Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma.

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.

Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa.

In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10-11 and 3.74×10-2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research.

IFNL4 Genotypes and Risk of Childhood Burkitt Lymphoma in East Africa.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele (IFNL4-dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4-dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4-dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations.

Minimally Invasive Postmortem Intestinal Tissue Sampling in Malnourished and Acutely Ill Children Is Feasible and Informative.

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

Localised release of matrix metallopeptidase 8 in fatal cerebral malaria.

OBJECTIVE: Cerebral malaria (CM) is a complication of Plasmodium falciparum malaria, in which progressive brain swelling is associated with sequestration of parasites and impaired barrier function of the cerebral microvascular endothelium. To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in CM, we examined its expression and association with extravascular fibrinogen leak in a case-control study of post-mortem retinal samples from 13 Malawian children who met the clinical case definition of CM during life. Cases were seven children who were found on post-mortem examination to have 'true-CM' (parasite sequestration in brain blood vessels), whilst controls were six children who had alternative causes of death ('faux-CM', no parasite sequestration in blood vessels). METHODS: We used immunofluorescence microscopy and independent scoring, by two assessors blinded to the CM status, to assess MMP8 expression, extravascular fibrinogen as an indicator of vascular leak and their co-localisation in the retinal microvasculature. RESULTS: In 'true-CM' subjects, MMP8 staining was invariably associated with sequestered parasites and a median of 88% (IQR = 74-91%) of capillaries showed MMP8 staining, compared with 14% (IQR = 3.8-24%) in 'faux-CM' (P-value = 0.001). 41% (IQR = 28-49%) of capillaries in 'true-CM' subjects showed co-localisation of extravascular fibrinogen leak and MMP8 staining, compared with 1.8% of capillaries in 'faux-CM' (IQR = 0-3.9%, P-value = 0.01). Vascular leak was rare in the absence of MMP8 staining. CONCLUSION: Matrix metallopeptidase 8 was extensively expressed in retinal capillaries of Malawian children with malarial retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 as a cause of the vascular endothelial barrier disruption in CM, which may precipitate fatal brain swelling.

Assessment of Mixed Plasmodium falciparum sera5 Infection in Endemic Burkitt Lymphoma: A Case-Control Study in Malawi.

BACKGROUND: Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in Africa and is linked to Plasmodium falciparum (Pf) malaria infection, one of the most common and deadly childhood infections in Africa; however, the role of Pf genetic diversity is unclear. A potential role of Pf genetic diversity in eBL has been suggested by a correlation of age-specific patterns of eBL with the complexity of Pf infection in Ghana, Uganda, and Tanzania, as well as a finding of significantly higher Pf genetic diversity, based on a sensitive molecular barcode assay, in eBL cases than matched controls in Malawi. We examined this hypothesis by measuring diversity in Pf-serine repeat antigen-5 (Pfsera5), an antigenic target of blood-stage immunity to malaria, among 200 eBL cases and 140 controls, all Pf polymerase chain reaction (PCR)-positive, in Malawi. METHODS: We performed Pfsera5 PCR and sequencing (~3.3 kb over exons II-IV) to determine single or mixed PfSERA5 infection status. The patterns of Pfsera5 PCR positivity, mixed infection, sequence variants, and haplotypes among eBL cases, controls, and combined/pooled were analyzed using frequency tables. The association of mixed Pfsera5 infection with eBL was evaluated using logistic regression, controlling for age, sex, and previously measured Pf genetic diversity. RESULTS: Pfsera5 PCR was positive in 108 eBL cases and 70 controls. Mixed PfSERA5 infection was detected in 41.7% of eBL cases versus 24.3% of controls; the odds ratio (OR) was 2.18, and the 95% confidence interval (CI) was 1.12-4.26, which remained significant in adjusted results (adjusted odds ratio [aOR] of 2.40, 95% CI of 1.11-5.17). A total of 29 nucleotide variations and 96 haplotypes were identified, but these were unrelated to eBL. CONCLUSIONS: Our results increase the evidence supporting the hypothesis that infection with mixed Pf infection is increased with eBL and suggest that measuring Pf genetic diversity may provide new insights into the role of Pf infection in eBL.

HLA-DRB1 alleles and cervical cancer: A meta-analysis of 36 case-control studies.

