Publications
11 results found
Walsh K, Delamare de la Villenaise de Chenevarin G, McGurk J, et 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
Olupot-Olupot P, Connon R, Kiguli S, et 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.
George EC, Uyoga S, M'baya B, et 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
Walsh K, Delamare de la Villenaise de Chenevarin G, McGurk J, et 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
Connon R, George EC, Olupot-Olupot P, et 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
Calder N, Walsh K, Olupot-Olupot P, et al., 2021, Modifying gut integrity and microbiome in children with severe acute malnutrition using LEgume-Based Feeds [MIMBLE]: A pilot trial, Cell Reports Medicine, Vol: 2, Pages: 1-17, ISSN: 2666-3791
Case fatality among African children with severe acute malnutrition remains high. We report a 3-arm pilot trial in 58 Ugandan children, comparing feeds targeting disordered gastrointestinal function containing cowpea (CpF, n = 20) or inulin (InF, n = 20) with conventional feeds (ConF, n = 18). Baseline measurements of gut permeability (lactulose:mannitol ratio 1.19 ± SD 2.00), inflammation (fecal calprotectin 539.0 μg/g, interquartile range [IQR] 904.8), and satiety (plasma polypeptide YY 62.6 pmol/l, IQR 110.3) confirm gastrointestinal dysfunction. By day 28, no differences are observable in proportion achieving weight gain >5 g/kg/day (87%, 92%, 86%; p > 0.05), mortality (16%, 30%, 17%; p > 0.05), or edema resolution (83%, 54%, 91%; p > 0.05) among CpF, InF, and ConF. Decreased fecal bacterial richness from day 1 (abundance-based coverage estimator [ACE] 53.2) to day 7 (ACE 40.8) is observed only in ConF (p = 0.025). Bifidobacterium relative abundance increases from day 7 (5.8% ± 8.6%) to day 28 (10.9% ± 8.7%) in CpF (corrected p = 1.000). Legume-enriched feeds support aspects of gut function and the microbiome. Trial registration PACTR201805003381361.
Maitland K, Olupot-Olupot P, Kiguli S, et al., 2019, Co-trimoxazole or multi-mineral multi-vitamins to improve post-discharge outcomes following severe anaemia in African children: a randomised controlled trial, The Lancet Global Health, Vol: 7, Pages: e1435-e1447, ISSN: 2214-109X
Background: Severe anaemia (haemoglobin<6g/dl) is a leading cause of paediatric admission inAfrica; post-discharge outcomes remain poor with high 6-month mortality (8%) and re-admission(17%). This trial aimed to investigate pragmatic post-discharge interventions that might improveoutcomes.Methods: Within the factorial open-label TRACT trial, Ugandan and Malawian children aged 2months-12 years with severe anaemia (haemoglobin <6g/dl) at hospital admission wererandomised (using sequentially-numbered envelopes linked to a second set of non-sequentiallynumbered allocations, stratified by centre and severity) to enhanced nutritional supplementationwith iron and folate-containing multi-vitamin multi-mineral supplements (MVMM) or iron/folateat treatment doses (usual care), and to cotrimoxazole versus no cotrimoxazole, both given for 3months post-discharge. Separately-reported randomisations investigated transfusionmanagement. The primary outcome was 180-day mortality analysed by intention-to-treat; followup was to 180-days (completed).Findings: 3983 eligible children were randomised and followed for 180-days [164(4%) lost-tofollow-up]. Treatment was initiated in 1901(95%) MVMM, 1911(96%) iron/folate and 1922(96%)cotrimoxazole. By day-180, 166(8%) MVMM vs 169(9%) iron/folate had died (hazardratio(HR)=0.97 (95% CI 0.79-1.21); p=0.81) and 172(9%) cotrimoxazole vs 163(8%) nocotrimoxazole had died (HR=1.07 (95% CI 0.86-1.32); p=0.56). No evidence was seen ofinteractions between these randomisations or with transfusion randomisations (p>0.2). By day180, 489(24%) MVMM vs 509(26%) iron/folate had experienced one or more SAEs (HR=0.95 (0.84-1.07), p=0.40) and 500(25%) cotrimoxazole vs 498(25%) no cotrimoxazole (HR=1.01 (0.89,1.15)p=0.85). Most SAEs were readmissions, occurring in 692(17%) children (175(4%) with ≥2 readmissions).Interpretation: Neither enhanced supplementation with MVMM versus iron/folate treatment orcotrimoxazole prophylaxis improved 6-month survival. H
