Background and aims: Maternal overweight and obesity are increasing worldwide, including Nepal. This study assessed BMI trajectories from early pregnancy to one year postpartum and trends in overweight and obesity over the past two decades in Bhaktapur, Nepal. Methods: In the most recent study, BMI was measured in 800 Nepalese women at three time points: at early pregnancy, 6 and 12 months postpartum (2017-2021). The prevalence of undernutrition, overweight, and obesity was estimated using the World Health Organization and the Asian specific cut-offs. Long-term trends were assessed by comparing these findings with three population-based studies conducted in Bhaktapur between 2001 and 2021 among 2400 women at similar life stages. Results: Mean (SD) BMI increased from 23.7 (3.0) kg/m^2 in early pregnancy to 26.1 (3.3) kg/meter squre at 6 and 25.2 (3.3) kg/m^2 and 12 months. The prevalence of overweight increased from 32.9% in early pregnancy to 48% at 6 months. Using the Asia-specific cut-offs, the prevalences were higher. Results from the three previous population-based studies demonstrated an upward trend where postpartum overweight increased from 11.4% in 2001- 2002 to 44.6% in 2017- 2021. The obesity prevalence rose from 1.8% to 10.9% during this period. Conclusion: Overweight and obesity among Nepalese women have risen dramatically over the past two decades, with postpartum overweight increasing nearly fourfold and obesity more than sixfold. These findings highlight the need for interventions to prevent excessive weight retention and reduce adverse health outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Nepal Health Research Council (NHRC), ethical review boards in Nepal (NHRC 253/2016) and the Regional Committee for Medical and Health Research Ethics in Norway (2016/1620/REK vest) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets generated and analyzed during the current study are not publicly available because they contain sensitive participant information and are subject to ethical and institutional restrictions. De-identified data may be made available upon reasonable request subject to approved by the Nepal Health research Council (NHRC) and Regional Committee for Medical and Health Research Ethics in Norway. Research Council of Norway through its Centres of Excellence scheme and the University of Bergen (UiB), Norway, to the Centre for Intervention Science in Maternal and Child Health (CISMAC), 223269 Innlandet Hospital Trust, Lillehammer, Norway.

BACKGROUND:Few data are available comparing the WHO diphtheria-tetanus-pertussis (DTP)-containing vaccine schedule with reduced-dose or delayed three-dose schedules in infants. We aimed to identify an alternative schedule that is non-inferior or superior to the WHO schedule in maintaining early pertussis antibody levels before booster, while creating space for integration of new vaccines. METHODS:In two parallel, open-label, randomised, non-inferiority trials in Uganda and Nepal, healthy infants aged 42-50 days were randomised in a 4:4:4:3:3 ratio via an online system to five diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae type b-hepatitis B (DTwP-Hib-HepB) vaccination schedules (WHO schedule [ages 6, 10, and 14 weeks]; reduced two-dose schedules at ages 6 and 14 weeks or ages 2 and 4 months; or delayed three-dose schedules at ages 2, 3, and 4 months or ages 2, 4, and 6 months), using site-stratified block randomisation with a block size of 18. The primary outcome was the pre-booster IgG antibody response against pertussis antigens (pertussis toxin; filamentous haemagglutinin [FHA]; pertactin; fimbriae 2 and 3 [Fim 2 and 3]). Antibody responses during and 1 month after the primary series were assessed as secondary endpoints. The two-dose schedules were compared with the WHO schedule as primary analyses, and the exploratory analyses were to compare delayed three-dose schedules with the WHO schedule. All these analyses were conducted in the per-protocol population. For the primary endpoint, non-inferiority margins for geometric mean ratios (GMRs) between two-dose and WHO schedules were calculated for each pertussis antigen separately as 35% of the standard deviation of the geometric mean concentrations of the WHO group, and non-inferiority was concluded if the lower bound of the 95% CI of the GMR exceeded the non-inferiority margin. A non-inferiority margin of 0·67 was used for all other non-inferiority comparisons. The trials were registered with ISRCTN (Uganda [ISRCTN60356654] and Nepal [ISRCTN12240140]) and are complete. FINDINGS:Between Oct 1, 2021, and July 12, 2022 (Uganda) and Dec 5, 2021, and Feb 26, 2023 (Nepal), 956 infants were recruited per country and randomly allocated across the five study groups; pre-booster analyses were conducted in 876 participants in Uganda and 851 participants in Nepal. Two-dose schedules at ages 6 and 14 weeks and ages 2 and 4 months did not meet non-inferiority criteria for pertussis antibodies pre-booster, except FHA (non-inferiority margin 0·59) in Nepal (6 and 14 weeks GMR 0·83 [95% CI 0·61-1·13]; 2 and 4 months 1·20 [0·88-1·64]). Delayed three-dose schedules at ages 2, 3, and 4 months and ages 2, 4, and 6 months produced similar or higher post-primary series and pre-booster responses compared with the WHO schedule, but the WHO schedule achieved higher antibody responses against all pertussis antigens, except FHA in Nepal, at age 3 months. INTERPRETATION:The WHO DTP schedule is the preferred schedule in high-pertussis-burden settings, as it elicits the greatest antibody responses in the first 3 months of life when infants are particularly vulnerable. Although delayed three-dose schedules may be considered in low-risk contexts and in settings with maternal immunisation programmes, early infant protection should guide policy decisions. FUNDING:Gates Foundation.