BACKGROUND: Human leukocyte antigens (HLA) are encoded by closely linked genetic loci, and are important in cervical carcinogenesis. The association between HLA-DRB1 alleles with cervical cancer has been studied extensively, but results reported thus far have been inconsistent. Hence, we performed a meta-analysis to precisely assess this association. METHODS: A literature search was conducted in various online databases to identify suitable articles. Case-control studies investigating the association between HLA-DRB1 alleles and cervical cancer were included in this study. Fixed and random-effect models were used to calculate the pooled odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: A total of 6645 cases and 9095 controls from 36 case-control studies were included. Of the 13 HLA-DRB1 family alleles, DRB1*09 (OR = 1.30) and DRB1 *15 (OR = 1.60) were associated with cervical cancer risk, whilst DRB1*13 (OR = 0.66) exerted a protective effect. Among the 44 HLA-DRB1 specific alleles, DRB1*04:01 (OR = 1.25), DRB1*10:01 (OR = 1.45), DRB1*11:01 (OR = 1.32), DRB1*15:01 (OR = 1.21) and DRB1*15:02 (OR = 1.55) were associated with an increased risk of cervical cancer. However, DRB1*04:06 (OR = 0.52), DRB1*12:02 (OR = 0.61), DRB1*13:01 (OR = 0.62), DRB1*13:02 (OR = 0.57), and DRB1*14:04 (OR = 0.37) were associated with a decreased risk of cervical cancer. Subgroup analysis also revealed that HLA-DRB1 alleles are associated with cervical cancer in Asian, Caucasian, Hispanic or Latin American and black sub-Saharan Africa populations. CONCLUSION: Our meta-analysis revealed that multiple HLA-DRB1 alleles are associated with cervical cancer in women of diverse ancestry populations.

Improvement of overall survival in the Collaborative Wilms Tumour Africa Project.

INTRODUCTION: The Collaborative Wilms Tumour (WT) Africa Project implemented an adapted WT treatment guideline in six centres in sub-Saharan Africa. The primary objectives were to describe abandonment of treatment, death during treatment, event-free survival (EFS) and relapse following implementation. An exploratory objective was to compare outcomes with the baseline evaluation, a historical cohort preceding implementation. METHODS: The Collaborative WT Africa Project is a multi-centre prospective clinical trial that began in 2014. Funding was distributed to all participating centres and used to cover treatment, travel and other associated costs for patients. Patient characteristics, tumour characteristics and events were described. RESULTS: In total, 201 WT patients were included. Two-year EFS was 49.9 ± 3.8% when abandonment of treatment was considered an event. Relapse of disease occurred in 21% (42 of 201) of all included patients and in 26% (42 of 161) of those who had a nephrectomy. Programme implementation was associated with significantly higher survival without evidence of disease at the end of treatment (52% vs 68.5%, P = .002), significantly reduced abandonment of treatment (23% vs 12%, P = .009) and fewer deaths during treatment (21% vs 13%, P = .06). CONCLUSION: This collaborative implementation of an adapted WT treatment guideline, using relatively simple and low-cost interventions, was feasible. Two-year EFS was almost 50%. In addition, a significant decrease in treatment abandonment and an increase in survival at the end of treatment were observed compared to a pre-implementation cohort. Future work should focus on decreasing deaths during treatment and will include enhancing supportive care.

Association of TP53 rs1042522 with cervical cancer in the sub-Saharan African population: a meta-analysis.

OBJECTIVE: TP53 plays a crucial role in preventing cancer development. Previous studies in sub-Saharan Africa (SSA) reported inconclusive findings for the association of the TP53 rs1042522 C > G variant with cervical cancer. We therefore performed a meta-analysis to summarise this association in the SSA population. METHODS: Online databases were searched to identify suitable articles according to the PRISMA guidelines. We included studies published in English or French that provided the sample sizes and genotype counts for both cases and controls and evaluated the association between TP53 rs1042522 and cervical cancer in the SSA population. A fixed-effect model was used to calculate the pooled odds ratio (OR) and 95% confidence intervals (95% CIs). RESULTS: A total of 699 cervical cancer cases and 1008 controls from eight studies in SSA were included in this meta-analysis. Women harbouring the variant G allele of the TP53 rs1042522 were at increased risk of cervical cancer in allelic (G vs. C; OR = 1.30, 95% Cl = 1.12-1.50), homozygous (GG vs. CC; OR = 1.62, 95% CI = 1.20-2.19) and recessive (GG vs. CG + GG; OR = 1.74, 95% CI = 1.34-2.25) genetic models. However, the dominant genetic model (CG + GG vs. CC; OR = 1.20, 95% CI = 0.96-1.48) was not significantly associated with cervical cancer. CONCLUSIONS: Our meta-analysis revealed that harbouring variant G allele of TP53 rs1042522 is associated with cervical cancer risk in the SSA population.