Consortium H, Drake L, Frost G, et al., 2019, Health outcomes in Undernutrition: the role of Nutrients, Gut dysfunction and the gut microbiome (HUNGer), Health outcomes in Undernutrition: the role of Nutrients, Gut dysfunction and the gut microbiome (HUNGer), Publisher: Imperial College London
The HUNGer consortium is comprised of a multi-disciplinary, multi-national consortium of world leading researchers, with expertise in physiology and nutrition, through to clinical research, public health and agriculture in LMIC settings. The HUNGer consortium was awarded the MRC Confidence in Global Nutrition and Health award in 2018.The HUNGer consortium is developing a programme of work that will directly address United Nations Sustainable Development Goal 2 (SDG-2): End hunger, achieve food security and improve nutrition, and promote sustainable agriculture. We believe there are a number of critical unanswered questions regarding the role of the gut in undernutrition, which if answered could significantly improve the effective management and prevention of undernutrition.The following document represents the consensus opinion of the HUNGer consortium concerning the key challenges that currently limit the effective management and prevention of undernutrition and the most promising potential solutions.
Walsh K, Calder N, Olupot-Olupot P, et al., 2018, Modifying Intestinal Integrity and Micro Biome in Severe Malnutrition with Legume-Based Feeds (MIMBLE 2.0): protocol for a phase II refined feed and intervention trial [version 1; referees: 2 approved], Wellcome Open Research, Vol: 3, Pages: 95-95, ISSN: 2398-502X
Background: Changes in intestinal mucosal integrity and gut microbial balance occur in severe acute malnutrition (SAM), resulting in treatment failure and adverse clinical outcomes (gram-negative sepsis, diarrhoea and high case-fatality). Transient lactose intolerance, due to loss of intestinal brush border lactase, also complicates SAM, thus milk based feeds may not be optimal for nutritional rehabilitation. Since the gut epithelial barrier can be supported by short chain fatty acids, derived from microbiota fermentation by particular fermentable carbohydrates, we postulated that an energy-dense nutritional feed comprising of legume-based fermentable carbohydrates, incorporated with lactose-free versions of standard World Health Organization (WHO) F75/F100 nutritional feeds will enhance epithelial barrier function in malnourished children, reduce and promote resolution of diarrhoea and improve overall outcome. Methods: We will investigate in an open-label trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference <11.5cm and/or presence of kwashiorkor. Children will be randomised to a lactose-free, chickpea-enriched feed containing 2 kcal/ml, provided in quantities to match usual energy provision (experimental) or WHO standard treatment F75 (0.75 kcal/ml) and F100 (1 kcal/ml) feeds on a 1:1 basis, conducted at Mbale Regional Referral Hospital nutritional rehabilitation unit. The primary outcomes are change in MUAC at day 90 and survival to day 90. Secondary outcomes include: i) moderate to good weight gain (>5 g/kg/day), ii) de novo development of diarrhoea (>3 loose stools/day), iii) time to diarrhoea resolution (if >3 loose stools/day), and iv) time to oedema resolution (if kwashiorkor) and change in intestinal biomarkers (faecal calprotectin). Discussion: We hypothesize that, if introduced early in the management of malnutrition, such lactose-free, fermentable carbohydrate-based feeds, could safely and cheaply improve global outco
