Publications
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2Engle-Stone R, Williams TN, Nankap M, et al., 2017, Prevalence of inherited hemoglobin disorders and relationships with anemia among children in Yaoundé and Douala, Cameroon, Nutrients, Vol: 9, ISSN: 2072-6643
Information on the etiology of anemia is necessary to design effective anemia control programs. Our objective was to measure the prevalence of inherited hemoglobin disorders (IHD) in a representative sample of children in urban Cameroon, and examine the relationships between IHD and anemia. In a cluster survey of children 12–59 months of age (n = 291) in Yaoundé and Douala, we assessed hemoglobin (Hb), malaria infection, and plasma indicators of inflammation and micronutrient status. Hb S was detected by HPLC, and α+thalassemia (3.7 kb deletions) by PCR. Anemia (Hb < 110 g/L), inflammation, and malaria were present in 45%, 46%, and 8% of children. A total of 13.7% of children had HbAS, 1.6% had HbSS, and 30.6% and 3.1% had heterozygous and homozygous α+thalassemia. The prevalence of anemia was greater among HbAS compared to HbAA children (60.3 vs. 42.0%, p = 0.038), although mean Hb concentrations did not differ, p = 0.38). Hb and anemia prevalence did not differ among children with or without single gene deletion α+thalassemia. In multi-variable models, anemia was independently predicted by HbAS, HbSS, malaria, iron deficiency (ID; inflammation-adjusted ferritin <12 µg/L), higher C-reactive protein, lower plasma folate, and younger age. Elevated soluble transferrin receptor concentration (>8.3 mg/L) was associated with younger age, malaria, greater mean reticulocyte counts, inflammation, HbSS genotype, and ID. IHD are prevalent but contribute modestly to anemia among children in urban Cameroon.
Leffler EM, Band G, Busby GBJ, et al., 2017, Resistance to malaria through structural variation of red blood cell invasion receptors, Science, Vol: 356, Pages: 1-12, ISSN: 0036-8075
The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB. We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.
Etyang AO, Wandabwa CK, Kapesa S, et al., 2017, Blood pressure and arterial stiffness in Kenyan adolescentswith the Sickle Cell Trait, American Journal of Epidemiology, Vol: 187, Pages: 199-205, ISSN: 1476-6256
The potential association between sickle cell trait (SCT) and increased arterial stiffness/blood pressure (BP) has not been evaluated in detail despite its association with stroke, sudden death and renal disease. We performed 24-hour ambulatory BP monitoring and arterial stiffness measurements in adolescents raised in a malaria free environment in Kenya.Between December 2015 and June 2016, 938 randomly selected adolescents that had been continuous residents of Nairobi from birth were invited to participate in the study. Standard clinic BP measurement was performed followed by 24-hour ambulatory BP monitoring and arterial stiffness measurement using an Arteriograph device. SCT status was determined using DNA genotyping on contemporaneously collected blood samples. Of 938 invited, 609 (65%) provided complete data for analysis. SCT was present in 103 (17%). Mean 24-hour systolic and diastolic BP, SD was (116, 11.5) and (64, 7) mmHg respectively in SCT; and (117, 11.4) and (64, 6.8) in non-SCT. Mean pulse wave velocity (PWV), SD was (7, 0.8) and (7, 0.8) ms-1 respectively in SCT and non-SCT. No differences were observed in PWV and any clinic or ambulatory BP derived measures between those with and without SCT. These data suggest that SCT does not independently influence BP or PWV.
