Imperial College London

ProfessorKathMaitland

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Tropical Paediatric Infectious Disease
 
 
 
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k.maitland CV

 
 
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Based full-time at KEMRI/Wellcome Programme, KenyaQueen Elizabeth and Queen Mary HospitalSt Mary's Campus

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Publications

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258 results found

Nalwanga D, Bakker C, Kiggwe A, Negash AA, Ocan M, Briend A, Maitland K, Musiiime V, Karamagi Cet al., 2024, Mortality among non-severely under nourished children with pneumonia globally: protocol for a systematic review and meta-analysis, Wellcome Open Research, Vol: 8, Pages: 551-551

<ns3:p>Background Pneumonia remains the commonest cause of ill health and mortality among children worldwide. Severe undernutrition increases the mortality risk among children with pneumonia. While children with pneumonia are at increased risk of developing malnutrition, the impact of pneumonia on mortality and nutritional status of non-severely undernourished children is not well described. The impact of nutritional supplementation on mortality and nutritional status in this population is not well understood. This review will collate available evidence on the all-cause mortality and anthropometric indices outcomes following pneumonia, as well as the impact of nutritional supplementation on mortality and anthropometry among non-severely malnourished children with pneumonia. Methods The review will be done using <ns3:italic>a priori</ns3:italic> criteria developed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data will be obtained from data bases, grey literature, and bibliographies. An experienced librarian will conduct article search in PUBMED, MEDLINE, EMBASE, Web of Science, Google scholar, and Scopus. Retrieved articles will be entered in Endnote <ns3:italic>ver</ns3:italic> 9.0, duplicates removed, and transferred to Epi-reviewer for screening and data abstraction. Risk of bias in the included articles will be assessed using standard criteria. Heterogeneity will be assessed using I2-statistic and sub-group analysis will be done. Data will be analysed using both narrative and quantitative synthesis. Quantitative synthesis will be done using DeSimonian and Laird Random-effects model in STATA <ns3:italic>ver</ns3:italic> 15.0. Conclusions The results will provide baseline information about the mortality and anthropometric outcomes of pneumonia among non-severely malnourished children as well as the potential effect of nutritional supplementation on these outcomes. This

Journal article

Maitland K, Maitland K, 2024, Legume-supplemented feed for children hospitalised with severe malnutrition: A Phase II trial, The British Journal of Nutrition: an international journal of nutritional science, ISSN: 0007-1145

Journal article

Nalwanga D, Bakker C, Kiggwe A, Negash AA, Ocan M, Briend A, Maitland K, Musiiime V, Karamagi Cet al., 2023, Mortality among non-severely under nourished children with pneumonia globally: protocol for a systematic review and meta-analysis, Wellcome Open Research, Vol: 8, ISSN: 2398-502X

BackgroundPneumonia remains the commonest cause of ill health and mortality among children worldwide. Severe undernutrition increases the mortality risk among children with pneumonia. While children with pneumonia are at increased risk of developing malnutrition, the impact of pneumonia on mortality and nutritional status of non-severely undernourished children is not well described. The impact of nutritional supplementation on mortality and nutritional status in this population is not well understood. This review will collate available evidence on the all-cause mortality, nutritional (anthropometric) outcomes following pneumonia, as well as the impact of nutritional supplementation on mortality and anthropometry among non-severely malnourished children with pneumonia.MethodsThe review will be done using a priori criteria developed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data will be obtained from data bases, grey literature, and bibliographies. An experienced librarian will conduct article search in PUBMED, MEDLINE, EMBASE, Web of Science, Google scholar, and Scopus. Retrieved articles will be entered in Endnote ver 9.0, duplicates removed, and transferred to Epi-reviewer for screening and data abstraction. Risk of bias in the included articles will be assessed using standard criteria. Heterogeneity will be assessed using I2-statistic and sub-group analysis will be done. Data will be analysed using both narrative and quantitative synthesis. Quantitative synthesis will be done using DeSimonian and Laird Random-effects model in STATA ver 15.0.ConclusionsThe results will provide baseline information about the mortality and nutritional (anthropometric) outcomes of pneumonia among non-severely malnourished children as well as the potential effect of nutritional supplementation on these outcomes. This will provide a basis to explore the potential for nutritional supplementation improving clinical outcomes like

Journal article

Obonyo NG, Sela DP, Raman S, Rachakonda R, Schneider B, Hoe LES, Fanning JP, Bassi GL, Maitland K, Suen JY, Fraser JFet al., 2023, Resuscitation-associated endotheliopathy (RAsE): a conceptual framework based on a systematic review and meta-analysis, Systematic Reviews, Vol: 12, ISSN: 2046-4053

