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Pharmaceutical companies subject all new molecular entities to a series of in vitro metabolic characterizations that guide the selection and/or design of compounds predicted to have favorable pharmacokinetic properties in humans. Current drug metabolism research is based on liver tissue predominantly obtained from people of European origin, with limited access to tissue from people of African origin. Given the interindividual and interpopulation genomic variability in genes encoding drug-metabolizing enzymes, efficacy and safety of some drugs are poorly predicted for African populations. To address this gap, we have established the first comprehensive liver tissue biorepository inclusive of people of African origin. The African Liver Tissue Biorepository Consortium currently includes three institutions in South Africa and one in Zimbabwe, with plans to expand to other African countries. The program has collected 67 liver samples as of July 2023. DNA from the donors was genotyped for 120 variants in 46 pharmacogenes and revealed variants that are uniquely found in African populations, including the low-activity, African-specific CYP2C9*5 and *8 variants relevant to the metabolism of diclofenac. Larger liver tissue samples were used to isolate primary human hepatocytes. Viability of the hepatocytes and microsomal fractions was demonstrated by the activity of selected cytochrome P450s. This resource will be used to ensure the safety and efficacy of existing and new drugs in African populations. This will be done by characterizing compounds for properties such as drug clearance, metabolite and enzyme identification, and drug-drug and drug-gene interactions. SIGNIFICANCE STATEMENT: Standard optimization of the drug metabolism of new molecular entities in the pharmaceutical industry uses subcellular fractions such as microsomes and isolated primary hepatocytes, being done mainly with tissue from donors of European origin. Pharmacogenetics research has shown that variants in genes coding for drug-metabolizing enzymes have interindividual and interpopulation differences. We established an African liver tissue biorepository that will be useful in ensuring drug discovery and development research takes into account drug responses in people of African origin.

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BACKGROUND: Supply-demand mismatch in solid organ transplantation is particularly pronounced in small children. For liver transplantation, advanced surgical techniques for reducing deceased and living donor grafts allow access to life-saving transplantation. Living donor left lateral segment liver grafts have been successfully transplanted in small children in our center since 2013, the only program providing this service in Sub-Saharan Africa. This type of partial graft remains too large for children below 6 kg body weight and generally requires reduction. METHODS: A left lateral segment graft was reduced in situ from a directed, altruistic living donor to yield a hyperreduced left lateral segment graft. RESULTS: The donor was discharged after 6 days without complications. The recipient suffered no technical surgical complications except for an infected cut-surface biloma and biliary anastomotic stricture and remains well 9 months post-transplant. CONCLUSIONS: We report the first known case in Africa of a hyperreduced left lateral segment, ABO incompatible, living donor liver transplant in a 4,5 kg child with pediatric acute liver failure (PALF).

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Biliary atresia (BA) is a progressive fibrosing cholangiopathy of infancy, the most common cause of cholestatic jaundice in infants and the top indication for liver transplantation in children. Kasai portoenterostomy (KPE) when successful may delay the requirement for liver transplantation, which in the majority offers the only cure. Good outcomes demand early surgical intervention, appropriate management of liver cirrhosis, and in most cases, liver transplantation. These parameters were audited of children with BA treated at the Steve Biko Academic Hospital (SBAH) in Pretoria, South Africa. Methods: All children with BA who were managed at SBAH between June 2007 and July 2018 were included. Parameters measured centered on patient demographics, timing of referral and surgical intervention, immediate and long-term outcomes of surgery, and follow-up management. Results: Of 104 children treated, 94 (90%) were KPE naive. Only 23/86 (26%) of children were referred before 60 days of life and 42/86 (49%) after 120 days. Median time to surgical assessment and surgery was 4 (IQR 1-70) and 5 (IQR 1-27) days post presentation, respectively. The median age at KPE was 91 days (IQR 28-165), with only 4/41 (12%) of KPEs performed before 60 days of life. Of those with recorded outcomes, 12/33 (36%) achieved resolution of jaundice. Only a third of the cohort were referred for transplantation. Conclusion: Children with BA have poor outcomes in the public health sector in South Africa. Late referrals, delayed diagnostics, advanced age at KPE with low drainage rates, poor follow-up, and low transplant rates account for low survival. Early referral to units offering expert intervention at all stages of care, including transplantation, would offer the best outcomes.

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INTRODUCTION: Necrotizing enterocolitis (NEC) is a devastating disease of infancy. Full-thickness bowel wall necrosis may lead to perforation, peritonitis, and death. Timeous clinical diagnosis of impending perforation is imperative. OBJECTIVE: The objective of this study was to determine whether a persistent tachycardia in an infant with proven NEC is indicative of full-thickness bowel wall necrosis and therefore impending perforation. STUDY DESIGN: This study was conducted at the University of Pretoria academic hospitals. Forty-five neonates with proven NEC were divided into a surgical group (32 progressed to full-thickness bowel necrosis) and a nonsurgical group (13 resolved on conservative treatment). Differences in the pulse rate between the groups were analyzed. RESULTS: The 24-hour leading average pulse rate data for the surgical group were analyzed over a period of 10 days leading up to surgery and compared with the nonsurgical group. A clear upward trend of the mean pulse rate was observed in the surgical group, 48 hours prior to surgery. This was statistically significant (p < 0.05). CONCLUSION: This study demonstrated that a persistent tachycardia in a neonate with NEC is a predictor of progression to full-thickness bowel wall necrosis. Pulse rate is therefore an important clinical tool when deciding on operative management in NEC.

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Colorectal carcinoma in children and adolescents is extremely rare, with an annual incidence <0.3 cases per million, most frequently reported in the second decade of life. It accounts for severe morbidity and poor prognosis owing to the low index of suspicion, delayed diagnosis, advanced stage at presentation and the aggressive tumor nature. Patients present with abdominal pain, vomiting, constipation, abdominal distension, rectal tenesmus, iron-deficiency anemia, change in bowel habit and weight loss. Rectal bleeding is an uncommon presentation in children. Bowel obstruction presents frequently in children compared to adults. In 90% of pediatric cases, colorectal carcinoma occurs sporadically. In 10%, predisposing conditions and syndromes are identified. We present a case study of a 12-year-old female with advanced colorectal cancer without a predisposing disease or syndrome, who received radio-chemotherapy ten weeks prior to radical abdominopelvic surgery, followed by radio-chemotherapy postoperatively, with a positive outcome.

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