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Background: Although mortality risk associated with HIV is well described, HIV-exposed uninfected (HEU) young children are also at increased risk of hospitalization and death as compared to HIV-unexposed uninfected (HUU) children. The drivers of poor outcomes among HEU children remain unknown, limiting the development of interventions to support this vulnerable population. Methods: We performed a secondary analysis of data from a large multi-country prospective cohort [Childhood Acute Illness and Nutrition (CHAIN) Network] study. Data from 5 sites in Uganda, Kenya, and Malawi were included. Hospitalized children aged 2–23 months were followed from an index admission for 6 months after discharge to determine acute and long-term outcomes. Using perinatal HIV exposure (HEU and HUU) as the primary exposure and adjusting for child, caregiver, and household characteristics, we compared inpatient and 30-day survival outcomes, nutritional status, hospital length of stay, illness severity, and utilization of inpatient resources. Results: We included 1486 children: 217 HEU and 1269 HUU. HEU children had an increased risk of mortality both during hospitalization [adjusted OR 1.96, 95% CI (1.14–3.37)] and in the 30 days following hospital admission [adjusted hazard ratio 2.20, 95% CI (1.10–4.42)]. Wasting and stunting were more frequent in HEU than HUU children, with adjusted OR 1.41, 95% CI (1.03–1.95) and adjusted OR 1.91, 95% CI (1.34–2.70), respectively. HEU children were also more likely to have a prolonged hospital stay compared to HUU children [adjusted OR 1.58, 95% CI (1.08–2.29)], although admission diagnoses, illness severity at admission, and use of inpatient resources (supplemental oxygen, nasogastric tube, and second-line antibiotics) did not differ significantly between groups. Conclusions: HEU children are more likely to die during hospitalization and within 30 days of admission, to be wasted and stunted upon hospital admission, and to require a prolonged hospital stay, as compared to HUU children. Hospitals in settings with a high prevalence of women-living-with-HIV should ensure that maternal HIV status is established among children requiring admission and build capacity to provide additional hospital monitoring and early post-discharge support for HEU children. [ABSTRACT FROM AUTHOR]

SUMMARY: The metabolism of tetrahydrofolate (H4PteGlun)‐bound one‐carbon (C1) units (C1 metabolism) is multifaceted and required for plant growth, but it is unclear what of many possible synthesis pathways provide C1 units in specific organelles and tissues. One possible source of C1 units is via formate‐tetrahydrofolate ligase, which catalyzes the reversible ATP‐driven production of 10‐formyltetrahydrofolate (10‐formyl‐H4PteGlun) from formate and tetrahydrofolate (H4PteGlun). Here, we report biochemical and functional characterization of the enzyme from Arabidopsis thaliana (AtFTHFL). We show that the recombinant AtFTHFL has lower Km and kcat values with pentaglutamyl tetrahydrofolate (H4PteGlu5) as compared to monoglutamyl tetrahydrofolate (H4PteGlu1), resulting in virtually identical catalytic efficiencies for the two substrates. Stable transformation of Arabidopsis plants with the EGFP‐tagged AtFTHFL, followed with fluorescence microscopy, demonstrated cytosolic signal. Two independent T‐DNA insertion lines with impaired AtFTHFL function had shorter roots compared to the wild type plants, demonstrating the importance of this enzyme for root growth. Overexpressing AtFTHFL led to the accumulation of H4PteGlun + 5,10‐methylene‐H4PteGlun and serine, accompanied with the depletion of formate and glycolate, in roots of the transgenic Arabidopsis plants. This metabolic adjustment supports the hypothesis that AtFTHFL feeds the cytosolic C1 network in roots with C1 units originating from glycolate, and that these units are then used mainly for biosynthesis of serine, and not as much for the biosynthesis of 5‐methyl‐H4PteGlun, methionine, and S‐adenosylmethionine. This finding has implications for any future attempts to engineer one‐carbon unit‐requiring products through manipulation of the one‐carbon metabolic network in non‐photosynthetic organs. Significance Statement: This study describes the cloning and biochemical characterization of a recombinant formate‐tetrahydrofolate ligase from plants and establishes the role of this enzyme in providing formate as an important source of one‐carbon units in roots. [ABSTRACT FROM AUTHOR]

One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and mortality in participants with advanced HIV randomised to cotrimoxazole or enhanced antimicrobial prophylaxis in the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374). Biomarkers were assayed using ELISA and Luminex. Associations between baseline values and all-cause 24-week mortality were analysed using Cox models, and for cause-specific mortality used Fine & Gray models, including prophylaxis randomisation, viral load, CD4, WHO stage, age, BMI, and site as covariates; and weighted according to inverse probability of selection into the substudy. Higher baseline CRP, IFN-γ, IL-6 and IP-10 were associated with higher all-cause mortality; and higher IL-23, IL-2 and RANTES with lower all-cause mortality. Associations varied by cause of death: tuberculosis-associated mortality was most strongly associated with higher CRP and sST2, and cryptococcosis-associated mortality with higher IL-4 and lower IL-8. Changes in I-FABP (p = 0.002), faecal alpha-1 antitrypsin (p = 0.01) and faecal myeloperoxidase (p = 0.005) between baseline and 4 weeks post-ART were greater in those receiving enhanced versus cotrimoxazole prophylaxis. Our findings highlight how the immune milieu shapes outcomes following ART initiation, and how adjunctive antimicrobials can modulate the gut environment in advanced HIV. In this study, by analysing immune biomarkers in a cohort of people with advanced HIV, the authors show that elevated levels of some biomarkers at baseline were associated with either increased (CRP, IFN-ƴ, IL-6 and IP-10) or decreased (IL-23, IL-2 and RANTES) likelihood of all-cause mortality. [ABSTRACT FROM AUTHOR]

The 'double burden of malnutrition' is a global health challenge that increasingly affects populations in both low‐ and middle‐income countries (LMICs). This phenomenon refers to the coexistence of undernutrition and overweight or obesity, as well as other diet‐related non‐communicable diseases, in the same population, household or even individual. While noteworthy progress has been made in reducing undernutrition in some parts of the world, in many of these areas, the prevalence of overweight and obesity is increasing, particularly in urban areas, resulting in greater numbers of people who were undernourished in childhood and have overweight or obesity in adulthood. This creates a complex and challenging situation for research experts and policymakers who must simultaneously address the public health burdens of undernutrition and overweight/obesity. This review identifies key challenges and limitations in the current research on the double burden of malnutrition in individuals, including the need for a more comprehensive and nuanced understanding of the drivers of malnutrition, the importance of context‐specific interventions and the need for greater attention to the food environment and food systems. We advocate for the re‐evaluation of research strategies and focus, with a greater emphasis on multidisciplinary and systems approaches and greater attention to the synergistic relationship between the biological, environmental, commercial and socio‐economic determinants of malnutrition. Addressing these key challenges can enable us to better comprehend and tackle the multifaceted and dynamic issues of the double burden of malnutrition, particularly in individuals and work towards more effective and sustainable solutions. [ABSTRACT FROM AUTHOR]

Background Blood culture collection practice in low-resource settings where routine blood culture collection is available has not been previously described. Methodology We conducted a secondary descriptive analysis of children aged 2–23 months enrolled in the Malawi Childhood Acute Illness and Nutrition (CHAIN) study, stratified by whether an admission blood culture had been undertaken and by nutritional status. Chi-square test was used to compare the differences between groups. Results A total of 347 children were included, of whom 161 (46%) had a blood culture collected. Children who had a blood culture collected, compared to those who did not, were more likely to present with sepsis (43% vs. 20%, p  < 0.001), gastroenteritis (43% vs. 26%, p  < 0.001), fever (86% vs. 73%, p  = 0.004), and with poor feeding/weight loss (30% vs. 18%, p  = 0.008). In addition, hospital stay in those who had a blood culture was, on average, 2 days longer (p  = 0.019). No difference in mortality was observed between those who did and did not have a blood culture obtained. Conclusion Blood culture collection was more frequent in children with sepsis and gastroenteritis, but was not associated with mortality. In low-resource settings, developing criteria for blood culture based on risk factors rather than clinician judgement may better utilize the existing resources. [ABSTRACT FROM AUTHOR]