BackgroundNegative early-life exposures, particularly during the first 1000 days of life, may disrupt organ development and lead to lifelong negative health consequences. ObjectiveUsing an exposome and deep phenotyping framework, this study aims to characterize established early-life risk factors, including environmental pollutants and nutritional status during pregnancy and infancy, and identify associated short- and long-term health and developmental outcomes. MethodsWe leverage a pregnancy cohort of 800 mother-infant pairs in Bhaktapur, Nepal, nested within a randomized controlled trial (ClinicalTrials.gov: NCT03071666) that evaluated daily vitamin B12 supplementation from before 15 weeks of gestation until 6 months post partum. The primary outcomes of the original trial were linear growth and neurodevelopment at 12 months. In this follow-up, children will be evaluated up to school age to obtain more robust estimates of long-term health outcomes. Exposures include clinical, dietary, cognitive, demographic, and anthropometric variables during pregnancy and infancy, as well as analyses of environmental pollutants, inflammation, micronutrient status, and hormonal status. Outcomes comprise neurodevelopment, morbidity, mental health, vaccine responses, thyroid function, growth, body composition, lung function, and biomarkers of health and development. Our main research questions for this phase of the project are: (1) what are the most common environmental pollutants among Nepalese women and children? (2) Is there a social gradient in exposure to these pollutants? (3) To what extent are these exposures associated with nutritional status, growth, neurodevelopment, and clinical outcomes? Associations will be examined using cross-sectional, case-control, and cohort designs applying advanced statistical methods to address confounding and complex exposure patterns. ResultsEnrollment began in March 2017, and the first child was born in August of the same year. More than 90% of the original cohort (734/800, 91.8%) have provided data up to the children’s fourth birthday. By December 2025, the project will have funding until July 2027, and the papers addressing the main research questions will be submitted for publication before the end of 2026. ConclusionsThis study draws on a well-characterized mother-child cohort in a South Asian setting with repeated biological samples from blood, breast milk, and urine and extensive high-quality longitudinal data on health, growth, and neurodevelopment. By integrating data on environmental exposures, nutrition, inflammation, and biological responses, the project aims to improve understanding of early-life determinants of health and inform policies and potential interventions to protect vulnerable women and children in marginalized settings. While the exploratory nature of exposome analyses entails a risk of spurious associations, careful interpretation and transparent communication of uncertainty will be prioritized. International Registered Report Identifier (IRRID)DERR1-10.2196/78593

