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Improving understanding of the pathogen-specific seasonality of enteric infections is critical to informing policy on the timing of preventive measures and to forecast trends in the burden of diarrhoeal disease. Data obtained from active surveillance of cohorts can capture the underlying infection status as transmission occurs in the community. The purpose of this study was to characterise rotavirus seasonality in eight different locations while adjusting for age, calendar time and within-subject clustering of episodes by applying an adapted Serfling model approach to data from a multi-site cohort study. In the Bangladesh and Peru sites, within-subject clustering was high, with more than half of infants who experienced one rotavirus infection going on to experience a second and more than 20% experiencing a third. In the five sites that are in countries that had not introduced the rotavirus vaccine, the model predicted a primary peak in prevalence during the dry season and, in three of these, a secondary peak during the rainy season. The patterns predicted by this approach are broadly congruent with several emerging hypotheses about rotavirus transmission and are consistent for both symptomatic and asymptomatic rotavirus episodes. These findings have practical implications for programme design, but caution should be exercised in deriving inferences about the underlying pathways driving these trends, particularly when extending the approach to other pathogens. [ABSTRACT FROM AUTHOR]

BackgroundSepsis is a common and severe complication in premature neonates, particularly those born with low birth weights (

BackgroundIn Pakistan, the prevalence of stunting in children younger than 5 years has remained above global critical levels over the past two decades, with the stunting rate being 40.2% in 2018. Children living in rural areas and in the poorest households suffer the most from stunting across the country—43.2% in rural areas and 51.4% in the lowest wealth quintile. As a continuing public health concern, it is essential that stunting prevention is a national priority in order to ensure human capital development, especially among the poorest households. ObjectiveThe primary objective of this study is to determine the effect of a medium quantity of a lipid-based nutrient supplement (LNS) combined with unconditional cash transfers and social and behavior change communication (SBCC) on reduction of stunting in children aged 6 to 23 months. MethodsA 5-arm cluster randomized controlled trial will be conducted in the district of Rahim Yar Khan in Punjab, Pakistan. The intervention packages will be (1) cash only, (2) cash with LNS, (3) cash with SBCC, and (4) cash with SBCC and LNS. The control arm will receive routine standard of care. We will enroll children at 6 months of age and follow up on a monthly basis up to 24 months of age. A total of 2000 children, 400 in each arm, will be enrolled to detect a 20% reduction in the prevalence of stunting among children aged 24 months. Length, weight, food intake, compliance to interventions, morbidities, and other relevant data will be collected at enrollment and on a monthly basis over the period of 18 months. The process evaluation will assess acceptability of the interventions and potential barriers to implementation through focus group discussions and in-depth interviews with the target population and relevant stakeholders. Furthermore, a cost analysis will be conducted to assess the cost-effectiveness of each intervention package. ResultsThe study protocol was approved by the Ethics Review Committee of Aga Khan University in Pakistan on January 4, 2017. Data collection began in May 2017 and was completed in July 2019. Data analyses are yet to be completed. This study will explore the effectiveness of intervention packages comprised of cash transfers from Benazir Income Support Programme with or without additional LNS and SBCC in preventing childhood stunting. We expect the results to be published in peer-reviewed journals by autumn of 2020. ConclusionsThe findings of this trial will provide robust evidence as to which intervention packages can have significant effects on linear growth of children and design effective intervention packages to prevent stunting in children aged 6 to 23 months. Trial RegistrationClinicalTrials.gov NCT03299218; https://clinicaltrials.gov/ct2/show/NCT03299218 International Registered Report Identifier (IRRID)DERR1-10.2196/19001

