Imperial College London

Professor Thomas N Williams

Faculty of MedicineDepartment of Infectious Disease

Chair in Haemoglobinopathy Research
 
 
 
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Contact

 

tom.williams Website

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
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319 results found

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 Research, Vol: 6, Pages: 221-221

<ns3:p><ns3:bold>Background: </ns3:bold>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.</ns3:p><ns3:p> <ns3:bold>Methods:</ns3:bold><ns3:bold> </ns3:bold>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<ns3:sub>2</ns3:sub> &lt;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 pneu

Journal article

Abuga K, Muriuki J, Uyoga S, Mwai K, Makale J, Mogire R, Macharia A, Mohammed S, Muthumbi E, Mwarumba S, Mturi N, Bejon P, Scott A, Nairz M, Williams T, Atkinson Set al., 2021, Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal Salmonella bacteremia, Haematologica: the hematology journal, ISSN: 0390-6078

Malaria and invasive non-typhoidal Salmonella (NTS) are life-threatening infections that often co-exist in African children. The iron-regulatory hormone hepcidin is highly upregulated during malaria and controls the availability of iron, a critical nutrient for bacterial growth. We investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged ≤5 years between August 1998 and October 2019 (n=75,034). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malarial anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA (n=33); (3) NTS (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. SMA and severe anemia without malaria were associated with a two-fold or more increased risk of NTS bacteremia, while other malaria phenotypes were not associated with increased NTS risk. Children with SMA had lower hepcidin/ferritin ratios (0.10 [IQR 0.03, 0.19]) than those with CM (0.24 [0.14, 0.69]; P=0.006) or asymptomatic malaria (0.19 [0.09, 0.46]; P=0.01) indicating suppressed hepcidin levels. Children with SMA+NTS had lower hepcidin levels (9.3 ng/mL [4.7, 49.8]) and hepcidin/ferritin ratios (0.03 [0.01, 0.22]) than those with NTS alone (105.8 ng/mL [17.3, 233.3]; P=0.02 and 0.31 [0.06, 0.66]; P=0.007, respectively). Since hepcidin degrades ferroportin on the Salmonella-containing vacuole (SCV), we hypothesize that reduced hepcidin in children with SMA might contribute to NTS growth by modulating iron availability for bacterial growth. Further studies are needed to understand how the hepcidin-ferroportin axis might mediate susceptibility to NTS in severely anemic children.

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

Chi PC, Owino EA, Jao I, Olewe F, Ogutu B, Bejon P, Kapulu M, Kamuya D, Marsh V, CHMI-SIKA Study Teamet al., 2021, Understanding the benefits and burdens associated with a malaria human infection study in Kenya: experiences of study volunteers and other stakeholders., Trials, Vol: 22

BACKGROUND: Human infection studies (HIS) that involve deliberately infecting healthy volunteers with a pathogen raise important ethical issues, including the need to ensure that benefits and burdens are understood and appropriately accounted for. Building on earlier work, we embedded social science research within an ongoing malaria human infection study in coastal Kenya to understand the study benefits and burdens experienced by study stakeholders in this low-resource setting and assess the wider implications for future research planning and policy. METHODS: Data were collected using qualitative research methods, including in-depth interviews (44), focus group discussions (10) and non-participation observation. Study participants were purposively selected (key informant or maximal diversity sampling), including volunteers in the human infection study, study staff, community representatives and local administrative authorities. Data were collected during and up to 18 months following study residency, from sites in Coastal and Western Kenya. Voice recordings of interviews and discussions were transcribed, translated, and analysed using framework analysis, combining data- and theory-driven perspectives. FINDINGS: Physical, psychological, economic and social forms of benefits and burdens were experienced across study stages. Important benefits for volunteers included the study compensation, access to health checks, good residential living conditions, new learning opportunities, developing friendships and satisfaction at contributing towards a new malaria vaccine. Burdens primarily affected study volunteers, including experiences of discomfort and ill health; fear and anxiety around aspects of the trial process, particularly deliberate infection and the implications of prolonged residency; anxieties about early residency exit; and interpersonal conflict. These issues had important implications for volunteers' families, study staff and the research institution's reputat

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

Bundi CK, Nalwoga A, Lubyayi L, Muriuki JM, Mogire RM, Opi H, Mentzer AJ, Mugyenyi CK, Mwacharo J, Webb EL, Bejon P, Williams T, Gikunju JK, Beeson JG, Elliott AM, Ndungu FM, Atkinson SHet al., 2021, Iron deficiency is associated with reduced levels of Plasmodium falciparum-specific antibodies in African children, Clinical Infectious Diseases, Vol: 73, Pages: 43-49, ISSN: 1058-4838