OBJECTIF: Le TP53 joue un rôle crucial dans la prévention du développement du cancer. Des études antérieures en Afrique subsaharienne (ASS) ont rapporté des résultats non concluants pour l'association de la variante TP53 rs1042522 C>G avec le cancer du col de l'utérus. Nous avons donc réalisé une méta-analyse pour résumer cette association dans la population SSA. MÉTHODES: Les bases de données en ligne ont été recherchées pour identifier les articles appropriés selon les directives PRISMA. Nous avons inclus des études publiées en anglais ou en français qui ont fourni la taille des échantillons et le nombre de génotypes pour les cas et les témoins et évalué l'association entre TP53 rs1042522 et le cancer du col de l'utérus dans la population SSA. Un modèle à effet fixe a été utilisé pour calculer le rapport de cotes combiné (OR) et les intervalles de confiance à 95% (IC95%). RÉSULTATS: Un total de 699 cas de cancer du col utérin et 1008 témoins de huit études en ASS ont été inclus dans cette méta-analyse. Les femmes hébergeant l'allèle variant G du TP53 rs1042522 présentaient un risque accru de cancer du col de l'utérus chez les modèles génétiques alléliques (G vs C; OR = 1,30, IC95%: 1,12-1,50), homozygotes (GG vs CC; OR = 1,62, IC95%: 1,20-2,19) et récessifs (GG vs.CG + GG; OR = 1,74, IC95%: 1,34-2,25). Cependant, le modèle génétique dominant (CG + GG vs CC; OR = 1,20, IC95%: 0,96-1,48) n'était pas significativement associé au cancer du col utérin. CONCLUSIONS: Notre méta-analyse a révélé que l'hébergement de l'allèle variant G de TP53 rs1042522 est associé au risque de cancer du col de l'utérus dans la population SSA.

Impact of Maternal HIV Infection and Placental Malaria on the Transplacental Transfer of Influenza Antibodies in Mother-Infant Pairs in Malawi, 2013-2014.

BACKGROUND: Maternal influenza vaccination protects infants against influenza virus infection. Impaired transplacental transfer of influenza antibodies may reduce this protection. METHODS: We conducted a cross-sectional study of influenza vaccine-naïve pregnant women recruited at delivery from Blantyre (urban, low malaria transmission) and Chikwawa (rural, high malaria transmission) in Southern Malawi. HIV-infected mothers were excluded in Chikwawa. Maternal and cord blood antibodies against circulating influenza strains A/California/7/2009, A/Victoria/361/2011, B/Brisbane/60/2008, and B/Wisconsin/1/2010 were measured by hemagglutination inhibition (HAI). We studied the impact of maternal HIV infection and placental malaria on influenza antibody levels in mother-infant pairs in Blantyre and Chikwawa, respectively. RESULTS: We included 454 mother-infant pairs (Blantyre, n = 253; Chikwawa, n = 201). HIV-infected mothers and their infants had lower seropositivity (HAI titer ≥1:40) against influenza A(H1N1)pdm09 (mothers, 24.3 vs 45.4%; P = .02; infants, 24.3 vs 50.5%; P = .003) and A(H3N2) (mothers, 37.8% vs 63.9%; P = .003; infants, 43.2 vs 64.8%; P = .01), whereas placental malaria had an inconsistent effect on maternal and infant seropositivity. In multivariable analyses, maternal HIV infection was associated with reduced infant seropositivity (A(H1N1)pdm09: adjusted odds ratio [aOR], 0.34; 95% confidence interval [CI], 0.15-0.79; A(H3N2): aOR, 0.43; 95% CI, 0.21-0.89). Transplacental transfer was not impaired by maternal HIV or placental malaria. CONCLUSIONS: Maternal HIV infection influenced maternal antibody response to influenza A virus infection, and thereby antibody levels in newborns, but did not affect transplacental antibody transfer.

Comparison of CD8+ T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria.