Background: Maternal micronutrient deficiencies are widespread in Pakistan and are potentially associated with maternal undernutrition and intrauterine growth retardation. Intervention strategies largely consist of administration of iron-folic acid supplements during pregnancy.Objective: We evaluated the acceptability of multiple micronutrient supplementation and its potential benefits on pregnancy outcomes and maternal micronutrient status in a cohort of pregnant women in rural and urban Sindh through a cluster-randomized design.Methods: We randomly assigned 2378 pregnant women to receive either iron-folic acid or multiple micronutrient supplements. The supplements were administered fortnightly by community health workers who performed home visits to assess tolerance and observe the mothers.Results: The women in both groups consumed about 75% of the supplements provided, and few reported adverse effects such as vomiting, abdominal pain, etc. There was a small (70 g) but significant increase in birthweight among infants of mothers receiving multiple micronutrients as compared with infants of mothers receiving iron-folic acid supplements (2.95 +/- 0.6 vs. 2.88 +/- 0.5 kg, p = .01). This translated into a 10% reduction (p < 0.17) in the proportion of low-birthweight infants among infants of mothers receiving multiple micronutrients. Although stillbirth rates were comparable in the two groups, the early neonatal mortality rate in the group receiving multiple micronutrients was higher, although not significantly, than that in the group receiving iron-folic acid (43.2 vs. 23.5 deaths per 1000 live births; RR = 1.64; 95% CI, 0.94 to 2.87). Comparable reductions in anemia (hemoglobin < 11 g/dL) were observed, although the proportion with low iron stores (assessed by serum ferritin) was lower in the iron-folic acid group in the postnatal period. Although the proportion of women with subclinical vitamin A deficiency after supplementation did not differ between the two groups, the iron-folic acid group had a higher proportion with lower serum zinc levels in the immediate postpartum period.Conclusions: These data suggest that multiple micronutrient supplements are well tolerated during pregnancy, but the effect on birthweight is modest. The observed effect on early neonatal mortality suggests the need for further studies and careful assessment of the intervention in health system settings. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This pilot study investigated the feasibility of delivering a package of community-based interventions for improving perinatal care using lady health workers (LHWs) and traditional birth attendants (Dais) in rural Pakistan. METHODS: The intervention was implemented in four of eight village clusters (315 villages, total population 138,600), while four served as a comparison group. The LHWs in intervention clusters received additional training focused on essential maternal and newborn care, conducted community education group sessions, and were encouraged to link up with local Dais. The intervention was delivered within the regular government LHW programme and was supported by the creation of voluntary community health committees. FINDINGS: In intervention villages, there were significant reductions from baseline in stillbirth (from 65.9 to 43.1 per 1000 births, P < 0.001) and neonatal mortality rates (from 57.3 to 41.3 per 1000 live births, P < 0.001). The proportion of deliveries conducted by skilled attendants at public sector facilities also increased, from 18% at baseline to 30%, while the proportion of home births decreased from 79% to 65%. A household survey indicated a higher frequency of key behaviours (e.g. early and exclusive breastfeeding, delayed bathing and cord care) in intervention villages. CONCLUSION: The improved stillbirth and neonatal mortality rates observed indicate that community health workers (i.e. LHWs and Dais) can be effective in implementing a community and outreach package that leads to improved home care practices by families, increased care-seeking behaviour and greater utilization of skilled care providers. These preliminary observations require confirmation in an adequately powered trial. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have investigated the efficacy of probiotics in treating acute and persistent diarrhoea. However, probiotics have not been established as a recommended management option for diarrhoeal illness by the World Health Organization (WHO). Therefore, we conducted a systematic review of randomised controlled trials to assess the efficacy of probiotics for the management of acute and persistent diarrhoea in children., Methods: A systematic search on PubMed, CINAHL, Wiley Cochrane Library, Scopus, Clinicaltrials.gov, and WHO International Clinical Trials Registry Platform (ICTRP) was performed. All studies published in the year 2000 and onwards that assessed the use of probiotics in the management of acute and persistent diarrhoea in children aged 0-10 years were included. The risk of bias was assessed using the Cochrane Risk of Bias II (RoB-2) tool and the quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. This review was commissioned by WHO for revision of their guidelines for childhood diarrhoea management., Results: The review included 98 studies with a total of 17 236 participants. Studies were categorised based on the WHO definition of diarrhoea or author-specified definition. In studies considering the WHO definition of diarrhoea, the probiotics group was more likely to achieve clinical cure (risk ratio = 1.12 (95% confidence interval (CI) = 1.01, 1.24, studies = 14)) and reduce the duration of diarrhoea (mean difference = -13.27 hours (95% CI = -16.72, -9.83, studies = 33)) than the control group in children with acute diarrhoea. However, the effect size was small, and statistical heterogeneity was very high, leading to low certainty of evidence. In children with persistent diarrhoea, probiotics reduced the duration of diarrhoea by 95 hours (mean difference = -96.45 (95% CI = -110.53, -82.37, studies = 2)), but the certainty of the evidence was very low., Conclusions: The results from this systematic review suggest low certainty of evidence for the effect of probiotics on clinical cure and duration of diarrhoea in children. There was significant diversity in the genus, species, dosages, and duration of treatment in the trial and administration. High levels of heterogeneity reduced the certainty of evidence. Large-scale randomised clinical trials are needed to evaluate specific probiotic strains and doses. In addition, cost-effective analysis studies are needed to be explored in future research., Registration: The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023449200)., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests. YBN is a staff member of the World Health Organization. The authors alone are responsible for the views expressed in this article, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: Zinc is a micronutrient that plays a role in immune system strengthening and regulation of intestinal epithelial cells, and can reduce the duration and severity of diarrhoea. We conducted a systematic review of randomised controlled trials (RCTs) to assess the effectiveness of zinc compared to no zinc for the management of acute and persistent diarrhoea in children., Methods: We searched PubMed, the Cochrane Library, Scopus, CINAHL, ClinicalTrials.gov, and World Health Organization (WHO) International Clinical Trials Registry Platform from inception until 31 July 2023 for studies published from year 2000 onwards that assessed the use of zinc in the management of acute and persistent diarrhoea in children aged less than 10 years. We conducted the meta-analysis in Cochrane's RevMan software, determined risk of bias in individual studies using the Risk of Bias 2 (RoB 2) tool, and assessed the quality of evidence through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This review was commissioned by the WHO for revision of their guidelines for childhood diarrhoea management., Results: We included 38 RCTs in this systematic review. Our findings suggest that, in children with acute diarrhoea, zinc supplementation resulted in a greater proportion of children who recovered from diarrhoea at last follow-up (risk ratio (RR) = 1.07; 95% confidence interval (CI) = 1.03, 1.1; moderate certainty of evidence) and a reduction in the duration of diarrhoea (mean difference (MD) = -13.27 hours; 95% CI = -17.66, -8.89; moderate certainty of evidence) when compared to placebo. A significant number of children in the zinc group compared to placebo experienced vomiting (RR = 1.46; 95% CI = 1.22, 1.76; moderate certainty of evidence), however, there were few vomiting episodes in low-dose zinc group compared to high-dose (RR = 0.80; 95% CI = 0.72, 0.89; moderate certainty of evidence). In children with persistent diarrhoea, zinc supplementation led to a greater proportion of children who recovered from diarrhoea (RR = 1.75; 95% CI = 1.34, 2.30; low certainty of evidence). The low certainty of evidence ratings were mostly due to high heterogeneity among the studies., Conclusions: Zinc should continue to be recommended in children under the age of 10 years with acute or persistent diarrhoea, but moderate certainty of evidence concludes that the dose of zinc should be reduced. However, further multi-country randomised clinical trials are required with a direct comparison to assess the appropriate dosage, duration and adverse effects., Registration: PROSPERO: CRD42023439028., Competing Interests: Disclosure of interests: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: YBN is staff member of the World Health Organization., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: Oral rehydration solution (ORS) is crucial in the management of diarrhoea. Until the early 2000s, the standard formulation of glucose-based ORS with a total osmolarity of 311 mmol/L was being used for this purpose. However, due to concerns about sodium levels and cases of hypernatremia, a low-osmolarity ORS solution (LORS) with an osmolarity of 245mmol/L or less was developed to replace the standard ORS. With this systematic review, we aimed to assess the effectiveness of LORS compared to standard ORS for the treatment of acute and persistent diarrhoea., Methods: We comprehensively searched PubMed, CINAHL, the Cochrane Library, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, and Scopus until 20 July 2023 for studies published after 1990 assessing the efficacy of LORS in acute and persistent diarrhoea in children under 10 years of age. Meta-analysis was conducted using the RevMan software. We performed log approximation for all the values for an outcome when studies reported arithmetic and geometric means per the Cochrane Handbook. We otherwise used the Cochrane Risk of Bias II tool to assess the risk of bias in individual studies, and assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. This review was commissioned by the WHO for revision of guidelines for childhood diarrhoea., Results: For the comparison of LORS to standard ORS in acute diarrhoea, our findings suggest that there was a significant decrease in the duration of diarrhoea (mean difference (MD) = -0.28; 95% confidence interval (CI) = -0.41, -0.15; moderate certainty of evidence), stool output (MD = -0.25; 95% CI = -0.35, -0.16; very low certainty of evidence), and ORS intake (MD = -0.18; 95% CI = -0.28, -0.07; moderate certainty of evidence) in patients receiving LORS. There was a comparable effect on the number of patients cured within five days, treatment failure, and frequency of unscheduled intravenous therapy (risk ratio (RR) = 0.77; 95% CI = 0.72, 9.38; low certainty of evidence). For persistent diarrhoea, there was a significant decrease in duration of diarrhoea (MD = -30.60; 95% CI = -48.95, -12.25), stool output (MD = -14.00; 95% CI = -26.63, -1.37), and ORS intake (MD = -21.40; 95% CI = -41.01, -1.79), while there was a comparable effect on the number of patients cured., Conclusion: Our findings suggest that LORS should continue to be recommended in children under the age of 10 years with acute watery or persistent diarrhoea and upholds the current WHO recommendations., Registration: PROSPERO: CRD42023438762., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: YBN is staff member of the World Health Organization., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: The use of antibiotics in the treatment of acute and persistent watery diarrhoea has long been a subject of contention. While the advantages of using antimicrobials are acknowledged, concerns remain regarding potential adverse effects and antibiotic resistance. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy of antibiotics compared to placebos for the treatment of diarrhoea., Methods: We searched PubMed, CINAHL, the Cochrane Library, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, and Scopus from inception until 20 July 2023 for studies published after the year 2000 assessing antibiotics vs placebo in acute and persistent diarrhoea and/or blood in stools in children less than 10 years of age. We conducted a meta-analysis for the included studies, assessed them using the Risk of Bias 2 tool, and evaluated their quality of evidence through the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. This review was commissioned by WHO for revision of their guidelines for childhood diarrhoea management., Results: We included five randomised controlled trials (RCTs) for acute watery diarrhoea and no study for bloody diarrhoea. Our findings suggest that there is a significant increase in clinical cure (risk ratio (RR) = 2.28; 95% confidence interval (CI) = 1.52, 3.41; low certainty evidence) and parasitological cure (RR = 2.86; 95% CI = 1.72 to 4.74; low certainty evidence) among children with acute watery diarrhoea in the antibiotic group when compared to the placebo group. The duration of diarrhoea (in hours) was significantly reduced (mean difference = -24.90; 95% CI = -34.09, -15.71; low certainty evidence) in the intervention group, while the effect on all-cause mortality (RR = 0.71; 95% CI = 0.40, 1.27; moderate certainty evidence) and the need for intravenous fluid infusion (RR = 0.50; 95% CI = 0.05, 5.17; very low certainty evidence) were comparable between the two groups., Conclusions: In children under 10 years of age suffering from acute watery or persistent diarrhoea, antibiotics led to an apparent increase in cure rates. However, considering the low certainty of evidence, low number of studies with small sample sizes, and the fact that most studies were conducted in a single country, further investigation and cautious interpretation are warranted, as is a large multi-country RCT that would allow for firmer conclusions., Registration: PROSPERO: CRD42023447133., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: YBN is staff member of the World Health Organization., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Approximately five billion people do not have access to necessary surgical treatment globally and up to 85% of children in LMICs are affected with conditions requiring surgical care by the age of 15 years. It is crucial to identify common surgical conditions in children in Pakistan to inform healthcare professionals and policymakers for effective resource allocation. This representative cross-sectional household survey conducted on children aged 5-10 years assessed existing surgical diseases and healthcare-seeking behaviors in the two largest provinces (Sindh and Punjab) of Pakistan. The data was collected through a validated cross-sectional survey tool [Surgeons OverSeas Assessment of Surgical Need (SOSAS)]. Caregivers were asked about their child's recent and past surgical conditions in six distinct anatomical regions and pictures were taken of identified conditions after appropriate consent for further diagnosis. Health-seeking behaviors including the kind of treatment sought, the nature of care received, and the reasons for not receiving care were noted. 13.5% of children surveyed reported a surgical condition, with a similar distribution across urban (13.2%) and rural (13.7) areas and the most common cause was trauma. The greatest number of surgical conditions were found to be on the head and neck region (57.7%), while the back accounted for the least number of conditions (1.7%). Our results outline a need for organizing all entities (governmental, non-governmental, and private) involved in child health to ensure efficient resource allocation to cater to existing surgical problems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Qazi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To describe presenting diagnoses and rates and causes of death by age category and sex among children with acute illness brought to a district headquarter hospital in Pakistan., Design: Prospective cohort study., Setting: Sanghar district headquarter hospital, Sindh, Pakistan between December 2019 and April 2020 and August 2020 and December 2020., Participants: 3850 children 0-14 years presenting with acute illness to the emergency and outpatient departments and 1286 children admitted to the inpatient department., Outcome Measures: The primary outcome was Global Burden of Disease diagnosis category. Secondary outcomes were 28-day mortality rate, cause of death and healthcare delays, defined as delay in care-seeking, delay in reaching the healthcare facility and delay in appropriate treatment., Results: Communicable diseases were the most common presenting diagnoses among outpatients and among inpatients aged 1 month to 9 years. Non-communicable diseases and nutritional disorders were more common with increasing age. Few children presented with injuries. Newborn period (age <28 days) was associated with increased odds of death (OR 4.34 [95% CI 2.38 to 8.18], p<0.001, reference age 28 days-14 years) and there was no significant difference in odds of death between female vs male children (OR 1.12, 95% CI 0.6 to 2.04, p=0.72). 47 children died in the hospital (3.6%) and three (0.2%) died within 28 days of admission. Most children who died were <28 days old (n=32/50, 64%); leading diagnoses included neonatal sepsis/meningitis (n=13/50, 26%), neonatal encephalopathy (n=7/50, 14%) and lower respiratory tract infections (n=6/50, 12%). Delays in care-seeking (n=15) and in receiving appropriate treatment (n=12) were common., Conclusion: This study adds to sparse literature surrounding the epidemiology of disease and hospital outcomes for children with acute illness seeking healthcare in rural Pakistan and, in particular, among children aged 5-14 years. Further studies should include public and private hospitals within a single region to comprehensively describe patterns of care-seeking and interfacility transfer in district health systems., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Undernutrition during pregnancy is linked to adverse pregnancy and birth outcomes and has downstream effects on the growth and development of children. The gut microbiome has a profound influence on the nutritional status of the host. This phenomenon is understudied in settings with a high prevalence of undernutrition, and further investigation is warranted to better understand such interactions., Methods and Analysis: This is a prospective, longitudinal observational study to investigate the relationship between prokaryotic and eukaryotic microbes in the gut and their association with maternal body mass index (BMI), gestational weight gain, and birth and infant outcomes among young mothers (17-24 years) in Matiari District, Pakistan. We aim to enrol 400 pregnant women with low and normal BMIs at the time of recruitment (<16 weeks of gestation). To determine the weight gain during pregnancy, maternal weight is measured in the first and third trimesters. Gut microbiome dynamics (bacterial and eukaryotic) will be assessed using 16S and 18S rDNA surveys applied to the maternal stool samples. Birth outcomes include birth weight, small for gestational age, large for gestational age, preterm birth and mortality. Infant growth and nutritional parameters include WHO z-scores for weight, length and head circumference at birth through infancy. To determine the impact of the maternal microbiome, including exposure to pathogens and parasites on the development of the infant microbiome, we will analyse maternal and infant microbiome composition, micronutrients in serum using metallomics (eg, zinc, magnesium and selenium) and macronutrients in the stool. Metatranscriptomics metabolomics and markers of inflammation will be selectively deployed on stool samples to see the variations in dietary intake and maternal nutritional status. We will also use animal models to explore the bacterial and eukaryotic components of the microbiome., Ethics and Dissemination: The study is approved by the National Bioethics Committee (NBC) in Pakistan, the Ethics Review Committee (ERC) at Aga Khan University and the Research Ethics Board (REB) at the Hospital for Sick Children, and findings will be published in peer-reviewed journals., Trial Registration Number: NCT05108675., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Infants are at a higher risk of severe illness with COVID-19 infection compared to older children. While COVID-19 vaccination is not recommended for young infants, they can acquire maternally-derived anti-SARS-CoV-2 antibodies passively through the placenta and breastmilk. We described the persistence of infection-induced maternal antibodies in infant circulation at 9-12 months of age., Methodology: This was a cross-sectional study nested within the INTERCOVID multinational cohort study. For each COVID positive pregnant woman, two unmatched consecutive COVID negative pregnant women were enrolled between April and September 2020. Women with a positive PCR test, radiographic signs consistent with COVID-19, or at least 2 predefined symptoms of COVID-19 were considered as COVID positive. For this nested cross-sectional study, all COVID positive and either one of the COVID negative participants recruited from the Aga Khan University, Pakistan were approached 9-12 months after delivery, and maternal and infant sera were collected for antibody detection., Results: Altogether, 83 mothers provided consent, of whom 32 (38.6 %) were COVID positive and 51 (61.4 %) were COVID negative during pregnancy. Anti-SARS-CoV-2 antibodies were present in 13 (41 %) infants born to COVID positive and 19 (39 %) infants born to COVID negative mothers (p = 0.87). The presence of reactive antibodies in infants at follow-up was associated with maternal antibodies at follow-up (OR:9.50, 95 % CI:2.03-44.42; p = 0.004). COVID infection occurred in 3 (6 %) infants born to COVID negative mothers while no infant born to a COVID positive mother had a history of infection (p = 0.27)., Conclusion: The presence of reactive anti-SARS-CoV-2 antibodies in infants at 9-12 months of age is associated with maternal seropositivity 9-12 months after delivery rather than maternal infection during pregnancy. Further studies are required to validate these findings and assess whether passive immunity in infants is protective against COVID-19 infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Introduction: After trivalent oral poliovirus vaccine (tOPV) cessation, Pakistan has maintained immunity to type 2 poliovirus by administering inactivated polio vaccine (IPV) in routine immunization, alongside monovalent OPV type 2 (mOPV2) and IPV in supplementary immunization activities (SIAs). This study assesses the change in poliovirus type 2 immunity after tOPV withdrawal and due to SIAs with mOPV2 and IPV among children aged 6-11 months., Methods: Three cross-sectional sequential serological surveys were conducted in 12 polio high-risk areas of Pakistan. 25 clusters from each geographical stratum were selected utilizing probability proportional to size., Results: Seroprevalence of type 2 poliovirus was 49%, with significant variation observed among surveyed areas; <30% in Pishin, >80% in Killa Abdullah, Mardan & Swabi, and Rawalpindi. SIAs with IPV improved immunity from 38 to 57% in Karachi and 60 to 88% in Khyber. SIAs with IPV following mOPV2 improved immunity from 62 to 65% in Killa Abdullah, and combined mOPV2 and IPV SIAs in Pishin improved immunity from 28 to 89%. Results also reflected that immunity rates for serotypes 1 and 3 were consistently above 90% during all three phases and across all geographical areas., Conclusion: The study findings highlight the importance of implementing effective vaccination strategies to prevent the re-emergence of poliovirus. Moreover, the results provide crucial information for policymakers working toward achieving global polio eradication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hussain, Umer, Khan, Sajid, Ahmed, Begum, Iqbal, Alam, Safdar, Baig, Voorman, Partridge and Soofi.)

