Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk.

Prostate cancer is the most common non-skin cancer in males, with a ∼1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33% of the familial risk. To explore the contribution of both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1×. We identified 395 220 coding variants down to 0.05% frequency [57% non-synonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P = 1.8 × 10(-6)) and PTPRR on 12q15 (rs73341069, Val239Ile, OR = 1.62, P = 2.5 × 10(-5)). In gene-level testing, the two most significant genes were C1orf100 (P = 2.2 × 10(-4)) and GORAB (P = 2.3 × 10(-4)). We did not observe exome-wide significant associations (after correcting for multiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings do not provide strong support for the hypothesis that NS coding variants down to 0.5-1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk.

Genetic risk of prostate cancer in Ugandan men.

BACKGROUND: Men of African-ancestry have elevated prostate cancer (PCa) incidence and mortality compared to men of other racial groups. There is support for a genetic contribution to this disparity, with evidence of genetic heterogeneity in the underlying risk alleles between populations. Studies of PCa among African men may inform the contribution of genetic risk factors to the elevated disease burden in this population. METHODS: We conducted an association study of >100 previously reported PCa risk alleles among 571 incidence cases and 485 controls among Uganda men. Unconditional logistic regression was used to test genetic associations and a polygenic risk score (PRS) was derived to assess the cumulative effect of the known risk alleles in association with PCa risk. In an exploratory analysis, we also tested associations of 17 125 421 genotyped and imputed markers genome-wide in association with PCa risk. RESULTS: Of the 111 known risk loci with a frequency >1%, 75 (68%) had effects that were directionally consistent with the initial discovery population,14 (13%) of which were nominally significantly associated with PCa risk at P < 0.05. Compared to men with average risk (25th -75th percentile in PRS distribution), Ugandan men in the top 10% of the PRS, constructed of alleles outside of 8q24, had a 2.9-fold (95%CI: 1.75, 4.97) risk of developing PCa; risk for the top 10% increased to 4.86 (95%CI: 2.70, 8.76) with the inclusion of risk alleles at 8q24. In genome-wide association testing, the strongest associations were noted with known risk alleles located in the 8q24 region, including rs72725854 (OR = 3.37, P = 2.14 × 10-11 ) that is limited to populations of African ancestry (6% frequency). CONCLUSIONS: The ∼100 known PCa risk variants were shown to effectively stratify PCa risk in Ugandan men, with 10% of men having a >4-fold increase in risk. The 8q24 risk region was also found to be a major contributor to PCa risk in Ugandan men, with the African ancestry-specific risk variant rs72725854 estimated to account for 12% of PCa in this population.

Research in surgery and anesthesia: challenges for post-graduate trainees in Uganda.

BACKGROUND: Research is critical to the training and practice of surgery and anesthesia in all settings, regardless of available resources. Unfortunately, the output of surgical and perioperative research from Africa is low. Makerere University College of Health Sciences' (MakCHS) surgical and anesthesia trainees are required to conduct research, though few publish findings or go on to pursue careers that incorporate research. We believe that early career experiences with research may greatly influence physicians' future conduct and utilization of research. We therefore sought to analyze trainee experiences and perceptions of research to identify interventions that could increase production of high-quality, locally led, surgical disease research in our resource-constrained setting. METHODS: Following ethical approval, a descriptive, cross-sectional survey was conducted among anesthesia and surgery trainees using a pretested, self-administered questionnaire. Data were tabulated and frequency tables generated. RESULTS: Of the 43 eligible trainees, 33 (77%) responded. Ninety-four percent identify research as important to career development, and 85% intend to publish their dissertations. The research dissertation is considered a financial burden by 64%. Also, 49% reported that their departments place low value on their research, and few of the findings are utilized. Trainees report that lack of protected research time, difficulty in finding research topics, and inadequate mentorship are the main challenges to conducting research projects. DISCUSSION: Our anesthesia and surgery trainees spend considerable resources on research endeavors. Most have significant interest in incorporating research into their careers, and most intend to publish their work in peer-reviewed journals. Here we identify several challenges facing trainees including research project development, financing and mentorship. We hope to use these results to improve support in these areas for our trainees and those in other resource-limited areas.

