Prevalence and risk factors for diabetic foot complications among people living with diabetes in Harare, Zimbabwe: a cross-sectional study.

BACKGROUND: Diabetic foot disease (DF) is a common diabetes-related complication; however, the prevalence and associated risk factors for DF are not well characterised among people living with diabetes (PLWD) in Zimbabwe. This may suggest the unavailability of adequate strategies to diagnose and treat DF in the country. This study aimed to determine the prevalence of DF and associated risk factors for PLWD in Harare, Zimbabwe. METHODS: This was a cross-sectional study, employing a quantitative approach. In total, 352 PLWD were recruited from 16 primary care clinics in Harare. Sociodemographic and clinical data were collected via face-to-face interviews and clinical records reviews. The DF screening included an evaluation for peripheral neuropathy, ankle-brachial index (ABI), ulceration, and amputation. Self-administered questionnaires were used to assess knowledge, attitudes, and practices (KAPs), and KAP was scored using Bloom's cut-off. Chi-Square goodness-of-fit tests were performed, and regression analyses were used for association analysis. The threshold for significance was p < 0.05. RESULTS: This group included 82 men and 279 women, with a combined mean age of 57.9 ± 14 years. Twenty one (~ 26%) men and 41 (15%) women had type 1 diabetes. The diabetes type distribution significantly differed by gender (p < 0.001). Oral hypoglycaemics (71%) were most commonly administered for management. DF was observed in 53% (95% CI = 50-56) of PLWD. Other DF symptoms observed were abnormal ABI (53%), peripheral neuropathy (53%), foot ulceration (17%) and amputation (3%). Peripheral neuropathy increased the risk of ulceration (OR = 1.7; 95% CI = 1.1-2.6; p = 0.019), while insulin use was protective against amputation (OR = 0.1; 95% CI = 0.1-0.9; p = 0.049). Most (87%) of the participants demonstrated good DF knowledge and the importance of adhering to medication to prevent DF. However, 96% did not know that smoking was a risk factor for DF. Nearly two-thirds (63%) demonstrated poor attitudes and practices. Poor attitudes and practices were not predictors of DF ulceration risk (p > 0.05). CONCLUSION: This study showed that there was a high prevalence of DF (53%) in PLWD in Zimbabwe, and insulin use was protective against DF. There is an urgent need for policy revisions to include foot screening in routine primary care and increasing insulin use for PLWD to prevent complications such as DF as an integral part of primary care.

Correction: Ten simple rules for organizing a bioinformatics training course in low- and middle-income countries.

[This corrects the article DOI: 10.1371/journal.pcbi.1009218.].

A cervical cancer biorepository for pharmacogenomics research in Zimbabwe.

BACKGROUND: Research infrastructures such as biorepositories are essential to facilitate genomics and its growing applications in health research and translational medicine in Africa. Using a cervical cancer cohort, this study describes the establishment of a biorepository consisting of biospecimens and matched phenotype data for use in genomic association analysis and pharmacogenomics research. METHOD: Women aged > 18 years with a recent histologically confirmed cervical cancer diagnosis were recruited. A workflow pipeline was developed to collect, store, and analyse biospecimens comprising donor recruitment and informed consent, followed by data and biospecimen collection, nucleic acid extraction, storage of genomic DNA, genetic characterization, data integration, data analysis and data interpretation. The biospecimen and data storage infrastructure included shared -20 °C to -80 °C freezers, lockable cupboards, secured access-controlled laptop, password protected online data storage on OneDrive software. The biospecimen or data storage, transfer and sharing were compliant with the local and international biospecimen and data protection laws and policies, to ensure donor privacy, trust, and benefits for the wider community. RESULTS: This initial establishment of the biorepository recruited 410 women with cervical cancer. The mean (± SD) age of the donors was 52 (± 12) years, comprising stage I (15%), stage II (44%), stage III (47%) and stage IV (6%) disease. The biorepository includes whole blood and corresponding genomic DNA from 311 (75.9%) donors, and tumour biospecimens and corresponding tumour DNA from 258 (62.9%) donors. Datasets included information on sociodemographic characteristics, lifestyle, family history, clinical information, and HPV genotype. Treatment response was followed up for 12 months, namely, treatment-induced toxicities, survival vs. mortality, and disease status, that is disease-free survival, progression or relapse, 12 months after therapy commencement. CONCLUSION: The current work highlights a framework for developing a cancer genomics cohort-based biorepository on a limited budget. Such a resource plays a central role in advancing genomics research towards the implementation of personalised management of cancer.