Etyang AO, Khayeka-Wandabwa C, Kapesa S, et al., 2017, Blood pressure and arterial stiffness in Kenyan adolescents with α+thalassemia, Journal of the American Heart Association, Vol: 6, ISSN: 2047-9980
Background Recent studies have discovered that α‐globin is expressed in blood vessel walls where it plays a role in regulating vascular tone. We tested the hypothesis that blood pressure (BP) might differ between normal individuals and those with α+thalassemia, in whom the production of α‐globin is reduced.Methods and Results The study was conducted in Nairobi, Kenya, among 938 adolescents aged 11 to 17 years. Twenty‐four‐hour ambulatory BP monitoring and arterial stiffness measurements were performed using an arteriograph device. We genotyped for α+thalassemia by polymerase chain reaction. Complete data for analysis were available for 623 subjects; 223 (36%) were heterozygous (−α/αα) and 47 (8%) were homozygous (−α/−α) for α+thalassemia whereas the remaining 353 (55%) were normal (αα/αα). Mean 24‐hour systolic BP ±SD was 118±12 mm Hg in αα/αα, 117±11 mm Hg in −α/αα, and 118±11 mm Hg in −α/−α subjects, respectively. Mean 24‐hour diastolic BP ±SD in these groups was 64±8, 63±7, and 65±8 mm Hg, respectively. Mean pulse wave velocity (PWV)±SD was 7±0.8, 7±0.8, and 7±0.7 ms−1, respectively. No differences were observed in PWV and any of the 24‐hour ambulatory BP monitoring‐derived measures between those with and without α+thalassemia.Conclusions These data suggest that the presence of α+thalassemia does not affect BP and/or arterial stiffness in Kenyan adolescents.
McCallum FJ, Persson KEM, Fowkes FJI, et al., 2017, Differing rates of antibody acquisition to merozoite antigens in malaria: implications for immunity and surveillance., J Leukoc Biol, Vol: 101, Pages: 913-925
Antibodies play a key role in acquired human immunity to Plasmodium falciparum (Pf) malaria and target merozoites to reduce or prevent blood-stage replication and the development of disease. Merozoites present a complex array of antigens to the immune system, and currently, there is only a partial understanding of the targets of protective antibodies and how responses to different antigens are acquired and boosted. We hypothesized that there would be differences in the rate of acquisition of antibodies to different antigens and how well they are boosted by infection, which impacts the acquisition of immunity. We examined responses to a range of merozoite antigens in 2 different cohorts of children and adults with different age structures and levels of malaria exposure. Overall, antibodies were associated with age, exposure, and active infection, and the repertoire of responses increased with age and active infection. However, rates of antibody acquisition varied between antigens and different regions within an antigen following exposure to malaria, supporting our hypothesis. Antigen-specific responses could be broadly classified into early response types in which antibodies were acquired early in childhood exposure and late response types that appear to require substantially more exposure for the development of substantial levels. We identified antigen-specific responses that were effectively boosted after recent infection, whereas other responses were not. These findings advance our understanding of the acquisition of human immunity to malaria and are relevant to the development of malaria vaccines targeting merozoite antigens and the selection of antigens for use in malaria surveillance.
Wang L, Ko ER, Gilchrist JJ, et al., 2017, Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis., Science Advances, Vol: 3, ISSN: 2375-2548
Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.
Omedo I, Mogeni P, Bousema T, et al., 2017, Micro-epidemiological structuring of Plasmodium falciparum parasite populations in regions with varying transmission intensities in Africa. [version 1; peer review: 4 approved], Wellcome Open Research, Vol: 2, ISSN: 2398-502X
Background: The first models of malaria transmission assumed a completely mixed and homogeneous population of parasites. Recent models include spatial heterogeneity and variably mixed populations. However, there are few empiric estimates of parasite mixing with which to parametize such models.Methods: Here we genotype 276 single nucleotide polymorphisms (SNPs) in 5199 P. falciparum isolates from two Kenyan sites and one Gambian site to determine the spatio-temporal extent of parasite mixing, and use Principal Component Analysis (PCA) and linear regression to examine the relationship between genetic relatedness and relatedness in space and time for parasite pairs.Results: We show that there are no discrete geographically restricted parasite sub-populations, but instead we see a diffuse spatio-temporal structure to parasite genotypes. Genetic relatedness of sample pairs is predicted by relatedness in space and time.Conclusions: Our findings suggest that targeted malaria control will benefit the surrounding community, but unfortunately also that emerging drug resistance will spread rapidly through the population.