Neutrophils are the most abundant innate immune cells. Multiple mechanisms allow them to engage a wide range of metabolic pathways for biosynthesis and bioenergetics for mediating biological processes such as development in the bone marrow and antimicrobial activity such as ROS production and NET formation, inflammation and tissue repair. We first discuss recent work on neutrophil development and functions and the metabolic processes to regulate granulopoiesis, neutrophil migration and trafficking as well as effector functions. We then discuss metabolic syndromes with impaired neutrophil functions that are influenced by genetic and environmental factors of nutrient availability and usage. Here, we particularly focus on the role of specific macronutrients, such as glucose, fatty acids, and protein, as well as micronutrients such as vitamin B3, in regulating neutrophil biology and how this regulation impacts host health. A special section of this review primarily discusses that the ways nutrient deficiencies could impact neutrophil biology and increase infection susceptibility. We emphasize biochemical approaches to explore neutrophil metabolism in relation to development and functions. Lastly, we discuss opportunities and challenges to neutrophil-centered therapeutic approaches in immune-driven diseases and highlight unanswered questions to guide future discoveries. [ABSTRACT FROM AUTHOR]

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes. [ABSTRACT FROM AUTHOR]

Background: Growth studies rely on longitudinal measurements, typically represented as trajectories. However, anthropometry is prone to errors that can generate outliers. While various methods are available for detecting outlier measurements, a gold standard has yet to be identified, and there is no established method for outlying trajectories. Thus, outlier types and their effects on growth pattern detection still need to be investigated. This work aimed to assess the performance of six methods at detecting different types of outliers, propose two novel methods for outlier trajectory detection and evaluate how outliers affect growth pattern detection. Methods: We included 393 healthy infants from The Applied Research Group for Kids (TARGet Kids!) cohort and 1651 children with severe malnutrition from the co-trimoxazole prophylaxis clinical trial. We injected outliers of three types and six intensities and applied four outlier detection methods for measurements (model-based and World Health Organization cut-offs-based) and two for trajectories. We also assessed growth pattern detection before and after outlier injection using time series clustering and latent class mixed models. Error type, intensity, and population affected method performance. Results: Model-based outlier detection methods performed best for measurements with precision between 5.72-99.89%, especially for low and moderate error intensities. The clustering-based outlier trajectory method had high precision of 14.93-99.12%. Combining methods improved the detection rate to 21.82% in outlier measurements. Finally, when comparing growth groups with and without outliers, the outliers were shown to alter group membership by 57.9 -79.04%. Conclusions: World Health Organization cut-off-based techniques were shown to perform well in few very particular cases (extreme errors of high intensity), while model-based techniques performed well, especially for moderate errors of low intensity. Clustering-based outlier trajectory detection performed exceptionally well across all types and intensities of errors, indicating a potential strategic change in how outliers in growth data are viewed. Finally, the importance of detecting outliers was shown, given its impact on children growth studies, as demonstrated by comparing results of growth group detection. [ABSTRACT FROM AUTHOR]

Introduction: Ready-to-use therapeutic foods (RUTFs) have successfully promoted recovery from severe wasting and increased treatment coverage. However, RUTFs do not sufficiently improve linear growth, leaving many survivors of severe wasting at risk of persistent stunting, which is associated with high mortality risk, poor child development and non-communicable diseases in adulthood. High protein quantity and quality can stimulate linear growth. Aim: The trial aims to assess whether higher-protein-RUTF leads to higher concentrations of markers of linear growth compared to standard RUTF among 6–23 months old children with severe wasting. Methods: We designed a higher protein quantity and quality RUTF for a proof-of-concept (PoC) double-blind randomized controlled trial. Outcomes: The primary outcome is a change in insulin-like growth factor-1 (IGF-1), a hormone positively associated with linear growth after four weeks of treatment. Secondary outcomes include changes in ponderal and linear growth and in body composition from baseline to eight weeks later; plasma amino acid profile at four weeks; acceptability and safety. Implications: These findings will help in informing the potential impact of increased protein in RUTF on linear growth when treating severe wasting towards conducting a larger clinical trial. Trial registration: The trial has been registered on clinicaltrial.gov (NCT05737472). [ABSTRACT FROM AUTHOR]

Introduction: Estimates suggest that one-third of snakebite cases in sub-Saharan Africa affect children. Despite children being at a greater risk of disability and death, there are limited published data. This study has determined the: population-incidence and mortality rate of hospital-attended paediatric snakebite; clinical syndromes of snakebite envenoming; and predictors of severe local tissue damage. Methods: All children presenting to Kilifi County Hospital, Kenya with snakebite were identified through the Kilifi Health and Demographic Surveillance System (KHDSS). Cases were prospectively registered, admitted for at least 24-hours, and managed on a paediatric high dependency unit (HDU). Households within the KHDSS study area have been included in 4-monthly surveillance and verbal autopsy, enabling calculation of population-incidence and mortality. Predictors of severe local tissue damage were identified using a multivariate logistic regression analysis. Results: Between 2003 and 2021, there were 19,606 admissions to the paediatric HDU, of which 584 were due to snakebite. Amongst young children (≤5-years age) the population-incidence of hospital-attended snakebite was 11.3/100,000 person-years; for children aged 6–12 years this was 29.1/100,000 person-years. Incidence remained consistent over the study period despite the population size increasing (98,967 person-years in 2006; and 153,453 person-years in 2021). Most cases had local envenoming alone, but there were five snakebite associated deaths. Low haemoglobin; raised white blood cell count; low serum sodium; high systolic blood pressure; and an upper limb bite-site were independently associated with the development of severe local tissue damage. Conclusion: There is a substantial burden of disease due to paediatric snakebite, and the annual number of cases has increased in-line with population growth. The mortality rate was low, which may reflect the species causing snakebite in this region. The identification of independent predictors of severe local tissue damage can help to inform future research to better understand the pathophysiology of this important complication. Author summary: The nature of disease caused by snakebite amongst children in rural Africa is poorly understood. All children presenting to Kilifi County Hospital, Kenya with snakebite between 2003 and 2021 were recruited into a study that was nested in an ongoing hospital and community surveillance study. 584 children presented following snakebite and the incidence was 29.1/100,000 person-years amongst children aged 6–12 years. The incidence remained consistent over the course of the study despite the population increasing by over 50%, highlighting that the burden of disease is increasing in-line with population growth. Many children initially sought traditional therapies, which was associated with delayed presentation to hospital. The mortality rate was low, and most children had local, rather than systemic, envenoming. Predictors of severe local envenoming at the time of admission included a high white blood cell count, low haemoglobin, and an upper limb bite site. The findings of this study highlight the need to strengthen strategies to prevent snakebite in children, to overcome barriers to attending hospital, and to develop therapeutics that better treat local envenoming. [ABSTRACT FROM AUTHOR]

Background: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. Methods and findings: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1—Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2—"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3—"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4—"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. Conclusion: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. Trial registration: ClinicalTrials.gov, (NCT03721302). James Neal Russell and colleagues report a global neonatal sepsis observational cohort study (NeoOBS) exploring patterns of antibiotic use, pathogens and prediction of mortality in hospitalised neonates and young infants with sepsis. Author summary: Why was this study done?: Increasing trends in antimicrobial resistance (AMR) disproportionately affect neonates and young infants with sepsis in LMIC settings and undermine the effectiveness of WHO-recommended antibiotics. Despite this, longitudinal data on antibiotic management strategies and outcomes of hospitalized neonates and young infants with sepsis in low- and middle-income country (LMIC) settings are extremely limited, impeding the design of robust antibiotic trials. There is limited data to define risk stratification, inclusion, and escalation criteria in trials of sepsis in hospitalized neonates and young infants. What did the researchers do and find?: In this large global, prospective, hospital-based observational study across 4 continents, including LMIC settings, there was a high mortality among infants with culture positive sepsis (almost 1 in 5), and a significant burden of antibiotic resistance. This study highlights wide variations in standard of care (SOC) for sepsis in neonates and young infants, with more than 200 different antibiotic combinations, significant divergence from WHO-recommended regimens, and frequent switching of antibiotics. A NeoSep Severity Score that defined patterns of mortality risk at baseline was developed from 4 non-modifiable and 6 modifiable factors that are feasible to measure across a range of LMIC hospital contexts. A NeoSep Recovery Score including the same modifiable factors (with the addition of cyanosis) predicted mortality on the following day during treatment. What do these findings mean?: These data demonstrate that patterns of routine antibiotic use are now markedly divergent from global guidance. There is an urgent need for large pragmatic randomized controlled trials to address optimal empiric first- and second-line antibiotic treatment strategies in LMIC hospital settings with a significant AMR burden. The wide range of multiple antibiotic regimens routinely used as SOC suggests the need for novel trial designs. The NeoSep Severity Score and NeoSep Recovery Score informed inclusion and escalation criteria in the NeoSep1 antibiotic trial (ISRCTN48721236) that aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. [ABSTRACT FROM AUTHOR]