BackgroundIron deficiency (ID) and malaria are common causes of ill-health and disability among children living in sub-Saharan Africa. Although iron is critical for the acquisition of humoral immunity, little is known about the effects of ID on antibody responses to Plasmodium falciparum malaria.MethodsThe study included 1,794 Kenyan and Ugandan children aged 0-7 years. We measured biomarkers of iron and inflammation, and antibodies to P falciparum antigens including apical merozoite antigen 1 (anti-AMA-1) and merozoite surface antigen 1 (anti-MSP-1) in cross-sectional and longitudinal studies.ResultsThe overall prevalence of ID was 31%. ID was associated with lower anti-AMA-1 and anti-MSP-1 antibody levels in pooled analyses adjusted for age, gender, study site, inflammation and P falciparum parasitemia (adjusted mean difference on a log-transformed scale (β) -0.46; 95 CI -0.66, -0.25 P <0.0001; β -0.33; 95 CI -0.50, -0.16 P <0.0001, respectively). Additional covariates for malaria exposure index, previous malaria episodes, and time since last malaria episode, were available for individual cohorts. Meta-analysis was used to allow for these adjustments giving β -0.34; -0.52, -0.16 for anti-AMA-1 antibodies and β -0.26; -0.41, -0.11 for anti-MSP-1 antibodies. Low transferrin saturation was similarly associated with reduced anti-AMA1 antibody levels. Lower AMA-1 and MSP-1 specific antibody levels persisted over time in iron-deficient children.ConclusionsReduced levels of P. falciparum-specific antibodies in iron-deficient children might reflect impaired acquisition of immunity to malaria and/or reduced malaria exposure. Strategies to prevent and treat ID may influence antibody responses to malaria for children living in sub-Saharan Africa.

Journal article

Maitland K, Kiguli S, Olupot-Olupot P, Opoka RO, Chimalizeni Y, Alaroker F, Uyoga S, Kyeyune Byabazaire D, Mbaya B, Bates I, Williams TN, Mbanya D, Munube D, Molyneux EM, South A, Walker AS, Gibb DM, George EMet al., 2021, Transfusion management of severe anaemia in African children: a consensus algorithm, British Journal of Haematology, Vol: 193, Pages: 1247-1259, ISSN: 0007-1048

The phase III Transfusion and Treatment of severe anaemia in African Children Trial(TRACT) found that conservative management of uncomplicated severe anaemia (haemoglobin(Hb)4-6g/dl) was safe and that transfusion volume(20 versus30 mls/kg whole blood equivalent)for children with severe anaemia (Hb<6g/dl) had strong but opposing effects on mortality, depending on fever status (>37.5oC). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all children (3196) receiving an initial transfusion, there was no evidence that nutritional status, presence of shock, malaria parasite burden, or sickle cell disease status influenced outcomes, or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating 3 additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practice

Journal article

Mogire RM, Morovat A, Muriuki JM, Mentzer AJ, Webb EL, Kimita W, Ndungu FM, Macharia AW, Cutland CL, Sirima SB, Diarra A, Tiono AB, Lule SA, Madhi SA, Sandhu MS, Prentice AM, Bejon P, Pettifor JM, Elliott AM, Adeyemo A, Williams T, Atkinson SHet al., 2021, Prevalence and predictors of vitamin D deficiency in young African children, BMC Medicine, Vol: 19, Pages: 1-14, ISSN: 1741-7015

BackgroundChildren living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children.MethodsWe measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0–8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses.ResultsMedian age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants.ConclusionsApproximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and p

Journal article

Maitland K, Kiguli S, Olupot-Olupot P, Hamaluba M, Thomas K, Alaroker F, Opoka RO, Tagoola A, Bandika V, Mpoya A, Mnjalla H, Nabawanuka E, Okiror W, Nakuya M, Aromut D, Engoru C, Oguda E, Williams TN, Fraser JF, Harrison D, Rowan K, on behalf of the COAST trial groupet al., 2021, Randomised controlled trial of oxygen therapy and high flow nasal therapy in African children with pneumonia, Intensive Care Medicine, Vol: 47, Pages: 566-576, ISSN: 0342-4642

PurposeThe life-saving role of oxygen therapy in African children with severe pneumonia is not yet established.MethodsThe open-label fractional-factorial COAST trial randomised eligible Ugandan and Kenyan children aged > 28 days with severe pneumonia and severe hypoxaemia stratum (SpO2 < 80%) to high-flow nasal therapy (HFNT) or low-flow oxygen (LFO: standard care) and hypoxaemia stratum (SpO2 80–91%) to HFNT or LFO (liberal strategies) or permissive hypoxaemia (ratio 1:1:2). Children with cyanotic heart disease, chronic lung disease or > 3 h receipt of oxygen were excluded. The primary endpoint was 48 h mortality; secondary endpoints included mortality or neurocognitive sequelae at 28 days.ResultsThe trial was stopped early after enrolling 1852/4200 children, including 388 in the severe hypoxaemia stratum (median 7 months; median SpO2 75%) randomised to HFNT (n = 194) or LFO (n = 194) and 1454 in the hypoxaemia stratum (median 9 months; median SpO2 88%) randomised to HFNT (n = 363) vs LFO (n = 364) vs permissive hypoxaemia (n = 727). Per-protocol 15% of patients in the permissive hypoxaemia group received oxygen (when SpO2 < 80%). In the severe hypoxaemia stratum, 48-h mortality was 9.3% for HFNT vs. 13.4% for LFO groups. In the hypoxaemia stratum, 48-h mortality was 1.1% for HFNT vs. 2.5% LFO and 1.4% for permissive hypoxaemia. In the hypoxaemia stratum, adjusted odds ratio for 48-h mortality in liberal vs permissive comparison was 1.16 (0.49–2.74; p = 0.73); HFNT vs LFO comparison was 0.60 (0.33–1.06; p = 0.08). Strata-specific 28 day mortality rates were, respectively: 18.6, 23.4 and 3.3, 4.1, 3.9%. Neurocognitive sequelae were rare.ConclusionsRespiratory support with HFNT showing potential benefit should prompt further trials.

