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Typhoid remains a major cause of illness and death globally. In this trial, the efficacy of a typhoid conjugate vaccine was assessed in children in Nepal. A total of 20,019 children were randomly assigned to receive either a TCV or a meningococcal A vaccine. The TCV was associated with a decrease of 81.6% in Salmonella Typhi bacteremia.

Serologic surveillance of at-risk populations can be used to directly estimate the incidence of typhoidal Salmonella infection across a variety of settings, including those without access to facility-based blood-culture surveillance. We collected paired blood samples approximately three months apart from an age-stratified random sample of healthy children and adults in Bangladesh, Malawi, and Nepal as part of the Strategic Typhoid Alliance Across Asia and Africa (STRATAA) study. We used a multiplex bead assay to measure the concentration of IgG antibodies against seven Salmonella typhi/paratyphi antigens (CdtB, FliC, HlyE, LPSO2, LPSO9, Vi, and YncE) in each sample and identified recently infected participants by fitting a regression mixture model to the change in IgG concentration between participants’ samples. We estimated the seroincidence of infection in a Bayesian framework for each study site, age group, and antigen target. Finally, we compared the seroincidence estimates with crude and adjusted estimates of clinical incidence based on blood-culture surveillance. Seroincidence estimates were significantly higher than enteric fever incidence across all study sites, age groups, and antigen targets, even after adjusting for underreporting (median ratio: 24.2, interquartile range: 11.4-58.9). Seroincidence consistently peaked in the 0–4-year age group and declined moderately between children and adults (33% to 58% decline in HlyE seroincidence between the 5–9 and 30 + year old age groups), while enteric fever incidence peaked in older children and fell sharply in adults (71% to 95% decline in adjusted clinical incidence). Seroincidence estimates based on the FliC, YncE, and HlyE antigens individually had the strongest correlation with observed enteric fever incidence across age groups and study sites (r = 0.72, 0.69, and 0.63, respectively). These findings suggest that in endemic settings, both children and adults are frequently infected by typhoidal Salmonella serotypes, although only a fraction of these infections present as clinically identifiable enteric fever cases.

In surveillance for typhoid fever, under-detection of cases occurs when patients with fever do not seek medical care, or seek medical care but do not receive a blood test. Missing data may result in incorrect estimates of disease incidence. We used data from an ongoing randomised clinical trial of typhoid conjugate vaccine among children in Nepal to determine if eligible patients attending our fever clinics who did not have blood taken for culture had a lower risk of disease than those who had blood drawn. We assessed clinical and demographic predictors of having blood taken for culture, and predictors of culture-positive results. Missing blood culture data were imputed using multiple imputations. During the first year of surveillance, 2392 fever presentations were recorded and 1615 (68%) of these had blood cultures. Children were more likely to have blood taken for culture if they were older, had fever for longer, a current temperature ≥38 degrees, or if typhoid or a urinary tract infection were suspected. Based on imputation models, those with blood cultures were 1.87 times more likely to have blood culture-positive fever than those with missing data. Clinical opinion on the cause of the fever may play a large part in the decision to offer blood culture, regardless of study protocol. Crude typhoid incidence estimates should be adjusted for the proportion of cases that go undetected due to missing blood cultures while adjusting for the lower likelihood of culture-positivity in the group with missing data.

RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood samples from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data. RGStraP is a computational pipeline to estimate RNA-seq-based genetic principal components and assess whether these can be used to control for population structure in gene expression analyses.

Fluoroquinolones are the most commonly used group of antimicrobials for the treatment of enteric fever, but no direct comparison between two fluoroquinolones has been performed in a large randomised trial. An open-label randomized trial was conducted to investigate whether gatifloxacin is more effective than ofloxacin in the treatment of uncomplicated enteric fever caused by nalidixic acid-resistant Salmonella enterica serovars Typhi and Paratyphi A. Adults and children clinically diagnosed with uncomplicated enteric fever were enrolled in the study to receive gatifloxacin (10 mg/kg/day) in a single dose or ofloxacin (20 mg/kg/day) in two divided doses for 7 days. Patients were followed for six months. The primary outcome was treatment failure in patients infected with nalidixic acid resistant isolates. 627 patients with a median age of 17 (IQR 9-23) years were randomised. Of the 218 patients with culture confirmed enteric fever, 170 patients were infected with nalidixic acid-resistant isolates. In the ofloxacin group, 6 out of 83 patients had treatment failure compared to 5 out of 87 in the gatifloxacin group (hazard ratio [HR] of time to failure 0.81, 95% CI 0.25 to 2.65, p = 0.73). The median time to fever clearance was 4.70 days (IQR 2.98-5.90) in the ofloxacin group versus 3.31 days (IQR 2.29-4.75) in the gatifloxacin group (HR = 1.59, 95% CI 1.16 to 2.18, p = 0.004). The results in all blood culture-confirmed patients and all randomized patients were comparable. Gatifloxacin was not superior to ofloxacin in preventing failure, but use of gatifloxacin did result in more prompt fever clearance time compared to ofloxacin. ISRCTN 63006567 (www.controlled-trials.com).