Background: Maternal and newborn mortality in Pakistan remains as a major public health challenge. Pakistan faces significant infrastructure challenges and inadequate access to quality health care, exacerbated by sociocultural factors. Facility-based audit systems coupled with community engagement are key elements in achieving improved health system performance. We describe an implementation approach adapted from the World Health Organization audit cycle in real-world settings, with a plan to scale-up through mixed methods evaluation plan., Objective: This study aims to implement a locally acceptable and relevant audit system and evaluate its feasibility within the rural health system of Pakistan for scale-up., Methods: The implementation of the audit system comprises six phases: (1) identify facility and community leadership through consultative meetings with government district health offices, (2) establish the audit committee under the supervision of district health officer, (3) initiate audit with ongoing community engagement, (4) train the audit committee members, (5) launch the World Health Organization audit cycle (monthly meetings), and (6) quarterly review and refresher training. Data from all deliveries, live births, maternal deaths, maternal near misses, stillbirths, and neonatal deaths will be identified and recorded from four sources: (1) secondary-level care rural health facilities, (2) lady health workers' registers, (3) community representatives, and (4) project routine survey team. Concurrent quantitative and qualitative data will be drawn from case assessments, process analysis, and recommendations as components of iterative improvement cycles during the project. Outcomes will be the geographic distribution of mortality to measure the reach, proportion of facilities initiated to implement an audit system for measuring the adoption, proportion of audit committees with community representation, and proportion of audit committee members' sharing feedback regularly to measure acceptability and feasibility. In addition, outcomes of effectiveness will be measured based on data recording and reporting trends, identified modifiable factors for mortality and morbidity as underpinned by the Three Delays framework. Qualitative data will be analyzed based on perceived facilitators, barriers, and lessons learned for policy implications. Results will be summarized in frequencies and percentages and triangulated by the project team. Data will be analyzed using Stata (version 16; StataCorp) and NVivo (Lumivero) software., Results: The study will be implemented for 20 months, followed by an additional 4-month period for follow-up. Initial results will be presented to the district health office and the District Health Program Management Team Meeting in the districts., Conclusions: This study will generate evidence about the feasibility and potential scale-up of a facility-based mortality audit system with integrated community engagement in rural Pakistan. Audit committees will complete the feedback loop linking health care providers, community representatives, and district health officials (policy makers). This implementation approach will serve decision makers in improving maternal and perinatal health outcomes., International Registered Report Identifier (irrid): DERR1-10.2196/49578., (©Zahid Memon, Wardah Ahmed, Shah Muhammad, Sajid Soofi, Shanti Chohan, Arjumand Rizvi, Paul Barach, Zulfiqar A Bhutta. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 30.11.2023.)