IntroductionShock-induced endotheliopathy (SHINE), defined as a profound sympathoadrenal hyperactivation in shock states leading to endothelial activation, glycocalyx damage, and eventual compromise of end-organ perfusion, was first described in 2017. The aggressive resuscitation therapies utilised in treating shock states could potentially lead to further worsening endothelial activation and end-organ dysfunction.ObjectiveThis study aimed to systematically review the literature on resuscitation-associated and resuscitation-induced endotheliopathy.MethodsA predetermined structured search of literature published over an 11-year and 6-month period (1 January 2011 to 31 July 2023) was performed in two indexed databases (PubMed/MEDLINE and Embase) per PRISMA guidelines. Inclusion was restricted to original studies published in English (or with English translation) reporting on endothelial dysfunction in critically ill human subjects undergoing resuscitation interventions. Reviews or studies conducted in animals were excluded. Qualitative synthesis of studies meeting the inclusion criteria was performed. Studies reporting comparable biomarkers of endothelial dysfunction post-resuscitation were included in the quantitative meta-analysis.ResultsThirty-two studies met the inclusion criteria and were included in the final qualitative synthesis. Most of these studies (47%) reported on a combination of mediators released from endothelial cells and biomarkers of glycocalyx breakdown, while only 22% reported on microvascular flow changes. Only ten individual studies were included in the quantitative meta-analysis based on the comparability of the parameters assessed. Eight studies measured syndecan-1, with a heterogeneity index, I2 = 75.85% (pooled effect size, mean = 0.27; 95% CI − 0.07 to 0.60; p = 0.12). Thrombomodulin was measured in four comparable studies (I2 = 78.93%; mean = 0.41; 95

Journal article

Maitland K, Hamaluba M, Obonyo N, Oguda E, Mogoka C, Williams T, Chaponda M, Miti S, Kamavu LK, Connon R, Gibb D, Dondorp A, Day N, White N, Walker S, George E, Severe Malaria in African Children A Research and Trials SMAART consortiumet al., 2023, SEVUparin as a potential Adjunctive Treatment in children with severe malaria: a phase I trial safety and dose finding trial (SEVUSMAART), Wellcome Open Research, Vol: 8, ISSN: 2398-502X

BackgroundEven on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to Plasmodium falciparum erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes . Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences.MethodsA Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (> 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods.ConclusionsThe results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes.RegistrationPACTR number: 202007890194806 (da

Journal article

Oymaboko MA, Olupot-Olupot P, Were W, Namayanja C, Onyas P, Titin H, Baseke J, Muhindo R, Kayembe D, Ndjowo P, Basara B, Okalebo C, Williams T, Uyoga S, Taya C, Bamisaiye A, Fanello C, Maitland K, Day N, Taylor W, Mukaka Met al., 2023, Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low dose primaquine or placebo, BMC Medicine, Vol: 21, ISSN: 1741-7015

Background:Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status.Methods:This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months–11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status.Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively.Results:One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status.The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more li

Journal article

Mukaka M, Onyamboko MA, Olupot-Olupot P, Peerawaranun P, Suwannasin K, Pagornrat W, Kouhathong J, Madmanee W, Were W, Namayanja C, Onyas P, Titin H, Baseke J, Muhindo R, Kayembe DK, Ndjowo PO, Basara BB, Bongo GS, Okalebo CB, Abongo G, Uyoga S, Williams TN, Taya C, Dhorda M, Dondorp AM, Waithira N, Imwong M, Maitland K, Fanello C, Day NPJ, Tarning J, White NJ, Taylor WRJet al., 2023, Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria, EBioMedicine, Vol: 96, ISSN: 2352-3964

Background:There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd).Methods:Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m–<1 y: 1.25 mg, 1–5 y: 2.5 mg, 6–9 y: 5 mg, 10–11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes.Findings:258 children (median age 5 [interquartile range (IQR) 3–7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10–0.40 (median 0.21, IQR 0.16–0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3–447 (median 103.0, IQR 72.1–140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m–<1 y, n = 12), 582.8 (1–5 y, n = 126), 871.1 (6–9 y, n = 80), and 931.0 (10–11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8–5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used.Int

Journal article

Jobarteh ML, McCrory MA, Lo B, Triantafyllidis KK, Qiu J, Griffin JP, Sazonov E, Sun M, Jia W, Baranowski T, Anderson AK, Maitland K, Frost Get al., 2023, Evaluation of acceptability, functionality, and validity of a passive image-based dietary intake assessment method in adults and children of Ghanaian and Kenyan origin living in London, UK, Nutrients, Vol: 15, ISSN: 2072-6643

BACKGROUND: Accurate estimation of dietary intake is challenging. However, whilst some progress has been made in high-income countries, low- and middle-income countries (LMICs) remain behind, contributing to critical nutritional data gaps. This study aimed to validate an objective, passive image-based dietary intake assessment method against weighed food records in London, UK, for onward deployment to LMICs. METHODS: Wearable camera devices were used to capture food intake on eating occasions in 18 adults and 17 children of Ghanaian and Kenyan origin living in London. Participants were provided pre-weighed meals of Ghanaian and Kenyan cuisine and camera devices to automatically capture images of the eating occasions. Food images were assessed for portion size, energy, nutrient intake, and the relative validity of the method compared to the weighed food records. RESULTS: The Pearson and Intraclass correlation coefficients of estimates of intakes of food, energy, and 19 nutrients ranged from 0.60 to 0.95 and 0.67 to 0.90, respectively. Bland-Altman analysis showed good agreement between the image-based method and the weighed food record. Under-estimation of dietary intake by the image-based method ranged from 4 to 23%. CONCLUSIONS: Passive food image capture and analysis provides an objective assessment of dietary intake comparable to weighed food records.

Journal article

Opi DH, Ndila CM, Uyoga S, Macharia AW, Fennell C, Ochola LB, Nyutu G, Siddondo BR, Ojal J, Shebe M, Awuondo KO, Mturi N, Peshu N, Tsofa B, Band G, Maitland K, Kwiatkowski DP, Rockett KA, Williams TN, Rowe JAet al., 2023, Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria, PLoS Genetics, Vol: 19, Pages: 1-23, ISSN: 1553-7390

Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that “double dose” non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than “single dose” heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (p = 0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO and BO genotypes rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.