Train-the-Trainer as an Effective Approach to Building Global Networks of Experts in Genomic Surveillance of Antimicrobial Resistance (AMR).

Advanced genomics and sequencing technologies are increasingly becoming critical for global health applications such as pathogen and antimicrobial resistance (AMR) surveillance. Limited resources challenge capacity development in low- and middle-income countries (LMICs), with few countries having genomics facilities and adequately trained staff. Training research and public health experts who are directly involved in the establishment of such facilities offers an effective, but limited, solution to a growing need. Instead, training them to impart their knowledge and skills to others provides a sustainable model for scaling up the much needed capacity and capability for genomic sequencing and analysis locally with global impact. We designed and developed a Train-the-Trainer course integrating pedagogical aspects with genomic and bioinformatics activities. The course was delivered to 18 participants from 12 countries in Africa, Asia, and Latin America. A combination of teaching strategies culminating in a group project created a foundation for continued development at home institutions. Upon follow-up after 6 months, at least 40% of trainees had initiated training programs and collaborations to build capacity at local, national, and regional level. This work provides a framework for implementing a training and capacity building program for the application of genomics tools and resources in AMR surveillance.

Clinical and demographic characteristics of cervical cancer patients presenting at Parirenyatwa Hospital, Zimbabwe.

Cervical cancer is the leading cause of cancer deaths in women in Africa, predominately due to late diagnosis. This study aims to identify risk factors, potential prognostic indicators, and optimal treatment modalities for Zimbabwean cervical cancer patients. Medical records for 1063 cervical cancer patients were reviewed for sociodemographic, clinical, treatment, and response data. All data were analysed using SPSS version 25. More than half of the cohort was pre-menopausal (63%) with low (2%) history of cervical cancer screening. Schistosoma ova were observed in 2.4% of the tumour specimens. More than 50% were diagnosed at stage 3 and later, with a high frequency of comorbidities (~68%). This study highlights a need for improving screening education and uptake in Zimbabwe. Moreover, the current data provides a dataset for understanding cervical cancer pathogenesis and treatment responses in an African cohort.

Engaging research ethics committees to develop an ethics and governance framework for best practices in genomic research and biobanking in Africa: the H3Africa model.

In the past decade, there has been an increase in genomic research and biobanking activities in Africa. Research initiatives such as the Human Heredity and Health in Africa (H3Africa) Consortium are contributing to the development of scientific capacity and infrastructure to support these studies on the continent. Despite this growth, genomic research and biobanking have raised important ethical challenges for key research stakeholders, including members of research ethics committees. One of these is the limited ethical and regulatory frameworks to guide the review and conduct of genomic studies, particularly in Africa. This paper is a reflection on a series of consultative activities with research ethics committees in Africa which informed the development of an ethics and governance framework for best practices in genomic research and biobanking in Africa. The paper highlights the engagement process and the lessoned learned.

Regulation of genomic and biobanking research in Africa: a content analysis of ethics guidelines, policies and procedures from 22 African countries.