Introduction: Anemia remains a global public health problem, especially in developing countries. It affects primarily children under five (CU5), women of reproductive age (WRA), and pregnant women due to their higher need for iron. The most common form of anemia is iron-deficiency anemia (IDA). IDA is estimated to cause half of all anemia cases and one million deaths per year worldwide. However, there remains a lack of well-documented and biochemically assessed prevalence of IDA based on the representative population-based samples globally and regionally. In this study, we aimed to assess the National Nutrition Survey (NNS) 2018 to identify the prevalence and risk factors of IDA in Pakistani CU5 and WRA., Methods: Secondary analysis was conducted on the NNS 2018, a cross-sectional survey, which collected data on dietary practices, malnutrition, and food insecurity. Anemia was defined as hemoglobin levels < 11.0 g/dL in children and 12.0 g/dL in women. IDA was defined as low hemoglobin and low ferritin (<12 ng/mL) levels, adjusted for inflammation using AGP and CRP biomarkers in CU5 and WRA. Univariate and multivariable logistic regressions were conducted using Stata statistical software (version 16). We also compared the IDA rates of NNS 2018 and 2011., Results: A total of 17,814 CU5 and 22,114 WRA were included in the analysis. Of the CU5, 28.9% had IDA, while 18.4% of WRA reported to experience IDA. Among the CU5, IDA was most prevalent among male children aged 6-23 months living in rural areas and with the presence of diarrhea and fevers in the last 2 weeks. Children whose mothers had no education, were aged 20-34 years, and employed, had a higher prevalence of IDA. Married WRA, who are employed, living in rural areas, and with no education, had a higher prevalence of IDA. In the multivariable logistic regression, children aged 6-23 months (AOR = 1.19, 95% CI [1.08-1.33], p < 0.001) and with the presence of diarrhea in the last 2 weeks (AOR = 1.32, 95% CI [1.13-1.54], p < 0.001) or fever (AOR = 1.16, 95% CI [1.02-1.32], p = 0.02) had higher odds of IDA. At the household level, the odds of IDA among CU5 were higher in the poorest households (AOR = 1.27, 95% CI [1.08-1.50], p = 0.005), with ≥5 CU5 (AOR = 1.99, 95% CI [1.28-3.11], p = 0.002), and with no access to improved sanitation facilities (AOR = 1.17, 95% CI [1.02-1.34], p = 0.026). For WRA, the multivariable logistic regression found that the odds of IDA were higher among women with vitamin A deficiency (Severe: AOR = 1.26, 95% CI [1.05-1.52], p = 0.013; Mild: AOR = 1.36, 95% CI [1.23-1.51], p < 0.001), zinc deficiency (AOR = 1.42, 95% CI [1.28-1.57], p < 0.001), no education (AOR = 1.53, 95% CI [1.30-1.81], p < 0.001), and from severely food insecure households (AOR = 1.20, 95% CI [1.07-1.34], p = 0.001). The odds of IDA were lower among women whose body mass index was overweight (AOR = 0.77, 95% CI [0.69-0.86], p < 0.001) or obese (AOR = 0.71, 95% CI [0.62-0.81], p < 0.001)., Conclusions: The child's age, presence of diarrhea or fever, place of residence, household size, wealth status, and access to sanitation facilities were significantly associated with IDA among CU5 in Pakistan. For WRA, education, body mass index, vitamin A and zinc status, household food security status, wealth status, and access to sanitation facilities were significantly associated with IDA. Large, well-established, government-funded programmes focused on micronutrient supplementation, food fortification, the diversification of food supplies, and the treatment and prevention of infectious and parasitic diseases are needed to prevent IDA and all forms of anemia among children and women in Pakistan., Competing Interests: No personal conflict of interest are declared.

Background: Adopted in 2015, the sustainable development goals (SDGs) have set specific targets (SDG 3.2) for countries to reduce their neonatal mortality rate (NMR) to below 12 deaths per 1000 live births and under 5 mortality rate (U5MR) to below 25 deaths per 1000 live births by 2030. For Pakistan to achieve these targets, there is a need to measure these rates and understand the predictors of child mortality at sub-national level. Launched in 2016, the Umeed-e-Nau (UeN) or New Hope project is based on scaling up proven and effective Maternal and Newborn Child Health (MNCH) interventions in 8 of the highest burden districts of the country, using existing public sector platforms in Pakistan at both the community and facility level. The primary aim of the project is to reduce perinatal mortality in these districts by 20% from baseline., Methods: We report overall neonatal and post neonatal mortality rates for the two years preceding the UeN baseline household survey. Rates were calculated using the synthetic cohort probability method and predictors of neonatal and post neonatal mortality examined using Cox regression. To investigate spatial variations in the mortality rates, we calculated Moran's I at the district level using predicted probabilities of mortality. Finally, we create district level maps of predicted under 5 child mortality using a stochastic partial differentiation approach., Findings: A total of 26,258 children contributed to the analysis of mortality with 838 deaths in the neonatal period and 2236 under-5 deaths during the observation period from March 1, 2015 to March 17, 2017. Overall, we estimated the NMR to be 29.2 per 1000 live births (95% CI: 26.9-31.4) and the U5MR to be 86.1 per 1000 live births (95% CI: 85.5-86.8). We found evidence of within-district geospatial clustering of under 5 mortality (P < 0.0001) and that social factors (poverty, illiteracy, multiparity), poor coverage of community health workers and distance from health facilities were strongly associated with child mortality., Interpretation: Important factors associated with neonatal and post-neonatal mortality in our study population included maternal education, parity, household size and gender. Additionally, antenatal care coverage (at least 4 visits) was specifically associated with neonatal mortality only, whereas, LHW coverage and distance to health facility were strongly associated with post-neonatal mortality. These findings emphasise the need for comprehensive, multisectoral strategies to be implemented for future maternal and child health programs and outreach services in rural areas., Funding: The study was funded by an unrestricted grant from the Bill & Melinda Gates Foundation to the Aga Khan University (Grant OPP 1148892)., Competing Interests: Primary funding from BMGF was received by the Aga Khan University and subcontract for analysis and support was extended to the Centre for Global Child Health in Toronto. None of the authors received individual funding. All the authors declare no relevant conflicts of interest., (© 2023 The Author(s).)

Background: Cervical cancer is a major cause of cancer-related deaths among women worldwide. Paucity of data on cervical cancer burden in countries like Pakistan hamper requisite resource allocation., Objective: To estimate the burden of cervical cancer in Pakistan using available data sources., Methods: We performed a systematic review to identify relevant data on Pakistan between 1995 to 2022. Study data identified through the systematic review that provided enough information to allow age specific incidence rates and age standardized incidence rates (ASIR) calculations for cervical cancer were merged. Population at risk estimates were derived and adjusted for important variables in the care-seeking pathway. The calculated ASIRs were applied to 2020 population estimates to estimate the number of cervical cancer cases in Pakistan., Results: A total of 13 studies reported ASIRs for cervical cancer for Pakistan. Among the studies selected, the Karachi Cancer Registry reported the highest disease burden estimates for all reported time periods: 1995-1997 ASIR = 6.81, 1998-2002 ASIR = 7.47, and 2017-2019 ASIR = 6.02 per 100,000 women. Using data from Karachi, Punjab and Pakistan Atomic Energy Cancer Registries from 2015-2019, we derived an unadjusted ASIR for cervical cancer of 4.16 per 100,000 women (95% UI 3.28, 5.28). Varying model assumptions produced adjusted ASIRs ranging from 5.2 to 8.4 per 100,000 women. We derived an adjusted ASIR of 7.60, (95% UI 5.98, 10.01) and estimated 6166 (95% UI 4833, 8305) new cases of cervical cancer per year., Conclusion: The estimated cervical cancer burden in Pakistan is higher than the WHO target. Estimates are sensitive to health seeking behavior, and appropriate physician diagnostic intervention, factors that are relevant to the case of cervical cancer, a stigmatized disease in a low-lower middle income country setting. These estimates make the case for approaching cervical cancer elimination through a multi-pronged strategy., (© 2023. The Author(s).)