Pretraining experience and structure of surgical training at a sub-Saharan African university.

BACKGROUND: The common goal of surgical training is to provide effective, well-rounded surgeons who are capable of providing a safe and competent service that is relevant to the society within which they work. In recent years, the surgical workforce crisis has gained greater attention as a component of the global human resources in health problems in low- and middle-income countries. The purpose of this study was to: (1) describe the models for specialist surgical training in Uganda; (2) evaluate the pretraining experience of surgical trainees; (3) explore training models in the United States and Canada and areas of possible further inquiry and intervention for capacity-building efforts in surgery and perioperative care. METHODS: This was a cross-sectional descriptive study conducted at Makerere University, College of Health Sciences during 2011-2012. Participants were current and recently graduated surgical residents. Data were collected using a pretested structured questionnaire and were entered and analyzed using an excel Microsoft spread sheet. The Makerere University, College of Health Sciences Institutional Review Board approved the study. RESULTS: Of the 35 potential participants, 23 returned the questionnaires (65 %). Mean age of participants was 29 years with a male/female ratio of 3:1. All worked predominantly in general district hospitals. Pretraining procedures performed numbered 2,125 per participant, which is twice that done by their US and Canadian counterparts during their entire 5-year training period. CONCLUSIONS: A rich pretraining experience exists in East Africa. This should be taken advantage of to enhance surgical specialist training at the institution and regional level.

Use of surgical task shifting to scale up essential surgical services: a feasibility analysis at facility level in Uganda.

BACKGROUND: The shortage and mal-distribution of surgical specialists in sub-Saharan African countries is born out of shortage of individuals choosing a surgical career, limited training capacity, inadequate remuneration, and reluctance on the part of professionals to work in rural and remote areas, among other reasons. This study set out to assess the views of clinicians and managers on the use of task shifting as an effective way of alleviating shortages of skilled personnel at a facility level. METHODS: 37 in-depth interviews with key informants and 24 focus group discussions were held to collect qualitative data, with a total of 80 healthcare managers and frontline health workers at 24 sites in 15 districts. Quantitative and descriptive facility data were also collected, including operating room log sheets to identify the most commonly conducted operations. RESULTS: Most health facility managers and health workers supported surgical task shifting and some health workers practiced it. The practice is primarily driven by a shortage of human resources for health. Personnel expressed reluctance to engage in surgical task shifting in the absence of a regulatory mechanism or guiding policy. Those in favor of surgical task shifting regarded it as a potential solution to the lack of skilled personnel. Those who opposed it saw it as an approach that could reduce the quality of care and weaken the health system in the long term by opening it to unregulated practice and abuse of privilege. There were enough patient numbers and basic infrastructure to support training across all facilities for surgical task shifting. CONCLUSION: Whereas surgical task shifting was viewed as a short-term measure alongside efforts to train and retain adequate numbers of surgical specialists, efforts to upscale its use were widely encouraged.

Effect of emergency major abdominal surgery on CD4 cell count among HIV positive patients in a sub-Saharan Africa tertiary hospital--a prospective study.

BACKGROUND: Surgery plays a key role in HIV palliative care, specifically in the diagnosis and treatment of HIV related and non-related conditions. Yet major surgery depresses the immune system. Whereas the surgical consequences of HIV infection are well described, there is a paucity of published data, in resource-limited settings, on the effects of major surgery on the immune system. The purpose of this study was to determine the effect of major abdominal surgery on CD4 count in HIV positive and HIV negative patients after emergency major surgery. METHODS: A prospective cohort study was done for patients who underwent emergency major abdominal surgery. Their peri-operative CD4 counts were done for both HIV- and HIV + patients. Median CD4s were used in analysis.Mann Whitney test of significance was used for continuous data and Fisher' exact test used for categorical data. IRB approval was obtained. RESULTS: A total of 101 patients were recruited, 25 HIV positive and 76 HIV negative. The median CD4 cell reduction was higher in the HIV negative group (-68 cells) than HIV positive group (-29 cells) (p = 0.480).There was a general increase in the median CD4 change by 72 cells for the HIV positives and 95 cells for the HIV negatives (p = 0.44). CD4 change rose in both the HIV positive and negative groups by 27 cells for the HIV positives and 28 cells for the HIV negatives (p = 0.94). Relative Risk was 0.96, {CI 0.60 - 1.53}. CONCLUSION: Major emergency abdominal surgery had no significant effect on CD4 cell count among HIV positive patients.