Objective: To compare the prognostic value of mid-upper arm circumference (MUAC), weight-for-height Z -score (WHZ) and weight-for-age Z -score (WAZ) for predicting death over periods of 1, 3 and 6 months follow-up in children. Design: Pooled analysis of twelve prospective studies examining survival after anthropometric assessment. Sensitivity and false-positive ratios to predict death within 1, 3 and 6 months were compared for three individual anthropometric indices and their combinations. Setting: Community-based, prospective studies from twelve countries in Africa and Asia. Participants: Children aged 6–59 months living in the study areas. Results: For all anthropometric indices, the receiver operating characteristic curves were higher for shorter than for longer durations of follow-up. Sensitivity was higher for death with 1-month follow-up compared with 6 months by 49 % (95 % CI (30, 69)) for MUAC < 115 mm (P < 0·001), 48 % (95 % CI (9·4, 87)) for WHZ < -3 (P < 0·01) and 28 % (95 % CI (7·6, 42)) for WAZ < -3 (P < 0·005). This was accompanied by an increase in false positives of only 3 % or less. For all durations of follow-up, WAZ < -3 identified more children who died and were not identified by WHZ < -3 or by MUAC < 115 mm, 120 mm or 125 mm, but the use of WAZ < -3 led to an increased false-positive ratio up to 16·4 % (95 % CI (12·0, 20·9)) compared with 3·5 % (95 % CI (0·4, 6·5)) for MUAC < 115 mm alone. Conclusions: Frequent anthropometric measurements significantly improve the identification of malnourished children with a high risk of death without markedly increasing false positives. Combining two indices increases sensitivity but also increases false positives among children meeting case definitions. [ABSTRACT FROM AUTHOR]

Background: Understanding spatial variations in health outcomes is a fundamental component in the design of effective, efficient public health strategies. Here we analyse the spatial heterogeneity of low birthweight (LBW) hospital deliveries from a demographic surveillance site on the Kenyan coast. Methods: A secondary data analysis on singleton livebirths that occurred between 2011 and 2021 within the rural areas of the Kilifi Health and demographic surveillance system (KHDSS) was undertaken. Individual-level data was aggregated at enumeration zone (EZ) and sub-location level to estimate the incidence of LBW adjusted for accessibility index using the Gravity model. Finally, spatial variations in LBW were assessed using Martin Kulldorf's spatial scan statistic under Discrete Poisson distribution. Results: Access adjusted LBW incidence was estimated as 87 per 1,000 person years in the under 1 population (95% CI: 80, 97) at the sub-location level similar to EZ. The adjusted incidence ranged from 35 to 159 per 1,000 person years in the under 1 population at sub-location level. There were six significant clusters identified at sub-location level and 17 at EZ level using the spatial scan statistic. Conclusions: LBW is a significant health risk on the Kenya coast, possibly under-estimated from previous health information systems, and the risk of LBW is not homogenously distributed across areas served by the County hospital. [ABSTRACT FROM AUTHOR]

Objective: To understand which anthropometric diagnostic criteria best discriminate higher from lower risk of death in children and explore programme implications. Design: A multiple cohort individual data meta-analysis of mortality risk (within 6 months of measurement) by anthropometric case definitions. Sensitivity, specificity, informedness and inclusivity in predicting mortality, face validity and compatibility with current standards and practice were assessed and operational consequences were modelled. Setting: Community-based cohort studies in twelve low-income countries between 1977 and 2013 in settings where treatment of wasting was not widespread. Participants: Children aged 6 to 59 months. Results: Of the twelve anthropometric case definitions examined, four (weight-for-age Z -score (WAZ) <−2), (mid-upper arm circumference (MUAC) <125 mm), (MUAC < 115 mm or WAZ < −3) and (WAZ < −3) had the highest informedness in predicting mortality. A combined case definition (MUAC < 115 mm or WAZ < −3) was better at predicting deaths associated with weight-for-height Z -score <−3 and concurrent wasting and stunting (WaSt) than the single WAZ < −3 case definition. After the assessment of all criteria, the combined case definition performed best. The simulated workload for programmes admitting based on MUAC < 115 mm or WAZ < −3, when adjusted with a proxy for required intensity and/or duration of treatment, was 1·87 times larger than programmes admitting on MUAC < 115 mm alone. Conclusions: A combined case definition detects nearly all deaths associated with severe anthropometric deficits suggesting that therapeutic feeding programmes may achieve higher impact (prevent mortality and improve coverage) by using it. There remain operational questions to examine further before wide-scale adoption can be recommended. [ABSTRACT FROM AUTHOR]

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018–February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28–34), and median birth weight was 1270 gr (interquartile range [IQR]: 990–1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n  = 45, 35%), C. parapsilosis (n  = 38, 30%), and Candida auris (n  = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines. [ABSTRACT FROM AUTHOR]

Background Intermittent preventive treatment (IPTp) for pregnant women with sulfadoxine–pyrimethamine (SP) is widely implemented for the prevention of malaria in pregnancy and adverse birth outcomes. The efficacy of SP is declining, and there are concerns that IPTp may have reduced impact in areas of high resistance. We sought to determine the protection afforded by SP as part of IPTp against adverse birth outcomes in an area with high levels of SP resistance on the Kenyan coast. Methods A secondary analysis of surveillance data on deliveries at the Kilifi County Hospital between 2015 and 2021 was undertaken in an area of low malaria transmission and high parasite mutations associated with SP resistance. A multivariable logistic regression model was developed to estimate the effect of SP doses on the risk of low birthweight (LBW) deliveries and stillbirths. Results Among 27 786 deliveries, 3 or more doses of IPTp-SP were associated with a 27% reduction in the risk of LBW (adjusted odds ratio [aOR], 0.73; 95% confidence interval [CI],.64–.83; P <.001) compared with no dose. A dose-response association was observed with increasing doses of SP from the second trimester linked to increasing protection against LBW deliveries. Three or more doses of IPTp-SP were also associated with a 21% reduction in stillbirth deliveries (aOR, 0.79; 95% CI,.65–.97; P =.044) compared with women who did not take any dose of IPTp-SP. Conclusions The continued significant association of SP on LBW deliveries suggests that the intervention may have a non-malaria impact on pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Risk of death from undernutrition is thought to be higher in younger than in older children, but evidence is mixed. Research also demonstrates sex differences whereby boys have a higher prevalence of undernutrition than girls. This analysis described mortality risk associated with anthropometric deficits (wasting, underweight and stunting) in children 6–59 months by age and sex. We categorised children into younger (6–23 months) and older (24–59 months) age groups. Age and sex variations in near‐term (within 6 months) mortality risk, associated with individual anthropometric deficits were assessed in a secondary analysis of multi‐country cohort data. A random effects meta‐analysis was performed. Data from seven low‐or‐middle‐income‐countries collected between 1977 and 2013 were analysed. One thousand twenty deaths were recorded for children with anthropometric deficits. Pooled meta‐analysis estimates showed no differences by age in absolute mortality risk for wasting (RR 1.08, p = 0.826 for MUAC < 125 mm; RR 1.35, p = 0.272 for WHZ < −2). For underweight and stunting, absolute risk of death was higher in younger (RR 2.57, p < 0.001) compared with older children (RR 2.83, p < 0.001). For all deficits, there were no differences in mortality risk for girls compared with boys. There were no differences in the risk of mortality between younger and older wasted children, supporting continued inclusion of all children under‐five in wasting treatment programmes. The risk of mortality associated with underweight and stunting was higher among younger children, suggesting that prevention programmes might be justified in focusing on younger children where resources are limited. There were no sex differences by age in mortality risk for all deficits. Key points: There is a high risk of mortality associated with child wasting. We found no difference in mortality risk between children 6–23 months and children 24–59 months, indicating the need to include all children under 5 years in wasting treatment programmes.For underweight and stunting, younger children had a significantly higher risk of mortality than older children. Where resources are limited, prevention programmes may be justified in targeting younger children.Despite sex differences in the prevalence of wasting, stunting and underweight, there were no differences in mortality risk between girls and boys in both younger and older age groups. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) viremia is associated with mortality in severely ill immunocompetent adults and hospitalized children with HIV (CWH). We measured CMV viremia in HIV-exposed and -unexposed Kenyan children aged 1-59 months discharged from hospital and determined its relationship with postdischarge mortality.Methods: CMV DNA levels were measured in plasma from 1024 children (97 of which were HIV exposed uninfected [HEU], and 15 CWH). Poisson and Cox proportional hazards regression models were used to identify correlates of CMV viremia ≥ 1000 IU/mL 
and estimate associations with 6-month mortality, respectively.Results: CMV viremia was detected in 31% of children, with levels ≥ 1000 IU/mL in 5.8%. HIV infection, age < 2 years, breastfeeding, and midupper arm circumference < 12.5 cm were associated with CMV viremia ≥ 1000 IU/mL. Among HEU children, CMV ≥ 1000 IU/mL (hazard ratio [HR] = 32.0; 95% confidence interval [CI], 2.9-354.0; P = .005) and each 1-log increase in CMV viral load (HR = 5.04; 95% CI, 1.7-14.6; P = .003) were associated with increased risk of mortality. CMV viremia was not significantly associated with mortality in HIV-unexposed children.Conclusions: CMV levels at hospital postdischarge predict increased risk of 6-month mortality in Kenyan HEU children. CMV suppression may be a novel target to reduce mortality in HEU children.Clinical Trial Registration: NCT02414399. [ABSTRACT FROM AUTHOR]