BackgroundAnnually, an estimated 2.3 million infants die within their first month of life, primarily in sub-Saharan Africa and South Asia. Infections, including sepsis are among the major contributors to these deaths. Effective interventions added to standard antimicrobial therapy can reduce sepsis mortality. A recent meta-analysis suggests that adjunct zinc treatment of young infants with sepsis could reduce case fatality risk. This study evaluated the efficacy of zinc as an adjunct to antibiotics in young infants with suspected sepsis, defined as clinical severe infection (CSI).Methods and findingsWe conducted a randomized, double-blind, placebo-controlled trial across seven hospitals in India and Nepal from February 28, 2017, to February 22, 2022. Infants aged 3-59 days hospitalized with suspected sepsis, defined as CSI, adapted from the WHO Integrated Management of Childhood Illness (IMCI) criteria, were randomly assigned to receive 10 mg of elemental zinc daily or placebo orally for 14 days, in addition to standard of care. The primary outcomes were death during hospitalization and death within 12 weeks after enrollment. Among 3,153 enrolled infants (1,203 [38%] females), the median age at enrollment was 25 days (interquartile range 13-41 days), and the mean weight was 2.9 kg (standard deviation 0.8). During the hospital stay, 64 (4.1%) of 1,576 infants died in the zinc arm compared to 77 (4.9%) of 1,577 in the placebo arm (relative risk [RR] 0.83 (95% CI [0.60, 1.15]; p = 0.267)). Among those who completed 12 weeks of follow-up, 140 of 1,554 infants (9.0%) died in the zinc arm, and 133 of 1,550 (8.6%) in the placebo arm (RR 1.05 (95% CI [0.84, 1.32]; p = 0.674)). Adverse events were similar across trial arms, except for a slight increase in vomiting in the zinc arm; no events were attributed to the intervention. The main limitation of the study is that it was underpowered due to lower-than-anticipated event rates and a shortfall in the achieved sample size.ConclusionsIn this setting, we found little evidence for an effect of adjunct zinc therapy on young infants with CSI on the risk of dying during hospitalization or for the subsequent 3 months. Our findings contrast previous studies that used more specific case definitions. This underscores the need for further RCTs to evaluate the effect of zinc in young infant sepsis before it can be recommended in treatment guidelines.Trial registrationClinical Trials Registry-India (CTRI/2017/02/007966) on February 27, 2017, and Universal Trial Number is U1111-1187-6479.

OBJECTIVES:To assess geographical variation in maternal measles antibody levels from birth to nine months of age, to inform recommendations for the timing of the first measles vaccine dose. METHODS:Stored infant serum samples from 11 countries taken at delivery and/or follow-up time points prior to measles vaccination (N=2845) were tested for measles plaque reduction neutralisation (PRNT) and measles, mumps, and rubella immunoglobulin G at a central laboratory. Antibody decay in infants was modelled using linear mixed effects models with participant-level random intercepts and random slopes. Proportions of infants with antibody concentrations above the clinical protection threshold (0.12 IU/mL) were estimated at each age. RESULTS:At birth, most (94%, 519/552) infants had PRNT ≥0.12 IU/mL, but geometric mean concentrations ranged from 0.32 IU/mL (Guatemala) to 1.60 IU/mL (Pakistan). There was no geographical variation in the decay rate of PRNT nor immunoglobulin G. Geometric mean PRNT fell below 0.12 IU/mL between ages 2.5 months (Guatemala) and 6.2 months (Pakistan). At age 6 months, <50% of infants had PRNT ≥0.12 IU/mL in all countries except Pakistan. CONCLUSIONS:Reliance on maternal antibodies for protection until age 9 months or later leaves most infants with insufficient direct protection against measles infection between ages 6-9 months.

Background: In a recent double-blind randomized controlled trial (RCT) in Nepal, we found a negative effect of maternal vitamin B-12 supplementation during pregnancy on motor performance in their young infants. Objectives: The objective of this study is to examine whether the negative effect of the vitamin B-12 supplementation on motor performance in these infants aged 8 to 12 wk differed by baseline maternal characteristics. Methods: These are secondary analyses of an RCT where 800 pregnant women were randomly assigned to receive vitamin B-12 or placebo from early pregnancy to 6 mo postpartum. The outcome was motor development measured by the test of infant motor performance (TIMP) in 712 infants at age 8 to 12 wk. We examined whether plasma markers of baseline maternal vitamin B-12 status [cobalamin, total homocysteine (tHcy), methylmalonic acid (MMA), and cB12], folate and hemoglobin concentration, and socioeconomic status (SES) modified the effect of vitamin B-12 on the TIMP scores. The subgrouping variables were categorized according to predefined cutoffs and included as interaction terms in generalized linear models, with treatment group as the exposure and TIMP scores (continuous and categorical) as the outcomes. Results: Overall, the negative effect of the vitamin B-12 supplementation was observed in most subgroups. Except for plasma folate concentration (P-interaction = 0.015), the maternal baseline characteristics did not significantly modify the effect of vitamin B-12 supplementation on the TIMP scores. There was a tendency for a stronger negative effect of vitamin B-12 among infants of women with adequate baseline vitamin B-12 status (i.e. concentrations of cobalamin >220, tHcy <10, MMA <0.26, and cB12 values >- 0.5) and with folate concentration in the lower tertile. Conclusions: The negative effect of vitamin B-12 supplementation on infant motor performance cannot be explained by any subgroup specific effects. However, the effect appears to be more pronounced in mothers with adequate B-12 status. This trial was registered at clinicaltrials.gov as NCT03071666 (https://www.clinicaltrials.gov/study/NCT03071666).