The profile of the intestinal microbiota is known to be altered in malnourished young children in low- and middle-income countries. However, there are limited studies longitudinally evaluating the intestinal microbiota in malnourished young children in resource-limited settings over the first two years of life. In this longitudinal pilot study, we determined the effect of age, residential location, and intervention on the composition, relative abundance, and diversity of the intestinal microbiota in a representative sample of children under 24 months of age with no diarrhea in the preceding 72 h in the urban and rural areas of Sindh, Pakistan nested within a cluster-randomized trial evaluating the effect of zinc and micronutrients on growth and morbidity (ClinicalTrials.gov Identifier: NCT00705445). The major findings were age-related with significant changes in alpha and beta diversity with increasing age. There was a significant increase in the relative abundance of the Firmicutes and Bacteroidetes phyla and a significant decrease in that of the Actinobacteria and Proteobacteria phyla ( p < 0.0001). There were significant increases in the relative abundances of the major genera Bifidobacterium, Escherichia/Shigella and Streptococcus ( p < 0.0001), and no significant change in the relative abundance of Lactobacillus . Using the LEfSE algorithm, differentially abundant taxa were identified between children in the first and second years of age, between those residing in rural and urban areas, and those who received different interventions at different ages from 3 to 24 months. The numbers of malnourished (underweight, wasted, stunted) or well-nourished children at each age, in each intervention arm, and at urban or rural sites were too small to determine if there were significant differences in alpha or beta diversity or differentially abundant taxa among them. Further longitudinal studies with larger numbers of well-nourished and malnourished children are required to fully characterize the intestinal microbiota of children in this region.

Background: Gender discrimination is any unequal treatment of a person based on their sex. Women and girls are most likely to experience the negative impact of gender discrimination. The aim of this study is to assess the factors that influence gender discrimination in Pakistan, and its impact on women's life., Methods: A mixed method approach was used in the study in which a systematic review was done in phase one to explore the themes on gender discrimination, and qualitative interviews were conducted in phase two to explore the perception of people regarding gender discrimination. The qualitative interviews (in-depth interviews and focus group discussions) were conducted from married men and women, adolescent boys and girls, Healthcare Professionals (HCPs), Lady Health Visitors (LHVs) and Community Midwives (CMWs). The qualitative interviews were analyzed both manually and electronically through QSR NVivo 10. The triangulation of data from the systematic review and qualitative interviews were done to explore the gender discrimination related issues in Pakistan., Results: The six major themes have emerged from the systematic review and qualitative interviews. It includes (1) Status of a woman in the society (2) Gender inequality in health (3) Gender inequality in education (4) Gender inequality in employment (5) Gender biased social norms and cultural practices and (6) Micro and macro level recommendations. In addition, a woman is often viewed as a sexual object and dependent being who lacks self identity unless being married. Furthermore, women are restricted to household and child rearing responsibilities and are often neglected and forced to suppress self-expression. Likewise, men are viewed as dominant figures in lives of women who usually makes all family decisions. They are considered as financial providers and source of protection. Moreover, women face gender discrimination in many aspects of life including education and access to health care., Conclusion: Gender discrimination is deeply rooted in the Pakistani society. To prevent gender discrimination, the entire society, especially women should be educated and gendered sensitized to improve the status of women in Pakistan., (© 2022. The Author(s).)

Afghanistan continues to experience challenges affecting polio eradication. Mass polio vaccination campaigns, which aim to protect children under the age of 5, are a key eradication strategy. To date, the polio program in Afghanistan has only employed facility-based seroprevalence surveys, which can be subject to sampling bias. We describe the feasibility in implementing a cross-sectional household poliovirus seroprevalence survey based on geographical information systems (GIS) in three districts. Digital maps with randomly selected predetermined starting points were provided to teams, with a total target of 1,632 households. Teams were instructed to navigate to predetermined starting points and enrol the closest household within 60 m. To assess effectiveness of these methods, we calculated percentages for total households enrolled with valid geocoordinates collected within the designated boundary, and whether the Euclidean distance of households were within 60 m of a predetermined starting point. A normalized difference vegetation index (NDVI) image ratio was conducted to further investigate variability in team performances. The study enrolled a total of 78% of the target sample with 52% of all households within 60 m of a pre-selected point and 79% within the designated cluster boundary. Success varied considerably between the four target areas ranging from 42% enrolment of the target sample in one place to 90% enrolment of the target sample in another. Interviews with the field teams revealed that differences in security status and amount of non-residential land cover were key barriers to higher enrolment rates. Our findings indicate household poliovirus seroprevalence surveys using GIS-based sampling can be effectively implemented in polio endemic countries to capture representative samples. We also proposed ways to achieve higher success rates if these methods are to be used in the future, particularly in areas with concerns of insecurity or spatially dispersed residential units.