Journal article

Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, Etyang AO, Kyobutungi C, Morovat A, Kimita W, Ndungu FM, Macharia AW, Ngetsa CJ, Makale J, Lule SA, Musani SK, Raffield LM, Cutland CL, Sirima SB, Diarra A, Tiono AB, Fried M, Gwamaka M, Adu-Afarwuah S, Wirth JP, Wegmueller R, Madhi SA, Snow RW, Hill AVS, Rockett KA, Sandhu MS, Kwiatkowski DP, Prentice AM, Byrd KA, Ndjebayi A, Stewart CP, Engle-Stone R, Green TJ, Karakochuk CD, Suchdev PS, Bejon P, Duffy PE, Davey Smith G, Elliott AM, Williams TN, Atkinson SHet al., 2021, Malaria is a cause of iron deficiency in African children, Nature Medicine, Vol: 27, Pages: 653-658, ISSN: 1078-8956

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.

Journal article

Petry N, Wirth JP, Adu-Afarwuah S, Wegmuller R, Woodruff BA, Tanumihardjo SA, Bentil H, Donkor WES, Williams TN, Shahab-Ferdows S, Selenje L, Mahama A, Steiner-Asiedu M, Rohner Fet al., 2021, Risk factors for anaemia among Ghanaian women and children vary by population group and climate zone., Matern Child Nutr, Vol: 17

Anaemia has serious effects on human health and has multifactorial aetiologies. This study aimed to determine putative risk factors for anaemia in children 6-59 months and 15- to 49-year-old non-pregnant women living in Ghana. Data from a nationally representative cross-sectional survey were analysed for associations between anaemia and various anaemia risk factors. National and stratum-specific multivariable regressions were constructed separately for children and women to calculate the adjusted prevalence ratio (aPR) for anaemia of variables found to be statistically significantly associated with anaemia in bivariate analysis. Nationally, the aPR for anaemia was greater in children with iron deficiency (ID; aPR 2.20; 95% confidence interval [CI]: 1.88, 2.59), malaria parasitaemia (aPR 1.96; 95% CI: 1.65, 2.32), inflammation (aPR 1.26; 95% CI: 1.08, 1.46), vitamin A deficiency (VAD; aPR 1.38; 95% CI: 1.19, 1.60) and stunting (aPR 1.26; 95% CI: 1.09, 1.46). In women, ID (aPR 4.33; 95% CI: 3.42, 5.49), VAD (aPR 1.61; 95% CI: 1.24, 2.09) and inflammation (aPR 1.59; 95% CI: 1.20, 2.11) were associated with anaemia, whereas overweight and obese women had lower prevalence of anaemia (aPR 0.74; 95% CI: 0.56, 0.97). ID was associated with child anaemia in the Northern and Middle belts, but not in the Southern Belt; conversely, inflammation was associated with anaemia in both children and women in the Southern and Middle belts, but not in the Northern Belt. Anaemia control programmes should be region specific and aim at the prevention of ID, malaria and other drivers of inflammation as they are the main predictors of anaemia in Ghanaian children and women.

Journal article

Wirth JP, Sesay F, Mbai J, Ali SI, Donkor WES, Woodruff BA, Pilane Z, Mohamud KM, Muse A, Yussuf HO, Mohamed WS, Veraguth R, Rezzi S, Williams TN, Mohamoud AM, Mohamud FM, Galvin M, Rohner F, Katambo Y, Petry Net al., 2021, Risk factors of anaemia and iron deficiency in Somali children and women: Findings from the 2019 Somalia Micronutrient Survey, Maternal and Child Nutrition, ISSN: 1740-8695

There are limited data on the prevalence of anaemia and iron deficiency (ID) in Somalia. To address this data gap, Somalia's 2019 micronutrient survey assessed the prevalence of anaemia and ID in children (6–59 months) and non-pregnant women of reproductive age (15–49 years). The survey also collected data on vitamin A deficiency, inflammation, malaria and other potential risk factors for anaemia and ID. Multivariable Poisson regressions models were used to identify the risk factors for anaemia and ID in children and women. Among children, the prevalence of anaemia and ID were 43.4% and 47.2%, respectively. Approximately 36% and 6% of anaemia were attributable to iron and vitamin A deficiencies, respectively, whereas household possession of soap was associated with approximately 11% fewer cases of anaemia. ID in children was associated with vitamin A deficiency and stunting, whereas inflammation was associated with iron sufficiency. Among women, 40.3% were anaemic, and 49.7% were iron deficient. In women, ID and number of births were significantly associated with anaemia in multivariate models, and approximately 42% of anaemia in women was attributable to ID. Increased parity was associated with ID, and incubation and early convalescent inflammation was associated with ID, whereas late convalescent inflammation was associated with iron sufficiency. ID is the main risk factor of anaemia in both women and children and contributed to a substantial portion of the anaemia cases. To tackle both anaemia and ID in Somalia, food assistance and micronutrient-specific programmes (e.g. micronutrient powders and iron supplements) should be enhanced.