Journal article

Taylor WR, Olupot-Olupot P, Onyamboko MA, Peerawaranun P, Weere W, Namayanja C, Onyas P, Titin H, Baseke J, Muhindo R, Kayembe DK, Ndjowo PO, Basara BB, Bongo GS, Okalebo CB, Abongo G, Uyoga S, Williams TN, Taya C, Dhorda M, Tarning J, Dondorp AM, Waithira N, Fanello C, Maitland K, Mukaka M, Day NJPet al., 2023, Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial, The Lancet Infectious Diseases, Vol: 23, Pages: 471-483, ISSN: 1473-3099

BackgroundWHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo.MethodsWe conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A− variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether–lumefantrine or dihydroartemisinin–piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants.FindingsParticipants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed

Journal article

Nabawanuka E, Ameda F, Erem G, Bugeza S, Opoka RO, Kiguli S, Amorut D, Aloroker F, Olupot-Olupot P, Mnjalla H, Mpoya A, Maitland Ket al., 2023, Cardiovascular abnormalities in chest radiographs of children with pneumonia, Uganda, Bulletin of the World Health Organization, Vol: 101, Pages: 202-210, ISSN: 0042-9686

Objective: To describe chest radiograph findings among children hospitalized with clinically diagnosed severe pneumonia and hypoxaemia at three tertiary facilities in Uganda.Methods: The study involved clinical and radiograph data on a random sample of 375 children aged 28 days to 12 years enrolled in the Children's Oxygen Administration Strategies Trial in 2017. Children were hospitalized with a history of respiratory illness and respiratory distress complicated by hypoxaemia, defined as a peripheral oxygen saturation (SpO2) < 92%. Radiologists blinded to clinical findings interpreted chest radiographs using standardized World Health Organization method for paediatric chest radiograph reporting. We report clinical and chest radiograph findings using descriptive statistics.Findings: Overall, 45.9% (172/375) of children had radiological pneumonia, 36.3% (136/375) had a normal chest radiograph and 32.8% (123/375) had other radiograph abnormalities, with or without pneumonia. In addition, 28.3% (106/375) had a cardiovascular abnormality, including 14.9% (56/375) with both pneumonia and another abnormality. There was no significant difference in the prevalence of radiological pneumonia or of cardiovascular abnormalities or in 28-day mortality between children with severe hypoxaemia (SpO2: < 80%) and those with mild hypoxaemia (SpO2: 80 to < 92%).Conclusion: Cardiovascular abnormalities were relatively common among children hospitalized with severe pneumonia in Uganda. The standard clinical criteria used to identify pneumonia among children in resource-poor settings were sensitive but lacked specificity. Chest radiographs should be performed routinely for all children with clinical signs of severe pneumonia because it provides useful information on both cardiovascular and respiratory systems.Methods: We studied chest x-rays of 375 children aged 28 days to 12 years enrolled into the Children’s Oxygen Administration Strategies Trial (COAST)(ISRCTN15622505).

Journal article

Olupot-Olupot P, Okiror W, Mnjalla H, Muhindo R, Uyoga S, Mpoya A, Williams T, terHeine R, Burger D, Urban B, Connon R, George E, Gibb D, Walker S, Maitland Ket al., 2023, Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial [version 2; peer review: 1 approved], Wellcome Open Research, Vol: 6, Pages: 1-23, ISSN: 2398-502X

Background: African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests.Methods: A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection.Discussion: We plan to study azithromycin because of its favourable microbiological spectrum, its inherent antimalarial and immunomodulatory properties and dosing and safety profile. This study

Journal article

Nalwanga D, Bakker C, Kiggwe A, Negash AA, Ocan M, Briend A, Maitland K, Musiiime V, Karamagi Cet al., 2023, Mortality among non-severely under nourished children with pneumonia globally: protocol for a systematic review and meta-analysis., Wellcome open research, Vol: 8, ISSN: 2398-502X

<h4>Background</h4>Pneumonia remains the commonest cause of ill health and mortality among children worldwide. Severe undernutrition increases the mortality risk among children with pneumonia. While children with pneumonia are at increased risk of developing malnutrition, the impact of pneumonia on mortality and nutritional status of non-severely undernourished children is not well described. The impact of nutritional supplementation on mortality and nutritional status in this population is not well understood. This review will collate available evidence on the all-cause mortality and anthropometric indices outcomes following pneumonia, as well as the impact of nutritional supplementation on mortality and anthropometry among non-severely malnourished children with pneumonia.<h4>Methods</h4>The review will be done using <i>a priori</i> criteria developed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data will be obtained from data bases, grey literature, and bibliographies. An experienced librarian will conduct article search in PUBMED, MEDLINE, EMBASE, Web of Science, Google scholar, and Scopus. Retrieved articles will be entered in Endnote <i>ver</i> 9.0, duplicates removed, and transferred to Epi-reviewer for screening and data abstraction. Risk of bias in the included articles will be assessed using standard criteria. Heterogeneity will be assessed using I <sup>2</sup>-statistic and sub-group analysis will be done. Data will be analysed using both narrative and quantitative synthesis. Quantitative synthesis will be done using DeSimonian and Laird Random-effects model in STATA <i>ver</i> 15.0.<h4>Conclusions</h4>The results will provide baseline information about the mortality and anthropometric outcomes of pneumonia among non-severely malnourished children as well as the potential effect of nutritional supplementation on these