BACKGROUND: The introduction of genomics and biobanking methodologies to the African research context has also introduced novel ways of doing science, based on values of sharing and reuse of data and samples. This shift raises ethical challenges that need to be considered when research is reviewed by ethics committees, relating for instance to broad consent, the feedback of individual genetic findings, and regulation of secondary sample access and use. Yet existing ethics guidelines and regulations in Africa do not successfully regulate research based on sharing, causing confusion about what is allowed, where and when. METHODS: In order to understand better the ethics regulatory landscape around genomic research and biobanking, we conducted a comprehensive analysis of existing ethics guidelines, policies and other similar sources. We sourced 30 ethics regulatory documents from 22 African countries. We used software that assists with qualitative data analysis to conduct a thematic analysis of these documents. RESULTS: Surprisingly considering how contentious broad consent is in Africa, we found that most countries allow the use of this consent model, with its use banned in only three of the countries we investigated. In a likely response to fears about exploitation, the export of samples outside of the continent is strictly regulated, sometimes in conjunction with regulations around international collaboration. We also found that whilst an essential and critical component of ensuring ethical best practice in genomics research relates to the governance framework that accompanies sample and data sharing, this was most sparingly covered in the guidelines. CONCLUSIONS: There is a need for ethics guidelines in African countries to be adapted to the changing science policy landscape, which increasingly supports principles of openness, storage, sharing and secondary use. Current guidelines are not pertinent to the ethical challenges that such a new orientation raises, and therefore fail to provide accurate guidance to ethics committees and researchers.

Application of Genomic Medicine in Africa: 14th Conference of the African Society of Human Genetics and the 2nd International Congress of the Moroccan Society of Genomics and Human Genetics, Rabat, Morocco 2022.

The 14th African Society of Human Genetics (AfSHG) Morocco Meeting and 2nd International Congress of the Moroccan Society of Genomics and Human Genetics (SM2GH), held in Rabat, Morocco, from December 12 through 17, 2022, brought together 298 attendees from 23 countries, organized by the AfSHG in collaboration with the SM2GH. The conference's overarching theme was "Applications of Genomics Medicine in Africa," covering a wide range of topics, including population genetics, genetics of infectious diseases, hereditary disorders, cancer genetics, and translational genetics. The conference aimed to address the lag in the field of genetics in Africa and highlight the potential for genetic research and personalized medicine on the continent. The goal was to improve the health of African populations and global communities while nurturing the careers of young African scientists in the field. Distinguished scientists from around the world shared their recent findings in genetics, immunogenetics, genomics, genome editing, immunotherapy, and ethics genomics. Precongress activities included a 2-day bioinformatics workshop, "NGS Analysis for Monogenic Disease in African Populations," and a Young Investigators Forum, providing opportunities for young African researchers to showcase their work. The vast genetic diversity of the African continent poses a significant challenge in investigating and characterizing public health issues at the genetic and functional levels. Training, research, and the development of expertise in genetics, immunology, genomics, and bioinformatics are vital for addressing these challenges and advancing genetics in Africa. The AfSHG is committed to leading efforts to enhance genetic research, coordinate training, and foster research collaborations on the continent.

Needs assessment of diabetic foot services in Zimbabwe.

INTRODUCTION: Due to the increasing incidence of diabetes in Zimbabwe, complications such as diabetic foot (DF) are anticipated. Establishing local gaps and needs in DF healthcare is paramount for tailoring management strategies. AIMS: To determine the status of DF services in the healthcare system and explore awareness of DF management and practices among registered general nurses (RGNs) in Zimbabwe. METHODS: A mixed-methods approach was applied. Thirty-one RGNs from 16 public health facilities in Harare, Zimbabwe attending a DF workshop were administered with a cross-sectional survey instrument and a semi-structured questionnaire. Data collected included presence/absence of DF services and podiatrists in healthcare facilities, healthcare system approaches in DF care and availability of DF training/education programs for RGNs. Analysis was performed using Stata and Nvivo software. RESULTS: No respondents reported availability of podiatrists. Only 1 (3%) of RGNs reported DF screening in primary care. Sixty percent (18) did not know or had never screened for DF. The RGNs reported inadequate DF educational programs/modules in primary care settings. CONCLUSION: This data highlights a need to improve DF education for RGNs at the frontline of managing PLWD. Understanding the needs for DF services may guide interventions to improve education and awareness programs that are appropriately tailored to local constraints in the health system. The non-communicable diseases director is encouraged to develop DF educational programmes for frontline health care workers.

