Derivation and Internal Validation of a Novel Risk Assessment Tool to Identify Infants and Young Children at Risk for Post-Discharge Mortality in Dar es Salaam, Tanzania and Monrovia, Liberia.

OBJECTIVE: To derive and validate internally a novel risk assessment tool to identify young children at risk for all-cause mortality ≤60 days of discharge from hospitals in sub-Saharan Africa. STUDY DESIGN: We performed a prospective observational cohort study of children aged 1-59 months discharged from Muhimbili National Hospital in Dar es Salaam, Tanzania and John F. Kennedy Medical Center in Monrovia, Liberia (2019 to 2022). Caregivers received telephone calls up to 60 days after discharge to ascertain participant vital status. We collected socioeconomic, demographic, clinical, and anthropometric data during hospitalization. Candidate variables with P<0.20 in bivariate analyses were included in a multivariable logistic regression model with best subset selection to identify risk factors for the outcome. We internally validated our tool using bootstrapping with 500 repetitions. RESULTS: There were 1,933 young children enrolled in the study. The median (interquartile range) age was 11 (4, 23) months and 58.7% were male. In total, 67 (3.5%) died during follow-up. Ten variables contributed to our tool (total possible score 82). Cancer (adjusted odds ratio [aOR] 10.6, 95% CI 2.58, 34.6), pedal edema (aOR 6.94, 95% CI 1.69, 22.6), and leaving against medical advice (aOR 6.46, 95% CI 2.46, 15.3) were most predictive of post-discharge mortality. Our risk assessment tool demonstrated good discriminatory value (optimism corrected area under the receiver operating characteristic curve 0.77), high precision, and sufficient calibration. CONCLUSIONS: After validation, this tool may be used to identify young children at risk for post-discharge mortality to direct resources for follow-up of high-risk children.

Systematic review and meta-analysis of the diagnostic value of four biomarkers in detecting neonatal sepsis in low- and middle-income countries.

BACKGROUND: Biomarkers may enhance diagnostic capability for common paediatric infections, especially in low- and middle-income countries (LMICs) where standard diagnostic modalities are frequently unavailable, but disease burden is high. A comprehensive understanding of the diagnostic capability of commonly available biomarkers for neonatal sepsis in LMICs is lacking. Our objective was to systematically review evidence on biomarkers to understand their diagnostic performance for neonatal sepsis in LMICs. METHODS: We conducted a systematic review and meta-analysis of studies published in English, Spanish, French, German, Dutch, and Arabic reporting the diagnostic performance of C reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell count (WBC) and procalcitonin (PCT) for neonatal sepsis. We calculated pooled test characteristics and the area under the curve (AUC) for each biomarker compared with the reference standards blood culture or clinical sepsis defined by each article. RESULTS: Of 6570 studies related to biomarkers in children, 134 met inclusion criteria and included 23 179 neonates. There were 80 (59.7%) studies conducted in LMICs. CRP of ≥60 mg/L (AUC 0.87, 95% CI 0.76 to 0.91) among 1339 neonates and PCT of ≥0.5 ng/mL (AUC 0.87, 95% CI 0.70 to 0.92) among 617 neonates demonstrated the greatest discriminatory value for the diagnosis of neonatal sepsis using blood culture as the reference standard in LMICs. CONCLUSIONS: PCT and CRP had good discriminatory value for neonatal sepsis in LMICs. ESR and WBC demonstrated poor discrimination for neonatal sepsis in LMICs. Future studies may incorporate biomarkers into clinical evaluation in LMICs to diagnose neonatal sepsis more accurately. PROSPERO REGISTRATION NUMBER: CRD42020188680.

Cash transfers and nutrition education to improve dietary diversity among children aged 6-23 months in Grand Gedeh County, Liberia: a cluster-randomized trial.

OBJECTIVES: To evaluate the efficacy of a cash transfer and nutrition education program on dietary diversity among children in Liberia. We hypothesized that a multi-pronged intervention would result in improved dietary diversity among children. METHODS: We conducted a three-armed, cluster-randomized study in 42 communities (12 children per community) in Grand Gedeh County, Liberia, over a 12-month period. We randomly assigned communities to control (n = 14 communities), those that received both bimonthly cash transfers and a structured nutrition education program (n = 14 communities) and those that received bimonthly cash transfers alone (n = 14 communities). Community health assistants conducted bimonthly assessments in participants' homes. The primary outcome was the proportion of children aged 6-23 months who met minimum dietary diversity score (i.e., ≥4 food groups consumed per day). Secondary outcomes included meal frequency and healthcare utilization for illnesses (NCT04101487). RESULTS: There were 599 children enrolled; 533 (88.9%) were retained through the trial period. The proportion of children who consumed ≥4 food groups per day did not differ among the three arms. However, children randomized to receive cash transfers had higher dietary diversity scores than the control group. Children in communities that received cash transfers alone and with nutrition education consumed significantly more meals per day and were less likely to have visits to clinics or hospitals for illnesses than children in control communities. CONCLUSION: Bimonthly, unconditional cash transfers and nutrition education were associated with higher dietary diversity scores, greater meal frequency, and fewer healthcare visits for illnesses among children aged 6-23 months.