Walsh K, Calder N, Olupot-Olupot P, et al., 2018, Modifying Intestinal Integrity and MicroBiome in Severe Malnutrition with Legume-Based Feeds (MIMBLE 2.0): protocol for a phase II refined feed and intervention trial, Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background: Changes in intestinal mucosal integrity and gut microbial balance occur in severe acute malnutrition (SAM), resulting in treatment failure and adverse clinical outcomes (gram-negative sepsis, diarrhoea and high case-fatality). Transient lactose intolerance, due to loss of intestinal brush border lactase, also complicates SAM, thus milk based feeds may not be optimal for nutritional rehabilitation. Since the gut epithelial barrier can be supported by short chain fatty acids, derived from microbiota fermentation by particular fermentable carbohydrates, we postulated that an energy-dense nutritional feed comprising of legume-based fermentable carbohydrates, incorporated with lactose-free versions of standard World Health Organization (WHO) F75/F100 nutritional feeds will enhance epithelial barrier function in malnourished children, reduce and promote resolution of diarrhoea and improve overall outcome. Methods: We will investigate in an open-label trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference <11.5cm and/or presence of kwashiorkor. Children will be randomised to a lactose-free, chickpea-enriched feed containing 2 kcal/ml, provided in quantities to match usual energy provision (experimental) or WHO standard treatment F75 (0.75 kcal/ml) and F100 (1 kcal/ml) feeds on a 1:1 basis, conducted at Mbale Regional Referral Hospital nutritional rehabilitation unit. The primary outcomes are change in MUAC at day 90 and survival to day 90. Secondary outcomes include: i) moderate to good weight gain (>5 g/kg/day), ii) de novo development of diarrhoea (>3 loose stools/day), iii) time to diarrhoea resolution (if >3 loose stools/day), and iv) time to oedema resolution (if kwashiorkor) and change in intestinal biomarkers (faecal calprotectin). Discussion: We hypothesize that, if introduced early in the management of malnutrition, such lactose-free, fermentable carbohydrate-based feeds, could safely and cheaply improve global outco
Maitland K, 2016, Validation of triple pass 24-hour dietary recall in Ugandan children by simultaneous weighed food assessment, BMC Nutrition, Vol: 2, Pages: 1-9, ISSN: 2055-0928
BackgroundUndernutrition remains highly prevalent in African children, highlighting the need for accurately assessing dietary intake. In order to do so, the assessment method must be validated in the target population. A triple pass 24 h dietary recall with volumetric portion size estimation has been described but not previously validated in African children. This study aimed to establish the relative validity of 24-h dietary recalls of daily food consumption in healthy African children living in Mbale and Soroti, eastern Uganda compared to simultaneous weighed food records.MethodsQuantitative assessment of daily food consumption by weighed food records followed by two independent assessments using triple pass 24-h dietary recall on the following day. In conjunction with household measures and standard food sizes, volumes of liquid, dry rice, or play dough were used to aid portion size estimation. Inter-assessor agreement, and agreement with weighed food records was conducted primarily by Bland-Altman analysis and secondly by intraclass correlation coefficients and quartile cross-classification.ResultsNineteen healthy children aged 6 months to 12 years were included in the study. Bland-Altman analysis showed 24-h recall only marginally under-estimated energy (mean difference of 149 kJ or 2.8 %; limits of agreement −1618 to 1321 kJ), protein (2.9 g or 9.4 %; −12.6 to 6.7 g), and iron (0.43 mg or 8.3 %; −3.1 to 2.3 mg). Quartile cross-classification was correct in 79 % of cases for energy intake, and 89 % for both protein and iron. The intraclass correlation coefficient between the separate dietary recalls for energy was 0.801 (95 % CI, 0.429–0.933), indicating acceptable inter-observer agreement.ConclusionsDietary assessment using 24-h dietary recall with volumetric portion size estimation resulted in similar and acceptable estimates of dietary intake compared with weighed food records and thus is considered a valid method for daily dietary in
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