Olupot-Olupot P, Engoru CE, Uyoga S, et al., 2017, High frequency of blackwater fever among children presenting to hospital with severe febrile illnesses in Eastern Uganda, Clinical Infectious Diseases, Vol: 64, Pages: 939-946, ISSN: 1537-6591
Background In the Fluid-Expansion-as-a-Supportive-Treatment (FEAST) trial an unexpectedly-high proportion of participants from Eastern Uganda presented with blackwater fever (BWF).Methods We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of three malaria-protective red blood cell polymorphisms in BWF-cases versus both trial (non-BWF) and population-controls. FindingsOf 3,170 trial participants 394 (12.4%) had BWF. The majority (318; 81.0%) presented in Eastern Uganda: the subjects of further analysis. BWF cases typically presented with both clinical jaundice 254/318 (80%) and severe-anaemia (Hb <5g/dl) 238/310 (77%). Plasmodium falciparum parasitaemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum Histidine Rich Protein-2 [192/246 (78.0%) versus 811/1154 (70.3%); p=0.014], suggesting recent anti-malarial treatment. Overall, 282/318 (88.7%) received transfusions, with 94/282 (33.3%) and 9/282 (3.4%) receiving 2 or 3 transfusions respectively. By day-28, 39/318 (12.3%) BWF cases and 154/1554 (9.9%) non-BWF controls had died (P=0.21) and 7/255 (3.0%) versus 13/1212 (1%; p=0.036) had severe anaemia. We found no association with G6PD deficiency. The prevalence of both the sickle cell trait [10/218 (4.6%)] and homozygous +thalassaemia [8/216 (3.7%)] were significantly lower among cases than population controls [334/2123 (15.7%) and 141/2114 (6.6%), respectively], providing further support for the role of malaria. InterpretationWe report the emergence of BWF in Eastern Uganda, a condition that according to local investigators was rare until the last 5 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required.
Clarke GM, Rockett K, Kivinen K, et al., 2017, Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia, eLife, Vol: 6, Pages: 1-30, ISSN: 2050-084X
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to conferprotection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effectsin males and females, and it has heterogeneous effects on the clinical outcome of P. falciparuminfection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multicentre case-control study of severe malaria, using the WHO classification of G6PD mutations toestimate each individual’s level of enzyme activity from their genotype. Aggregated across allgenotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk ofcerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selectionbased on these findings indicate that an evolutionary trade-off between different clinical outcomesof P. falciparum infection could have been a major cause of the high levels of G6PD polymorphismseen in human populations.
Wang H, Bhutta ZA, Coates MM, et al., 2017, Erratum: Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 (The Lancet (2016) 388(10053) (1725–1774)(S0140673616315756)(10.1016/S0140-6736(16)31575-6)), The Lancet, Vol: 389, Pages: e1-e1, ISSN: 0140-6736
© 2017 Elsevier Ltd GBD 2015 Child Mortality Collaborators. Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388: 1725–74—In this Article, Mohsen Naghavi, Michael J Kutz, Chantal Huynh, Samer Hamidi, Addisu Shunu Beyene, and Stephen S Lim should have been listed as authors. The affiliation details for Simon I Hay have been updated. The funding statement for Simon I Hay has been added. These corrections have been made to the online version as of Jan 5, 2017.
Williams TN, Weatherall DJ, 2017, A Classification of the Common Inherited Hemoglobin Disorders, Infectious Diseases, 2-Volume Set, Pages: 1053-1058.e1, ISBN: 9780702063398
4Adetifa IMO, Bwanaali T, Wafula J, et al., 2016, Cohort profile: the Kilifi Vaccine Monitoring Study, International Journal of Epidemiology, ISSN: 1464-3685
The Kilifi Vaccine Monitoring Study (KiVMS) is a long-term continuous cohort study set up to investigate effectiveness, impact, coverage, safety and indirect vaccine effects by recruiting birth cohorts and, where applicable, cohorts of older and adults.It is based in the area covered by the Kilifi Health and Demographic Surveillance System, Kilifi, Kenya, and currently has records of 33 962 children in the birth cohort database.A major strength of KiVMS is its unique integration of a vaccine registry, a morbidity surveillance system and the largest health and demographic surveillance system (HDSS) in Africa.