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Male genital mutilation (amputation) and its complications: a case report.

BACKGROUND: Genital losses from ritual attacks are often reported in the media and often discussed in the social media but are hardly reported in medical literature. Male genital mutilation (MGM) refers to permanent modification of the external genitalia that involves ablation of genital tissues.When found, it is usually as a consequence of poor circumcision skills, auto mutilation/castration or genital injuries caused by attacks or accidents. Male circumcision on its own is widely regarded as a rather safe and acceptable practice which is known to have some health benefits and in keeping with several religious customs as rite of passage. Outside of professional performed circumcision, MGM is usually associated with dark arts and malicious intentions like witchcraft or as a consequence of torture of prisoners of war for information. CASE PRESENTATION: In this case we describe a 5-year old Ugandan boy who had his genitals mutilated in bizarre circumstances within a ritual attack. He survived and a urethrostomy was fashioned. CONCLUSION: There is need to document more of these cases in order to gather enough information to inform prevention and treatment strategies. Issues of hormonal replacement therapy (HRT) and possible sex change require much debate. These genital sex changing operations should preferably be avoided until a child can fully participate in decision making.

The clinical presentation and early outcomes of necrotizing fasciitis in a Ugandan Tertiary Hospital--a prospective study.

BACKGROUND: Necrotizing fasciitis is an infectious process characterized by rapidly progressing necrosis of superficial fascia and subcutaneous tissue with subsequent necrosis of overlying skin.Necrotizing fasciitis is a rare but fatal infection. The worldwide incidence is at 0.4 per 100,000. Mortality is up to 80% with no intervention, and 30-50% with intervention. Delay in intervention is associated with poor outcome. The risk factors for necrotizing fasciitis are diabetes mellitus, HIV, malignancy, illicit drug use, malnutrition among others.The aim of this study was to describe the clinical presentation and early outcomes of necrotizing fasciitis amongst Ugandan patients. METHODS: A prospective descriptive case series study conducted at Mulago National Referral and Teaching hospital from 5th January to 30th April 2011. Patients with necrotizing fasciitis were consecutively recruited after clinical evaluation, laboratory and microbiological tests were performed. Aggressive debridement was done and broad-spectrum antibiotics administered. Patients were followed up on surgical wards. Ethical approval was obtained. RESULTS: Thirty five patients were recruited over a 4 months period. More males were affected with, M: F 3:1. The 20-40 years age group was most affected. Attainment of healthy granulation tissue took 19 days on average. Mortality rate was 14% (5/35). Limbs were the most affected body parts 20/35 (57%), the scrotum and perineum (23%). Among infants the scalp was the most affected. Co-morbidities included HIV 8/35 (17%), and DM (5%) among others. The commonest organisms were gram negative. Split skin grafting was necessary in 74% (26/35) of patients. CONCLUSION: There were a high number of patients with necrotizing fasciitis; it was associated with low mortality but high morbidity (long hospital stay). There was a high preponderance to males and limbs were the more affected body parts.

Evaluating international global health collaborations: perspectives from surgery and anesthesia trainees in Uganda.