Journal article

Walsh K, Delamare de la Villenaise de Chenevarin G, McGurk J, Maitland K, Frost Get al., 2023, Development of a legume-enriched feed for treatment of severe acute malnutrition, Wellcome Open Research, Vol: 6, ISSN: 2398-502X

Background: Outcomes in children hospitalised with severe acute malnutrition (SAM) remain poor. The current milk-based formulations focus on restoring weight-gain but fail to address modification of the integrity of the gut barrier and may exacerbate malabsorption owing to functional lactase, maltase and sucrase deficiency. We hypothesise that nutritional feeds should be designed to promote bacterial diversity and restore gastrointestinal (GI) barrier function. Methods: Our major objective was to develop a lactose-free, fermentable carbohydrate-containing alternative to traditional F75 and F100 formulae for the inpatient treatment of SAM. New target nutritional characteristics were developed and relevant food and infant food specific legislation were reviewed. Suitable certified suppliers of ingredients were identified. Processing and manufacture steps were evaluated and optimised for safety (nutritional, chemical and microbiological), and efficacy at meeting target characteristics (lactose-free, containing resistant starch 0.4-0.5% final product weight). Results: A final validated production process was developed and implemented to produce a novel food product for the inpatient treatment of SAM in children in Africa designed to reduce risk of osmotic diarrhoea and support symbiotic gut microbial populations. The final product matched the macronutrient profile of double-concentrated F100, adhered to all relevant legislation regulating infant foods, was lactose free, and contained 0.6% resistant starch. Chickpeas were selected as the source of resistant starch, since they are widely grown and eaten throughout Africa. Micronutrient content could not be matched in this ready-to-use product, so this was replaced at the point of feeding, as was fluid lost through concentration. Conclusions: The processes and product described illustrate the development steps for a novel nutritional product. The new feed product was ready for evaluation for safety and efficacy in a phase

Journal article

Lucey O, Acana S, Olupot-Olupot P, Muhindo R, Ayikobua R, Uyoga S, Kyeyune D, Cooke G, Maitland Ket al., 2022, High false discovery rate of the Architect anti-HCV screening test in blood donors in Uganda and evaluation of an algorithm for confirmatory testing, Vox Sanguinis: international journal of transfusion medicine, Vol: 117, Pages: 1360-1367, ISSN: 0042-9007

Background and Objectives:Adequate supplies of donor blood remains a major challenge in sub-Saharan Africa. This is exacerbated by lack of confirmatory testing for transfusion transmitted infections by Blood Transfusion Services (BTS) leading to significant blood disposal owing to putatively high seroprevalence rates amongst Ugandan blood donors. We aimed to ascertain the false discoveryrate of the Architect anti-HCV screening assay, categorise screen-reactive samples into 3 groups: presumed false-positive, active and past infection, and develop an algorithm for confirmatory testing.Materials and Methods:470 screen-reactive HCV blood donations were re-tested using the Architect anti-HCV assay, an alternative antibody test (SD biosensor) and a core antigen test. Sample-to-cut-off (S/CO) ratios and pre-analytical factors (centrifugation speed, haemolysis check, time between collection and testing) were recorded. Based on S/CO ratio evaluation, we propose a testing algorithm to guide supplemental tests.Results:The false discovery rate of the Architect anti-HCV assay was 0.84 as 395/470 (84%) screen-reactive samples had no evidence of HCV infection (SD biosensor and core antigen negative) (presumed false-positive). 38/470 (8.1%) were antigenaemic and 32/470 (6.8%) had evidence of past infection.The median S/CO ratios of the presumed false-positive and active infection samples were 1.8 and 17.3 respectively. The positive predictive value of HCV positivity in samples with ratios above 12 was 91.8%. On re-testing, 104/470 (22.1%) samples became negative.Conclusion:The Architect anti-HCV assay has a very high false discovery rate in Ugandan BTSs leading to excessive blood disposal. Pre-analytical factors likely contribute to this. Introduction of confirmatory testing using an algorithm based on S/CO ratio evaluation could limit unnecessary blood wastage and donor deferral.

Journal article

White NJ, Watson JA, Uyoga S, Williams TN, Maitland KMet al., 2022, Substantial misdiagnosis of severe malaria in African children, The Lancet, Vol: 400, Pages: 807-807, ISSN: 0140-6736

Journal article

Uyoga S, Olupot-Olupot P, Connon R, Kiguli S, Opoka R, Alaroker F, Muhindo R, Macharia AW, Dondorp A, Gibb D, Walker AS, George E, Maitland K, Williams Tet al., 2022, Sickle cell anaemia and severe P. falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children (TRACT) trial, The Lancet Child & Adolescent Health, Vol: 6, Pages: 606-613, ISSN: 2352-4642