Williams TN, 2016, Host genetics, Recent Advances in Malaria, Pages: 465-494, ISBN: 9781118493793
The relationship between malaria and host genetics has come a long way since Haldane first suggested that β-thalassaemia may have risen to its current population frequencies as a result of natural selection by P. falciparum disease. In the case of the Duffy antigen receptor for chemokines (DARC) blood group antigens, the observation that DARC-negative subjects are refractory to P. vivax infections has spawned a wide range of important scientific discoveries that have culminated in the development of a new vaccine, giving hope that observations regarding other malaria-protective genes will similarly result, eventually, in novel approaches to prevention and treatment. One such protein is the Ok blood group antigen basigin, a protein that has been implicated as a receptor for the P. falciparum parasite ligand PfRh5, a protein that is essential for blood-stage growth. The opportunities to translate the lessons learned from the study of host-protective factors into clinically useful solutions have never been greater.
Mogeni P, Williams TN, Fegan G, et al., 2016, Age, Spatial, and Temporal Variations in Hospital Admissions with Malaria in Kilifi County, Kenya: A 25-Year Longitudinal Observational Study, Plos Medicine, Vol: 13, ISSN: 1549-1676
BackgroundEncouraging progress has been seen with reductions in Plasmodium falciparum malariatransmission in some parts of Africa. Reduced transmission might lead to increasing susceptibilityto malaria among older children due to lower acquired immunity, and this hasimplications for ongoing control strategies.Methods and FindingsWe conducted a longitudinal observational study of children admitted to Kilifi County Hospitalin Kenya and linked it to data on residence and insecticide-treated net (ITN) use. Thisincluded data from 69,104 children aged from 3 mo to 13 y admitted to Kilifi County Hospitalbetween 1 January 1990 and 31 December 2014. The variation in malaria slide positivityamong admissions was examined in logistic regression models using the following predictors:location of the residence, calendar time, the child’s age, ITN use, and the enhancedvegetation index (a proxy for soil moisture). The proportion of malaria slide-positive admissionsdeclined from 0.56 (95% confidence interval [CI] 0.54–0.58) in 1998 to 0.07 (95% CI0.06–0.08) in 2009 but then increased again through to 0.24 (95% CI 0.22–0.25) in 2014.Older children accounted for most of the increase after 2009 (0.035 [95% CI 0.030–0.040]among young children compared to 0.22 [95% CI 0.21–0.23] in older children). There was anonlinear relationship between malaria risk and prevalence of ITN use within a 2 km radiusof an admitted child’s residence such that the predicted malaria positive fraction varied from~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis, we were unable to determine the cause of the decline in malaria between 1998and 2009, which pre-dated the dramatic scale-up in ITN distribution and use.ConclusionFollowing a period of reduced transmission, a cohort of older children emerged who haveincreased susceptibility to malaria. Further reductions in malaria transmission are neededto mitigate the increasing
Busby GBJ, Band G, Si Le Q, et al., 2016, Admixture into and within sub-Saharan Africa, eLife, Vol: 5, ISSN: 2050-084X
Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology.
Rautanen A, Pirinen M, Mills TC, et al., 2016, Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children, The American Journal of Human Genetics, Vol: 98, Pages: 1092-1100, ISSN: 0002-9297
Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10−9; OR = 2.47, 95% CI = 1.84–3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.
Opi DH, Uyoga S, Orori EN, et al., 2016, Red blood cell complement receptor one level varies with Knops blood group, α+thalassaemia and age among Kenyan children, Genes and Immunity, Vol: 17, Pages: 171-178, ISSN: 1476-5470
Both the invasion of red blood cells (RBCs) by Plasmodium falciparum parasites and the sequestration of parasite-infected RBCs in the microvasculature are mediated in part by complement receptor one (CR1). RBC surface CR1 level can vary between individuals by more than 20-fold and may be associated with the risk of severe malaria. The factors that influence RBC CR1 level variation are poorly understood, particularly in African populations. We studied 3535 child residents of a malaria-endemic region of coastal Kenya and report, for the first time, that the CR1 Knops blood group alleles Sl2 and McCb, and homozygous HbSS are positively associated with RBC CR1 level. Sickle cell trait and ABO blood group did not influence RBC CR1 level. We also confirm the previous observation that α+thalassaemia is associated with reduced RBC CR1 level, possibly due to small RBC volume, and that age-related changes in RBC CR1 expression occur throughout childhood. RBC CR1 level in malaria-endemic African populations is a complex phenotype influenced by multiple factors that should be taken into account in the design and interpretation of future studies on CR1 and malaria susceptibility.