Journal article

Malinga J, Mogeni P, Omedo I, Rockett K, Hubbart C, Jeffreys A, Williams TN, Kwiatkowski D, Bejon P, Ross Aet al., 2020, Author Correction: Investigating the drivers of the spatio-temporal patterns of genetic differences between Plasmodium falciparum malaria infections in Kilifi County, Kenya., Scientific Reports, Vol: 10, Pages: 22416-22416, ISSN: 2045-2322

Journal article

Ndila CM, Nyirongo V, Macharia AW, Jeffreys AE, Rowlands K, Hubbart C, Busby GBJ, Band G, Harding RM, Rockett KA, Williams TNet al., 2020, Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data, Wellcome Open Research, Vol: 5, Pages: 287-287

<ns3:p><ns3:bold>Background: </ns3:bold>The -α<ns3:sup>3.7I</ns3:sup>-thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations.</ns3:p><ns3:p> <ns3:bold>Methods: </ns3:bold>In this study we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR.</ns3:p><ns3:p> <ns3:bold>Results: </ns3:bold>We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha (<ns3:italic>HBA</ns3:italic>) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results.</ns3:p><ns3:p> <ns3:bold>Conclusions: </ns3:bold>We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies.</ns3:p>

Journal article

Uyoga S, Alex W M, Ndila CM, Nyutu G, Shebe M, Awuondo KO, Mturi N, Peshu N, Tsofa B, Scott JAG, Maitland K, Williams Tet al., 2020, Glucose-6-phosphate dehydrogenase deficiency and susceptibility to childhood diseases in Kilifi, Kenya, Blood Advances, Vol: 4, Pages: 5942-5950, ISSN: 2473-9529

Few previous studies have reported the effects of glucose-6-phosphate dehydrogenase (G6PD)–deficiency on child health in Africa. We conducted a case-control study in which cases (n = 6829) were children admitted, for any reason, to Kilifi County Hospital, Kenya, while controls (n = 10 179) were recruited from the surrounding community. Cases were subclassified based on their clinical and laboratory findings at admission. We calculated the prevalence of specific diseases by G6PD c.202 genotype, the only significant cause of G6PD-deficiency in this area, then estimated the association between genotype and admission with specific conditions using logistic regression. Among neonates, the prevalence of jaundice was higher in both G6PD c.202T heterozygotes (40/88; 45.5%; P = .004) and homo/hemizygotes (81/134; 60.5%; P < .0001) than in wild-type homozygotes (157/526; 29.9%). Median bilirubin levels also increased across the groups, being highest (239 mmol/L; interquartile range 96-390 mmol/L) in G6PD c.202T homo/hemizygotes. No differences were seen in admission hemoglobin concentrations or the prevalence of anemia or severe anemia by G6PD c.202 genotype. On case control analysis, G6PD heterozygosity was negatively associated with all-cause hospital admission (odds ratio 0.81; 95% confidence interval 0.73-0.90; P < .0001) and, specifically, admission with either pneumonia or Plasmodium falciparum parasitemia; while, conversely, it was positively associated with Gram-positive bacteremia. G6PD c.202T homo/heterozygosity was positively associated with neonatal jaundice, severe pneumonia, the receipt of a transfusion, and in-patient death. Our study supports the conclusion that G6PD c.202T is a balanced polymorphism in which a selective advantage afforded to heterozygous females against malaria is counterbalanced by increased risks of neonatal jaundice, invasive bacterial infections, and anemia.

Journal article

Ssewanyana D, Abubakar A, Newton C, Otiende M, Mochamah G, Nyundo C, Walumbe D, Nyutu G, Amadi D, Doyle A, Ross D, Nyaguara A, Williams T, Bauni Eet al., 2020, Clustering of health risk behaviors among adolescents in Kilifi, Kenya, a rural Sub-Saharan African setting, PLoS One, Vol: 15, Pages: 1-19, ISSN: 1932-6203

BackgroundAdolescents tend to experience heightened vulnerability to risky and reckless behavior. Adolescents living in rural settings may often experience poverty and a host of risk factors which can increase their vulnerability to various forms of health risk behavior (HRB). Understanding HRB clustering and its underlying factors among adolescents is important for intervention planning and health promotion. This study examines the co-occurrence of injury and violence, substance use, hygiene, physical activity, and diet-related risk behaviors among adolescents in a rural setting on the Kenyan coast. Specifically, the study objectives were to identify clusters of HRB; based on five categories of health risk behavior, and to identify the factors associated with HRB clustering.MethodsA cross-sectional survey was conducted of a random sample of 1060 adolescents aged 13–19 years living within the area covered by the Kilifi Health and Demographic Surveillance System. Participants completed a questionnaire on health behaviors which was administered via an Audio Computer-Assisted Self–Interview. Latent class analysis on 13 behavioral factors (injury and violence, hygiene, alcohol tobacco and drug use, physical activity, and dietary related behavior) was used to identify clustering and stepwise ordinal logistic regression with nonparametric bootstrapping identified the factors associated with clustering. The variables of age, sex, education level, school attendance, mental health, form of residence and level of parental monitoring were included in the initial stepwise regression model.ResultsWe identified 3 behavioral clusters (Cluster 1: Low-risk takers (22.9%); Cluster 2: Moderate risk-takers (67.8%); Cluster 3: High risk-takers (9.3%)). Relative to the cluster 1, membership of higher risk clusters (i.e. moderate or high risk-takers) was strongly associated with older age (p<0.001), being male (p<0.001), depressive symptoms (p = 0.005), school non-attend