Introduction: Post-hospital discharge mortality is high among undernourished children in many low and middle-income countries. Although a number of quantitative studies have highlighted a range of potential socio-cultural, economic and health system factors influencing paediatric post-discharge treatment-seeking and recovery, few studies have explored family and provider perspectives of the post-discharge period in-depth. Methods: This work was part of a large, multi-country prospective cohort study, the Childhood Acute Illness and Nutrition (CHAIN) Network. We conducted a qualitative sub-study to understand the post-discharge treatment-seeking and recovery experiences of families of undernourished children aged 2–23 months admitted in a rural and urban icddr,b (International Centre for Diarrhoeal Disease Research, Bangladesh) hospital. Methods included repeat in-depth interviews (73 interviews in total) with 29 family members of 17 purposively selected children. These data were supplemented by interviews with 33 health workers, and by observations in hospitals and homes. Results: Important drivers of treatment-seeking perceived to support recovery included advice provided to family members while in hospital, media campaigns on hygiene practice, availability of free treatment, and social and financial support from family members, relatives and neighbours. Key perceived challenges included low household incomes, mothers having to juggle multiple responsibilities in addition to caring for the sick child, lack of support (sometimes violence) from the child's father, and family members' preference for relatively accessible drug shops, physicians or healers over hospital admission. Conclusion: Development of interventions that address the challenges that families face is essential to support post-discharge adherence to medical advice and recovery. Potential interventions include strengthening information giving during hospitalization on what post-discharge care is needed and why, reducing direct and indirect costs associated with hospital visits, engaging fathers and other 'significant others' in post-discharge advice, and building mobile phone-based support for follow-up care. [ABSTRACT FROM AUTHOR]

Objective: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.Design: A single-centre open-label randomised controlled trial.Setting: Kilifi County Hospital, Kenya.Patients: 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.Intervention: We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days.Main Outcomes and Measures: Serum sodium, AEs and fosfomycin pharmacokinetics.Results: 61 and 59 infants aged 0-23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference -0.95 events/100 infant-days (95% CI -2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g.Conclusion and Relevance: Fosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial.Trial Registration Number: NCT03453177. [ABSTRACT FROM AUTHOR]

Severely ill children in low- and middle-income countries (LMICs) experience high rates of mortality from a broad range of infectious diseases, with the risk of infection-related death compounded by co-existing undernutrition. How undernutrition and acute illness impact immune responses in young children in LMICs remains understudied, and it is unclear what aspects of immunity are compromised in this highly vulnerable population. To address this knowledge gap, we profiled longitudinal whole blood cytokine responses to Toll-like receptor (TLR) ligands among severely ill children (n=63; 2-23 months old) with varied nutritional backgrounds, enrolled in the CHAIN Network cohort from Kampala, Uganda, and Kilifi, Kenya, and compared these responses to similar-aged well children in local communities (n=41). Cytokine responses to ligands for TLR-4 and TLR-7/8, as well as Staphylococcus enterotoxin B (SEB), demonstrated transient impairment in T cell function among acutely ill children, whereas innate cytokine responses were exaggerated during both acute illness and following clinical recovery. Nutritional status was associated with the magnitude of cytokine responses in all stimulated conditions. Among children who died following hospital discharge or required hospital re-admission, exaggerated production of interleukin-7 (IL-7) to all stimulation conditions, as well as leukopenia with reduced lymphocyte and monocyte counts, were observed. Overall, our findings demonstrate exaggerated innate immune responses to pathogen-associated molecules among acutely ill young children that persist during recovery. Heightened innate immune responses to TLR ligands may contribute to chronic systemic inflammation and dysregulated responses to subsequent infectious challenges. Further delineating mechanisms of innate immune dysregulation in this population should be prioritized to identify novel interventions that promote immune homeostasis and improve outcomes. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.Methods: Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens.Results: A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains.Conclusions: PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis. [ABSTRACT FROM AUTHOR]

Background Intestinal disorders such as environmental enteric dysfunction (EED) are prevalent in low- and middle-income countries (LMICs) and important contributors to childhood undernutrition and mortality. Autopsies are rarely performed in LMICs but minimally invasive tissue sampling is increasingly deployed as a more feasible and acceptable procedure, although protocols have been devoid of intestinal sampling to date. We sought to determine (1) the feasibility of postmortem intestinal sampling, (2) whether autolysis precludes enteric biopsies' utility, and (3) histopathologic features among children who died during hospitalization with acute illness or undernutrition. Methods Transabdominal needle and endoscopic forceps upper and lower intestinal sampling were conducted among children aged 1 week to 59 months who died while hospitalized in Blantyre, Malawi. Autolysis ratings were determined for each hematoxylin and eosin slide, and upper and lower intestinal scoring systems were adapted to assess histopathologic features and their severity. Results Endoscopic and transabdominal sampling procedures were attempted in 28 and 14 cases, respectively, with >90% success obtaining targeted tissue. Varying degrees of autolysis were present in all samples and precluded histopathologic scoring of 6% of 122 biopsies. Greater autolysis in duodenal samples was seen with longer postmortem interval (Beta = 0.06, 95% confidence interval, 0.02–0.11). Histopathologic features identified included duodenal Paneth and goblet cell depletion. Acute inflammation was absent but chronic inflammation was prevalent in both upper and lower enteric samples. Severe chronic rectal inflammation was identified in children as young as 5.5 weeks. Conclusions Minimally invasive postmortem intestinal sampling is feasible and identifies histopathology that can inform mortality contributors. [ABSTRACT FROM AUTHOR]