Worldwide, more than one in five children suffers from chronic malnutrition. Children aged <2 years who do not eat a diverse diet are at risk of chronic malnutrition and stunting of their height. Thus, interventions are needed to combat the common problem of chronic malnutrition, particularly in settings like rural Liberia where as much as 30% of children are stunted. In this study, caregivers of children aged 6­23 months in rural communities in Eastern Liberia were randomly assigned to receive either bimonthly cash transfers, bimonthly cash transfers and specific nutrition education, or routine support from community health assistants to see if giving caregivers money and nutrition education would increase the dietary diversity of their young children. There were 599 children enrolled and 533 were retained over a 12-month study period. Children in communities randomized to receive cash transfers had higher dietary diversity scores than the control group. Children in communities that received cash transfers alone and with nutrition education consumed significantly more meals per day and were less likely to have visits to clinics or hospitals for illnesses than children in control communities. Unconditional cash transfers in rural Liberia may be one way to reduce inadequate dietary diversity among young children.

Prioritizing Health Care Strategies to Reduce Childhood Mortality.

Importance: Although child mortality trends have decreased worldwide, deaths among children younger than 5 years of age remain high and disproportionately circumscribed to sub-Saharan Africa and Southern Asia. Tailored and innovative approaches are needed to increase access, coverage, and quality of child health care services to reduce mortality, but an understanding of health system deficiencies that may have the greatest impact on mortality among children younger than 5 years is lacking. Objective: To investigate which health care and public health improvements could have prevented the most stillbirths and deaths in children younger than 5 years using data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network. Design, Setting, and Participants: This cross-sectional study used longitudinal, population-based, and mortality surveillance data collected by CHAMPS to understand preventable causes of death. Overall, 3390 eligible deaths across all 7 CHAMPS sites (Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) between December 9, 2016, and December 31, 2021 (1190 stillbirths, 1340 neonatal deaths, 860 infant and child deaths), were included. Deaths were investigated using minimally invasive tissue sampling (MITS), a postmortem approach using biopsy needles for sampling key organs and fluids. Main Outcomes and Measures: For each death, an expert multidisciplinary panel reviewed case data to determine the plausible pathway and causes of death. If the death was deemed preventable, the panel identified which of 10 predetermined health system gaps could have prevented the death. The health system improvements that could have prevented the most deaths were evaluated for each age group: stillbirths, neonatal deaths (aged <28 days), and infant and child deaths (aged 1 month to <5 years). Results: Of 3390 deaths, 1505 (44.4%) were female and 1880 (55.5%) were male; sex was not recorded for 5 deaths. Of all deaths, 3045 (89.8%) occurred in a healthcare facility and 344 (11.9%) in the community. Overall, 2607 (76.9%) were deemed potentially preventable: 883 of 1190 stillbirths (74.2%), 1010 of 1340 neonatal deaths (75.4%), and 714 of 860 infant and child deaths (83.0%). Recommended measures to prevent deaths were improvements in antenatal and obstetric care (recommended for 588 of 1190 stillbirths [49.4%], 496 of 1340 neonatal deaths [37.0%]), clinical management and quality of care (stillbirths, 280 [23.5%]; neonates, 498 [37.2%]; infants and children, 393 of 860 [45.7%]), health-seeking behavior (infants and children, 237 [27.6%]), and health education (infants and children, 262 [30.5%]). Conclusions and Relevance: In this cross-sectional study, interventions prioritizing antenatal, intrapartum, and postnatal care could have prevented the most deaths among children younger than 5 years because 75% of deaths among children younger than 5 were stillbirths and neonatal deaths. Measures to reduce mortality in this population should prioritize improving existing systems, such as better access to antenatal care, implementation of standardized clinical protocols, and public education campaigns.

Association of International Editorial Staff With Published Articles From Low- and Middle-Income Countries.