BackgroundSickle cell anaemia (SCA; HbSS) has historically been associated with high levels of childhood mortality in Africa. While malaria plays a major contribution to this mortality to date, the clinical pathology of malaria among children with SCA has been poorly described. Methods We investigated the burden and severity of malaria infections among children recruited with severe anaemia to the TRACT trial of blood transfusion in Africa. This secondary analysis, conducted after trial completion, is restricted to Uganda, where the birth prevalence of SCA is approximately 1% and malaria transmission is high. Children were classified as normal (HbAA), heterozygous (HbAS) or homozygous (HbSS; SCA) for the rs334 A>T sickle mutation in HBB following batch-genotyping by PCR at the end of trial. To avoid confounding from SCA-specific medical interventions, we considered children with an existing diagnosis of SCA (known-SCA) separately from those diagnosed at the end of the trial (unknown-SCA). Findings Overall, 1,038 of 3,483 (30%) of the Ugandan children recruited to TRACT had SCA. While 1,815/2,321 (78%) of the non-SCA (HbAA) children tested positive for P. falciparum malaria, the prevalence was significantly lower in children with SCA (347/1,038; 33%; p<0.001). Concentrations of plasma P. falciparum Histidine Rich Protein 2 (PfHRP2), a marker of the total burden of malaria parasites within an individual, were significantly lower in children with either known-SCA (median 8 ng/mL; IQR 0-57) or unknown-SCA (7 ng/mL (0-50 ng/mL) than in HbAA children (346 ng/mL; 21-2,121; p<0.001). By contrast to HbAA children, few HbSS children presented with classic features of severe and complicated malaria, but both the frequency and severity of anaemia were higher in HbSS children.Interpretation The current study suggests that children with SCA are innately protected against classic severe malaria. However, it also shows that even low-level infections can precipitate severe

Journal article

Gilchrist JJ, Kariuki S, Watson JA, Band G, Uyoga S, Ndila CM, Mturi N, Mwarumba S, Mohammed S, Mosobo M, Alasoo K, Rockett KA, Mentzer A, Kwiatkowski DP, Hill AVS, Maitland K, Scott JAG, Williams Tet al., 2022, BIRC6 modifies risk of invasive bacterial infection in Kenyan children, eLife, Vol: 11, Pages: 1-23, ISSN: 2050-084X

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with P. falciparum parasitaemia. We construct a joint dataset including 1,445 bacteraemia cases and 1,143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.

Journal article

Watson J, Uyoga S, Wanjiku P, Makale J, Nyutu G, Mturi N, George E, Woodrow C, Day N, Bejon P, Opoka R, Dondorp A, John C, Maitland K, Williams T, White Net al., 2022, Improving the diagnosis of severe malaria in African children using platelet counts and plasma Pf HRP2 concentrations, Science Translational Medicine, Vol: 14, Pages: 1-10, ISSN: 1946-6234

Severe falciparum malaria is difficult to diagnose accurately in children inhigh transmission settings. Using data from 2,649 patients enrolled in fourstudies of severe illness in three countries (Bangladesh, Kenya, and Uganda),we fitted Bayesian latent class models using two diagnostic biomarkers: theplatelet count and the plasma PfHRP2 concentration. In severely ill patientswith clinical features consistent with severe malaria, a combined platelet count≤ 150,000 per µL and a plasma PfHRP2 concentration ≥ 1,000 ng/mL had anestimated sensitivity of 74% and specificity of 93% in identifying ‘true’ severefalciparum malaria. Compared to misdiagnosed children, patients with truesevere malaria had higher parasite densities, lower hematocrits, lower ratesof invasive bacterial disease, and a lower prevalence of both HbAS and HbSS.We estimate one third of African children enrolled in clinical studies of severemalaria in high transmission settings had another cause of severe illness.

Journal article

Obonyo N, Olupot-Olupot P, Mpoya A, Nteziyaremye J, Chebet M, Uyoga S, Muhindo R, Fanning J, Shiino K, Chan J, Fraser JF, Maitland Ket al., 2022, A clinical and physiological prospective observational study on the management of pediatric shock in the post-fluid expansion as supportive therapy trial era, Pediatric Critical Care Medicine, Vol: 23, Pages: 502-513, ISSN: 1529-7535

Objectives: Fluid bolus resuscitation in African children is harmful. Little research has evaluated physiologic effects of maintenance-only fluid strategy.Design: We describe the efficacy of fluid-conservative resuscitation of septic shock using case-fatality, hemodynamic, and myocardial function endpoints.Setting: Pediatric wards of Mbale Regional Referral Hospital, Uganda, and Kilifi County Hospital, Kenya, conducted between October 2013 and July 2015. Data were analysed from August 2016 to July 2019.Patients: Children (≥ 60 d to ≤ 12 yr) with severe febrile illness and clinical signs of impaired perfusion.Interventions: IV maintenance fluid (4 mL/kg/hr) unless children had World Health Organization (WHO) defined shock (≥ 3 signs) where they received two fluid boluses (20 mL/kg) and transfusion if shock persisted. Clinical, electrocardiographic, echocardiographic, and laboratory data were collected at presentation, during resuscitation and on day 28. Outcome measures were 48-hour mortality, normalization of hemodynamics, and cardiac biomarkers.Measurement and Main Results: Thirty children (70% males) were recruited, six had WHO shock, all of whom died (6/6) versus three of 24 deaths in the non-WHO shock. Median fluid volume received by survivors and nonsurvivors were similar (13 [interquartile range (IQR), 9–32] vs 30 mL/kg [28–61 mL/kg], z = 1.62, p = 0.23). By 24 hours, we observed increases in median (IQR) stroke volume index (39 mL/m2 [32–42 mL/m2] to 47 mL/m2 [41–49 mL/m2]) and a measure of systolic function: fractional shortening from 30 (27–33) to 34 (31–38) from baseline including children managed with no-bolus. Children with WHO shock had a higher mean level of cardiac troponin (t = 3.58; 95% CI, 1.24–1.43; p = 0.02) and alpha-atrial natriuretic peptide (t = 16.5; 95% CI, 2.80–67.5; p < 0.01) at admission compared with non-WHO shock. Elevate