Journal article

Kariuki SN, Marin-Menendez A, Introini V, Ravenhill BJ, Lin Y-C, Makale J, Tendwa M, Nyamu W, Kotar J, Carrasquilla M, Rowe A, Rockett KA, Kwiatkowski D, Weekes MP, Cicuta P, Williams T, Rayner JCet al., 2020, Red blood cell tension protects against severe malaria in the Dantu blood group, Nature, Vol: 585, Pages: 579-583, ISSN: 0028-0836

Malaria has had a major effect on the human genome, many protective polymorphismssuch as sickle cell trait having been selected to high frequencies in malaria endemicregions1,2. Recently, it was shown that the blood group variant Dantu provides 74%protection against all forms of severe malaria in homozygous individuals3-5. This is a similardegree of protection to sickle cell trait and considerably greater than the best malariavaccine, but until now the protective mechanism has been unknown. Here, we demonstratea significant impact of Dantu on Plasmodium falciparum-merozoite RBC invasion. Dantuwas associated with extensive changes to the RBC surface protein repertoire, butunexpectedly, inhibition did not correlate with specific RBC-parasite receptor-ligandinteractions. By following invasion using video microscopy, we found a strong link betweenRBC tension and merozoite invasion and identified a tension threshold above whichinvasion rarely occurred, even in non-Dantu RBCs. Dantu RBCs had higher average tension,meaning that a greater proportion resisted invasion. These findings provide both anexplanation for the malaria-protective effect of Dantu, and fresh insights into why theefficiency of P. falciparum invasion might vary across the heterogenous populations of RBCsboth within and between individuals.

Journal article

Abuga KM, Muriuki JM, Williams T, Atkinson SHet al., 2020, How severe anaemia might influence the risk of invasive bacterial infections in African children, International Journal of Molecular Sciences, Vol: 21, ISSN: 1422-0067

Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.

Journal article

Olupot-Olupot P, Engoru C, Nteziyaremye J, Chebet M, Ssenyondo T, Muhindo R, Nyutu G, Macharia A, Uyoga S, Ndila CM, Karamagi C, Maitland K, Williams Tet al., 2020, The clinical spectrum of severe childhood malaria in Eastern Uganda, Malaria Journal, Vol: 19, ISSN: 1475-2875

BackgroundFew recent descriptions of severe childhood malaria have been published from high-transmission regions. In the current study, the clinical epidemiology of severe malaria in Mbale, Eastern Uganda, is described, where the entomological inoculation rate exceeds 100 infective bites per year.MethodsA prospective descriptive study was conducted to determine the prevalence, clinical spectrum and outcome of severe Plasmodium falciparum malaria at Mbale Regional Referral Hospital in Eastern Uganda. All children aged 2 months–12 years who presented on Mondays to Fridays between 8.00 am and 5.00 pm from 5th May 2011 until 30th April 2012 were screened for parasitaemia. Clinical and laboratory data were then collected from all P. falciparum positive children with features of WHO-defined severe malaria by use of a standardized proforma.ResultsA total of 10 208 children were screened of which 6582 (64%) had a positive blood film. Of these children, 662 (10%) had clinical features of severe malaria and were consented for the current study. Respiratory distress was the most common severity feature (554; 83.7%), while 365/585 (62.4%) had hyperparasitaemia, 177/662 (26.7%) had clinical jaundice, 169 (25.5%) had severe anaemia, 134/660 (20.2%) had hyperlactataemia (lactate ≥ 5 mmol/L), 93 (14.0%) had passed dark red or black urine, 52 (7.9%) had impaired consciousness and 49/662 (7.4%) had hypoxaemia (oxygen saturations < 90%). In-hospital mortality was 63/662 (9.5%) overall but was higher in children with either cerebral malaria (33.3%) or severe anaemia (19.5%). Factors that were independently associated with mortality on multivariate analysis included severe anaemia [odds ratio (OR) 5.36; 2.16–1.32; P = 0.0002], hyperlactataemia (OR 3.66; 1.72–7.80; P = 0.001), hypoxaemia (OR) 3.64 (95% CI 1.39–9.52; P = 0.008), and hepatomegaly (OR 2.29; 1.29–4.06; P = 

Journal article

Petry N, Wirth J, Adu-Afarwuah S, Wegmuller R, Woodruff B, Tanumihardjo S, Bentil H, Donkor W, Williams T, Shahab-Ferdows S, Selenje L, Mahama A, Steiner-Asiedu M, Rohner Fet al., 2020, Putative risk factors for anemia vary by population group and climate zone – results from a national survey in Ghana among women of reproductive age and pre-school children, Maternal and Child Nutrition, ISSN: 1740-8695

