The Tools for Integrated Management of Childhood Illness (TIMCI) study protocol: a multi-country mixed-method evaluation of pulse oximetry and clinical decision support algorithms.

Effective and sustainable strategies are needed to address the burden of preventable deaths among children under-five in resource-constrained settings. The Tools for Integrated Management of Childhood Illness (TIMCI) project aims to support healthcare providers to identify and manage severe illness, whilst promoting resource stewardship, by introducing pulse oximetry and clinical decision support algorithms (CDSAs) to primary care facilities in India, Kenya, Senegal and Tanzania. Health impact is assessed through: a pragmatic parallel group, superiority cluster randomised controlled trial (RCT), with primary care facilities randomly allocated (1:1) in India to pulse oximetry or control, and (1:1:1) in Tanzania to pulse oximetry plus CDSA, pulse oximetry, or control; and through a quasi-experimental pre-post study in Kenya and Senegal. Devices are implemented with guidance and training, mentorship, and community engagement. Sociodemographic and clinical data are collected from caregivers and records of enrolled sick children aged 0-59 months at study facilities, with phone follow-up on Day 7 (and Day 28 in the RCT). The primary outcomes assessed for the RCT are severe complications (mortality and secondary hospitalisations) by Day 7 and primary hospitalisations (within 24 hours and with referral); and, for the pre-post study, referrals and antibiotic. Secondary outcomes on other aspects of health status, hypoxaemia, referral, follow-up and antimicrobial prescription are also evaluated. In all countries, embedded mixed-method studies further evaluate the effects of the intervention on care and care processes, implementation, cost and cost-effectiveness. Pilot and baseline studies started mid-2021, RCT and post-intervention mid-2022, with anticipated completion mid-2023 and first results late-2023. Study approval has been granted by all relevant institutional review boards, national and WHO ethical review committees. Findings will be shared with communities, healthcare providers, Ministries of Health and other local, national and international stakeholders to facilitate evidence-based decision-making on scale-up.Study registration: NCT04910750 and NCT05065320.

Pulse oximetry and clinical decision support algorithms show potential for supporting healthcare providers to identify and manage severe illness among children under-five attending primary care in resource-constrained settings, whilst promoting resource stewardship but scale-up has been hampered by evidence gaps.This study design article describes the largest scale evaluation of these interventions to date, the results of which will inform country- and global-level policy and planning .

A digital health algorithm to guide antibiotic prescription in pediatric outpatient care: a cluster randomized controlled trial.

Excessive antibiotic use and antimicrobial resistance are major global public health threats. We developed ePOCT+, a digital clinical decision support algorithm in combination with C-reactive protein test, hemoglobin test, pulse oximeter and mentorship, to guide health-care providers in managing acutely sick children under 15 years old. To evaluate the impact of ePOCT+ compared to usual care, we conducted a cluster randomized controlled trial in Tanzanian primary care facilities. Over 11 months, 23,593 consultations were included from 20 ePOCT+ health facilities and 20,713 from 20 usual care facilities. The use of ePOCT+ in intervention facilities resulted in a reduction in the coprimary outcome of antibiotic prescription compared to usual care (23.2% versus 70.1%, adjusted difference -46.4%, 95% confidence interval (CI) -57.6 to -35.2). The coprimary outcome of day 7 clinical failure was noninferior in ePOCT+ facilities compared to usual care facilities (adjusted relative risk 0.97, 95% CI 0.85 to 1.10). There was no difference in the secondary safety outcomes of death and nonreferred secondary hospitalizations by day 7. Using ePOCT+ could help address the urgent problem of antimicrobial resistance by safely reducing antibiotic prescribing. Clinicaltrials.gov Identifier: NCT05144763.

ePOCT+ and the medAL-suite: Development of an electronic clinical decision support algorithm and digital platform for pediatric outpatients in low- and middle-income countries.