Guideline for feedback of individual genetic research findings for genomics research in Africa.

As human genomics research in Africa continues to generate large amounts of data, ethical issues arise regarding how actionable genetic information is shared with research participants. The Human Heredity and Health in Africa Consortium (H3Africa) Ethics and Community Engagement Working group acknowledged the need for such guidance, identified key issues and principles relevant to genomics research in Africa and developed a practical guideline for consideration of feeding back individual genetic results of health importance in African research projects. This included a decision flowchart, providing a logical framework to assist in decision-making and planning for human genomics research projects. Although presented in the context of the H3Africa Consortium, we believe the principles described, and the decision flowchart presented here is applicable more broadly in African genomics research.

Gene set analysis of purine and pyrimidine antimetabolites cancer therapies.

OBJECTIVE: Responses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or functional gene set. Therefore, pathways or gene sets, as opposed to single genes, may better reflect the true underlying biology and may be more appropriate units for analysis of pharmacogenomic studies. Application of such methods to pharmacogenomic studies may enable the detection of more subtle effects of multiple genes in the same pathway that may be missed by assessing each gene individually. METHODS: A gene set analysis of 3821 gene sets is presented assessing the association between basal messenger RNA expression and drug cytotoxicity using ethnically defined human lymphoblastoid cell lines for two classes of drugs: pyrimidines [gemcitabine (dFdC) and arabinoside] and purines [6-thioguanine and 6-mercaptopurine]. RESULTS: The gene set nucleoside-diphosphatase activity was found to be significantly associated with both dFdC and arabinoside, whereas gene set γ-aminobutyric acid catabolic process was associated with dFdC and 6-thioguanine. These gene sets were significantly associated with the phenotype even after adjusting for multiple testing. In addition, five associated gene sets were found in common between the pyrimidines and two gene sets for the purines (3',5'-cyclic-AMP phosphodiesterase activity and γ-aminobutyric acid catabolic process) with a P value of less than 0.0001. Functional validation was attempted with four genes each in gene sets for thiopurine and pyrimidine antimetabolites. All four genes selected from the pyrimidine gene sets (PSME3, CANT1, ENTPD6, ADRM1) were validated, but only one (PDE4D) was validated for the thiopurine gene sets. CONCLUSION: In summary, results from the gene set analysis of pyrimidine and purine therapies, used often in the treatment of various cancers, provide novel insight into the relationship between genomic variation and drug response.

Pain management strategies among cervical cancer patients in Zimbabwe.

Aim: To describe pain management regulations, prevalence of pain and pain management practices in a Zimbabwean setting. Materials & methods: A multi-methods approach was used, consisting of: policy and guideline review; review of 410 cervical cancer patient records for pain symptoms and pain management data; and semistructured interviews with oncology healthcare practitioners. Results: We found a lack of policies that are specific for cervical cancer pain management. Although prevalence of pain was 68% (n = 278), only 42% of the patient records indicated pain drugs had been prescribed. Barriers to pain management included inadequate use of pain assessment tools, inaccessibility of key drugs and limited capacity. Conclusion: Cancer pain management in Zimbabwe can be improved by tailoring assessment protocols, improving drug accessibility and strengthening healthcare systems.

Lay abstract Although cancer pain has potential life-altering impact, it is not well studied in developing countries. This study aims to report on cancer pain management in Zimbabwe by reviewing policies of pain management, patient records for prevalence and assessing the practices of cancer pain management, using 410 cervical cancer patients as a model. In total, 278 (68%) cancer patients presented with pain, yet only 42% of patient records had documented prescribed pain management. We report that these findings can be consequences of restrictive policies, inadequate patient pain assessment, inaccessible pain drugs, unrecorded prescriptions and limitations of resources in the facility. Our study is important because it identifies gaps that can be addressed to improve care for cancer patients in resource-limited settings.