Importance: The association between geographic diversity of medical journal editorial staff and publications reporting research conducted in low- and middle-income countries (LMICs) is unclear. Objective: To examine the association between having editorial staff members affiliated with LMICs and publishing research articles from LMICs in leading biomedical journals. Design, Setting, and Participants: This cross-sectional study included biomedical journals in fields representing the largest disease burden globally from January 1 to December 31, 2020. Websites of the 5 leading journals in general medicine, pediatrics, surgery, obstetrics and gynecology, cancer, cardiovascular diseases, infectious diseases, psychiatry, and nutrition were reviewed to obtain the country affiliations of editorial staff members. To determine article study countries, original research articles in each journal were reviewed through MEDLINE. Editorial staff country affiliations and study country locations were classified according to World Bank income brackets and regions. Exposure: Editorial staff country affiliation. Main Outcomes and Measures: Descriptive statistics of the proportion of editorial staff affiliated with each income bracket and region and Spearman rank correlation coefficients were used to assess the association between the proportion of editorial staff affiliated with LMICs and the proportion of published articles reporting work conducted in these countries. Results: There were 3819 editorial staff members in the 45 included journals: 3637 (95.2%) were affiliated with high-income countries, 140 (3.7%) with upper-middle-income countries, 37 (1.0%) with lower-middle-income countries, and 5 (0.1%) with low-income countries. All 48 editors-in-chief were affiliated with a high-income country. Editorial staff members were mostly affiliated with North American countries (n = 2120 [55.5%]) and European or Central Asian countries (n = 1256 [32.9%]). Of the 10 096 original research articles included in our analysis, 7857 (77.8%) reported research conducted in high-income countries, 1562 (15.5%) reported research conducted in upper-middle-income countries, 507 (5.0%) reported research conducted in lower-middle-income countries, and 170 (1.7%) reported research conducted in low-income countries. Greater editorial staff representation correlated moderately with more published articles reporting research conducted in LMICs (Spearman ρ = 0.51; 95% CI, 0.25-0.70; P < .001). Conclusions and Relevance: In this cross-sectional study, editorial staff in leading biomedical journals were largely composed of individuals affiliated with high-income countries in North America and Europe. A correlation was found between greater editorial staff representation and publication of research focused on LMICs, suggesting that the inclusion of editorial staff affiliated with LMICs may promote the publication of research conducted in those countries.

Association between Antiretroviral Therapy and Cancers among Children Living with HIV in Sub-Saharan Africa.

Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0-18 years from 2004-2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART.

Factors influencing drainage setting and cost for cutaneous abscesses among pediatric patients.

OBJECTIVE: To evaluate the clinical and microbiological factors associated with skin and soft tissue infections drained in the emergency department (ED) vs operative drainage (OD) in a tertiary care children's hospital. METHODS: This was a cross-sectional study among children aged 2 months to 17 years who required incision and drainage (I&D). Demographic information, signs and symptoms, abscess size and location, and wound culture/susceptibility were recorded. Patient-specific charges were collected from the billing database. Multivariate regression analysis was used to determine factors determining setting for I&D and the effect of abscess drainage location on cost. RESULTS: Of 335 abscesses, 241 (71.9%) were drained in the ED. OD for abscesses was favored in children with prior history of abscess (odds ratio [OR], 3.18; 95% confidence interval [CI], 1.36-7.44; P = .01) and labial location (OR, 37.81; 95% CI, 8.12-176.03; P < .001). For every 1-cm increase in size, there was approximately a 26% increase in the odds of having OD (OR, 1.26; 95% CI, 1.11-1.44, P < .001). Methicillin-resistant Staphylococcus aureus was identified in 72% of the 300 abscesses cultured and 12.3% were clindamycin resistant. OD was more expensive than I&D in the ED. Per abscess that underwent I&D, OD is $3804.29 more expensive than I&D in the ED while controlling for length of stay. DISCUSSION: Clinical factors associated with OD rather than I&D in the ED included history of abscess, increased abscess length, and labial location. Microbiological factors did not differ based on I&D setting. For smaller, nonlabial abscesses, ED drainage may result in significant cost savings.

Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review.

Children with human immunodeficiency virus (HIV) have an increased risk of developing Kaposi Sarcoma (KS) and non-Hodgkin lymphoma (NHL) compared to HIV-negative children. We compiled currently published epidemiologic data on KS and NHL among children in sub-Saharan Africa (SSA). Among countries with available data, the median incidence of KS was 2.05/100,000 in the general pediatric population and 67.35/100,000 among HIV-infected children. The median incidence of NHL was 1.98/100,000 among the general pediatric population, while data on NHL incidence among HIV-infected children were lacking. Larger regional studies are needed to better address the dearth of epidemiologic information on pediatric KS and NHL in SSA.