Photorespiration recovers carbon that would be otherwise lost following the oxygenation reaction of rubisco and production of glycolate. Photorespiration is essential in plants and recycles glycolate into usable metabolic products through reactions spanning the chloroplast, mitochondrion, and peroxisome. Catalase in peroxisomes plays an important role in this process by disproportionating H2O2 resulting from glycolate oxidation into O2 and water. We hypothesize that catalase in the peroxisome also protects against nonenzymatic decarboxylations between hydrogen peroxide and photorespiratory intermediates (glyoxylate and/or hydroxypyruvate). We test this hypothesis by detailed gas exchange and biochemical analysis of Arabidopsis thaliana mutants lacking peroxisomal catalase. Our results strongly support this hypothesis, with catalase mutants showing gas exchange evidence for an increased stoichiometry of CO2 release from photorespiration, specifically an increase in the CO2 compensation point, a photorespiratory‐dependent decrease in the quantum efficiency of CO2 assimilation, increase in the 12CO2 released in a 13CO2 background, and an increase in the postillumination CO2 burst. Further metabolic evidence suggests this excess CO2 release occurred via the nonenzymatic decarboxylation of hydroxypyruvate. Specifically, the catalase mutant showed an accumulation of photorespiratory intermediates during a transient increase in rubisco oxygenation consistent with this hypothesis. Additionally, end products of alternative hypotheses explaining this excess release were similar between wild type and catalase mutants. Furthermore, the calculated rate of hydroxypyruvate decarboxylation in catalase mutant is much higher than that of glyoxylate decarboxylation. This work provides evidence that these nonenzymatic decarboxylation reactions, predominately hydroxypyruvate decarboxylation, can occur in vivo when photorespiratory metabolism is genetically disrupted. [ABSTRACT FROM AUTHOR]

Background: Undernourished children in low- and middle-income countries remain at elevated risk of death following hospital discharge, even when treated during hospitalisation using World Health Organisation recommended guidelines. The role of community health workers (CHWs) in supporting post-discharge recovery to improve outcomes has not been adequately explored.Methods: This paper draws on qualitative research conducted as part of the Childhood Acute Illnesses and Nutrition (CHAIN) Network in Bangladesh and Kenya. We interviewed family members of 64 acutely ill children admitted across four hospitals (a rural and urban hospital in each country). 27 children had severe wasting or kwashiorkor on admission. Family members were interviewed in their homes soon after discharge, and up to three further times over the following six to fourteen months. These data were supplemented by observations in facilities and homes, key informant interviews with CHWs and policy makers, and a review of relevant guidelines.Results: Guidelines suggest that CHWs could play a role in supporting recovery of undernourished children post-discharge, but the mechanisms to link CHWs into post-discharge support processes are not specified. Few families we interviewed reported any interactions with CHWs post-discharge, especially in Kenya, despite our data suggesting that opportunities for CHWs to assist families post-discharge include providing context sensitive information and education, identification of danger signs, and supporting linkages with community-based services and interventions. Although CHWs are generally present in communities, challenges they face in conducting their roles include unmanageable workloads, few incentives, lack of equipment and supplies and inadequate support from supervisors and some community members.Conclusion: A multi-pronged approach before or on discharge is needed to strengthen linkages between CHWs and children vulnerable to poor outcomes, supported by clear guidance. To encourage scale-ability and cost-effectiveness of interventions, the most vulnerable, high-risk children, should be targeted, including undernourished children. Intervention designs must also take into account existing health worker shortages and training levels, including for CHWs, and how any new tasks or personnel are incorporated into hospital and broader health system hierarchies and systems. Any such interventions will need to be evaluated in carefully designed studies, including tracking for unintended consequences. [ABSTRACT FROM AUTHOR]

Background: There is increasing global focus on small and nutritionally at-risk infants aged <6 months (<6 m). Current WHO guidelines recommend weight-for-length z -score (WLZ) for enrolment to malnutrition treatment programmes but acknowledge a weak evidence-base. This review aims to inform future guidelines by examining which anthropometric criteria best identify infants <6 m at high risk of mortality/morbidity. Methods: We searched Medline, EMBASE, CINAHL, Global Health, Cochrane Library and POPLINE for studies conducted in low- and middle-income countries and published between 1990 and October 2020. We included studies reporting anthropometric assessment of nutritional status in infants <6 m and assessed the association with subsequent morbidity or mortality. Results: A total of 19 studies were included in the final review, covering 20 countries, predominantly in sub-Saharan Africa. WLZ had poor reliability and poor prognostic ability to identify infants at risk of death. Mid-upper arm circumference (MUAC) and weight-for-age z -score (WAZ) were better at identifying infants at risk of mortality/morbidity. MUAC-for-age z -score did not perform better than using a single MUAC cut-off. Suggested MUAC cut-offs for this age group varied by context, ranging from 10.5 to 11.5 cm. The assessment for reliability showed that length was difficult to measure, making WLZ the least reliable indicator overall. Conclusion: Evidence from our review suggests that a change in current practice is necessary. To better identify small and nutritionally at-risk infants <6 m WAZ and/or MUAC rather than WLZ should be used. Future research should explore possible benefits for programme coverage, impact and cost-effectiveness. Research should also examine if context-specific MUAC thresholds are needed. [ABSTRACT FROM AUTHOR]

Background: Despite adherence to WHO guidelines, inpatient mortality among sick children admitted to hospital with complicated severe acute malnutrition (SAM) remains unacceptably high. Several studies have examined risk factors present at admission for mortality. However, risks may evolve during admission with medical and nutritional treatment or deterioration. Currently, no specific guidance exists for assessing daily treatment response. This study aimed to determine the prognostic value of monitoring clinical signs on a daily basis for assessing mortality risk during hospitalization in children with SAM.Methods: This is a secondary analysis of data from a randomized trial (NCT02246296) among 843 hospitalized children with SAM. Daily clinical signs were prospectively collected during ward rounds. Multivariable extended Cox regression using backward feature selection was performed to identify daily clinical warning signs (CWS) associated with time to death within the first 21 days of hospitalization. Predictive models were subsequently developed, and their prognostic performance evaluated using Harrell's concordance index (C-index) and time-dependent area under the curve (tAUC).Results: Inpatient case fatality ratio was 16.3% (n=127). The presence of the following CWS during daily assessment were found to be independent predictors of inpatient mortality: symptomatic hypoglycemia, reduced consciousness, chest indrawing, not able to complete feeds, nutritional edema, diarrhea, and fever. Daily risk scores computed using these 7 CWS together with MUAC<10.5cm at admission as additional CWS predict survival outcome of children with SAM with a C-index of 0.81 (95% CI 0.77-0.86). Moreover, counting signs among the top 5 CWS (reduced consciousness, symptomatic hypoglycemia, chest indrawing, not able to complete foods, and MUAC<10.5cm) provided a simpler tool with similar prognostic performance (C-index of 0.79; 95% CI 0.74-0.84). Having 1 or 2 of these CWS on any day during hospitalization was associated with a 3 or 11-fold increased mortality risk compared with no signs, respectively.Conclusions: This study provides evidence for structured monitoring of daily CWS as recommended clinical practice as it improves prediction of inpatient mortality among sick children with complicated SAM. We propose a simple counting-tool to guide healthcare workers to assess treatment response for these children.Trial Registration: NCT02246296. [ABSTRACT FROM AUTHOR]

Background: Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking.Objectives: To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data.Methods: The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed.Results: In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347-0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272-0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio.Conclusions: Through this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant's PMA, PNA and weight. [ABSTRACT FROM AUTHOR]

Pediatric clinical research in low-resourced countries involves individuals defined as "vulnerable" in research ethics guidance. Insights from research participants can strengthen the design and oversight of studies. We share family members' perspectives and experiences of an observational clinical study conducted in one Kenyan hospital as part of an integrated empirical ethics study. Employing qualitative methods, we explored how research encounters featured in family members' care-seeking journeys. Our data reveals that children's vulnerability is intricately interwoven with that of their families, and that research processes and procedures can inadvertently add to hidden burdens for families. In research, the potential for layered and intersecting situational and structural vulnerability should be considered, and participants' agency in constrained research contexts actively recognized and protected. [ABSTRACT FROM AUTHOR]