Journal article

Uyoga S, Watson J, Wanjiku P, Rop J, Makale J, Macharia A, Kariuki S, Nyutu G, Shebe M, Mosobo M, Mturi N, Rockett K, Woodrow C, Dondorp A, Maitland K, White N, Williams Tet al., 2022, The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria, Nature Communications, Vol: 13, Pages: 1-7, ISSN: 2041-1723

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.

Journal article

Olupot-Olupot P, Connon R, Kiguli S, Opoka RO, Alaroker F, Uyoga S, Nakuya M, Okiror W, Nteziyaremye J, Ssenyondo T, Nabawanuka E, Kayaga J, Williams Mukisa C, Amorut D, Muhindo R, Frost G, Walsh K, Macharia AW, Gibb DM, Walker AS, George EC, Maitland K, Williams TN, Williams Tet al., 2022, A predictive algorithm for identifying children with sickle cell anemia among children admitted to hospital with severe anemia in Africa, American Journal of Hematology, Vol: 97, Pages: 527-536, ISSN: 0361-8609

Sickle cell anemia (SCA) is common in sub-Saharan Africa where approximately 1% of births are affected. Severe anemia is a common cause for hospital admission within the region yet few studies have investigated the contribution made by SCA. The Transfusion and Treatment of severe anemia in African Children Trial (ISRCTN84086586) investigated various treatment strategies in 3983 children admitted with severe anemia (hemoglobin < 6.0 g/dl) based on two severity strata to four hospitals in Africa (three Uganda and one Malawi). Children with known-SCA were excluded from the uncomplicated stratum and capped at 25% in the complicated stratum. All participants were genotyped for SCA at trial completion. SCA was rare in Malawi (six patients overall), so here we focus on the participants recruited in Uganda. We present baseline characteristics by SCA status and propose an algorithm for identifying children with unknown-SCA. Overall, 430 (12%) and 608 (17%) of the 3483 Ugandan participants had known- or unknown-SCA, respectively. Children with SCA were less likely to be malaria-positive and more likely to have an affected sibling, have gross splenomegaly, or to have received a previous blood transfusion. Most outcomes, including mortality and readmission, were better in children with either known or unknown-SCA than non-SCA children. A simple algorithm based on seven admission criteria detected 73% of all children with unknown-SCA with a number needed to test to identify one new SCA case of only two. Our proposed algorithm offers an efficient and cost-effective approach to identifying children with unknown-SCA among all children admitted with severe anemia to African hospitals where screening is not widely available.

Journal article

George EC, Uyoga S, M'baya B, Byabazair DK, Kiguli S, Olupot-Olupot P, Opoka RO, Chagaluka G, Alaroker F, Williams TN, Bates I, Mbanya D, Gibb DM, Walker AS, Maitland K, TRACT trail study groupet al., 2022, Whole blood versus red cell concentrates for children with severe anaemia: a secondary analysis of the Transfusion and Treatment of African Children (TRACT) trial, The Lancet Global Health, Vol: 10, Pages: e360-e368, ISSN: 2214-109X

Background:The multicentre Transfusion and Treatment of African Children (TRACT) trial established best evidence on the timing of transfusion in children with uncomplicated anaemia (haemoglobin 4-6g/dl) and optimal volume (20 versus 30ml/kg whole blood (or 10 vs 15ml/kg red cell concentrates) for transfusion in children hospitalised with severe anaemia (Hb <6g/dl) on Day 28 mortality (primary endpoint) and secondary endpoints including safety. As evidence on the safety of blood components is limited we undertook a secondary analysis comparing children receiving whole blood versus red cell concentrates as their initial transfusion on clinical outcomes. Methods :This analysis includes 3188 children with severe anaemia (Hb <6g/dl) who received either whole blood or red cell concentrates. Whole blood or cell concentrates were issued routinely by the blood transfusion services, but not prespecified on the request form. The impact of blood pack type on haematological correction, re-transfusion, and other clinical endpoints was explored using multivariate regression models. Findings:1632/3992 (41%) transfusions in 3188 children were whole blood. Compared with whole blood, children receiving cell concentrates in their first transfusion had less haemoglobin recovery at 8 hours (packed cells mean(95%CI): -1.3(-1.5,-1.0) 20ml/kg arm,-1.4(-1.6,-1.1) 30ml/kg; settled cells mean(95%CI) -1.1g/dl(-1.2,-0.9) 20ml/kg arm, -1.5g/dl(-1.7,-1.3) 30ml/kg arm; p<0.001 for pack type comparisons, p=0.003 heterogeneity by arm), higher odds of receiving a second transfusion [ORs 2.32 (95%CI 1.30,4.12) and 2.97 (2.18,4.05) respectively; p<0.001], and had a longer time to discharge [sub-Hazard Ratios 0.94 (95%CI 0.81,1.10) and 0.86 (95% CI 0.79,0.94) respectively; p=0.002]. No child developed features of cardio-pulmonary overload. Interpretation: Whole blood is safe to use in children, resulting in superior aematologic