A Case of an 11-year-old With Cough, Diarrhea, and Findings of Concern in His Lungs and Spleen.

This is the case of a previously healthy, 11-year-old male of Indian descent who presented to the emergency department with a 2-month history of nausea, vomiting, diarrhea, fatigue, cough, and 7-lb weight loss. Acutely, he developed 5 days of fever as high as 39.4°C. He had a remote travel history to the Middle East. On physical examination, he was febrile and tachycardic, was thin but otherwise had a normal examination. His inflammatory markers were elevated: erythrocyte sedimentation rate was 93 mm/hour and his C-reactive protein was 25.4 mg/L. A complete blood count revealed a white blood cell count of 17,000 × 10(3)/µL with increased bands. His hemoglobin level was 8.8 g/dL with a mean corpuscular volume of 81 fl. Platelets were 556 × 10(3)/µL. A chest radiograph was concerning for a cavitary lung lesion and an abdominal ultrasound revealed multiple hypoechoic lesions in his spleen. Our panel of experts reviews his case and examines the workup of this patient with diverse symptoms and focal findings on chest radiograph and abdominal ultrasound.

Lost opportunities to identify and treat HIV-positive patients: results from a baseline assessment of provider-initiated HIV testing and counselling (PITC) in Malawi.

OBJECTIVE: To assess implementation of provider-initiated testing and counselling (PITC) for HIV in Malawi. METHODS: A review of PITC practices within 118 departments in 12 Ministry of Health (MoH) facilities across Malawi was conducted. Information on PITC practices was collected via a health facility survey. Data describing patient visits and HIV tests were abstracted from routinely collected programme data. RESULTS: Reported PITC practices were highly variable. Most providers practiced symptom-based PITC. Antenatal clinics and maternity wards reported widespread use of routine opt-out PITC. In 2014, there was approximately 1 HIV test for every 15 clinic visits. HIV status was ascertained in 94.3% (5293/5615) of patients at tuberculosis clinics, 92.6% (30,675/33,142) of patients at antenatal clinics and 49.4% (6871/13,914) of patients at sexually transmitted infection clinics. Reported challenges to delivering PITC included test kit shortages (71/71 providers), insufficient physical space (58/71) and inadequate number of HIV counsellors (32/71) while providers from inpatient units cited the inability to test on weekends. CONCLUSIONS: Various models of PITC currently exist at MoH facilities in Malawi. Only antenatal and maternity clinics demonstrated high rates of routine opt-out PITC. The low ratio of facility visits to HIV tests suggests missed opportunities for HIV testing. However, the high proportion of patients at TB and antenatal clinics with known HIV status suggests that routine PITC is feasible. These results underscore the need to develop clear, standardised PITC policy and protocols, and to address obstacles of limited health commodities, infrastructure and human resources.

Peru's national folic acid fortification program and its effect on neural tube defects in Lima / Programa nacional del Perú de fortificación con ácido fólico y su efecto sobre los defectos del tubo neural en Lima

OBJECTIVE: To evaluate the impact of Peru's national folic acid fortification program on folic acid content in wheat flour, and the effect on birth prevalence of neural tube defects (NTDs) in Lima, and to compare the program's legislative requirements with international standards. METHODS: Bread was sampled from six sites across Peru and tested for folic acid. Data were obtained from the largest obstetric hospital in Lima on the prevalence of births (live and still) with NTDs during both the pre-fortification period (2004-2005) and post-fortification years (2007-2008). RESULTS: Folic acid content in the sampled bread met national legislative requirements but was less than one-half of the level recommended for Peru by the World Health Organization (WHO) (2.6 mg/kg wheat flour). Birth prevalence of NTDs was 18.4/10 000 in the pre-fortification period and 20.0/10 000 during post-fortification years. Relative risk for NTDs after fortification was 1.02 (95% confidence interval 0.77-1.35, P = 0.90). CONCLUSIONS: Peruvian legislative requirements for folic acid fortification are below international (WHO) recommendations; birth prevalence of NTDs in Lima is higher than international benchmarks; and no decrease in NTDs following fortification of flour with folic acid (according to Peruvian national standards) was observed. As increasing the level of folic acid in flour remains the most sustainable way of preventing NTDs, it is recommended that Peru increase its folic acid fortification requirements to meet those recommended by WHO (2.6 mg/kg).