Objective: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship., Methods: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection., Results: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99)., Conclusion: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Systematic assessment of childhood asthma is challenging in low- and middle-income country (LMIC) settings due to the lack of standardised and validated methodologies. We describe the contextual challenges and adaptation strategies in the implementation of a community-based asthma assessment in four resource-constrained settings in Bangladesh, India, and Pakistan., Method: We followed a group of children of age 6-8 years for 12 months to record their respiratory health outcomes. The study participants were enrolled at four study sites of the 'Aetiology of Neonatal Infection in South Asia (ANISA)' study. We standardised the research methods for the sites, trained field staff for uniform data collection and provided a 'Child Card' to the caregiver to record the illness history of the participants. We visited the children on three different occasions to collect data on respiratory-related illnesses. The lung function of the children was assessed in the outreach clinics using portable spirometers before and after 6-minute exercise, and capillary blood was examined under light microscopes to determine eosinophil levels., Results: We enrolled 1512 children, 95.5% (1476/1512) of them completed the follow-up, and 81.5% (1232/1512) participants attended the lung function assessment tests. Pre- and post-exercise spirometry was performed successfully in 88.6% (1091/1232) and 85.7% (1056/1232) of children who attempted these tests. Limited access to health care services, shortage of skilled human resources, and cultural diversity were the main challenges in adopting uniform procedures across all sites. Designing the study implementation plan based on the local contexts and providing extensive training of the healthcare workers helped us to overcome these challenges., Conclusion: This study can be seen as a large-scale feasibility assessment of applying spirometry and exercise challenge tests in community settings of LMICs and provides confidence to build capacity to evaluate children's respiratory outcomes in future translational research studies., Competing Interests: Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Introduction: The oral polio vaccine (OPV) has substantial results in eliminating wild poliovirus and the vaccine of choice in polio eradication. However, the mucosal immunity induced by the OPV is still uncertain. Literature has shown that bovine lactoferrin (BLF) is a safe and useful protein found in cow's milk with extraordinary antimicrobial, antiviral, antiinflammatory and immune-modulatory functions that help children's gut to fight against micro-organisms like poliovirus. However, limited data exist regarding the effect of BLF on polio vaccine immune response. The primary objective is to evaluate the effect of BLF in enhancing mucosal and humoral immunity in children following the administration of oral and inactivated polio vaccines., Methods and Analysis: This is a two-arm double-blinded randomised controlled trial comparing 462 neonates (231 in both groups) receiving either BLF or placebo with breast milk. The intervention is administered from day 1 till 6 weeks of age to a full-term healthy singleton newborn born at the Aga Khan University Hospitals, Karachi, Pakistan. The primary outcome is the seroconversion, 1 month after the receipt of two doses of OPV (at 10 weeks). For descriptive statistical analysis, Stata will be used, the frequency with percentages will be reported to describe baseline characteristics of the participants. A χ 2 test will be used to compare categorical variables and a simple t test to compare continuous variables. The proportion of seroconversion and shedding will be compared using χ 2 test or Fisher's exact test., Ethics and Dissemination: The Ethics approval has been granted by the Ethics Review Committee (ERC) of Aga Khan University for the proposed trial (ID: 2019-1955-5013). Furthermore, the National Bioethics Committee (NBC) of Pakistan has also approved the study for human subject research (ID: 4-87/NBC-443/19/669). Study findings will be disseminated through presentations at scientific conferences and educational practice workshops and will be published in an international peer-reviewed scientific journal., Trial Registration Number: NCT04432935; ClinicalTrials.gov., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the cost-effectiveness of distribution of the integrated neonatal care kit (iNCK) by community health workers from the healthcare payer perspective in Rahimyar Khan, Pakistan., Setting: Rahimyar Khan, Pakistan., Participants: N/A., Intervention: Cost-utility analysis using a Markov model based on cluster randomised controlled trial (cRCT: NCT02130856) data and a literature review. We compared distribution of the iNCK to pregnant mothers to local standard of care and followed infants over a lifetime horizon., Primary and Secondary Outcome Measures: The primary outcome was incremental net monetary benefit (INMB, at a cost-effectiveness threshold of US$15.50), discounted at 3%. Secondary outcomes were life years, disability-adjusted life years (DALYs) and costs., Results: At a cost-effectiveness threshold of US$15.50, distribution of the iNCK resulted in lower expected DALYs (28.7 vs 29.6 years) at lower expected cost (US$52.50 vs 55.20), translating to an INMB of US$10.22 per iNCK distributed. These results were sensitive to the baseline risk of infection, cost of the iNCK and the estimated effect of the iNCK on the relative risk of infection. At relative risks of infection below 0.79 and iNCK costs below US$25.90, the iNCK remained cost-effective compared with current local standard of care., Conclusion: The distribution of the iNCK dominated the current local standard of care (ie, the iNCK is less costly and more effective than current care standards). Most of the cost-effectiveness of the iNCK was attributable to a reduction in neonatal infection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Puerperal sepsis (PP sepsis) is a leading cause of maternal mortality globally. The majority of maternal sepsis cases and deaths occur at home and remain undiagnosed and under-reported. In this paper, we present findings from a nested case-control study in Bangladesh and Pakistan which sought to assess the validity of community health worker (CHW) identification of PP sepsis using a clinical diagnostic algorithm with physician assessment and classification used as the gold standard., Methods: Up to 300 postpartum women were enrolled in each of the 3 sites 1) Sylhet, Bangladesh (n = 278), 2) Karachi, Pakistan (n = 278) and 3) Matiari, Pakistan (n = 300). Index cases were women with suspected PP Sepsis as diagnosed by CHWs clinical assessment of one or more of the following signs and symptoms: temperature (recorded fever ≥38.1°C, reported history of fever, lower abdominal or pelvic pain, and abnormal or foul-smelling discharge. Each case was matched with 3 control women who were diagnosed by CHWs to have no infection. Cases and controls were assessed by trained physicians using the same algorithm implemented by the CHWs. Using physician assessment as the gold standard, Kappa statistics for reliability and diagnostic validity (sensitivity and specificity) are presented with 95% CI. Sensitivity and specificity were adjusted for verification bias., Results: The adjusted sensitivity and specificity of CHW identification of PP sepsis across all sites was 82% (Karachi: 78%, Matiari: 78%, Sylhet: 95%) and 90% (Karachi: 95%, Matiari: 85%, Sylhet: 90%) respectively. CHW-Physician agreement was highest for moderate and high fever (range across sites: K = 0.84-0.97) and lowest for lower abdominal pain (K = 0.30-0.34). The clinical signs and symptoms for other conditions were reported infrequently, however, the CHW-physician agreement was high for all symptoms except severe headache/ blurred vision (K = 0.13-0.38) and reported "lower abdominal pain without fever" (K = 0.39-0.57)., Conclusion: In all sites, CHWs with limited training were able to identify signs and symptoms and to classify cases of PP sepsis with high validity. Integrating postpartum infection screening into existing community-based platforms and post-natal visits is a promising strategy to monitor women for PP sepsis - improving delivery of cohesive maternal and child health care in low resource settings., Competing Interests: Competing interests: The authors completed the ICMJE Declaration of Interest Form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2021 by the Journal of Global Health. All rights reserved.)

Supplementation with micronutrients, including vitamins, iron and zinc, is a key strategy to alleviate child malnutrition. However, association of gastrointestinal disorders with iron has led to ongoing debate over their administration. To better understand their impact on gut microbiota, we analyse the bacterial, protozoal, fungal and helminth communities of stool samples collected from a subset of 80 children at 12 and 24 months of age, previously enrolled into a large cluster randomized controlled trial of micronutrient supplementation in Pakistan (ClinicalTrials.gov identifier NCT00705445). We show that while bacterial diversity is reduced in supplemented children, vitamins and iron (as well as residence in a rural setting) may promote colonization with distinct protozoa and mucormycetes, whereas the addition of zinc appears to ameliorate this effect. We suggest that the risks and benefits of micronutrient interventions may depend on eukaryotic communities, potentially exacerbated by exposure to a rural setting. Larger studies are needed to evaluate the clinical significance of these findings and their impact on health outcomes., (© 2021. The Author(s).)

Background: Pneumonia is a leading cause of death among children under 5 specifically in South Asia and sub-Saharan Africa. Hypoxaemia is a life-threatening complication among children under 5 with pneumonia. Hypoxaemia increases risk of mortality by 4.3 times in children with pneumonia than those without hypoxaemia. Prevalence of hypoxaemia varies with geography, altitude and severity (9%-39% Asia, 3%-10% African countries). In this protocol paper, we describe research methods for assessing impact of Lady Health Workers (LHWs) identifying hypoxaemia in children with signs of pneumonia during household visits on acceptance of hospital referral in district Jamshoro, Sindh., Methods and Analysis: A cluster randomised controlled trial using pulse oximetry as intervention for children with severe pneumonia will be conducted in community settings. Children aged 0-59 months with signs of severe pneumonia will be recruited by LHWs during routine visits in both intervention and control arms after consent. Severe pneumonia will be defined as fast breathing and/or chest in-drawing, and, one or more danger sign and/or hypoxaemia (Sa02 <92%) in PO (intervention) group and fast breathing and/or chest in-drawing and one or more danger sign in clinical signs (control) group. Recruits in both groups will receive a stat dose of oral amoxicillin and referral to designated tertiary health facility. Analysis of variance will be used to compare baseline referral acceptance in both groups with that at end of study., Ethics and Dissemination: Ethical approval was granted by the Ethics Review Committee of the Aga Khan University (4722-Ped-ERC-17), Karachi. Study results will be shared with relevant government and non-governmental organisations, presented at national and international research conferences and published in international peer-reviewed scientific journals., Trial Registration Number: NCT03588377., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

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Background: Maternal morbidity occurs several times more frequently than mortality, yet data on morbidity burden and its effect on maternal, foetal, and newborn outcomes are limited in low- and middle-income countries. We aimed to generate prospective, reliable population-based data on the burden of major direct maternal morbidities in the antenatal, intrapartum, and postnatal periods and its association with maternal, foetal, and neonatal death in South Asia and sub-Saharan Africa., Methods and Findings: This is a prospective cohort study, conducted in 9 research sites in 8 countries of South Asia and sub-Saharan Africa. We conducted population-based surveillance of women of reproductive age (15 to 49 years) to identify pregnancies. Pregnant women who gave consent were include in the study and followed up to birth and 42 days postpartum from 2012 to 2015. We used standard operating procedures, data collection tools, and training to harmonise study implementation across sites. Three home visits during pregnancy and 2 home visits after birth were conducted to collect maternal morbidity information and maternal, foetal, and newborn outcomes. We measured blood pressure and proteinuria to define hypertensive disorders of pregnancy and woman's self-report to identify obstetric haemorrhage, pregnancy-related infection, and prolonged or obstructed labour. Enrolled women whose pregnancy lasted at least 28 weeks or those who died during pregnancy were included in the analysis. We used meta-analysis to combine site-specific estimates of burden, and regression analysis combining all data from all sites to examine associations between the maternal morbidities and adverse outcomes. Among approximately 735,000 women of reproductive age in the study population, and 133,238 pregnancies during the study period, only 1.6% refused consent. Of these, 114,927 pregnancies had morbidity data collected at least once in both antenatal and in postnatal period, and 114,050 of them were included in the analysis. Overall, 32.7% of included pregnancies had at least one major direct maternal morbidity; South Asia had almost double the burden compared to sub-Saharan Africa (43.9%, 95% CI 27.8% to 60.0% in South Asia; 23.7%, 95% CI 19.8% to 27.6% in sub-Saharan Africa). Antepartum haemorrhage was reported in 2.2% (95% CI 1.5% to 2.9%) pregnancies and severe postpartum in 1.7% (95% CI 1.2% to 2.2%) pregnancies. Preeclampsia or eclampsia was reported in 1.4% (95% CI 0.9% to 2.0%) pregnancies, and gestational hypertension alone was reported in 7.4% (95% CI 4.6% to 10.1%) pregnancies. Prolonged or obstructed labour was reported in about 11.1% (95% CI 5.4% to 16.8%) pregnancies. Clinical features of late third trimester antepartum infection were present in 9.1% (95% CI 5.6% to 12.6%) pregnancies and those of postpartum infection in 8.6% (95% CI 4.4% to 12.8%) pregnancies. There were 187 pregnancy-related deaths per 100,000 births, 27 stillbirths per 1,000 births, and 28 neonatal deaths per 1,000 live births with variation by country and region. Direct maternal morbidities were associated with each of these outcomes., Conclusions: Our findings imply that health programmes in sub-Saharan Africa and South Asia must intensify their efforts to identify and treat maternal morbidities, which affected about one-third of all pregnancies and to prevent associated maternal and neonatal deaths and stillbirths., Trial Registration: The study is not a clinical trial., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: ZAB is a member of the Editorial Board of PLOS Medicine. Remaining authors declared no competing interests.