BACKGROUND:Hypoxaemia predicts mortality at all levels of care, and appropriate management can reduce preventable deaths. However, pulse oximetry and oxygen therapy remain inaccessible in many primary care health facilities. We aimed to develop and validate a simple risk score comprising commonly evaluated clinical features to predict hypoxaemia in 2-59-month-old children with pneumonia. METHODS:Data from seven studies conducted in five countries from the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) dataset were included. Readily available clinical features and demographic variables were used to develop a multivariable logistic regression model to predict hypoxemia (oxygen saturation <90%) at presentation to care. The adjusted log coefficients were transformed to derive the PREPARE hypoxemia risk score and its diagnostic value was assessed in a held-out, temporal validation dataset. The model and risk score were analysed by evaluating the area under the receiver operating characteristic curve (AUC), sensitivity and specificity. RESULTS:We included 14 509 children in the analysis; 9.8% (n=2515) were hypoxemic at presentation. The multivariable regression model to predict hypoxemia included age, sex, respiratory distress (nasal flaring, grunting and/or head nodding), lower chest indrawing, respiratory rate, body temperature and weight-for-age z-score. The model showed fair discrimination (AUC 0.70, 95% CI 0.67 to 0.73) and calibration in the validation dataset. The simplified PREPARE hypoxaemia risk score includes five variables: age, respiratory distress, lower chest indrawing, respiratory rate and weight-for-age z-score. CONCLUSION:The PREPARE hypoxemia risk score, comprising five easily available characteristics, has the potential to be used to identify hypoxemia in children with pneumonia with a fair degree of certainty for use in health facilities without pulse oximetry. Its implementation would require careful consideration to limit the burden of inappropriate referrals on patients and the health system. Further external validation in community settings in low- and middle-income countries is required.

Background: Vitamin B 12 is essential for deoxyribonucleic acid synthesis and genome stability. A deficiency fi ciency of vitamin B 12 is associated with telomere shortening, genomic aging, and increased risk of chronic disease and mortality. Objectives: The study aims to determine the effect of vitamin B 12 supplementation on leukocyte telomere length (LTL) in infants at risk of vitamin B 12 deficiency. fi ciency. Methods: The study was a predefined fi ned secondary analysis of a randomized controlled trial enrolling 600 Nepalese infants aged 6 - 11 mo, who were supplemented with 2 mu g mu g (2-3 - 3 recommended daily allowances) vitamin B 12 or placebo daily for 1 y. At the end of the study, LTL was measured in 497 participants. Mean LTL was compared between the treatment arms in the full sample and predefined fi ned subgroups based on markers of vitamin B 12 status, hemoglobin, sex, and growth indices. Results: LTL at end-study did not differ between the vitamin B 12 and placebo arm with a standardized mean difference (95% confidence fi dence interval) of 0.04 (-0.14, - 0.14, 0.21). There was no effect of vitamin B 12 on LTL in any of the subgroups. Conclusions: Providing daily vitamin B 12 for 1 y during infancy in a population at risk of vitamin B 12 deficiency fi ciency does not affect LTL. This trial was registered at clinicaltrials.gov as NCT02272842.