High-risk HPV genotypes in Zimbabwean women with cervical cancer: Comparative analyses between HIV-negative and HIV-positive women.

BACKGROUND: High-risk human papillomavirus HPV (HR-HPV) modifies cervical cancer risk in people living with HIV, yet African populations are under-represented. We aimed to compare the frequency, multiplicity and consanguinity of HR-HPVs in HIV-negative and HIV-positive Zimbabwean women. METHODS: This was a cross-sectional study consisting of women with histologically confirmed cervical cancer attending Parirenyatwa Group of Hospitals in Harare, Zimbabwe. Information on HIV status was also collected for comparative analysis. Genomic DNA was extracted from 258 formalin fixed paraffin embedded tumour tissue samples, and analysed for 14 HR-HPV genotypes. Data was analysed using Graphpad Prism and STATA. RESULTS: Forty-five percent of the cohort was HIV-positive, with a median age of 51 (IQR = 42-62) years. HR-HPV positivity was detected in 96% of biospecimens analysed. HPV16 (48%), was the most prevalent genotype, followed by HPV35 (26%), HPV18 (25%), HPV58 (11%) and HPV33 (10%), irrespective of HIV status. One third of the cohort harboured a single HPV infection, and HPV16 (41%), HPV18 (21%) and HPV35 (21%) were the most prevalent. HIV status did not influence the prevalence and rate of multiple HPV infections (p>0.05). We reported significant (p<0.05) consanguinity of HPV16/18 (OR = 0.3; 95% CI = 0.1-0.9), HPV16/33 (OR = 0.3; 95% CI = 0.1-1.0), HPV16/35 (OR = 3.3; 95% CI = 2.0-6.0), HPV35/51 (OR = 6.0; 95%CI = 1.8-15.0); HPV39/51 (OR = 6.4; 95% CI = 1.8-15), HPV31/52 (OR = 6.2; 95% CI = 1.8-15), HPV39/56 (OR = 11 95% CI = 8-12), HPV59/68 (OR = 8.2; 95% CI = 5.3-12.4), HPV66/68 (OR = 7; 95% CI = 2.4-13.5), independent of age and HIV status. CONCLUSION: We found that HIV does not influence the frequency, multiplicity and consanguinity of HR-HPV in cervical cancer. For the first time, we report high prevalence of HPV35 among women with confirmed cervical cancer in Zimbabwe, providing additional evidence of HPV diversity in sub-Saharan Africa. The data obtained here probes the need for larger prospective studies to further elucidate HPV diversity and possibility of selective pressure on genotypes.

Ecto-5'-nucleotidase and thiopurine cellular circulation: association with cytotoxicity.

Thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat acute lymphoblastic leukemia of childhood. To test the hypothesis that variation in the expression of genes within the "thiopurine pathway" might influence 6-MP and 6-TG sensitivity, we generated basal gene expression profiles and IC(50) values for both of these thiopurine drugs using a model system consisting of 194 Human Variation Panel lymphoblastoid cell lines. Association analysis showed that thiopurine S-methyltransferase, ecto-5'-nucleotidase (NT5E), and multidrug resistance protein 4 (ABCC4) expression were correlated with thiopurine cytotoxicity. Those observations suggested the possible existence of a "thiopurine cellular circulation" involving nucleotide efflux by ABCC4, hydrolysis of thiopurine nucleotide monophosphates outside of the cell by NT5E, and subsequent transport of thiopurine nucleosides back into the cell by nucleoside transporters. The existence of this cellular circulation was confirmed by a series of functional experiments performed with cultured cells stably or transiently transfected with ABCC4 and/or NT5E. Because of the central role of NT5E in this cellular circulation, the NT5E gene was resequenced using 287 DNA samples from three ethnic groups, with the identification of 68 single nucleotide polymorphisms (SNPs), 46 of which were novel. Several SNPs in the 5'-flanking region of NT5E were highly correlated with expression, rs9450278 having the lowest p value (p = 2.4 × 10(-10), R = -0.376). The thiopurine cellular circulation and genetic polymorphisms for genes encoding the proteins involved should be incorporated into future studies of thiopurine drug therapy and effect.

Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects.

Pharmacogenetics enables personalised therapy based on genetic profiling and is increasingly applied in drug discovery. Medicines are developed and used together with pharmacodiagnostic tools to achieve desired drug efficacy and safety margins. Genetic polymorphism of drug-metabolising enzymes such as cytochrome P450s (CYPs) and N-acetyltransferases (NATs) has been widely studied in Caucasian and Asian populations, yet studies on African variants have been less extensive. The aim of the present study was to search for novel variants of CYP2C9 , CYP2C19 , CYP2D6 and NAT2 genes in Africans, with a particular focus on their prevalence in different populations, their relevance to enzyme functionality and their potential for personalised therapy. Blood samples from various ethnic groups were obtained from the AiBST Biobank of African Populations. The nine exons and exon-intron junctions of the CYP genes and exon 2 of NAT2 were analysed by direct DNA sequencing. Computational tools were used for the identification, haplotype analysis and prediction of functional effects of novel single nucleotide polymorphisms (SNPs). Novel SNPs were discovered in all four genes, grouped to existing haplotypes or assigned new allele names, if possible. The functional effects of non-synonymous SNPs were predicted and known African-specific variants were confirmed, but no significant differences were found in the frequencies of SNPs between African ethnicities. The low prevalence of our novel variants and most known functional alleles is consistent with the generally high level of diversity in gene loci of African populations. This indicates that profiles of rare variants reflecting interindividual variability might become the most relevant pharmacodiagnostic tools explaining Africans' diversity in drug response.

Understanding Ethical, Legal and Societal Issues (ELSIs) in Human Biobanking and Genomics for Research and Healthcare in Zimbabwe: The Genomics Inheritance Law Ethics and Society (GILES) initiative.

Biobanks and human genomics applications are key for understanding health, disease and heredity in Africa and globally. Growing interest in these technologies calls for strengthening relevant legal, ethical and policy systems to address knowledge disparities and ensure protection of society, while supporting advancement of science. In Zimbabwe there is limited understanding of ethical, legal, and societal issues (ELSI) for biobanking and genomics. The Genomics Inheritance Law Ethics and Society (GILES) initiative was established in 2015 to explore the current status and gaps in the ethical and legal frameworks, knowledge among various stakeholders, and to establish capacity for addressing ELSI of biobanking and genomics as applied in biomedical and population research, and healthcare. A multi-methods approach was applied including document reviews, focus group discussions and in-depth interviews among health and research professionals, and community members in six provinces comprising urban, peri-urban and rural areas. Emerging findings indicates a need for updating guidelines and policies for addressing ELSI in biobanking and genomics research in Zimbabwe. Emerging terminologies such as biobanking and genomics lack clarity suggesting a need for increased awareness and educational tools for health professionals, research scientists and community members. Common concerns relating to consent processes, sample and data use and sharing, particularly where there is trans-national flow of biospecimens and data, call for nationally tailored ELSI frameworks aligned to regional and international initiatives. This paper describes the strategy undertaken for the development and implementation of the GILES project and discusses the importance of such an initiative for characterisation of ELSI of human biobanking and genomics in Zimbabwe and Africa. Conducting this explorative study among a wide range of stakeholders over a countrywide geographical regions, established one of the most comprehensive studies for ELSI of human biobanking and genomics in Africa.

Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics.

Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.