Electronic clinical decision support algorithms (CDSAs) have been developed to address high childhood mortality and inappropriate antibiotic prescription by helping clinicians adhere to guidelines. Previously identified challenges of CDSAs include their limited scope, usability, and outdated clinical content. To address these challenges we developed ePOCT+, a CDSA for the care of pediatric outpatients in low- and middle-income settings, and the medical algorithm suite (medAL-suite), a software for the creation and execution of CDSAs. Following the principles of digital development, we aim to describe the process and lessons learnt from the development of ePOCT+ and the medAL-suite. In particular, this work outlines the systematic integrative development process in the design and implementation of these tools required to meet the needs of clinicians to improve uptake and quality of care. We considered the feasibility, acceptability and reliability of clinical signs and symptoms, as well as the diagnostic and prognostic performance of predictors. To assure clinical validity, and appropriateness for the country of implementation the algorithm underwent numerous reviews by clinical experts and health authorities from the implementing countries. The digitalization process involved the creation of medAL-creator, a digital platform which allows clinicians without IT programming skills to easily create the algorithms, and medAL-reader the mobile health (mHealth) application used by clinicians during the consultation. Extensive feasibility tests were done with feedback from end-users of multiple countries to improve the clinical algorithm and medAL-reader software. We hope that the development framework used for developing ePOCT+ will help support the development of other CDSAs, and that the open-source medAL-suite will enable others to easily and independently implement them. Further clinical validation studies are underway in Tanzania, Rwanda, Kenya, Senegal, and India.

Cumulative Antibiotic Exposure in the First 5 Years of Life: Estimates for 45 Low- and Middle-Income Countries From Demographic and Health Survey Data.

BACKGROUND: Estimates of the total cumulative exposure to antibiotics of children in low-resource settings, and the source of these treatments, are limited. METHODS: We estimated the average number of antibiotic treatments children received in the first 5 years of life in 45 low- and middle-income countries (LMICs) using Demographic and Health Survey data. The 2-week point prevalence of fever, diarrhea, or cough and antibiotic treatment for these illnesses were estimated for ages 0-59 months and aggregated to estimate cumulative illness and antibiotic treatment for each country. We estimated treatment rates and contribution to total antibiotic use attributable to medical care, informal care, and self-medication. RESULTS: Forty-five countries contributed 438 140 child-observations. The proportion of illness episodes treated with antibiotics ranged from 10% (95% confidence interval [CI], 9%-12%]) in Niger to 72% (95% CI, 69%-75%) in Jordan. A mean of 42.7% (95% CI, 42.1%-43.3%) of febrile and 32.9% of nonfebrile (95% CI, 32.4%-33.5%) illness episodes received antibiotics. In their first 5 years, we estimate children received 18.5 antibiotic treatments on average (interquartile range [IQR], 11.6-24.6) in LMICs. Cumulative antibiotic exposure ranged from 3.7 treatments in Niger (95% CI, 2.8%-4.6%) to 38.6 treatments in the Democratic Republic of Congo (95% CI, 34.7%-42.4%). A median of 9.0% of antibiotic treatments was attributable to informal care (IQR, 5.9%-21.2%), and 16.9% to self-medication (IQR, 9.5%-26.2%). CONCLUSIONS: Childhood antibiotic exposure is high in some LMICs, with considerable variability. While access to antibiotics for children is still not universal, important opportunities for reducing excess use also exist, particularly with respect to the informal care sector and self-medication.

Mobile nudges and financial incentives to improve coverage of timely neonatal vaccination in rural areas (GEVaP trial): A 3-armed cluster randomized controlled trial in Northern Ghana.