Background: Diagnosing bacterial meningitis is essential to optimise the type and duration of antimicrobial therapy to limit mortality and sequelae. In sub-Saharan Africa, many public hospitals lack laboratory capacity, relying on clinical features to empirically treat or not treat meningitis. We investigated whether clinical features of bacterial meningitis identified prior to the introduction of conjugate vaccines still discriminate meningitis in children aged ≥60 days.Methods: We conducted a retrospective cohort study to validate seven clinical features identified in 2002 (KCH-2002): bulging fontanel, neck stiffness, cyanosis, seizures outside the febrile convulsion age range, focal seizures, impaired consciousness, or fever without malaria parasitaemia and Integrated Management of Childhood Illness (IMCI) signs: neck stiffness, lethargy, impaired consciousness or seizures, and assessed at admission in discriminating bacterial meningitis after the introduction of conjugate vaccines. Children aged ≥60 days hospitalised between 2012 and 2016 at Kilifi County Hospital were included in this analysis. Meningitis was defined as positive cerebrospinal fluid (CSF) culture, organism observed on CSF microscopy, positive CSF antigen test, leukocytes ≥50/μL, or CSF to blood glucose ratio <0.1.Results: Among 12,837 admissions, 98 (0.8%) had meningitis. The presence of KCH-2002 signs had a sensitivity of 86% (95% CI 77-92) and specificity of 38% (95% CI 37-38). Exclusion of 'fever without malaria parasitaemia' reduced sensitivity to 58% (95% CI 48-68) and increased specificity to 80% (95% CI 79-80). IMCI signs had a sensitivity of 80% (95% CI 70-87) and specificity of 62% (95% CI 61-63).Conclusions: A lower prevalence of bacterial meningitis and less typical signs than in 2002 meant the lower performance of KCH-2002 signs. Clinicians and policymakers should be aware of the number of lumbar punctures (LPs) or empirical treatments needed for each case of meningitis. Establishing basic capacity for CSF analysis is essential to exclude bacterial meningitis in children with potential signs. [ABSTRACT FROM AUTHOR]

Objective: Prognostic models aid clinical decision making and evaluation of hospital performance. Existing neonatal prognostic models typically use physiological measures that are often not available, such as pulse oximetry values, in routine practice in low-resource settings. We aimed to develop and validate two novel models to predict all cause in-hospital mortality following neonatal unit admission in a low-resource, high-mortality setting.Study Design and Setting: We used basic, routine clinical data recorded by duty clinicians at the time of admission to derive (n=5427) and validate (n=1627) two novel models to predict in-hospital mortality. The Neonatal Essential Treatment Score (NETS) included treatments prescribed at the time of admission while the Score for Essential Neonatal Symptoms and Signs (SENSS) used basic clinical signs. Logistic regression was used, and performance was evaluated using discrimination and calibration.Results: At derivation, c-statistic (discrimination) for NETS was 0.92 (95% CI 0.90 to 0.93) and that for SENSS was 0.91 (95% CI 0.89 to 0.93). At external (temporal) validation, NETS had a c-statistic of 0.89 (95% CI 0.86 to 0.92) and SENSS 0.89 (95% CI 0.84 to 0.93). The calibration intercept for NETS was -0.72 (95% CI -0.96 to -0.49) and that for SENSS was -0.33 (95% CI -0.56 to -0.11).Conclusion: Using routine neonatal data in a low-resource setting, we found that it is possible to predict in-hospital mortality using either treatments or signs and symptoms. Further validation of these models may support their use in treatment decisions and for case-mix adjustment to help understand performance variation across hospitals. [ABSTRACT FROM AUTHOR]

Background: There is increasing global focus on small and nutritionally at-risk infants aged <6 months (<6 m). Current WHO guidelines recommend weight-for-length z -score (WLZ) for enrolment to malnutrition treatment programmes but acknowledge a weak evidence-base. This review aims to inform future guidelines by examining which anthropometric criteria best identify infants <6 m at high risk of mortality/morbidity. Methods: We searched Medline, EMBASE, CINAHL, Global Health, Cochrane Library and POPLINE for studies conducted in low- and middle-income countries and published between 1990 and October 2020. We included studies reporting anthropometric assessment of nutritional status in infants <6 m and assessed the association with subsequent morbidity or mortality. Results: A total of 19 studies were included in the final review, covering 20 countries, predominantly in sub-Saharan Africa. WLZ had poor reliability and poor prognostic ability to identify infants at risk of death. Mid-upper arm circumference (MUAC) and weight-for-age z -score (WAZ) were better at identifying infants at risk of mortality/morbidity. MUAC-for-age z -score did not perform better than using a single MUAC cut-off. Suggested MUAC cut-offs for this age group varied by context, ranging from 10.5 to 11.5 cm. The assessment for reliability showed that length was difficult to measure, making WLZ the least reliable indicator overall. Conclusion: Evidence from our review suggests that a change in current practice is necessary. To better identify small and nutritionally at-risk infants <6 m WAZ and/or MUAC rather than WLZ should be used. Future research should explore possible benefits for programme coverage, impact and cost-effectiveness. Research should also examine if context-specific MUAC thresholds are needed. [ABSTRACT FROM AUTHOR]

Background: Post-hospital discharge mortality risk is high among young children in many low and middle-income countries (LMICs). The available literature suggests that child, caregiver and health care provider gender all play important roles in post-discharge adherence to medical advice, treatment-seeking and recovery for ill children in LMICs, including those with undernutrition. Methods: A qualitative study was embedded within a larger multi-country multi-disciplinary observational cohort study involving children aged less than 2 years conducted by the Childhood Acute Illness and Nutrition (CHAIN) Network. Primary data were collected from family members of 22 purposively selected cohort children. Family members were interviewed several times in their homes over the 6 months following hospital discharge (total n = 78 visits to homes). These in-depth interviews were complemented by semi-structured individual interviews with 6 community representatives, 11 community health workers and 12 facility-based health workers, and three group discussions with a total of 24 community representatives. Data were analysed using NVivo11 software, using both narrative and thematic approaches. Results: We identified gender-related influences at health service/system and household/community levels. These influences interplayed to family members' adherence to medical advice and treatment-seeking after hospital discharge, with potentially important implications for children's recovery. Health service/system level influences included: fewer female medical practitioners in healthcare facilities, which influenced mothers' interest and ability to consult them promptly for their child's illnesses; gender-related challenges for community health workers in supporting mothers with counselling and advice; and male caregivers' being largely absent from the paediatric wards where information sessions to support post-discharge care are offered. Gendered household/community level influences included: women's role as primary caretakers for children and available levels of support; male family members having a dominant role in decision-making related to food and treatment-seeking behaviour; and greater reluctance among parents to invest money and time in the treatment of female children, as compared to male children. Conclusions: A complex web of gender related influences at health systems/services and household/community levels have important implications for young children's recovery post-discharge. Immediate interventions with potential for positive impact include awareness-raising among all stakeholders – including male family members - on how gender influences child health and recovery, and how to reduce adverse consequences of gender-based discrimination. Specific interventions could include communication interventions in facilities and homes, and changes in routine practices such as who is present in facility interactions. To maximise and sustain the impact of immediate actions and interventions, the structural drivers of women's position in society and gender inequity must also be tackled. This requires interventions to ensure equal equitable opportunities for men and women in all aspects of life, including access to education and income generation activities. Given patriarchal norms locally and globally, men will likely need special targeting and support in achieving these objectives. [ABSTRACT FROM AUTHOR]

Background: Detection of meningitis is essential to optimise the duration and choice of antimicrobial agents to limit mortality and sequelae. In low and middle-income countries most health facilities lack laboratory capacity and rely on clinical features to empirically treat meningitis.Objective: We conducted a diagnostic validation study to investigate the performance of clinical features (fever, convulsions, irritability, bulging fontanel and temperature ≥39°C) and WHO-recommended signs (drowsiness, lethargy, unconsciousness, convulsions, bulging fontanel, irritability or a high-pitched cry) in discriminating meningitis in young infants.Design: Retrospective cohort study.Setting: Kilifi County Hospital.Patients: Infants aged <60 days hospitalised between 2012 and 2016.Main Outcome Measure: Definite meningitis defined as positive cerebrospinal fluid (CSF) culture, microscopy or antigen test, or leucocytes ≥0.05 x 10∧9/L.Results: Of 4809 infants aged <60 days included, 81 (1.7%) had definite meningitis. WHO-recommended signs had sensitivity of 58% (95% CI 47% to 69%) and specificity of 57% (95% CI 56% to 59%) for definite meningitis. Addition of history of fever improved sensitivity to 89% (95% CI 80% to 95%) but reduced specificity to 26% (95% CI 25% to 27%). Presence of ≥1 of 5 previously identified signs had sensitivity of 79% (95% CI 69% to 87%) and specificity of 51% (95% CI 50% to 53%).Conclusions: Despite a lower prevalence of definite meningitis, the performance of previously identified signs at admission in predicting meningitis was unchanged. Presence of history of fever improves the sensitivity of WHO-recommended signs but loses specificity. Careful evaluation, repeated assessment and capacity for lumbar puncture and CSF microscopy to exclude meningitis in most young infants with potential signs are essential to management in this age group. [ABSTRACT FROM AUTHOR]

