection against rotavirus infection and RVGE, and to understand how differences in susceptibility among children impacted estimates. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 rotavirus-unvaccinated children experienced 1418 rotavirus infections and 371 episodes of RVGE over 17,636 child-months. We developed a model that characterized susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings. We tested whether model-generated susceptibility measurements were associated with demographic and anthropometric factors, and with the severity of RVGE symptoms. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of rotavirus-negative diarrhea, and higher risk of moderate-to-severe symptoms when experiencing RVGE. Simulations suggested that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in susceptibility of children, but result primarily from the interaction of transmission rates with age-dependent risk for infections to cause RVGE. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that unmeasured individual- and age-dependent susceptibility may influence estimates of naturally-acquired immune protection against RVGE.

Anti-vascular endothelial growth factor for neovascular glaucoma.

BACKGROUND: Neovascular glaucoma (NVG) is a potentially blinding, secondary glaucoma. It is caused by the formation of abnormal new blood vessels, which prevent normal drainage of aqueous from the anterior segment of the eye. Anti-vascular endothelial growth factor (anti-VEGF) medications are specific inhibitors of the primary mediators of neovascularization. Studies have reported the effectiveness of anti-VEGF medications for the control of intraocular pressure (IOP) in NVG. OBJECTIVES: To assess the effectiveness of intraocular anti-VEGF medications, alone or with one or more type of conventional therapy, compared with no anti-VEGF medications for the treatment of NVG. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register); MEDLINE; Embase; PubMed; and LILACS to 22 March 2019; metaRegister of Controlled Trials to 13 August 2013; and two additional trial registers to 22 March 2019. We did not use any date or language restrictions in the electronic search for trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people treated with anti-VEGF medications for NVG. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for trials, extracted data, and assessed risk of bias, and the certainty of the evidence. We resolved discrepancies through discussion. MAIN RESULTS: We included four RCTs (263 participants) and identified one ongoing RCT. Each trial was conducted in a different country: China, Brazil, Egypt, and Japan. We assessed the trials to have an unclear risk of bias for most domains due to insufficient information. Two trials compared intravitreal bevacizumab combined with Ahmed valve implantation and panretinal photocoagulation (PRP) with Ahmed valve implantation and PRP. We did not combine these two trials due to substantial clinical and statistical heterogeneity. One trial randomised participants to receive an injection of either an intravitreal anti-VEGF medication or placebo at the first visit, followed by non-randomised treatment according to clinical findings after one week. The last trial randomised participants to PRP with and without ranibizumab, but details of the study were unavailable for further analysis. Two trials that examined IOP showed inconsistent results. One found inconclusive results for mean IOP between participants who received anti-VEGF medications and those who did not, at one month (mean difference [MD] -1.60 mmHg, 95% confidence interval [CI] -4.98 to 1.78; 40 participants), and at one year (MD 1.40 mmHg, 95% CI -4.04 to 6.84; 30 participants). Sixty-five percent of the participants with anti-VEGF medications achieved IOP ≤ 21 mmHg, versus 60% without anti-VEGF medications. In another trial, those who received anti-VEGF medications were more likely to reduce their IOP than those who did not receive them, at one month (MD -6.50 mmHg, 95% CI -7.93 to -5.07; 40 participants), and at one year (MD -12.00 mmHg, 95% CI -16.79 to -7.21; 40 participants). Ninety-five percent of the participants with anti-VEGF medications achieved IOP ≤ 21 mmHg, versus 50% without anti-VEGF medications. The certainty of a body of evidence was low for this outcome due to limitations in the design and inconsistency of results between studies. Post-operative complications included anterior chamber bleeding (3 eyes) and conjunctival hemorrhage (2 participants) in the anti-VEGF medications group, and retinal detachment and phthisis bulbi (1 participant each) in the control group. The certainty of evidence is low due to imprecision of results and indirectness of evidence. No trial reported the proportion of participants with improvement in visual acuity, proportion of participants with complete regression of new iris vessels, or the proportion of participants with relief of pain and resolution of redness at four- to six-week, or one-year follow-up. AUTHORS' CONCLUSIONS: Currently available evidence is uncertain regarding the long-term effectiveness of anti-VEGF medications, such as intravitreal ranibizumab or bevacizumab or aflibercept, as an adjunct to conventional treatment in lowering IOP in NVG. More research is needed to investigate the long-term effect of these medications compared with, or in addition to, conventional surgical or medical treatment in lowering IOP in NVG.