Journal article

Kiguli S, Olopot-Olupot P, Alaroker F, Engoru C, Opoka R, Tagoola A, Hamaluba M, Mnjalla H, Mpoya A, Mogaka C, Nalwanga D, Nabawanuka E, Nokes J, Nyaigoti C, Briend A, van Woensel J, Grieve R, Sadique Z, Williams T, Thomas K, Harrison D, Rowan K, Maitland Ket al., 2021, Children’s Oxygen Administration Strategies And Nutrition Trial (COAST-Nutrition): a protocol for a phase II randomised controlled trial, Wellcome Open Research, Vol: 6, Pages: 1-23, ISSN: 2398-502X

Background: To prevent poor long-term outcomes (deaths and readmissions) the integrated global action plan for pneumonia and diarrhoea recommends under the ‘Treat’ element of Protect, Prevent and Treat interventions the importance of continued feeding but gives no specific recommendations for nutritional support. Early nutritional support has been practiced in a wide variety of critically ill patients to provide vital cell substrates, antioxidants, vitamins, and minerals essential for normal cell function and decreasing hypermetabolism. We hypothesise that the excess post-discharge mortality associated with pneumonia may relate to the catabolic response and muscle wasting induced by severe infection and inadequacy of the diet to aid recovery. We suggest that providing additional energy-rich, protein, fat and micronutrient ready-to-use therapeutic feeds (RUTF) to help meet additional nutritional requirements may improve outcome.Methods: COAST-Nutrition is an open, multicentre, Phase II randomised controlled trial in children aged 6 months to 12 years hospitalised with suspected severe pneumonia (and hypoxaemia, SpO2 <92%) to establish whether supplementary feeds with RUTF given in addition to usual diet for 56-days (experimental) improves outcomes at 90-days compared to usual diet alone (control). Primary endpoint is change in mid-upper arm circumference (MUAC) at 90 days and/or as a composite with 90-day mortality. Secondary outcomes include anthropometric status, mortality, readmission at days 28 and 180. The trial will be conducted in four sites in two countries (Uganda and Kenya) enrolling 840 children followed up to 180 days. Ancillary studies include cost-economic analysis, molecular characterisation of bacterial and viral pathogens, evaluation of putative biomarkers of pneumonia, assessment of muscle and fat mass and host genetic studies. Discussion: This study is the first step in providing an option for nutritional support following severe pn

Journal article

Kiguli S, Olopot-Olupot P, Alaroker F, Engoru C, Opoka RO, Tagoola A, Hamaluba M, Mnjalla H, Mpoya A, Mogaka C, Nalwanga D, Nabawanuka E, Nokes J, Nyaigoti C, Briend A, van Woensel JBM, Grieve R, Sadique Z, Williams TN, Thomas K, Harrison DA, Rowan K, Maitland Ket al., 2021, Children's Oxygen Administration Strategies And Nutrition Trial (COAST-Nutrition): a protocol for a phase II randomised controlled trial., Wellcome Open Res, Vol: 6, Pages: 221-221, ISSN: 2398-502X

Background: To prevent poor long-term outcomes (deaths and readmissions) the integrated global action plan for pneumonia and diarrhoea recommends under the 'Treat' element of Protect, Prevent and Treat interventions the importance of continued feeding but gives no specific recommendations for nutritional support. Early nutritional support has been practiced in a wide variety of critically ill patients to provide vital cell substrates, antioxidants, vitamins, and minerals essential for normal cell function and decreasing hypermetabolism. We hypothesise that the excess post-discharge mortality associated with pneumonia may relate to the catabolic response and muscle wasting induced by severe infection and inadequacy of the diet to aid recovery. We suggest that providing additional energy-rich, protein, fat and micronutrient ready-to-use therapeutic feeds (RUTF) to help meet additional nutritional requirements may improve outcome. Methods: COAST-Nutrition is an open, multicentre, Phase II randomised controlled trial in children aged 6 months to 12 years hospitalised with suspected severe pneumonia (and hypoxaemia, SpO 2 <92%) to establish whether supplementary feeds with RUTF given in addition to usual diet for 56-days (experimental) improves outcomes at 90-days compared to usual diet alone (control). Primary endpoint is change in mid-upper arm circumference (MUAC) at 90 days and/or as a composite with 90-day mortality. Secondary outcomes include anthropometric status, mortality, readmission at days 28 and 180. The trial will be conducted in four sites in two countries (Uganda and Kenya) enrolling 840 children followed up to 180 days. Ancillary studies include cost-economic analysis, molecular characterisation of bacterial and viral pathogens, evaluation of putative biomarkers of pneumonia, assessment of muscle and fat mass and host genetic studies.   Discussion: This study is the first step in providing an option for nutritional support following severe p

Journal article

Walsh K, Delamare de la Villenaise de Chenevarin G, McGurk J, Maitland K, Frost Get al., 2021, Development of a legume-enriched feed for treatment of severe acute malnutrition [version 1; peer review: 1 approved with reservations], Wellcome Open Research, Vol: 6, ISSN: 2398-502X