Objectives: We determined the pulse oximetry benefit in pediatric pneumonia mortality risk stratification and chest-indrawing pneumonia in-hospital mortality risk factors. Methods: We report the characteristics and in-hospital pneumonia-related mortality of children aged 2-59 months who were included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest-indrawing pneumonia to identify mortality risk factors. Results: Among 285,839 children, 164,244 (57.5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5.8%, 95% confidence interval [CI] 5.6-5.9% vs 2.1%, 95% CI 1.9-2.4%). One in five children with chest-indrawing pneumonia was hypoxemic (19.7%, 95% CI 19.0-20.4%), and the hypoxemic CFR was 10.3% (95% CI 9.1-11.5%). Other mortality risk factors were younger age (either 2-5 months [adjusted odds ratio (aOR) 9.94, 95% CI 6.67-14.84] or 6-11 months [aOR 2.67, 95% CI 1.71-4.16]), moderate malnutrition (aOR 2.41, 95% CI 1.87-3.09), and female sex (aOR 1.82, 95% CI 1.43-2.32). Conclusion: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest-indrawing pneumonia were hypoxemic and one in 10 died. Young age and moderate malnutrition were risk factors for in-hospital chest-indrawing pneumonia-related mortality. Pulse oximetry should be integrated in pneumonia hospital care for children under 5 years.

Background Vitamin B12 is required for healthy infant growth and development, but low and marginal vitamin B12 status is endemic in low-income and middle-income countries. We aimed to measure the effect of vitamin B12 supplementation from early pregnancy until 6 months post partum on infant growth and neurodevelopment.Methods In this community-based, double-blind, placebo-controlled trial, we randomly assigned (1:1) 800 pregnant women (aged 20-40 years) who were up to 15 weeks pregnant-recruited from home visits and outpatient departments at three hospitals in Nepal-to daily supplementation with 50 mu g oral vitamin B12 or placebo until 6 months postpartum. Independent scientists generated the list that linked allocation to participants' study identification number. Participants were masked to group assignment and all investigators were masked until data cleaning was completed. The primary outcomes were length-for-age Z score (LAZ) at age 12 months and the cognitive composite score of the Bayley Scales of Infant and Toddler Development (3rd edition) at age 6 months and 12 months. The primary and secondary outcomes, including adverse events, were assessed in the intention-to-treat population, for all participants with available outcome data. This trial is registered with ClinicalTrials.gov, NCT03071666.Findings 800 eligible pregnant women were enrolled in the trial between March 28, 2017, and Oct 15, 2020, with 400 women randomly assigned to each group. Follow-up was completed on May 18, 2022. At baseline, 569 (71%) of 800 women had plasma vitamin B12 indicating low or marginal status (<221 pmol/L). We found no effect of vitamin B12 on the primary outcomes. The mean LAZ at age 12 months were -0 center dot 57 (SD 1 center dot 03) in the B12 group and -0 center dot 55 (1.03) in the placebo group (366 infants in the vitamin B12 group vs 363 infants in the placebo group) with a mean difference of -0 center dot 02 (95% CI -0 center dot 16 to 0 center dot 13). The mean cognitive composite scores were 97 center dot 7 (SD 10 center dot 5) in the B12 group and 97 center dot 1 (10 center dot 2) in the placebo group, with a mean difference of 0 center dot 5 (95% CI -0 center dot 6 to 1 center dot 7) measured in 364 and 361 infants. Stillbirths or infant deaths occurred in three (1%) of 374 women in the vitamin B12 group and nine (2%) of 379 women in the placebo group.Interpretation Although vitamin B12 deficiency was prevalent in our study population and vitamin B12 supplementation from early pregnancy substantially improved vitamin B12 status, supplementation did not improve infant growth or neurodevelopment. Our findings support the current WHO recommendations of no routine vitamin B12 supplementation during pregnancy.Funding Research Council of Norway.Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Background Universal immunisation is the cornerstone of preventive medicine for children, The World Health Organisation (WHO) recommends diphtheria-tetanus-pertussis (DTP) vaccine administered at 6, 10 and 14 weeks of age as part of routine immunisation. However, globally, more than 17 unique DTP-containing vaccine schedules are in use. New vaccines for other diseases continue to be introduced into the infant immunisation schedule, resulting in an increasingly crowded schedule. The OptImms trial will assess whether antibody titres against pertussis and other antigens in childhood can be maintained whilst adjusting the current Expanded Programme on Immunisation (EPI) schedule to provide space for the introduction of new vaccines. Methods The OptImms studies are two randomised, five-arm, non-inferiority clinical trials in Nepal and Uganda. Infants aged 6 weeks will be randomised to one of five primary vaccination schedules based on age at first DTwP-vaccination (6 versus 8 weeks of age), number of doses in the DTwP priming series (two versus three), and spacing of priming series vaccinations (4 versus 8 weeks). Additionally, participants will be randomised to receive their DTwP booster at 9 or 12 months of age. A further sub-study will compare the co-administration of typhoid vaccine with other routine vaccines at one year of age. The primary outcome is anti-pertussis toxin IgG antibodies measured at the time of the booster dose. Secondary outcomes include antibodies against other vaccine antigens in the primary schedule and their safety. Discussion These data will provide key data to inform policy decisions on streamlining vaccination schedules in childhood. Trial registrations ISRCTN12240140 (Nepa1, 7 th January 2021) and ISRCTN6036654 (Uganda, 17 th February 2021).