Introduction: Birth spacing is a critical pathway to improving reproductive health. WHO recommends a minimum of 33-month interval between two consecutive births to reduce maternal, perinatal, infant morbidity and mortality. Our study evaluated factors associated with short birth intervals (SBIs) of less than 33 months between two consecutive births, in Karachi, Pakistan., Methods: We used data from a cross-sectional study among married women of reproductive age (MWRA) who had at least one live birth in the 6 years preceding the survey (N=2394). Information regarding their sociodemographic characteristics, reproductive history, fertility preferences, family planning history and a 6-year reproductive calendar were collected. To identify factors associated with SBIs, we fitted simple and multiple Cox proportional hazards models and computed HRs with their 95% CIs., Results: The median birth interval was 25 months (IQR: 14-39 months), with 22.9% (833) of births occurring within 33 months of the index birth. Women's increasing age (25-30 years (aHR 0.63 (0.53 to 0.75), 30+ years (aHR 0.29, 95% CI 0.22 to 0.39) compared with 20-24 years; secondary education (aHR 0.75, 95% CI 0.63 to 0.88), intermediate education (aHR 0.62, 95% CI 0.48 to 0.80), higher education (aHR 0.69, 95% CI 0.51 to 0.92) compared with no education, and a male child of the index birth (aHR 0.81, 95% CI 0.70 to 0.94) reduced the likelihood of SBIs. Women's younger age <20 years (aHR 1.24, 95% CI 1.05 to 1.24) compared with 20-24 years, and those who did not use contraception within 9 months of the index birth had a higher likelihood for SBIs for succeeding birth compared with those who used contraception (aHR 2.23, 95% CI 1.93 to 2.58)., Conclusion: Study shows that birth intervals in the study population are lower than the national average. To optimise birth intervals, programmes should target child spacing strategies and counsel MWRA on the benefits of optimal birth spacing, family planning services and contraceptive utilisation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In 2018, Pakistan had the world's highest neonatal mortality rate. Within Pakistan, most neonatal deaths occur in rural areas where access to health facilities is limited, and robust vital registration systems are lacking. To improve newborn survival, there is a need to better understand the causes of neonatal death in high burden settings and engage caregivers in the promotion of newborn health., Objective: To describe the causes of neonatal death in a rural area in Pakistan and to estimate the effect of an integrated neonatal care kit (iNCK) on cause-specific neonatal mortality., Methods: We analyzed data from a community-based, cluster-randomized controlled trial of 5286 neonates in Rahim Yar Khan (RYK), Punjab, Pakistan between April 2014 and August 2015. In intervention clusters, Lady Health Workers (LHW) delivered the iNCK and education on its use to pregnant women while control clusters received the local standard of care. The iNCK included interventions to prevent and identify signs of infection, identify low birthweight (LBW), and identify and manage hypothermia. Verbal autopsies were attempted for all deaths. The primary outcome was cause-specific neonatal mortality., Results: Verbal autopsies were conducted for 84 (57%) of the 147 reported neonatal deaths. The leading causes of death were infection (44%), intrapartum-related complications (26%) and prematurity/LBW (20%). There were no significant differences in neonatal mortality due to prematurity/LBW (RR 0.43; 95% CI 0.15-1.24), infection (RR 1.10; 95% CI 0.58-2.10) or intrapartum-related complications (RR 1.04; 95% CI 0.0.45-2.41) among neonates who died in the intervention arm compared to those who died in the control arm., Conclusion: The major causes of neonatal deaths in RYK, Pakistan mirror the global landscape of neonatal deaths. The iNCK did not significantly reduce any cause-specific neonatal mortality.

Context: Abortion is particularly difficult to measure, especially in legally restrictive settings such as Pakistan. The List Experiment-a technique for measuring sensitive health behaviors indirectly-may minimize respondents' underreporting of abortion due to stigma or legal restrictions, but has not been previously applied to estimate abortion prevalence in Pakistan., Methods: A sample of 4,159 married women of reproductive age were recruited from two communities of Karachi in 2018. Participants completed a survey that included a double list experiment to measure lifetime abortion prevalence, as well as direct questions about abortion and other background characteristics. Data were used to calculate direct and indirect estimates of abortion prevalence for the overall sample and by sociodemographic characteristics, as well as to test for a design effect. Regression analyses were conducted to examine associations between characteristics and abortion reporting from direct questioning and the list experiment., Results: The estimate of abortion prevalence from the list experiment was 16%; the estimate from the direct question was 8%. No evidence of a design effect was found. Abortion reporting was associated with most selected characteristics in the regression model for direct questioning, but with few in the list experiment models., Conclusions: That the estimate of abortion prevalence in Karachi generated from the list experiment was twice that generated from direct questioning suggests that the indirect method reduced underreporting, and may have utility to estimate abortion in similar settings and to improve the accuracy of data collecting for other sensitive health topics.

Objectives: To assess: (1) the impact of a reproductive health program on modern contraceptive use from baseline to program close; (2) the sustained impact from baseline to follow-up 36 months later; and (3) the exposure-adjusted impact at program close and follow-up., Design: Retrospective, cross-sectional matched control study., Setting: Karachi, Pakistan., Participants: 2561 married women aged 16-49 years., Interventions: The Willows Program, a community-based family planning counselling and referral program implemented from 2013 to 2015., Primary and Secondary Outcome Measures: The primary outcome was community-level modern contraceptive prevalence rate (mCPR), measured for January 2013 (baseline), June 2015 (program close) and at follow-up 36 months later. A secondary outcome was exposure-adjusted mCPR (among women reporting a family planning home visit) at program close and at follow-up., Results: There was no significant effect on community-level mCPR at program close (2.4 percentage point increase in intervention over comparison; 95% CI -2.2 to 7.0) or at follow-up (1.9 percentage point decrease; 95% CI -6.7 to 2.8). Only 18% of women in the intervention area reported receiving a family planning visit in the preceding 5 years. Among those reporting a visit, we observed a significant 10.3 percentage point increase (95% CI 4.6 to 15.9) from baseline to close, and a non-significant 2.0 percentage point increase (95% CI -3.8 to 7.8) from baseline to follow-up, relative to matched women in the comparison area. The cost per new modern method user was US$1089, while the cost per user-year during the intervention period was US$455., Conclusions: The program had a positive short-term effect on women who received a family planning visit; however, this effect was not sustained. Program coverage was low and did not significantly increase community-level family planning use. Findings highlight the need to increase community coverage of high-quality counselling and contextually relevant interventions for family planning demand generation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

(1) Background: Little is known on impacts of ready-to-use therapeutic food (RUTF) treatment on lipid metabolism in children with severe acute malnutrition (SAM). (2) Methods: We analyzed glycerophospholipid fatty acids (FA) and polar lipids in plasma of 41 Pakistani children with SAM before and after 3 months of RUTF treatment using gas chromatography and flow-injection analysis tandem mass spectrometry, respectively. Statistical analysis was performed using univariate, multivariate tests and evaluated for the impact of age, sex, breastfeeding status, hemoglobin, and anthropometry. (3) Results: Essential fatty acid (EFA) depletion at baseline was corrected by RUTF treatment which increased EFA. In addition, long-chain polyunsaturated fatty acids (LC-PUFA) and the ratio of arachidonic acid (AA)/linoleic acid increased reflecting greater EFA conversion to LC-PUFA, whereas Mead acid/AA decreased. Among phospholipids, lysophosphatidylcholines (lyso.PC) were most impacted by treatment; in particular, saturated lyso.PC decreased. Higher child age and breastfeeding were associated with great decrease in total saturated FA (ΣSFA) and lesser decrease in monounsaturated FA and total phosphatidylcholines (ΣPC). Conclusions: RUTF treatment improves EFA deficiency in SAM, appears to enhance EFA conversion to biologically active LC-PUFA, and reduces lipolysis reflected in decreased ΣSFA and saturated lyso.PC. Child age and breastfeeding modify treatment-induced changes in ΣSFA and ΣPC.