Background: Anemia has serious effects on human health and has multifactorial etiologies.Objective: To determine putative risk factors for anemia in children 6-59 months and 15-49 years old non-pregnant women living in Ghana.Methods: Data from a nationally representative cross-sectional survey were analyzed for associations between anemia and various anemia risk factors. National and stratum specific multivariable regressions were constructed separately for children and women to calculate the adjusted prevalence ratio (aPR) for anemia of variables found to be statistically significantly associated with anemia in bivariate analysis.Results: Nationally, the aPR for anemia was greater in children with iron deficiency (ID; aPR 2.20; 95%CI:1.88, 2.59), malaria parasitemia (aPR 1.96; 95%CI:1.65, 2.32), inflammation (aPR 1.26; 95%CI:1.08, 1.46), vitamin A deficiency (VAD; aPR 1.38; 95%CI:1.19, 1.60) and stunting (aPR 1.26; 95%CI:1.09; 1.46). In women, ID (aPR 4.33; 95%CI:3.42, 5.49), VAD (aPR 1.61; 95%CI:1.24, 2.09) and inflammation (aPR 1.59, 95%CI:1.20, 2.11) were associated with anemia, whereas overweight and obese women had lower prevalence of anemia (aPR 0.74; 95%CI:0.56, 0.97). ID was associated with child anemia in the Northern and Middle Belts, but not in the south; conversely, inflammation was associated with anemia in both children and women in the Southern and Middle Belts, but not in the north. Conclusion: Anemia control programs should be region specific and aim at the prevention of ID, malaria and other drivers of inflammation as they are the main predictors of anemia in Ghanaian children and women.

Journal article

Uyoga S, Wanjiku P, Rop J, Makale J, Macharia A, Nyutu G, Shebbe M, Awuondo K, Mturi N, Woodrow C, Dondorp A, Maitland K, Williams T, Williams TNet al., 2020, Plasma Plasmodium falciparum Histidine-Rich Protein-2 concentrations in children with malaria infections of differing severity in Kilifi, Kenya, Clinical Infectious Diseases, ISSN: 1058-4838

BackgroundMost previous studies support a direct link between total parasite load and the clinical severity of Plasmodium falciparum malaria infections.MethodsWe estimated P. falciparum parasite loads in three groups of children with malaria infections of differing severity: (1) children with WHO-defined severe malaria (n=1,544); (2) children admitted with malaria but without features of severity (n=200) and; (3) children in the community with asymptomatic parasitemia (n=33).ResultsPeripheral parasitemias were highest in those with uncomplicated malaria (geometric mean 111,064; 95%CI 86,798-141,819 parasites/μl), being almost three times higher than those with severe malaria (39,588; 34,990-44,791 parasites/μl) and >100 times higher than in those with asymptomatic malaria (1,092; 523-2,280 parasites/μl). However, geometric mean PfHRP2 values (95% CI) increased with severity, being 7 (4-12) ng/ml in asymptomatic malaria, 843 (655-1,084) ng/ml in uncomplicated malaria and 1,369 (1,244-1,506) ng/ml in severe malaria. PfHRP2 concentrations were markedly lower in the sub-group of severe malaria patients with concomitant invasive bacterial infections (IBIs) of blood or CSF (GM 312 ng/ml; 95%CI 175-557; p<0.0001) than in those without IBIs (GM 1,439 ng/ml; 1,307-1,584; P<0.001).ConclusionsThe clinical severity of malaria infections related strongly to the total burden of P. falciparum parasites. A quantitative test for plasma concentrations of PfHRP2 could be useful in identifying children at the greatest clinical risk and to identify critically ill children in whom malaria is not the primary cause.

Journal article

Olupot-Olupot P, Wabwire H, Ndila C, Adong R, Ochen L, Amorut D, Abongo G, Okalebo CB, Akello SR, Oketcho JB, Okiror W, Asio S, Odiit A, Alaroker F, Nyutu G, Maitland K, Williams TNet al., 2020, Characterising demographics, knowledge, practices and clinical care among patients attending sickle cell disease clinics in Eastern Uganda [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 5, Pages: 87-87, ISSN: 2398-502X

Background: In Uganda to date, there are neither established registries nor descriptions of facility-based sickle cell disease (SCD) patient characteristics beyond the central region. Here, we summarize data on the baseline clinical characteristics and routine care available to patients at four clinics in Eastern Uganda as a prelude to a clinical trial.Methods: Between February and August 2018, we conducted a cross-sectional survey of patients attending four SCD clinics in Mbale, Soroti, Atutur and Ngora, all in Eastern Uganda, the planned sites for an upcoming clinical trial (H-PRIME: ISRCTN15724013). Data on socio-demographic characteristics, diagnostic methods, clinic schedules, the use of prophylactic and therapeutic drugs, clinical complications and patient understanding of SCD were collected using a structured questionnaire.Results: Data were collected on 1829 patients. Their ages ranged from 0 to 64 years with a median (IQR) of 6 (3-11) years. 49.1% of participants were male. The majority (1151; 62.9%) reported a positive family history for SCD. Approximately half knew that SCD is inherited from both parents but a substantial proportion did not know how SCD is transmitted and small numbers believed that it is acquired by either transfusion or from other people. Only 118/1819 (6.5%) participants had heard about or were using hydroxyurea while 356/1794 (19.8%) reported stigmatization. Participants reported a median of three (IQR 1-4) hospital admissions during the preceding 12 months; 80.8% had been admitted at least once, while 14.2% had been admitted more than five times. Pain was the most common symptom, while 83.9% of those admitted had received at least one blood transfusion.Conclusion: The majority of patients attending SCD clinics in Eastern Uganda are children and few are currently being treated with hydroxyurea. The data collected through this facility-based survey will provide background data that will be useful in planning for the H-PRIME trial.