BACKGROUND: Despite progress in vaccination coverage, timeliness of childhood vaccination remains a challenge in many settings. We aimed to assess if mobile phone-based reminders and incentives to health workers and caregivers could increase timely neonatal vaccination in a rural, low-resource setting. METHODS: We conducted an open-label cluster randomized controlled 1:1:1 trial with three arms in 15 communities in Northern Ghana. Communities were randomized to 1) a voice call reminder intervention; 2) a community health volunteer (CHV) intervention with incentivized rewards; 3) control. In the voice call reminder arm, a study staff member made voice calls to mothers shortly after birth to encourage vaccination and provide personalized information about available vaccination services. In the incentive arm, CHVs promoted infant vaccination and informed women with recent births about available vaccination opportunities. Both CHVs and women were provided small monetary incentives for on-time early infant vaccination in this arm, delivered using mobile phone-based banking applications. No study activities were conducted in control communities. A population-based survey compared vaccination coverage across arms in the pre-intervention and intervention periods. The primary endpoint was completion of at least one dose of Polio vaccine within 14 days of life and BCG vaccination within 28 days of life. RESULTS: Six-hundred ninety births were identified; 106, 88, and 88 from pre-intervention and 150, 135, and 123 in the intervention period, in the control, voice call reminder and CHV incentive arms, respectively. In adjusted intent-to-treat analysis, voice call reminders were associated with 10.5 percentage point (95% CI: 4.0, 17.1) higher coverage of on-time vaccination, while mobile phone-based incentives were associated with 49.5 percentage point (95% CI: 26.4, 72.5) higher coverage. CONCLUSION: Community-based interventions using mobile phone technologies can improve timely early vaccination coverage. A CHV approach with incentives to community workers and caregivers was a more effective strategy than voice call reminders. The impact of vaccination "nudges" via voice calls may be constrained in settings where network coverage and phone ownership are limited. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov; NCT03797950.

Breastfeeding, Physical Growth, and Cognitive Development.

BACKGROUND AND OBJECTIVES: Breastfeeding is an evidence-based recommendation for all countries, but breastfeeding rates have been declining in many middle-income settings. One reason behind this decline is the perception that breastfeeding may not be necessary in modern urban settings, where clean water is available and alternative foods are abundant. We investigate the importance of breastfeeding for early childhood development in the modern urban context of São Paulo, Brazil. METHODS: In our study, we used data from the ongoing prospective Western Region Birth cohort in São Paulo, Brazil. Children were recruited at birth and managed for 3 years. Durations of exclusive and mixed breastfeeding were our primary independent variables. Our secondary independent variable was an indicator for compliance with World Health Organization (WHO) breastfeeding recommendations. Our primary outcomes of interest were indicators of children's physical, cognitive, language, and social-emotional development at 3 years of age. Adjusted estimates and 95% confidence intervals were calculated by using linear and logistic regression. RESULTS: Complying with WHO recommendations to exclusively breastfeed for 6 months followed by complementary feeding until 2 years of age was associated with a 0.4-SD increase in overall child development (ß: .38; confidence limit = 0.23 to 0.53), a 0.6-SD increase in height-for-age z score (ß: .55; confidence limit = 0.31 to 0.79), and a 67% decrease in the odds of stunting (odds ratio = 0.33; 95% confidence interval = 0.20 to 0.54). CONCLUSIONS: Our results suggest that even in settings with easy access to complementary foods, complying with WHO breastfeeding recommendations is important for healthy physical growth and cognitive development.

Clinical Outcome of Febrile Tanzanian Children with Severe Malnutrition Using Anthropometry in Comparison to Clinical Signs.