Seale AC, Davies MR, Anampiu K, et al., 2016, Invasive group A Streptococcus amongst children in rural Kenya, Emerging Infectious Diseases, Vol: 22, Pages: 224-232, ISSN: 1080-6059
There are minimal data on the burden of Streptococcus pyogenes (group A Streptococcus; GAS) in sub-Saharan Africa and none on serotypes causing disease. We analyzed systematically collected clinical and microbiological surveillance data from 64,741 hospital admissions in Kilifi, Kenya (1998-2011), to describe incidence, clinical presentations and emm-types of invasive GAS (iGAS). There were 370 cases; commonly skin and soft tissue infections (258/369,70%), severe pneumonia (86/369,23%), and primary bacteremia (53/369,14%); overall case fatality risk was 45/369 (12%). Incidence of iGAS was, in neonates 0.6/1000 live-births; <1 year 101/100,000, and <5 years 35/100,000. Using genome sequencing, 88 different emm-types were observed, highlighting extensive circulating GAS heterogeneity. GAS is an important cause of serious bacterial disease in this setting, especially in neonates, with considerable genotypic diversity. There may be limited benefit from the most advanced GAS type-specific vaccines and efforts must be directed to protect against disease in high burden regions.
Williams TN, 2016, Sickle cell disease in Sub-Saharan Africa, Hematology/Oncology Clinics of North America, Vol: 30, Pages: 343-358, ISSN: 1558-1977
In Africa, at least 240,000 children are born each year with sickle cell disease. Historically, in the absence of newborn screening and appropriate treatment, most such children died undiagnosed in early childhood. However, with increasing awareness of the condition and economic and epidemiologic transition, increasing numbers are surviving. Greater investments in basic and applied research in the African context, and increased sensitization or African ministries of health regarding the importance of this condition, could make a substantial difference to the lives and livelihoods of millions of people living with sickle cell disease on the continent and their families.
Piel FB, Williams TN, 2016, Sickle cell Anemia: History and Epidemiology, Sickle Cell Anemia From Basic Science to Clinical Practice, Editors: Conran, Costa, Publisher: Springer, ISBN: 9783319067124
Mackinnon MJ, Ndila C, Uyoga S, et al., 2016, Environmental correlation analysis for genes associated with protection against malaria, Molecular Biology and Evolution, Vol: 33, Pages: 1188-1204, ISSN: 1537-1719
Genome-wide searches for loci involved in human resistance to malaria are currently being conducted on a large scale in Africa using case-control studies. Here, we explore the utility of an alternative approach – “environmental correlation analysis, ECA”, which tests for clines in allele frequencies across a gradient of an environmental selection pressure - to identify genes that have historically protected against death from malaria. We collected genotype data from 12,425 newborns on 57 candidate malaria resistance loci and 9,756 SNPs selected at random from across the genome, and examined their allele frequencies for geographic correlations with long-term malaria prevalence data based on 84,042 individuals living under different historical selection pressures from malaria in coastal Kenya. None of the 57 candidate SNPs showed significant (P < 0.05) correlations in allele frequency with local malaria transmission intensity after adjusting for population structure and multiple testing. By contrast, two of the random SNPs that had highly significant correlations (P < 0.01) were in genes previously linked to malaria resistance, namely, CDH13, encoding cadherin 13, and HS3ST3B1, encoding heparan sulphate 3-O-sulfotransferase 3B1. Both proteins play a role in glycoprotein-mediated cell-cell adhesion which has been widely implicated in cerebral malaria, the most life-threatening form of this disease. Other top genes, including CTNND2 which encodes δ-catenin, a molecular partner to cadherin, were significantly enriched in cadherin-mediated pathways affecting inflammation of the brain vascular endothelium. These results demonstrate the utility of ECA in the discovery of novel genes and pathways affecting infectious disease.