Journal article

Macharia AW, Mochamah G, Uyoga S, Ndila CM, Nyutu G, Tendwa M, Nyatichi E, Makale J, Ware RE, Williams TNet al., 2020, β-Thalassemia pathogenic variants in a cohort of children from the East African coast, Molecular Genetics and Genomic Medicine, Vol: 8, ISSN: 2324-9269

BACKGROUND: β-Thalassemia is rare in sub-Saharan Africa. Previous studies have suggested that it is limited to specific parts of West Africa. Based on hemoglobin A2 (HbA2 ) concentrations measured by HPLC, we recently speculated that β-thalassemia might also be present on the East African coast of Kenya. Here, we follow this up using molecular methods. METHODS: We used raised hemoglobin A2 (HbA2 ) values (> 4.0% of total Hb) to target all HbAA members of a cohort study in Kilifi, Kenya, for HBB sequencing for β-thalassemia (n = 99) together with a sample of HbAA subjects with lower HbA2 levels. Because HbA2 values are artifactually raised in subjects carrying sickle hemoglobin (HbS) we sequenced all participants with an HPLC pattern showing HbS without HbA (n = 116) and a sample with a pattern showing both HbA and HbS. RESULTS: Overall, we identified 83 carriers of four separate β-thalassemia pathogenic variants: three β0 -thalassemia [CD22 (GAA→TAA), initiation codon (ATG→ACG), and IVS1-3' end del 25bp] and one β+ -thalassemia pathogenic variants (IVS-I-110 (G→A)). We estimated the minimum allele frequency of all variants combined within the study population at 0.3%. CONCLUSIONS: β-Thalassemia is present in Kilifi, Kenya, an observation that has implications for the diagnosis and clinical care of children from the East Africa region.

Journal article

Gilchrist JJ, Uyoga S, Pirinen M, Rautanen A, Mwarumba S, Njuguna P, Mturi N, Hill AVS, Scott JAG, Williams Tet al., 2020, Risk of pneumococcal bacteremia in Kenyan children with glucose-6-phosphate dehydrogenase deficiency, BMC Medicine, Vol: 18, Pages: 1-10, ISSN: 1741-7015

BackgroundGlucose-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.MethodsWe performed a genetic case-control study of pneumococcal bacteremia in Kenyan children stratified across a period of falling malaria transmission between 1998 and 2010.ResultsFour 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.ConclusionsOur 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 substantia

Journal article

Mutua A, Mogire R, Elliott A, Williams T, Webb E, Abubakar A, Atkinson Set al., 2020, Effects of vitamin D deficiency on neurobehavioural outcomes in children: a systematic review, Wellcome Open Research, Vol: 5, Pages: 1-27, ISSN: 2398-502X

Introduction: Vitamin D plays an important role in brain development in experimental studies; however, the effect of vitamin D deficiency on child development remains inadequately characterized. We aimed to estimate the effects of vitamin D deficiency on neurobehavioural outcomes in children up to 18 years of age. Methods: We searched PubMed, EMBASE, PsycINFO, Scopus, Cochrane Library, Web of Science and Open Grey for published studies up to 10th January 2020. We included all studies that assessed the effects of maternal or child vitamin D status or vitamin D supplementation on neurobehavioural outcomes in children. Study findings were synthesized qualitatively as the high level of heterogeneity in study populations and methodologies precluded a quantitative meta-analysis. Results: Our search identified 5,633 studies, of which 31 studies with 31,375 participants from 18 countries were included in the systematic review. Of the studies identified, one was a randomised controlled trial (RCT) of vitamin D supplementation in children, while 30 were observational. The RCT (n=55) reported a beneficial effect of supplementation with lower doses compared to higher doses of vitamin D on motor development. Twelve mother-child studies (n=17,136) and five studies in children (n=1,091) reported an association between low maternal or child 25-hydroxyvitamin D levels and impaired neurobehavioural outcomes in children, while 15 mother-child studies (n=20,778) and eight studies in children (n=7,496) reported no association. Conclusions: Although animal studies point to an effect of vitamin D deficiency on brain development, there are few studies on the effects of vitamin D deficiency on neurobehavioural outcomes in children and their findings are inconsistent. There is a need for well-conducted, adequately powered studies to further determine these effects in children. Registration: PROSPERO ID CRD42018087619 ; registered on 15 February 2018.

Journal article

Mutua AM, Nampijja M, Elliott AM, Pettifor JM, Williams TN, Abubakar A, Webb EL, Atkinson SHet al., 2020, Vitamin D status is not associated with cognitive or motor function in pre-school Ugandan children, Nutrients, Vol: 12, ISSN: 2072-6643

Vitamin D deficiency is common worldwide and young children are among the most affected groups. Animal studies suggest a key role for vitamin D in brain development. However, studies investigating the effects of vitamin D on neurobehavioural outcomes in children are inconclusive and evidence is limited in sub-Saharan Africa. We evaluated the effect of vitamin D status on cognitive and motor outcomes using prospective data from the Entebbe Mother and Baby Study birth cohort. We analysed data from 302 Ugandan children with 25-hydroxyvitamin D (25(OH)D) measurements below five years and developmental measures at five years of age. We used multivariable linear regression, adjusted for potential confounders, to estimate the effect of 25(OH)D on cognitive and motor outcomes. Of 302 children, eight (2.7%) had 25(OH)D levels <50 nmol/L, 105 (35.8%) had levels 50-75 nmol/L and 189 (62.6%) had levels >75 nmol/L. There was no evidence that earlier vitamin D status was associated with cognitive and motor outcomes in five-year-old Ugandan children. This study adds to the sparse literature and highlights the need for further longitudinal studies on vitamin D and neurobehavioural outcomes in children living in sub-Saharan Africa.