CD8+ T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. Thus, in this study we have provided the first direct contrast of the accumulation of CD8+ T cells in the brain during HCM and ECM. HCM cases were from children who died of Plasmodium falciparum cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 and 2010. ECM was induced by infecting C57BL/6J mice with P. berghei ANKA. We demonstrate similarities in the intracerebral CD8+ T cell responses in ECM and HCM, in particular an apparent shared choroid plexus-meningeal route of CD8+ T cell accumulation in the brain. Nevertheless, we also reveal some potentially important differences in compartmentalization of CD8+ T cells within the cerebrovascular bed in HCM and ECM.

Survival of children with a Wilms tumor in Blantyre, Malawi.

Wilms tumor (WT) has a survival rate above 90% in high income countries. Reported survival rates in sub-Saharan Africa are much lower and long-term outcome is not well known as follow-up is challenging. In Blantyre, Malawi, an adapted WT treatment guideline with preoperative chemotherapy, supportive care, and strategies to enable children and parents to complete treatment was introduced in 2006. Between 2006 and 2011, 73 children with a unilateral WT were treated. Follow-up, including home visits when needed, was done. Median follow-up time is 5 years (range 14-95 months). Two and five-year event free survivals are 46 and 42%. Causes of treatment failure are: 7% (5/73) abandonment of treatment, 15% (11/73) death during treatment and 30% (22/73) disease-related deaths (persistent disease and relapse). Long-term follow-up is challenging but necessary to be able to assess outcome and the true impact of interventions.

Neurovascular sequestration in paediatric P. falciparum malaria is visible clinically in the retina.

Retinal vessel changes and retinal whitening, distinctive features of malarial retinopathy, can be directly observed during routine eye examination in children with P. falciparum cerebral malaria. We investigated their clinical significance and underlying mechanisms through linked clinical, clinicopathological and image analysis studies. Orange vessels and severe foveal whitening (clinical examination, n = 817, OR, 95% CI: 2.90, 1.96-4.30; 3.4, 1.8-6.3, both p<0.001), and arteriolar involvement by intravascular filling defects (angiographic image analysis, n = 260, 2.81, 1.17-6.72, p<0.02) were strongly associated with death. Orange vessels had dense sequestration of late stage parasitised red cells (histopathology, n = 29; sensitivity 0.97, specificity 0.89) involving 360° of the lumen circumference, with altered protein expression in blood-retinal barrier cells and marked loss/disruption of pericytes. Retinal whitening was topographically associated with tissue response to hypoxia. Severe neurovascular sequestration is visible at the bedside, and is a marker of severe disease useful for diagnosis and management.

Co-causation of reduced newborn size by maternal undernutrition, infections, and inflammation.

More than 20 million babies are born with low birthweight annually. Small newborns have an increased risk for mortality, growth failure, and other adverse outcomes. Numerous antenatal risk factors for small newborn size have been identified, but individual interventions addressing them have not markedly improved the health outcomes of interest. We tested a hypothesis that in low-income settings, newborn size is influenced jointly by multiple maternal exposures and characterized pathways associating these exposures with newborn size. This was a prospective cohort study of pregnant women and their offspring nested in an intervention trial in rural Malawi. We collected information on maternal and placental characteristics and used regression analyses, structural equation modelling, and random forest models to build pathway maps for direct and indirect associations between these characteristics and newborn weight-for-age Z-score and length-for-age Z-score. We used multiple imputation to infer values for any missing data. Among 1,179 pregnant women and their babies, newborn weight-for-age Z-score was directly predicted by maternal primiparity, body mass index, and plasma alpha-1-acid glycoprotein concentration before 20 weeks of gestation, gestational weight gain, duration of pregnancy, placental weight, and newborn length-for-age Z-score (p < .05). The latter 5 variables were interconnected and were predicted by several more distal determinants. In low-income conditions like rural Malawi, maternal infections, inflammation, nutrition, and certain constitutional factors jointly influence newborn size. Because of this complex network, comprehensive interventions that concurrently address multiple adverse exposures are more likely to increase mean newborn size than focused interventions targeting only maternal nutrition or specific infections.

The Medical Education Partnership Initiative (MEPI): Innovations and Lessons for Health Professions Training and Research in Africa.