Maitland K, 2015, Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomized controlled trial, Trials, Vol: 16, ISSN: 1745-6215
BackgroundIn sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9–10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.Methods/DesignTRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children.The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4–6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity
Muthumbi E, Morpeth SC, Ooko M, et al., 2015, Invasive Salmonellosis in Kilifi, Kenya, Clinical Infectious Diseases, Vol: 61, Pages: S290-S301, ISSN: 1537-6591
Background: Invasive salmonelloses are a major cause of morbidity and mortality in Africa but the incidence and case-fatality of each disease varies markedly by region.Objectives: To describe the incidence, clinical characteristics and antimicrobial susceptibility patterns of invasive salmonelloses among children and adults in Kilifi, KenyaMethods: We analyzed integrated clinical and laboratory records for patients presenting to the Kilifi County Hospital between 1998 and 2014. We calculated incidence, summarised clinical features and multidrug resistance (MDR).Results: Non-typhoidal Salmonella (NTS) accounted for 10.8% and 5.8% of bacteremia cases, in children and adults respectively while Salmonella Typhi accounted for 0.5% and 2.1% of bacteremia cases, respectively. Among 351 NTS isolates serotyped, 160 (45.5%) were Salmonella Enteritidis and 152 (43.3%) were Salmonella Typhimurium. The incidence of NTS in children aged <5 years was 36.6/100,000 person-years being highest in infants aged <7 days (174/100,000 person-years). The overall incidence of NTS in children varied markedly by location and declined significantly during the study period; the pattern of dominance of the NTS serotypes also shifted from Salmonella Enteritidis to Salmonella Typhimurium. Risk factors for invasive NTS disease were HIV infection, malaria, and malnutrition; the case fatality ratio was 22.1% (71/321) in children under 5 years and 36.7% (11/30) in adults. MDR was present in 23.9% (84/351) of NTS isolates and 46.2% (12/26) of Salmonella Typhi isolates. Conclusions: In Kilifi, the incidence of invasive NTS was high, especially among newborn infants but typhoid fever was uncommon. NTS remains an important cause of bacteremia in children under 5 years.
Williams TN, Band G, Kwiatkowski DP, et al., 2015, A novel locus of resistance to severe malaria in a region of ancient balancing selection, Nature, Vol: 526, Pages: 253-257, ISSN: 0028-0836
The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies1, 2, 3. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60–0.76, P value = 9.5 × 10−11) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees4. Taken together with previous observations on the malaria-protective role of blood group O1, 2, 3, 5, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host–parasite interactions that are critical in determining the outcome of malaria infection.
Williams TN, 2015, An accurate and affordable test for the rapid diagnosis of sickle cell disease could revolutionize the outlook for affected children born in resource-limited settings, BMC Medicine, Vol: 13, ISSN: 1741-7015
Each year, at least 280,000 children are born with sickle cell disease (SCD) in resource-limited settings. For cost, logistic and political reasons, the availability of SCD testing is limited in such settings and consequently 50–90 % of affected children die undiagnosed before their fifth birthday. The recent development of a point of care method for the diagnosis of SCD – the Sickle SCAN™ device – could afford such children the prompt access to appropriate services that has transformed the outlook for affected children in resource-rich areas. In research published in BMC Medicine, Kanter and colleagues describe a small but carefully conducted study involving 208 children and adults, in which they found that by using Sickle SCAN™ it was possible to diagnose the common forms of SCD with 99 % sensitivity and 99 % specificity, in under 5 minutes. If repeatable both in newborn babies and under real-life conditions, and if marketed at an affordable price, Sickle SCAN™ could revolutionize the survival prospects for children born with SCD in resource-limited areas.