OBJETIVO: Evaluar la repercusión que el programa nacional del Perú de fortificación con ácido fólico tiene en el contenido de ácido fólico de la harina de trigo y en la prevalencia de nacimientos de niños con defectos del tubo neural en Lima, así como comparar los requisitos legislativos del programa con las normas internacionales. MÉTODOS: Se hizo un muestreo del pan en seis zonas de Perú y se analizó su contenido de ácido fólico. Se obtuvieron datos del mayor hospital obstétrico de Lima referentes a la prevalencia de nacimientos de niños vivos o mortinatos con defectos del tubo neural durante el período anterior a la fortificación (2004-2005) y el posterior a la misma (2007-2008). RESULTADOS: El contenido de ácido fólico en las muestras de pan obtenidas satisfizo los requisitos legislativos nacionales, si bien fue inferior a la mitad de la concentración que la Organización Mundial de la Salud (OMS) recomienda para el Perú (2,6 mg/kg de harina de trigo). La prevalencia de nacimientos de niños con defectos del tubo neural fue de 18,4/10 000 en el período anterior a la fortificación y de 20,0/10 000 en los años posteriores a la fortificación. El riesgo relativo de los defectos del tubo neural después de la fortificación fue de 1,02 (intervalo de confianza de 95%: 0,77-1,35; P = 0,90). CONCLUSIONES: Los valores que la legislación peruana exige en lo que respecta a la fortificación con ácido fólico son inferiores a los que se recomiendan internacionalmente (OMS). La prevalencia de nacimientos de niños con defectos del tubo neural en Lima es superior a las cifras de referencia internacionales. Por otra parte, no se observó ninguna disminución de los defectos del tubo neural después de fortificar la harina con ácido fólico (según los valores normalizados nacionales peruanos). Dado que el aumento de la concentración de ácido fólico en la harina sigue siendo la manera más sostenible de prevenir los defectos del tubo neural, se recomienda que el Perú haga más estrictos los requisitos relativos a la fortificación con ácido fólico para ajustarse a los valores recomendados por la OMS (2,6 mg/kg).

Peru's national folic acid fortification program and its effect on neural tube defects in Lima.

OBJECTIVE: To evaluate the impact of Peru's national folic acid fortification program on folic acid content in wheat flour, and the effect on birth prevalence of neural tube defects (NTDs) in Lima, and to compare the program's legislative requirements with international standards. METHODS: Bread was sampled from six sites across Peru and tested for folic acid. Data were obtained from the largest obstetric hospital in Lima on the prevalence of births (live and still) with NTDs during both the pre-fortification period (2004-2005) and post-fortification years (2007-2008). RESULTS: Folic acid content in the sampled bread met national legislative requirements but was less than one-half of the level recommended for Peru by the World Health Organization (WHO) (2.6 mg/kg wheat flour). Birth prevalence of NTDs was 18.4/10 000 in the pre-fortification period and 20.0/10 000 during post-fortification years. Relative risk for NTDs after fortification was 1.02 (95% confidence interval 0.77-1.35, P = 0.90). CONCLUSIONS: Peruvian legislative requirements for folic acid fortification are below international (WHO) recommendations; birth prevalence of NTDs in Lima is higher than international benchmarks; and no decrease in NTDs following fortification of flour with folic acid (according to Peruvian national standards) was observed. As increasing the level of folic acid in flour remains the most sustainable way of preventing NTDs, it is recommended that Peru increase its folic acid fortification requirements to meet those recommended by WHO (2.6 mg/kg).

An assay to quantitate reducible cysteines from nanograms of GST-fusion proteins.

Cysteine residues in proteins are targets of numerous post-translational modifications and play important roles in protein structure and enzymatic function. Consequently, understanding the full biochemistry of proteins depends on determining the oxidation state and availability of the residues to be modified. We have developed a highly sensitive assay that accurately determines the number of unmodified cysteine residues in GST-fusion proteins. Only picomoles of protein are required for each reaction, which are carried out in 96-well glutathione-coated plates. Free unmodified cysteine residues are labeled and quantified using biotin and HRP-conjugated streptavidin. Our assay can be used to quantify reactions targeting sulfhydryl groups in proteins. We demonstrate this assay using full-length and truncation mutants of the SNARE proteins syntaxin1A, SNAP-25B, and synaptobrevin2, which have 0-4 cysteines. We are able to accurately determine the number of cysteine residues in each protein and follow the modification of these cysteines by oxidation and reaction with NEM (N-ethylmaleimide). This assay is as simple as running an ELISA or Western blot and, because of its high resolution, should allow detailed analysis of the chemistry of cysteine residues in proteins.