Background: In many African settings, gender strongly influences household treatment-seeking and decision-making for childhood illnesses. While mothers are often the primary engagers with health facilities, their independence in illness-related decisions is shaped by various factors. Drawing on a gender lens, we explored treatment-seeking pathways pre- and post-hospital admission for acutely ill young children living in low income settlements in Nairobi, Kenya; and the gendered impact of child illness both at the household and health system level. Methods: Household members of 22 children admitted to a public hospital were interviewed in their homes several times post hospital discharge. In-depth interviews covered the child's household situation, health and illness; and the family's treatment-seeking choices and experiences. Children were selected from an observational cohort established by the Childhood Acute Illness and Nutrition (CHAIN) Network. Results: Treatment-seeking pathways were often long and complex, with mothers playing the key role in caring for their children and in treatment decision-making. Facing many anxieties and dilemmas, mothers often consulted with significant influencers - primarily women - particularly where illnesses were prolonged or complex. In contrast to observations in rural African contexts, fathers were less prominent as influencers than (often female) neighbours, grandparents and other relatives. Mothers were sometimes blamed for their child's condition at home and at health facilities. Children's illness episode and associated treatment-seeking had significant gendered socio-economic consequences for households, including through mothers having to take substantial time off work, reduce their working hours and income, or even losing their jobs. Conclusion: Women in urban low-income settings are disproportionately impacted by acute child illness and the related treatment-seeking and recovery process. The range of interventions needed to support mothers as they navigate their way through children's illnesses and recovery include: deliberate engagement of men in child health to counteract the dominant perception of child health and care as a 'female-domain'; targeted economic strategies such as cash transfers to safeguard the most vulnerable women and households, combined with more robust labour policies to protect affected women; as well as implementing strategies at the health system level to improve interactions between health workers and community members. [ABSTRACT FROM AUTHOR]

Background: Maternal immunisation to boost respiratory syncytial virus (RSV) specific antibodies in pregnant women is a strategy to enhance infant protection. The timing of maternal vaccination during pregnancy may be critical for its effectiveness. However, Kenya has no documented published data on gestational age distribution of pregnant women attending antenatal care (ANC), or the proportion of women attending ANC during the proposed window period for vaccination, to inform appropriate timing for delivery or estimate potential uptake of this vaccine.Methods: A cross-sectional survey was conducted within the Kilifi Health and Demographic Surveillance System (KHDSS), coastal Kenya. A simple random sample of 1000 women who had registered pregnant in 2017 to 2018 and with a birth outcome by the time of data collection was taken. The selected women were followed at their homes, and individually written informed consent was obtained. Records of their antenatal attendance during pregnancy were abstracted from their ANC booklet. The proportion of all pregnant women from KHDSS (55%) who attended for one or more ANC in 2018 was used to estimate vaccine coverage.Results: Of the 1000 women selected, 935 were traced with 607/935 (64.9%) available for interview, among whom 470/607 (77.4%) had antenatal care booklets. The median maternal age during pregnancy was 28.6 years. The median (interquartile range) gestational age in weeks at the first to fifth ANC attendance was 26 (21-28), 29 (26-32), 32 (28-34), 34 (32-36) and 36 (34-38), respectively. The proportion of women attending for ANC during a gestational age window for vaccination of 28-32 weeks (recommended), 26-33 weeks and 24-36 weeks was 76.6% (360/470), 84.5% (397/470) and 96.2% (452/470), respectively. Estimated vaccine coverage was 42.1, 46.5 and 52.9% within the narrow, wide and wider gestational age windows, respectively.Conclusions: In a random sample of pregnant women from Kilifi HDSS, Coastal Kenya with card-confirmed ANC clinic attendance, 76.6% would be reached for maternal RSV vaccination within the gestational age window of 28-32 weeks. Widening the vaccination window (26-33 weeks) or (24-36 weeks) would not dramatically increase vaccine coverage and would require consideration of antibody kinetics data that could affect vaccine efficacy. [ABSTRACT FROM AUTHOR]

Background. Infants under 6 months (U6M) contribute a significant proportion of the burden and mortality of severe malnutrition globally. Evidence of underlying aetiology in this population is sparse, but it is known that the group includes ex-preterm and low birthweight (LBW) infants. They represent a unique population given their dependence on breastmilk or a safe, secure alternative. Nutrition agencies and health providers struggle to make programming decisions on which interventions should be provided to this group based upon the 2013 WHO Guidelines for the 'Management of Severe Acute Malnutrition in Infants and Young Children' since there are no published interventional trial data focussed on this population. Interim guidance for this group might be informed by evidence of safety and efficacy in adjacent population groups. Methodology. A narrative literature review was performed of systematic reviews, meta-analyses and randomised controlled trials of antimicrobial and micronutrient interventions (antibiotics, deworming, vitamin A, vitamin D, iron, zinc, folic acid and oral rehydration solution (ORS) for malnutrition) across the population groups of low birthweight/preterm infants, infants under 6 months, infants and children over 6 months with acute malnutrition or through supplementation to breastfeeding mothers. Outcomes of interest were safety and efficacy, in terms of mortality and morbidity. Results. Ninety-four articles were identified for inclusion within this review. None of these studied interventions exclusively in severely malnourished infants U6M. 64% reported on the safety of studied interventions. Significant heterogeneity was identified in definitions of study populations, interventions provided, and outcomes studied. The evidence for efficacy and safety across population groups is reviewed and presented for the interventions listed. Conclusions. The direct evidence base for medical interventions for severely mal- nourished infants U6M is sparse. Our review identifies a specific need for accurate micronutrient profiling and interventional studies of micronutrients and oral fluid management of diarrhoea amongst infants U6M meeting anthropometric criteria for severe malnutrition. Indirect evidence presented in this review may help shape interim policy and programming decisions as well as the future research agenda for the management of infants U6M identified as malnourished. [ABSTRACT FROM AUTHOR]

Background: Child mortality rates during hospitalisation for acute illness and after discharge are unacceptably high in many under-resourced settings. Childhood vulnerability to recurrent illness, and death, is linked to their families' situations and ability to make choices and act (their agency). We examined vulnerability and agency across treatment-seeking journeys for acutely ill children and considered the implications for policy and practice. Method: A qualitative sub-study was embedded within the prospective CHAIN Network cohort study, which is investigating mechanisms of inpatient and post-hospital discharge mortality among acutely ill young children across a spectrum of nutritional status. Primary data were collected from household members of 20 purposively selected cohort children over 18 months through formal interviews (total n = 74), complemented by informal discussions and observations. Data were analysed using narrative and thematic approaches. Results: Treatment-seeking pathways were often long and complex, particularly for children diagnosed as severely malnourished. Family members' stories reveal that children's carers, usually mothers, navigate diverse challenges related to intersecting vulnerabilities at individual, household and facility levels. Specific challenges include the costs of treatment-seeking, confusing and conflicting messaging on appropriate care and nutrition, and poor continuity of care. Strong power inequities were observed between family members and health staff, with many mothers feeling blamed for their child's condition. Caregivers' agency, as demonstrated in decision-making and actions, often drew on the social support of others but was significantly constrained by their situation and broader structural drivers. Conclusion: To support children's care and recovery, health systems must be more responsive to the needs of families facing multiple and interacting vulnerabilities. Reducing incurred treatment costs, improving interpersonal quality of care, and strengthening continuity of care across facilities is essential. Promising interventions need to be co-designed with community representatives and health providers and carefully tested for unintended negative consequences and potential for sustainable scale-up. [ABSTRACT FROM AUTHOR]

HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p < 0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc-α-2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p < 0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM. [ABSTRACT FROM AUTHOR]