Uyoga S, Ndila CM, Macharia AW, et al., 2015, Glucose-6-phosphate dehydrogenase defi ciency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study, The Lancet. Haematology, Vol: 2, Pages: e437-e444, ISSN: 2352-3026
Background The global prevalence of X-linked glucose-6-phosphate dehydrogenase (G6PD) defi ciency is thought to bea result of selection by malaria, but epidemiological studies have yielded confusing results. We investigated therelationships between G6PD defi ciency and both malaria and non-malarial illnesses among children in Kenya.Methods We did this study in Kilifi County, Kenya, where the G6PD c.202T allele is the only signifi cant cause of G6PDdefi ciency. We tested the associations between G6PD defi ciency and severe and complicated Plasmodium falciparummalaria through a case-control study of 2220 case and 3940 control children. Cases were children aged younger than14 years, who visited the high dependency ward of Kilifi County Hospital with severe malaria between March 1, 1998,and Feb 28, 2010. Controls were children aged between 3–12 months who were born within the same study areabetween August 2006, and September 2010. We assessed the association between G6PD defi ciency and bothuncomplicated malaria and other common diseases of childhood in a cohort study of 752 children aged younger than10 years. Participants of this study were recruited from a representative sample of households within the Ngerenya andChonyi areas of Kilifi County between Aug 1, 1998, and July 31, 2001. The primary outcome measure for the casecontrolstudy was the odds ratio for hospital admission with severe malaria (computed by logistic regression) while forthe cohort study it was the incidence rate ratio for uncomplicated malaria and non-malaria illnesses (computed byPoisson regression), by G6PD defi ciency category.Findings 2863 (73%) children in the control group versus 1643 (74%) in the case group had the G6PD normalgenotype, 639 (16%) versus 306 (14%) were girls heterozygous for G6PD c.202T, and 438 (11%) versus 271 (12%)children were either homozygous girls or hemizygous boys. Compared with boys and girls without G6PD defi ciency,we found signifi cant protection from severe m
Piel FB, Adamkiewicz TV, Amendah D, et al., 2015, Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: Deviations from Hardy-Weinberg equilibrium, Genetics in Medicine, ISSN: 1530-0366
Purpose:Our objective was to compare observed and expected genotype proportions from newborn screening surveys of structural hemoglobin variants. Methods: We conducted a systematic review of newborn screening surveys of hemoglobins S and C in Africa and the Middle-East. We compared observed frequencies to those expected assuming Hardy-Weinberg equilibrium (HWE). Significant deviations were identified by an exact test. The fixation index FIS was calculated to assess excess homozygosity. We compared newborn estimates corrected and uncorrected for HWE deviations using demographic data. Results: Sixty samples reported genotype counts for hemoglobin variants in Africa and the Middle-East. Observed and expected counts matched in 27%. The observed number of sickle-cell anemia (SCA) individuals was higher than expected in 42 samples, reaching significance (p<0.05) in 24. High FIS were common across the study regions. The estimated total number of newborns with SCA, corrected based on FIS, were 33,261 annual births instead of 24,958 for the 38 samples across sub-Saharan Africa and 1,109 annual births instead of 578 for 12 samples from the Middle East.Conclusion: Differences between observed and expected genotype frequencies are common in surveys of hemoglobin variants in the study regions. Further research is required to identify and quantify factors responsible for such deviations. Estimates based on HWE might substantially underestimate the annual number of SCA affected newborns (up to one third in sub-Saharan Africa and one half in the Middle East).
Shelton JMG, Corran P, Risley P, et al., 2015, Genetic determinants of anti-malarial acquired immunity in a large multi-centre study, Malaria Journal, Vol: 14, ISSN: 1475-2875
BackgroundMany studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels.MethodsSera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms (SNPs) with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens (AMA1, MSP1, MSP2, and (NANP)4) plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels.ResultsMalaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein (CSP), while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2.ConclusionAlthough the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonst
Vos T, Barber RM, Bell B, et al., 2015, Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013, The Lancet, Vol: 386, Pages: 743-800, ISSN: 0140-6736
BackgroundUp-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.MethodsEstimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries.FindingsDisease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communic
McGann PT, Tshilolo L, Santos B, et al., 2015, Hydroxyurea therapy for children with sickle cell anemia in sub-Saharan Africa: Rationale and design of the REACH trial, Pediatric Blood & Cancer, Vol: 63, Pages: 98-104, ISSN: 1545-5017
Background: Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease-modifying therapy for SCA, and has proven safety and efficacy in high-resource countries. In sub-Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence-based guidelines, and inexperience among healthcare providers.Procedure: A partnership was established between investigators in North America and sub-Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. Results: The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open-label dose escalation study of hydroxyurea that will treat a total of 600 children age 1-10 years with SCA: 150 at each of 4 different clinical sites within sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed-dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose.Conclusions: REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub-Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa
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