Children with malnutrition compared with those without are at higher risk of infection, with more severe outcomes. How clinicians assess nutritional risk factors in febrile children in primary care varies. We conducted a post hoc subgroup analysis of febrile children with severe malnutrition enrolled in a randomized, controlled trial in primary care centers in Tanzania. The clinical outcome of children with severe malnutrition defined by anthropometric measures and clinical signs was compared between two electronic clinical diagnostic algorithms: ePOCT, which uses weight-for-age and mid-upper arm circumference to identify and manage severe malnutrition, and ALMANACH, which uses the clinical signs of edema of both feet and visible severe wasting. Those identified as having severe malnutrition by the algorithms in each arm were prescribed antibiotics and referred to the hospital. From December 2014 to February 2016, 106 febrile children were enrolled and randomized in the parent study, and met the criteria to be included in the present analysis. ePOCT identified 56/57 children with severe malnutrition using anthropometric measures, whereas ALMANACH identified 2/49 children with severe malnutrition using clinical signs. The proportion of clinical failure, defined as the development of severe symptoms by day 7 or persisting symptoms at day 7 (per-protocol), was 1.8% (1/56) in the ePOCT arm versus 16.7% (8/48) in the Algorithm for the MANagement of Childhood illnesses arm (risk difference -14.9%, 95% CI -26.0%, -3.8%; risk ratio 0.11, 95% CI 0.01, 0.83). Using anthropometric measures to identify and manage febrile children with severe malnutrition may have resulted in better clinical outcomes than by using clinical signs alone.

Defining Pediatric Diarrhea in Low-Resource Settings.

Differences in definitions of acute pediatric diarrhea result in variable estimates of morbidity and mortality, treatment coverage, and associations with risk factors and outcomes. We reviewed published literature and guidelines focused on acute pediatric diarrhea in low- and middle-income countries. Clinical guidelines most commonly defined diarrhea in terms of quantity of loose or watery stool with consideration of normal stool patterns, whereas research studies often relied exclusively on a quantitative definition. The most commonly used quantitative definition, ≥3 loose or watery stools in a 24-hour period, has been compared to gold standards of caregiver perception and visual inspection of stool, with variable agreement. Age, breast-feeding status, and setting (facility vs household-based) influence the performance of quantitative diarrhea definitions in children. Universal adoption of a set of valid gold standard definitions specifically aligned with various programmatic and research goals will lead to more accurate coverage estimates and better-informed resource prioritization.

People living with HIV travel farther to access healthcare: a population-based geographic analysis from rural Uganda.

INTRODUCTION: The availability of specialized HIV services is limited in rural areas of sub-Saharan Africa where the need is the greatest. Where HIV services are available, people living with HIV (PLHIV) must overcome large geographic, economic and social barriers to access healthcare. The objective of this study was to understand the unique barriers PLHIV face when accessing healthcare compared with those not living with HIV in a rural area of sub-Saharan Africa with limited availability of healthcare infrastructure. METHODS: We conducted a population-based cross-sectional study of 447 heads of household on Bugala Island, Uganda. Multiple linear regression models were used to compare travel time, cost and distance to access healthcare, and log binomial models were used to test for associations between HIV status and access to nearby health services. RESULTS: PLHIV travelled an additional 1.9 km (95% CI (0.6, 3.2 km), p=0.004) to access healthcare compared with those not living with HIV, and they were 56% less likely to access healthcare at the nearest health facility to their residence, so long as that facility lacked antiretroviral therapy (ART) services (aRR=0.44, 95% CI (0.24 to 0.83), p=0.011). We found no evidence that PLHIV travelled further for care if the nearest facility supplies ART services (aRR=0.95, 95% CI (0.86 to 1.05), p=0.328). Among those who reported uptake of care at one of two facilities on the island that provides ART (81% of PLHIV and 68% of HIV-negative individuals), PLHIV tended to seek care at a higher tiered facility that provides ART, even when this facility was not their closest facility (30% of PLHIV travelled further than the closest ART facility compared with 16% of HIV-negative individuals), and travelled an additional 2.2 km (p=0.001) to access that facility, relative to HIV-negative individuals (aRR=1.91, 95% CI (1.00 to 3.65), p=0.05). Among PLHIV, residential distance was associated with access to facilities providing ART (RR=0.78, 95% CI (0.61 to 0.99), p=0.044, comparing residential distances of 3-5 km to 0-2 km; RR=0.71, 95% CI (0.58 to 0.87), p=0.001, comparing residential distances of 6-10 km to 0-2 km). CONCLUSIONS: PLHIV travel longer distances for care, a phenomenon that may be driven by both the limited availability of specialized HIV services and preference for higher tiered facilities.