MEPI was a $130 million competitively awarded grant by President's Emergency Plan for AIDS Relief (PEPFAR) and National Institutes of Health (NIH) to 13 Medical Schools in 12 Sub-Saharan African countries and a Coordinating Centre (CC). Implementation was led by Principal investigators (PIs) from the grantee institutions supported by Health Resources and Services Administration (HRSA), NIH and the CC from September, 2010 to August, 2015. The goals were to increase the capacity of the awardees to produce more and better doctors, strengthen locally relevant research, promote retention of the graduates within their countries and ensure sustainability. MEPI ignited excitement and stimulated a broad range of improvements in the grantee schools and countries. Through in-country consortium arrangements African PIs expanded the programme from the 13 grantees to over 60 medical schools in Africa, creating vibrant South-South and South-North partnerships in medical education, and research. Grantees revised curricular to competency based models, created medical education units to upgrade the quality of education and established research support centres to promote institutional and collaborative research. MEPI stimulated the establishment of ten new schools, doubling of the students' intake, in some schools, a three-fold increase in post graduate student numbers, and faculty expansion and retention.Sustainability of the MEPI innovations was assured by enlisting the support of universities and ministries of education and health in the countries thus enabling integration of the new programs into the regular national budgets. The vibrant MEPI annual symposia are now the largest medical education events in Africa attracting global participation. These symposia and innovations will be carried forward by the successor of MEPI, the African Forum for Research and Education in Health (AFREhealth). AFREhealth promises to be more inclusive and transformative bringing together other health professionals including nurses, pharmacists, and dentists.

Evaluating the use of pathology in improving diagnosis in rural Malawi.

Introduction: Limited data exists on histologically confirmed cancers and tuberculosis in rural Malawi, despite the high burden of both conditions. One of the main reasons for the limited data is the lack of access to pathology services for diagnosis. We reviewed histopathology results of patients in Neno District, one of the poorest rural districts in Malawi, from May 2011 to July 2017, with an emphasis on cancers and tuberculosis. Methods: This is a retrospective descriptive study reviewing pathology results of samples collected at Neno health facilities and processed at Kamiza Pathology Laboratory. Data was entered into Microsoft Excel and cleaned and analysed using Stata 14. Results: A total of 532 specimens were collected, of which 87% (465) were tissue biopsies (incision or core biopsies), and 13% (67) were cytology samples. Of all specimens, 7% (n=40) of the samples had non-diagnostic results. Among the results that were diagnostic (n=492), 37% (183) were malignancies, 33% (112) were infections and inflammatory conditions other than tuberculosis, 20% (97) were benign tumours, 7% (34) were tuberculosis, 4% (21) were pre-malignant lesions, 5% (23) were normal samples, and 4% (22) were other miscellaneous conditions. Among the malignancies (n=183), 62% (114) were from females and 38% (69) from males. Among females, almost half of the cancers were cervical (43%, n= 49), followed by Kaposi sarcoma (14%, n=16), skin cancers (9%, n=10), and breast cancer (8%, n=9). In males, Kaposi sarcoma was the most common cancer (35%, n=24), followed by skin cancers (17%, n=12). About 75% (n=137) of the cancers occurred in persons aged 15 to 60 years. Conclusion: Histopathology services at a rural hospital in Malawi provides useful diagnostic information on malignancies, tuberculosis and other diagnoses, and can inform management at the district level.

The Role of Human Immunodeficiency Virus-Associated Vasculopathy in the Etiology of Stroke.

Background: Human immunodeficiency virus (HIV) infection is a recognized risk factor for stroke among young populations, but the exact mechanisms are poorly understood. We studied the clinical, radiologic, and histologic features of HIV-related ischemic stroke to gain insight into the disease mechanisms. Methods: We conducted a prospective, in-depth analysis of adult ischemic stroke patients presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, in 2011. Results: We recruited 64 HIV-infected and 107 HIV-uninfected patients. Those with HIV were significantly younger (P < .001) and less likely to have established vascular risk factors. Patients with HIV were more likely to have large artery disease (21% vs 10%; P < .001). The commonest etiology was HIV-associated vasculopathy (24 [38%]), followed by opportunistic infections (16 [25%]). Sixteen of 64 (25%) had a stroke soon after starting antiretroviral therapy (ART), suggesting an immune reconstitution-like syndrome. In this group, CD4+ T-lymphocyte count was low, despite a significantly lower HIV viral load in those recently started on treatment (P < .001). Conclusions: HIV-associated vasculopathy and opportunistic infections are common causes of HIV-related ischemic stroke. Furthermore, subtypes of HIV-associated vasculopathy may manifest as a result of an immune reconstitution-like syndrome after starting ART. A better understanding of this mechanism may point toward new treatments.

Extranodal natural killer/T-cell lymphoma in Malawi: a report of three cases.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV. CASE PRESENTATIONS: At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis. CONCLUSIONS: Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population.