Journal article

Kariuki S, Williams T, 2020, Human genetics and malaria resistance, Human Genetics, Vol: 139, Pages: 801-811, ISSN: 0340-6717

Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure on the human genome yet described. Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects. Many individual variants have been identified that are associated with malaria protection, but the most important all relate to the structure or function of red blood cells. They include the classical polymorphisms that cause sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. More recently however, with improving technology and experimental design, others have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein ATP2B4, and several variants related to the immune response. Characterising how these genes confer their effects could eventually inform novel therapeutic approaches to combat malaria. Nevertheless, all together, only a small proportion of the heritable component of malaria resistance can be explained by the variants described so far, underscoring its complex genetic architecture and the need for continued research.

Journal article

Olupot-Olupot P, Wabwire H, Ndila C, Adong R, Ochen L, Amorut D, Abongo G, Okalebo CB, Akello SR, Okecho JB, Okiror W, Asio S, Odiit A, Alaroker F, Nyutu G, Maitland K, Williams Tet al., 2020, Characterising demographics, knowledge, practices and clinical care among patients attending sickle cell disease clinics in Eastern Uganda [version 1; peer review: 1 approved, 1 approved with reservations], Wellcome Open Research, Vol: 5, Pages: 1-13, ISSN: 2398-502X

Background: In Uganda to date, there are neither established registries nor descriptions of facility-based sickle cell disease (SCD) patient characteristics beyond the central region. Here, we summarize data on the baseline clinical characteristics and routine care available to patients at four clinics in Eastern Uganda as a prelude to a clinical trial.Methods: Between February and August 2018, we conducted a cross-sectional survey of patients attending four SCD clinics in Mbale, Soroti, Atutur and Ngora, all in Eastern Uganda, the planned sites for an upcoming clinical trial (H-PRIME: ISRCTN15724013). Data on socio-demographic characteristics, diagnostic methods, clinic schedules, the use of prophylactic and therapeutic drugs, clinical complications and patient understanding of SCD were collected using a structured questionnaire.Results: Data were collected on 1829 patients. Their ages ranged from 0 to 64 years with a median (IQR) of 6 (3-11) years. 50.9% of participants were male. The majority (1151; 62.9%) reported a positive family history for SCD. Approximately half knew that SCD is inherited from both parents but a substantial proportion did not know how SCD is transmitted and small numbers believed that it is acquired by either transfusion or from other people. Only 118/1819 (6.5%) participants had heard about or were using hydroxyurea while 356/1794 (19.8%) reported stigmatization. Participants reported a median of three (IQR 1-4) hospital admissions during the preceding 12 months; 80.8% had been admitted at least once, while 14.2% had been admitted more than five times. Pain was the most common symptom, while 83.9% of those admitted had received at least one blood transfusion.Conclusion: The majority of patients attending SCD clinics in Eastern Uganda are children and few are currently being treated with hydroxyurea. The data collected through this facility-based survey will provide background data that will be useful in planning for the H-PRIME trial.

Journal article

Oron A, Chao D, Ezeanolue E, Ezenwa L, Piel F, Ojogun O, Ojogun T, Uyoga S, Williams T, Nnodu Oet al., 2020, Caring for Africa’s Sickle Cell children: will we rise to the challenge?, BMC Medicine, Vol: 18, ISSN: 1741-7015

BackgroundMost of the world’s sickle cell disease (SCD) burden is in Africa, where it is a major contributor to child morbidity and mortality. Despite the low cost of many preventive SCD interventions, insufficient resources have been allocated, and progress in alleviating the SCD burden has lagged behind other public-health efforts in Africa. The recent announcement of massive new funding for research into curative SCD therapies is encouraging in the long term, but over the next few decades, it is unlikely to help Africa’s SCD children substantially.Main discussionA major barrier to progress has been the absence of large-scale early-life screening. Most SCD deaths in Africa probably occur before cases are even diagnosed. In the last few years, novel inexpensive SCD point-of-care test kits have become widely available and have been deployed successfully in African field settings. These kits could potentially enable universal early SCD screening. Other recent developments are the expansion of the pneumococcal conjugate vaccine towards near-universal coverage, and the demonstrated safety, efficacy, and increasing availability and affordability of hydroxyurea across the continent. Most elements of standard healthcare for SCD children that are already proven to work in the West, could and should now be implemented at scale in Africa. National and continental SCD research and care networks in Africa have also made substantial progress, assembling care guidelines and enabling the deployment and scale-up of SCD public-health systems. Substantial logistical, cultural, and awareness barriers remain, but with sufficient financial and political will, similar barriers have already been overcome in efforts to control other diseases in Africa.Conclusion and recommendationsDespite remaining challenges, several high-SCD-burden African countries have the political will and infrastructure for the rapid implementation and scale-up of comprehensive SCD childcare programs. A

Journal article

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