Outcomes in children hospitalised with severe acute malnutrition (SAM) remain poor. The current milk-based formulations focus on restoring weight-gain but fail to address modification of the integrity of the gut barrier and may exacerbate malabsorption owing to functional lactase, maltase and sucrase deficiency. We hypothesise that nutritional feeds should be designed to promote bacterial diversity and restore gastrointestinal (GI) barrier function.</ns3:p><ns3:p> <ns3:bold>Methods:</ns3:bold> Our major objective was to develop a lactose-free, fermentable carbohydrate-containing alternative to traditional F75 and F100 formulae for the inpatient treatment of SAM. New target nutritional characteristics were developed and relevant food and infant food specific legislation were reviewed. Suitable certified suppliers of ingredients were identified. Processing and manufacture steps were evaluated and optimised for safety (nutritional, chemical and microbiological), and efficacy at meeting target characteristics (lactose-free, containing resistant starch 0.4-0.5% final product weight).</ns3:p><ns3:p> <ns3:bold>Results:</ns3:bold> A final validated production process was developed and implemented to produce a novel food product for the inpatient treatment of SAM in children in Africa designed to reduce risk of osmotic diarrhoea and support symbiotic gut microbial populations. The final product matched the macronutrient profile of double-concentrated F100, adhered to all relevant legislation regulating infant foods, was lactose free, and contained 0.6% resistant starch. Chickpeas were selected as the source of resistant starch, since they are widely grown and eaten throughout Africa. Micronutrient content could not be matched in this ready-to-use product, so this was replaced at the point of feeding, as was fluid lost through concentration.</ns3:p><ns3:p> <ns3:bold>Conclusions:</ns3:bold> The processes a

Journal article

Connon R, George EC, Olupot-Olupot P, Kiguli S, Chagaluka G, Alaroker F, Opoka RO, Mpoya A, Walsh K, Engoru C, Nteziyaremye J, Mallewa M, Kennedy N, Nakuya M, Namayanja C, Nabawanuka E, Sennyondo T, Amorut D, Williams Musika C, Bates I, Boele van Hensbroek M, Evans JA, Uyoga S, Williams TN, Frost G, Gibb DM, Maitland K, Walker AS, TRACT trial groupet al., 2021, Incidence and predictors of hospital readmission in children presenting with severe anaemia in Uganda and Malawi: a secondary analysis of TRACT trial data, BMC Public Health, Vol: 21, ISSN: 1471-2458

BACKGROUND: Severe anaemia (haemoglobin < 6 g/dL) is a leading cause of recurrent hospitalisation in African children. We investigated predictors of readmission in children hospitalised with severe anaemia in the TRACT trial (ISRCTN84086586) in order to identify potential future interventions. METHODS: Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. RESULTS: Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63-3.78), p < 0.001); ≥2 hospital admissions in the preceding 12 months (1.44(1.19-1.74), p < 0.001); history of transfusion (1.48(1.13-1.93), p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21-1.69), p < 0.001). Children with uncomplicated severe anaemia (Hb 4-6 g/dL and no severity features), who never received a transfusion (per trial protocol) during the initial admission had a substantially lower risk of readmission (0.67(0.47-0.96), p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47-0.76), p < 0.001); younger-age (1.07 (1.03-1.10) per 1 year younger, p < 0.001) and known sickle cell disease (0.62(0.46-0.82), p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross

Journal article

Watson JA, Ndila CM, Uyoga S, Macharia A, Nyutu G, Mohammed S, Ngetsa C, Mturi N, Peshu N, Tsofa B, Rockett K, Leopold S, Kingston H, George EC, Maitland K, Day NP, Dondorp AM, Bejon P, Williams T, Holmes CC, White NJet al., 2021, Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision., eLife, Vol: 10, Pages: 1-39, ISSN: 2050-084X

Severe falciparum malaria has substantially affected human evolution. Genetic association studies of patients with clinically defined severe malaria and matched population controls have helped characterise human genetic susceptibility to severe malaria, but phenotypic imprecision compromises discovered associations. In areas of high malaria transmission the diagnosis of severe malaria in young children and, in particular, the distinction from bacterial sepsis, is imprecise. We developed a probabilistic diagnostic model of severe malaria using platelet and white count data. Under this model we re-analysed clinical and genetic data from 2,220 Kenyan children with clinically defined severe malaria and 3,940 population controls, adjusting for phenotype mis-labelling. Our model, validated by the distribution of sickle trait, estimated that approximately one third of cases did not have severe malaria. We propose a data-tilting approach for case-control studies with phenotype mis-labelling and show that this reduces false discovery rates and improves statistical power in genome-wide association studies.

Journal article

Olupot-Olupot P, Aloroker F, Mpoya A, Mnjalla H, Passi G, Nakuya M, Houston K, Obonyo N, Hamaluba M, Evans J, Connon R, George E, Gibb D, Maitland Ket al., 2021, Gastroenteritis rehydration of children with severe acute malnutrition (GASTROSAM): a phase II randomised controlled trial: trial protocol, Wellcome Open Research, Vol: 6, Pages: 1-16, ISSN: 2398-502X

Background: Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea ( ≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial is the first step in reappraising current recommendations. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling Ugandan and Kenyan children aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is urine output (mls/kg/hour at 8 hours post-randomisation), and for oral rehydration a change in sodium levels at 24 hours post-randomisation. This trial will also generate feasibility, safety and preliminary data on survival to 28 days. Discussion. If current rehydration strategies for non-maln

Journal article

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