Prioritizing countries for interventions to reduce child mortality: tools for maximizing the impact of mass drug administration of azithromycin.

BACKGROUND: As new interventions to reduce childhood mortality are identified, careful consideration must be given to identifying populations that could benefit most from them. Promising reductions in childhood mortality reported in a large cluster randomized trial of mass drug administration (MDA) of azithromycin (AZM) prompted the development of visually compelling, easy-to-use tools that synthesize country-specific data on factors that would influence both potential AZM benefit and MDA implementation success. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the opportunity to reduce mortality and the feasibility of implementing such a program, creating Opportunity and Feasibility Indices, respectively. Countries with high childhood mortality were included. A Country Ranking Index combined key variables from the previous two Indices and applied a scoring system to identify high-priority countries. We compared four scenarios with varying weights given to each variable. Twenty-five countries met inclusion criteria. We created easily visualized tools to display the results of the Opportunity and Feasibility Indices. The Opportunity Index revealed substantial variation in the opportunity for an MDA of AZM program to reduce mortality, even among countries with high overall childhood mortality. The Feasibility Index demonstrated that implementing such a program would be most challenging in the countries that could see greatest benefit. Based on the Country Ranking Index, Equatorial Guinea would benefit the most from the MZA of AZM in three of the four scenarios we tested. CONCLUSIONS/SIGNIFICANCE: These visually accessible tools can be adapted or refined to include other metrics deemed important by stakeholders, and provide a quantitative approach to prioritization for intervention implementation. The need to explicitly state metrics and their weighting encourages thoughtful and transparent decision making. The objective and data-driven approach promoted by the three Indices may foster more efficient use of resources.

Health-related quality of life and social support among women treated for abortion complications in western Uganda.

BACKGROUND: While the impact of abortion complications on clinical outcomes and healthcare costs has been reported, we found no reports of their impact on Health-Related Quality of Life (HRQoL), nor the role of social support in moderating such outcomes. In this study, we performed an assessment of the relationship between abortion complications, HRQoL and social support among women in Uganda. METHODS: We interviewed women who were discharged after treatment for abortion complications and, as a comparison, women visiting a regional referral hospital for routine obstetric care. We administered the EuroQol instrument and the Social Support Questionnaire Short-Form, and collected demographic and socioeconomic data. We performed descriptive analyses using t-tests, Wilcoxon rank-sum tests and chi-square tests, and multivariable linear regressions with interaction effects to examine the associations between abortion complications, EQ-5D utility scores and social support. RESULTS: Our study included 139 women (70 with abortion complications, and 69 receiving routine obstetric care). In four out of the 5 dimensions of the EQ-5D, a larger proportion of women with abortion complications reported "some or severe" problems than women receiving routine obstetric care (self-care: 42% v 24%, p=0.033; usual activities: 49% v 16%, p<0.001; pain/discomfort: 68% v 25%, p<0.001; and anxiety/depression: 60% v 22%, p<0.001). After adjusting for age, social support, wealth tertile, employment status, marital status, and HIV status, women with abortion complications had a 0.12 (95% CI: 0.07, 0.18, p < 0.001) lower mean EQ-5D utility score than those receiving routine obstetric care. An analysis of the modifying effect of social support showed that a one-unit higher average number of people providing social support was associated with larger mean difference in EQ-5D utility score when comparing the two groups, while a one unit higher average satisfaction score with social support was associated with smaller mean differences in EQ-5D utility score. CONCLUSIONS: Our study suggests that abortion complications are associated with diminished HRQoL and the magnitude of the association depends on social support. However, the mediating role of social support in a setting of social and legal proscriptions to induced abortion is complex.