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency state in humans. The clinical phenotype is variable and includes asymptomatic individuals, episodic hemolysis induced by oxidative stress, and chronic hemolysis. G6PD deficiency is common in malaria-endemic regions, an observation hypothesized to be due to balancing selection at the G6PD locus driven by malaria. G6PD deficiency increases risk of severe malarial anemia, a key determinant of invasive bacterial disease in malaria-endemic settings. The pneumococcus is a leading cause of invasive bacterial infection and death in African children. The effect of G6PD deficiency on risk of pneumococcal disease is undefined. We hypothesized that G6PD deficiency increases pneumococcal disease risk and that this effect is dependent upon malaria.Methods: We performed a genetic case-control study of pneumococcal bacteremia in Kenyan children stratified across a period of falling malaria transmission between 1998 and 2010.Results: Four hundred twenty-nine Kenyan children with pneumococcal bacteremia and 2677 control children were included in the study. Among control children, G6PD deficiency, secondary to the rs1050828 G>A mutation, was common, with 11.2% (n = 301 of 2677) being hemi- or homozygotes and 33.3% (n = 442 of 1329) of girls being heterozygotes. We found that G6PD deficiency increased the risk of pneumococcal bacteremia, but only during a period of high malaria transmission (P = 0.014; OR 2.33, 95% CI 1.19-4.57). We estimate that the population attributable fraction of G6PD deficiency on risk of pneumococcal bacteremia in areas under high malaria transmission is 0.129.Conclusions: Our data demonstrate that G6PD deficiency increases risk of pneumococcal bacteremia in a manner dependent on malaria. At the population level, the impact of G6PD deficiency on invasive pneumococcal disease risk in malaria-endemic regions is substantial. Our study highlights the infection-associated morbidity and mortality conferred by G6PD deficiency in malaria-endemic settings and adds to our understanding of the potential indirect health benefits of improved malaria control. [ABSTRACT FROM AUTHOR]

Background: The 2013 WHO guidelines for nutritional rehabilitation of hospitalized and non-hospitalized malnourished infants under six months (u6m) recommend the re-establishment of exclusive breastfeeding. However, in most low-income settings these recommendations are not consistently applied. A recently concluded pilot study on the effects of implementing these guidelines among hospitalized malnourished infants u6m of age in Kilifi, Kenya introduced breastfeeding peer supporters (BFPS) to the inpatient setting to support guideline implementation. Here we report a sub-study investigating mothers' experiences and perceptions of the process of re-establishing exclusive breastfeeding during their infant's admission to hospital. Methods: Interviews were conducted with mothers just prior to their infant's discharge to explore their experiences and perceptions of the breastfeeding support process. A trained social science researcher conducted the interviews in Kiswahili language using a structured interview guide with open questions. Interviews were tape recorded, transcribed and translated into English for analysis. Data were managed and organized using NVIVO version 10 and analyzed using a framework approach. Results: Twenty mothers were interviewed. While some mothers found re-establishing breastfeeding challenging, they all reported improved knowledge on the relationships between maternal nutrition, stress management, hygiene practices and breastmilk production. They also reported gaining skills in breast care, breastfeeding techniques, hand expression and handling of expressed breastmilk. The breastfeeding peer supporters were said to have provided technical, social and emotional support which facilitated the process of re-establishing exclusive breastfeeding. The mothers identified the key characteristics of an effective and trustworthy BFPS as well as gaps in support. Conclusion: BFPS are able share knowledge and skills in a way that is understood and appreciated by the mothers of inpatient malnourished infants u6m of age, enhancing the reestablishment of exclusive breastfeeding. Central to the success of BFPS is their ability to develop close and supportive relationships with the mothers based on shared social and cultural backgrounds. Future studies should focus on evaluating the long-term impact of inpatient breastfeeding support strategies on the quality of breastfeeding and growth, as well as on understanding where, when and how BFPS might be incorporated into routine hospital settings. [ABSTRACT FROM AUTHOR]

The reduction in childhood mortality noted in trials investigating azithromycin mass drug administration (MDA) for trachoma control has been confirmed by a recent large randomized controlled trial. Population-level implementation of azithromycin MDA may lead to selection of multiresistant pathogens. Evidence suggests that repeated azithromycin MDA may result in a sustained increase in macrolide and other antibiotic resistance in gut and respiratory bacteria. Current evidence comes from standard microbiological techniques in studies focused on a time-limited intervention, while MDA implemented for mortality benefits would likely repeatedly expose the population over a prolonged period and may require a different surveillance approach. Targeted short-term and long-term surveillance of resistance emergence to key antibiotics, especially those from the World Health Organization Access group, is needed throughout any implementation of azithromycin MDA, focusing on a genotypic approach to overcome the limitations of resistance surveillance in indicator bacteria. [ABSTRACT FROM AUTHOR]

Hospital readmission is common among children with complicated severe acute malnutrition (cSAM) but not well‐characterised. Two distinct cSAM phenotypes, marasmus and kwashiorkor, exist, but their pathophysiology and whether the same phenotype persists at relapse are unclear. We aimed to test the association between cSAM phenotype at index admission and readmission following recovery. We performed secondary data analysis from a multicentre randomised trial in Kenya with 1‐year active follow‐up. The main outcome was cSAM phenotype upon hospital readmission. Among 1,704 HIV‐negative children with cSAM discharged in the trial, 177 children contributed a total of 246 readmissions with cSAM. cSAM readmission was associated with age<12 months (p =.005), but not site, sex, season, nor cSAM phenotype. Of these, 42 children contributed 44 readmissions with cSAM that occurred after a monthly visit when SAM was confirmed absent (cSAM relapse). cSAM phenotype was sustained during cSAM relapse. The adjusted odds ratio for presenting with kwashiorkor during readmission after kwashiorkor at index admission was 39.3 [95% confidence interval (95% CI) [2.69, 1,326]; p =.01); and for presenting with marasmus during readmission after kwashiorkor at index admission was 0.02 (95% CI [0.001, 0.037]; p =.01). To validate this finding, we examined readmissions to Kilifi County Hospital, Kenya occurring at least 2 months after an admission with cSAM. Among 2,412 children with cSAM discharged alive, there were 206 readmissions with cSAM. Their phenotype at readmission was significantly influenced by their phenotype at index admission (p <.001). This is the first report describing the phenotype and rate of cSAM recurrence. [ABSTRACT FROM AUTHOR]

Background: Exclusive breastfeeding up to 6 months of age is recommended by the World Health Organization as the optimal mode of infant feeding, providing adequate nutrition for the baby and protection against infectious diseases. Breastfeeding can be adversely affected by individual, cultural and socio-economic factors. The study aimed to explore barriers of exclusive breastfeeding in the first 6 months of life among first-time mothers in rural Kenya. Methods: An observational longitudinal design aimed to provide rich data on breastfeeding behaviour. Twenty pregnant first-time mothers were recruited through antenatal clinics and snowballing. Mothers were visited nine times at home from late pregnancy, at 1 week and 2 weeks post-delivery, then monthly until the baby was aged 6 months. Visits were conducted between November 2016 and April 2018. At the first visit, participants were asked about breastfeeding intentions and infant feeding education received. At each postnatal visit, direct observation of breastfeeding, a recorded semi-structured interview on feeding, mother's and baby's health was performed. Interviews were transcribed, checked, content was grouped into categories and analyzed using a qualitative descriptive approach. Results: Most participants were adolescent (75%) and unmarried (65%). All 20 mothers intended to and did breastfeed, however additional fluids and semi-solids were commonly given. Only two mothers exclusively breastfed from birth up to 6 months of age. Prelacteal feeds, home remedies and traditional medicine were given by over a third of mothers in the first week of life. Concern over babies' bowel habits and persistent crying perceived as abdominal colic led to several mothers receiving advice to give gripe water and traditional remedies. Early introduction of maize porridge from 3 months of age because of perceived hunger of the child was recommended by other family members. Breastfeeding observation showed persistent problems with positioning and attachment of infants. Conclusions: Exclusive breastfeeding from birth to 6 months was uncommon. Prioritization of capacity to detect mothers with breastfeeding problems and provide breastfeeding education and support is necessary, particularly during the antenatal and early postnatal period. It is important to engage with other women resident in the household who may offer conflicting feeding advice. [ABSTRACT FROM AUTHOR]