Background: Vitamin B12 is required for normal growth and development, but low and marginal status is endemic in low- and middle-income countries. We aimed to measure the effect of vitamin B12 supplementation from early pregnancy until 6 months postpartum on infant growth and neurodevelopment.Methods: We randomised (1:1) 800 pregnant women within 15 weeks of gestation in a community-based, double-blind, placebo-controlled trial in Nepal to daily supplementation with 50 μg oral vitamin B12 or placebo until 6 months postpartum. The randomisation list was generated by scientists not involved in the study. Treatment allocation was linked to the participants unique study ID. The primary outcomes were length-for-age z-scores (LAZ) at 12 months, and the cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), measured at 6 and 12 months. All participants with outcomes were included in the analyses. The trial was registered at ClinicalTrials.gov: NCT03071666.Findings: Women were enrolled between March 28, 2017, and October 15, 2020, and follow up was completed May 18, 2022. At baseline, 71·5% of the women had plasma cobalamin indicating low or marginal status (<221 pmol/L). Vitamin B12supplementation substantially improved status in mothers and infants. We found no effect of vitamin B12 on the primary outcomes. The mean (±SD) LAZ-score at 12 months was -0·6 (1·0) in both study arms (366 and 363 infants). The mean difference (95% CI) in cognitive composite scores was 0·5 (-0·6, 1·7) (measured in 364 and 361 infants). Stillbirths or infant deaths occurred in 3 (0·8%) of 374 women in the vitamin B12 group and 9 (2·3%) of 379 women in the placebo group. Interpretation: Although poor status was prevalent and vitamin B12 supplementation from early pregnancy substantially improved vitamin B12 status, supplementation did not improve infant growth or neurodevelopment.Funding: This work was supported by the Research Council of Norway through its Centres of Excellence scheme (project number 223269) and the University of Bergen (UiB), Norway, to the Centre for Intervention Science in Maternal and Child Health (CISMAC) and the Innlandet Hospital Trust, Lillehammer, Norway.Declaration of Interests: The authors declare they have no actual or potential competing conflict interests.Ethics Approval: The ethical review boards in Nepal (NHRC 253/2016) and Norway (2016/1620/REK vest) approved the studyTrial Registration: The trial was registered at ClinicalTrials. gov, NCT03071666

Background:The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. Methods:Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. Results:Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males. Conclusions:This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.

Introduction:The high burden of respiratory syncytial virus (RSV) infection in young children disproportionately occurs in low- and middle-income countries (LMICs). The PROUD (Preventing RespiratOry syncytial virUs in unDerdeveloped countries) Taskforce of 24 RSV worldwide experts assessed key needs for RSV prevention in LMICs, including vaccine and newer preventive measures.Methods:A global, survey-based study was undertaken in 2021. An online questionnaire was developed following three meetings of the Taskforce panellists wherein factors related to RSV infection, its prevention and management were identified using iterative questioning. Each factor was scored, by non-panellists interested in RSV, on a scale of zero (very-low-relevance) to 100 (very-high-relevance) within two scenarios: (1) Current and (2) Future expectations for RSV management.Results:Ninety questionnaires were completed: 70 by respondents (71.4% physicians; 27.1% researchers/scientists) from 16 LMICs and 20 from nine high-income (HI) countries (90.0% physicians; 5.0% researchers/scientists), as a reference group. Within LMICs, RSV awareness was perceived to be low, and management was not prioritised. Of the 100 factors scored, those related to improved diagnosis particularly access to affordable point-of-care diagnostics, disease burden data generation, clinical and general education, prompt access to new interventions, and engagement with policymakers/payers were identified of paramount importance. There was a strong need for clinical education and local data generation in the lowest economies, whereas upper-middle income countries were more closely aligned with HI countries in terms of current RSV service provision.Conclusion:Seven key actions for improving RSV prevention and management in LMICs are proposed.