A 23-year-old man, on treatment for Graves’ disease, presented to the emergency department, with 2 separate episodes of loss of consciousness. During the first episode, the initial serum glucose was 19 mg/mL, and 44 mg/dL during the second episode. The patient was non-diabetic, and had elevated blood insulin, C peptide and insulin antibody levels. His abdominal radiographic findings were normal. He was diagnosed with Hirata disease, and put on propylthiouracil as a replacement for carbimazole. Hypoglycaemia was managed with dextrose infusions and frequent meals. The patient's condition improved and he had no further episodes of hypoglycaemia during the follow-up period.

Human metapneumovirus (hMPV) is an important cause of respiratory illness. However, information about hMPV incidence, patient characteristics, and symptoms outside hospital settings is limited. During June 2022-March 2024, participants aged 6 months-49 years who were enrolled in the CASCADIA community-based cohort study submitted weekly illness surveys and nasal swabs, and completed follow-up illness surveys. Swabs collected 0-3 days before reporting new or worsening symptoms were tested for hMPV and other respiratory viruses by multiplex polymerase chain reaction. Incidence was analyzed using an exponential survival model. Among 3,549 participants, 306 had symptomatic hMPV infection, representing an average of 7.5 cases per 100 persons per year (95% CI = 6.7-8.4). Incidence was highest during January-March (adjusted hazard ratio [aHR] = 4.3; 95% CI = 3.0-6.0) compared with October-December, and among those aged 2-4 years (aHR = 5.8; 95% CI = 3.8-9.0) compared with those aged ≥40 years. The most frequently reported symptoms were cough (80.4%) and nasal congestion (71.9%). Among 252 (82.4%) participants who completed a post-illness follow-up survey, 68 (27.0%) missed work, school, or child care facility attendance. Together, these findings indicate that hMPV is a common cause of respiratory illness during late winter to spring, particularly among young children, and frequently disrupts daily activities. Understanding hMPV epidemiology can guide surveillance definitions, clinical testing, and prioritization of prevention strategies.

In many rural areas at risk for enteric fever, there are few data on Salmonella enterica serotypes Typhi (S. Typhi) and Paratyphi (S. Paratyphi) incidence, due to limited laboratory capacity for microbiologic culture. Here, we describe an approach that permits recovery of the causative agents of enteric fever in such settings. This approach involves the use of an electricity-free incubator based upon use of phase-change materials. We compared this against conventional blood culture for detection of typhoidal Salmonella. Three hundred and four patients with undifferentiated fever attending the outpatient and emergency departments of a public hospital in the Kathmandu Valley of Nepal were recruited. Conventional blood culture was compared against an electricity-free culture approach. Blood from 66 (21.7%) patients tested positive for a Gram-negative bacterium by at least one of the two methods. Sixty-five (21.4%) patients tested blood culture positive for S. Typhi (30; 9.9%) or S. Paratyphi A (35; 11.5%). From the 65 individuals with culture-confirmed enteric fever, 55 (84.6%) were identified by the conventional blood culture and 60 (92.3%) were identified by the experimental method. Median time-to-positivity was 2 days for both procedures. The experimental approach was falsely positive due to probable skin contaminants in 2 of 239 individuals (0.8%). The percentages of positive and negative agreement for diagnosis of enteric fever were 90.9% (95% CI: 80.0%-97.0%) and 96.0% (92.7%-98.1%), respectively. After initial incubation, Salmonella isolates could be readily recovered from blood culture bottles maintained at room temperature for six months. A simple culture approach based upon a phase-change incubator can be used to isolate agents of enteric fever. This approach could be used as a surveillance tool to assess incidence and drug resistance of the etiologic agents of enteric fever in settings without reliable local access to electricity or local diagnostic microbiology laboratories.

A 51-year-old man presented with intermittent fever, mild cough and loss of appetite of 1-month duration. His sputum smear was positive for acid-fast bacilli and his chest radiograph revealed apical infiltrations. The patient was treated with antitubercular therapy (ATT), recovered and was well for 1 month, after which he suddenly developed focal seizures. MRI of the brain with gadolinium enhancement showed high intensity nodular foci in the frontal, parietal and occipital regions. The patient was diagnosed as a case of paradoxical reaction to ATT, and was successfully managed with continued ATT and adjunctive steroid therapy.

Electronic data capture systems (EDCs) have the potential to achieve efficiency and quality in collection of multisite data. We quantify the volume, time, accuracy and costs of an EDC using large-scale census data from the STRATAA consortium, a comprehensive programme assessing population dynamics and epidemiology of typhoid fever in Malawi, Nepal and Bangladesh to inform vaccine and public health interventions. A census form was developed through a structured iterative process and implemented using Open Data Kit Collect running on Android-based tablets. Data were uploaded to Open Data Kit Aggregate, then auto-synced to MySQL-defined database nightly. Data were backed-up daily from three sites centrally, and auto-reported weekly. Pre-census materials’ costs were estimated. Demographics of 308,348 individuals from 80,851 households were recorded within an average of 14.7 weeks range (13-16) using 65 fieldworkers. Overall, 21.7 errors (95% confidence interval: 21.4, 22.0) per 10,000 data points were found: 13.0 (95% confidence interval: 12.6, 13.5) and 24.5 (95% confidence interval: 24.1, 24.9) errors on numeric and text fields respectively. These values meet standard quality threshold of 50 errors per 10,000 data points. The EDC’s total variable cost was estimated at US$13,791.82 per site. In conclusion, the EDC is robust, allowing for timely and high-volume accurate data collection, and could be adopted in similar epidemiological settings.