Introduction: Pakistan has a high burden of maternal, newborn and child morbidity and mortality. Several factors including weak scale-up of evidence-based interventions within the existing health system; lack of community awareness regarding health conditions; and poverty contribute to poor outcomes. Deaths and morbidity are largely preventable if a combination of community and facility-based interventions are rolled out at scale., Methods and Analysis: Umeed-e-Nau (UeN) (New Hope) project aims is to improve maternal, newborn and child health (MNCH) in eight high-burden districts of Pakistan by scaling up of evidence-based interventions. The project will assess interventions focused on, first, improving the quality of MNCH care at primary level and secondary level. Second, interventions targeting demand generation such as community mobilisation, creating awareness of healthy practices and expanding coverage of outreach services will be evaluated. Third, we will also evaluate interventions targeting the improvement in quality of routine health information and promotion of use of the data for decision-making. Hypothesis of the project is that roll out of evidence-based interventions at scale will lead to at least 20% reduction in perinatal mortality and 30% decrease in diarrhoea and pneumonia case fatality in the target districts whereas two intervention groups will serve as internal controls. Monitoring and evaluation of the programme will be undertaken through conducting periodical population level surveys and quality of care assessments. Descriptive and multivariate analytical methods will be used for assessing the association between different factors, and difference in difference estimates will be used to assess the impact of the intervention on outcomes., Ethics and Dissemination: The ethics approval was obtained from the Aga Khan University Ethics Review Committee. The findings of the project will be shared with relevant stakeholders and disseminated through open access peer-reviewed journal articles., Trial Registration Number: NCT04184544; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Adolescence is a time of significant physical and emotional change, and there is emerging concern that adolescents living in low- and middle-income countries (LMIC) may face substantial challenges in relation to linear growth and mental health. Data on the global burden of stunting after 5 years of age are limited, but estimates suggest up to 50 per cent of all adolescents in some LMIC are stunted. Additionally, many LMIC lack robust mental health care delivery systems. Pakistan has one of the world's largest populations of adolescents (10 to 19 years) at approximately 40 million. The Nash-wo-Numa study's primary objective is to assess the prevalence and risk factors for stunting among early adolescents in rural Pakistan. The study also aims to determine the prevalence of poor mental health and identify factors associated with common mental health concerns during the childhood to adulthood transition., Methods: This cross-sectional study will include girls (n= 738) 9.0 to 14.9 years of age and boys (n=687) 10.0 to 15.9 years of age who live in the rural district of Matiari, Pakistan. Participants will be assessed for anthropometrical measures, puberty development, nutritional biomarkers as well as symptoms of depression, anxiety and trauma using validated scales., Ethics and Dissemination: The proposed study aims to complete the picture of child and adolescent health concerning linear growth and mental health by including puberty indicators. Ethics approval has been granted by the Ethics Review Committee at the Aga Khan University, Karachi, Pakistan, #5251-WCH-ERC-18 and Research Ethics Board at SickKids Hospital, Toronto, Canada, #:1000060684. Study results will be presented at relevant conferences and published in peer-reviewed journals., Trial Registration Number: NCT03647553; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In 2016, 2.6 million children died during their first month of life. We assessed the effectiveness of an integrated neonatal care kit (iNCK) on neonatal survival and other health outcomes in rural Pakistan., Methods: We conducted a community-based, cluster randomised, pragmatic, open-label, controlled intervention trial in Rahim Yar Khan, Punjab, Pakistan. Clusters, 150 villages and their lady health workers (LHWs), were randomly assigned to deliver the iNCK (intervention) or standard of care (control). In intervention clusters, LHWs delivered the iNCK and education on its use to pregnant women. The iNCK contained a clean birth kit, chlorhexidine, sunflower oil, a continuous temperature monitor (ThermoSpot), a heat reflective blanket and reusable heat pack. LHWs were also given a hand-held scale. The iNCK was implemented primarily by caregivers. The primary outcome was all-cause neonatal mortality. Outcomes are reported at the individual level, adjusted for cluster allocation. Enrolment took place between April 2014 and July 2015 and participant follow-up concluded in August 2015., Results: 5451 pregnant women (2663 and 2788 in intervention and control arms, respectively) and their 5286 liveborn newborns (2585 and 2701 in intervention and control arms, respectively) were enrolled. 147 newborn deaths were reported, 65 in the intervention arm (25.4 per 1000 live births) compared with 82 in the control arm (30.6 per 1000 live births). Neonatal mortality was not significantly different between treatment groups (risk ratio 0.83, 95% CI 0.58 - 1.18; p = 0.30)., Conclusion: Providing co-packaged interventions directly to women did not significantly reduce neonatal mortality. Further research is needed to improve compliance with intended iNCK use., Competing Interests: Competing interests: None declared.

Background: Due to the limited evidence of the cost-effectiveness of Community Health Workers (CHW) delivering treatment for severe acute malnutrition (SAM), there is a need to better understand the costs incurred by both implementing institutions and beneficiary households. This study assessed the costs and cost-effectiveness of treatment for cases of SAM without complications delivered by government-employed Lady Health Workers (LHWs) and complemented with non-governmental organisation (NGO) delivered outpatient facility-based care compared with NGO delivered outpatient facility-based care only alongside a two-arm randomised controlled trial conducted in Sindh Province, Pakistan., Methods: An activity-based cost model was used, employing a societal perspective to include costs incurred by beneficiaries and the wider community. Costs were estimated through accounting records, interviews and informal group discussions. Cost-effectiveness was assessed for each arm relative to no intervention, and incrementally between the two interventions, providing information on both absolute and relative costs and effects., Results: The cost per child recovered in outpatient facility-based care was similar to LHW-delivered care, at 363 USD and 382 USD respectively. An additional 146 USD was spent per additional child recovered by outpatient facilities compared to LHWs. Results of sensitivity analyses indicated considerable uncertainty in which strategy was most cost-effective due to small differences in cost and recovery rates between arms. The cost to the beneficiary household of outpatient facility-based care was double that of LHW-delivered care., Conclusions: Outpatient facility-based care was found to be slightly more cost-effective compared to LHW-delivered care, despite the potential for cost-effectiveness of CHWs managing SAM being demonstrated in other settings. The similarity of cost-effectiveness outcomes between the two models resulted in uncertainty as to which strategy was the most cost-effective. Similarity of costs and effectiveness between models suggests that whether it is appropriate to engage LHWs in substituting or complementing outpatient facilities may depend on population needs, including coverage and accessibility of existing services, rather than be purely a consideration of cost. Future research should assess the cost-effectiveness of LHW-delivered care when delivered solely by the government., Trial Registration: NCT03043352 , ClinicalTrials.gov. Retrospectively registered.

Objective: To estimate the cost-effectiveness of price subsidies on fortified packaged complementary foods (FPCF) in reducing iodine deficiency, iron-deficiency anaemia and vitamin A deficiency in Pakistani children., Design: The study proceeded in three steps: (i) we determined the current lifetime costs of the three micronutrient deficiencies with a health economic model; (ii) we assessed the price sensitivity of demand for FPCF with a market survey in two Pakistani districts; (iii) we combined the findings of the first two steps with the results of a systematic review on the effectiveness of FPCF in reducing micronutrient deficiencies. The cost-effectiveness was estimated by comparing the net social cost of price subsidies with the disability-adjusted life years (DALY) averted., Setting: Districts of Faisalabad and Hyderabad in Pakistan., Subjects: Households with 6-23-month-old children stratified by socio-economic strata., Results: The lifetime social costs of iodine deficiency, iron-deficiency anaemia and vitamin A deficiency in 6-23-month-old children amounted to production losses of $US 209 million and 175 000 DALY. Poor households incurred the highest costs, yet even wealthier households suffered substantial losses. Wealthier households were more likely to buy FPCF. The net cost per DALY of the interventions ranged from a return per DALY averted of $US 783 to $US 65. Interventions targeted at poorer households were most cost-effective., Conclusions: Price subsidies on FPCF might be a cost-effective way to reduce the societal costs of micronutrient deficiencies in 6-23-month-old children in Pakistan. Interventions targeting poorer households are especially cost-effective.