Background Lung cancer is one of the leading cause of cancer related death. Most common histopathology of lung cancer is non-small cell carcinoma of which adenocarcinoma is the most common. There are limited number of studies done in Nepal to know different aspects of lung cancer. Objective To know demographic parameters of patients diagnosed as lung cancer in a university hospital. The study also aims to know the different histopathological diagnosis of lung cancer. Method All the patients presenting to outpatient department (Cardio Thoracic and Vascular unit) of Dhulikhel Hospital, if are diagnosed as cancer of lung/bronchus will be included in the study. The duration of the study was January 2017 to December 2021. The details on age, gender, presenting symptoms, histopathology of lung cancer, operability will be included in database and will be analyzed. Result There were total of 127 patients diagnosed as lung cancer. Male:female ratio was 1.7:1. Overall mean age was 63.23 years (SD 13.5 years, Range 19-89 years). Non small cell carcinoma was the most common type of lung cancer with 83.7%. In non small cell carcinoma, most common type was Squamous cell carcinoma followed by undifferentiated and Adenocarcinoma. Only five (3.93%) cases were in operable stage. Conclusion Despite the fact that lung cancer is one of the most common cancer, patients usually present late and moslty are not in operable stage. This study shows that squamous cell carcinoma is the most common histopathology in lung cancer cases.

IntroductionExisting risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2–59 months at risk of hospitalised pneumonia-related mortality across various settings.MethodsWe used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool.ResultsA total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84).ConclusionsThe PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality.

Introduction: Acute abdominal pain is a very common complaint for children presenting to the emergency department (ED). The purpose of this study was to compare efficacy of hyoscine and drotaverine for relieving acute nonspecific abdominal pain in children presenting to ED. Methods: Total of 52 children aged six years to 16 years were enrolled in a non-randomized trial at Paediatric ED of TUTH from Dec 2017 to June 2018, and randomly allocated to drotaverine or hyoscine groups; 26 in each group. Face pain score-revised tool was used to measure the efficacy of the drug. The primary outcome was to measure the reduction of face pain score (Self-reported) by at least 2 / 10 at 60 minutes after ingestion of study intervention. Other outcomes were requirement of rescue analgesia and adverse effects of drugs. Results: A total of 20 (77%) in hyoscine and 21 (81%) in drotaverine group responded to oral medication at the end of 60 minutes of oral administration and the difference was not statistically significant (p=0.808). Vomiting was only adverse event present in five (19%) in drotaverine and two (8%) in hyoscine groups, respectively. Conclusions: In this single center randomized controlled trial, both hyoscine and drotaverine were found to be equally efficacious for relieving acute non-specific abdominal pain in children.

Sepsis, an important and preventable cause of death in the newborn, is associated with high out of pocket hospitalization costs for the parents/guardians. The government of Nepal’s Free Newborn Care (FNC) service that covers hospitalization costs has set a maximum limit of Nepalese rupees (NPR) 8000 i.e. USD 73.5, the basis of which is unclear. We aimed to estimate the costs of treatment in neonates and young infants fulfilling clinical criteria for sepsis, defined as clinical severe infection (CSI) to identify determinants of increased cost. This study assessed costs for treatment of 206 infants 3–59 days old, enrolled in a clinical trial, and admitted to the Kanti Children’s Hospital in Nepal through June 2017 to December 2018. Total costs were derived as the sum of direct costs for bed charges, investigations, and medicines and indirect costs calculated by using work time loss of parents. We estimated treatment costs for CSI, the proportion exceeding NPR 8000 and performed multivariable linear regression to identify determinants of high cost. Of the 206 infants, 138 (67%) were neonates (3–28 days). The median (IQR) direct costs for treatment of CSI in neonates and young infants (29–59 days) were USD 111.7 (69.8–155.5) and 65.17 (43.4–98.5) respectively. The direct costs exceeded NPR 8000 (USD 73.5) in 69% of neonates with CSI. Age <29 days, moderate malnutrition, presence of any sign of critical illness and documented treatment failure were found to be important determinants of high costs for treatment of CSI. According to this study, the average treatment cost for a newborn with CSI in a public tertiary level hospital is substantial. The maximum limit offered for free newborn care in public hospitals needs to be revised for better acceptance and successful implementation of the FNC service to avert catastrophic health expenditures in developing countries like Nepal. Trial Registration: CTRI/2017/02/007966 (Registered on: 27/02/2017).