BACKGROUND: The number of international academic partnerships and global health programs is expanding rapidly worldwide. Although the benefits of such programs to visiting international partners have been well documented, the perceived impacts on host institutions in resource-limited settings have not been assessed adequately. We sought to describe the perspectives of postgraduate, Ugandan trainees toward international collaborations and to discuss how these perceptions can be used to increase the positive impact of international collaborations for the host institution. METHODS: We conducted a descriptive, cross-sectional survey among anesthesia and surgery trainees at Makerere College of Health Sciences (Kampala, Uganda) using a pretested, self-administered questionnaire. Data were summarized as means or medians where applicable; otherwise, descriptive statistical analyses were performed. RESULTS: Of 43 eligible trainees, 77% completed the questionnaire. The majority (75%) agreed that visiting groups improve their training, mostly through skills workshops and specialist camps. A substantial portion of trainees reported that international groups had a neutral or negative impact on patient care (40%). Only 15% agreed that research projects conducted by international groups are in priority areas for Uganda. Among those surveyed, 28% reported participation in these projects, but none has published as a coauthor. Nearly one-third of trainees (31%) reported discomfort with the ethics of some clinical decisions made by visiting faculty. CONCLUSION: The current perspective from the surgery and anesthesia trainees of Makerere College of Health Sciences demonstrates rich ground for leveraging international collaborations to improve training, primarily through skills workshops, specialist camps, and more visiting faculty involvement. This survey also identified potential challenges in collaborative research and ethical dilemmas that warrant further examination.

Validation of supra-pubic ultrasonography for preoperative prostate volume measurement in sub-Saharan Africa.

BACKGROUND: Advances in urological techniques in sub-Saharan Africa need to be supported with practical ancillary diagnostics. This study aimed at determining the accuracy of suprapubic ultrasonography (SPUS) relative to transrectal ultrasonography (TRUS), the current gold standard, in estimating preoperative prostate volume in a sub-Saharan African hospital. METHODS: Cross-sectional study of prospectively enrolled patients with severe lower urinary tract symptoms and histologically confirmed benign prostatic hyperplasia. The volume of the prostate was estimated using two modalities, SPUS and TRUS. Open prostatectomy was performed on all patients, and the mass of the enucleated prostate adenoma was measured directly. RESULTS: Fifty patients were enrolled, with a mean age of 69 years. The mean prostate volume as determined by TRUS, SPUS, and direct measurement of enucleated prostatic tissue was 96.0, 95.9 and 83.5 mL, respectively. Prostate volume determined by SPUS correlated strongly with the TRUS measurement (ρ = 0.98, P < 0.001). The mean difference between the volume estimates by TRUS and SPUS was 0.09 mL [95% CI -2.07 to 1.89, P = 0.93], with upper and lower limits of agreement of -13.8 and +13.6 mL, respectively. Sensitivity, specificity, positive and negative predictive value for SPUS relative to TRUS for classifying patients according to the indication for TURP (prostate volume ≤80 mL) versus open prostatectomy (>80 mL) were 95% or higher. The volume of the enucleated adenoma was less than the volume estimated by ultrasonography by approximately 12.5 mL. CONCLUSION: SPUS is accurate relative to TRUS in assessing preoperative volume of the prostate and can be used in the African context to assign patients to open prostatectomy or TURP.

Surgical training and global health: initial results of a 5-year partnership with a surgical training program in a low-income country.

HYPOTHESIS: Surgical trainees in the United States have a growing interest in both clinical experiences and structured training opportunities in global health. Global health training and exposure can be integrated into a surgical residency program. DESIGN: The global health activities of surgical residents and faculty in 1 department were evaluated from January 1, 1998, to June 1, 2008, using a survey and personal interviews. RESULTS: From January 1, 1998, to December 31, 2002, 4 faculty members made more than 20 overseas volunteer medical expeditions, but only 1 resident participated in global health activities. In 2003, a relationship with a surgical training program in a developing country was established. Ten residents and 12 faculty members have made overseas trips during the last 5 years, and 1 international surgeon has visited the United States. During their research block, 4 residents completed 1- to 3-month clinical rotations and contributed to mentored research projects. Three residents completed a university-based Global Health Clinical Scholars Program, and 3 obtained master's degrees in public health. A joint conference in injury-trauma research was also conducted. A faculty member is based overseas with clinical and research responsibilities, and another is completing a master's degree in public health. CONCLUSIONS: Global health training and exposure for residents can be effectively integrated into an academic surgical residency program through relationships with training programs in low-income countries. Legitimate academic experiences improve the success of these programs. Reciprocity with collaborative partners must be ensured, and sustained commitment and funding remain a great challenge to such programs. The long-term effect on the development of global health careers is yet to be determined.