BackgroundHuman parainfluenza virus (hPIV) is a common virus in childhood acute lower respiratory infections (ALRI). However, no estimates have been made to quantify the global burden of hPIV in childhood ALRI. We aimed to estimate the global and regional hPIV-associated and hPIV-attributable ALRI incidence, hospital admissions, and mortality for children younger than 5 years and stratified by 0–5 months, 6–11 months, and 12–59 months of age.MethodsWe did a systematic review of hPIV-associated ALRI burden studies published between Jan 1, 1995, and Dec 31, 2020, found in MEDLINE, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Global Health Library, three Chinese databases, and Google search, and also identified a further 41 high-quality unpublished studies through an international research network. We included studies reporting community incidence of ALRI with laboratory-confirmed hPIV; hospital admission rates of ALRI or ALRI with hypoxaemia in children with laboratory-confirmed hPIV; proportions of patients with ALRI admitted to hospital with laboratory-confirmed hPIV; or in-hospital case–fatality ratios (hCFRs) of ALRI with laboratory-confirmed hPIV. We used a modified Newcastle-Ottawa Scale to assess risk of bias. We analysed incidence, hospital admission rates, and hCFRs of hPIV-associated ALRI using a generalised linear mixed model. Adjustment was made to account for the non-detection of hPIV-4. We estimated hPIV-associated ALRI cases, hospital admissions, and in-hospital deaths using adjusted incidence, hospital admission rates, and hCFRs. We estimated the overall hPIV-associated ALRI mortality (both in-hospital and out-hospital mortality) on the basis of the number of in-hospital deaths and care-seeking for child pneumonia. We estimated hPIV-attributable ALRI burden by accounting for attributable fractions for hPIV in laboratory-confirmed hPIV cases and deaths. Sensitivity analyses were done to validate the estimates of overall hPIV-associated ALRI mortality and hPIV-attributable ALRI mortality. The systematic review protocol was registered on PROSPERO (CRD42019148570).Findings203 studies were identified, including 162 hPIV-associated ALRI burden studies and a further 41 high-quality unpublished studies. Globally in 2018, an estimated 18·8 million (uncertainty range 12·8–28·9) ALRI cases, 725 000 (433 000–1 260 000) ALRI hospital admissions, and 34 400 (16 400–73 800) ALRI deaths were attributable to hPIVs among children younger than 5 years. The age-stratified and region-stratified analyses suggested that about 61% (35% for infants aged 0–5 months and 26% for 6–11 months) of the hospital admissions and 66% (42% for infants aged 0–5 months and 24% for 6–11 months) of the in-hospital deaths were in infants, and 70% of the in-hospital deaths were in low-income and lower-middle-income countries. Between 73% and 100% (varying by outcome) of the data had a low risk in study design; the proportion was 46–65% for the adjustment for health-care use, 59–77% for patient groups excluded, 54–93% for case definition, 42–93% for sampling strategy, and 67–77% for test methods. Heterogeneity in estimates was found between studies for each outcome.InterpretationWe report the first global burden estimates of hPIV-associated and hPIV-attributable ALRI in young children. Globally, approximately 13% of ALRI cases, 4–14% of ALRI hospital admissions, and 4% of childhood ALRI mortality were attributable to hPIV. These numbers indicate a potentially notable burden of hPIV in ALRI morbidity and mortality in young children. These estimates should encourage and inform investment to accelerate the development of targeted interventions.FundingBill & Melinda Gates Foundation.