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.

Evaluation of the safety and efficiency of the dorsal slit and sleeve methods of male circumcision provided by physicians and clinical officers in Rakai, Uganda.

OBJECTIVE: To assess the safety and efficiency of the dorsal slit and sleeve male circumcision (MC) procedures performed by physicians and clinical officers (COs). PATIENTS AND METHODS: We evaluated the time required for the MC procedure (efficiency) and moderate/severe adverse events (AEs) for MC (safety) by trained physicians and COs using the sleeve and dorsal slit MC methods in a service programme. Univariate and multiple regressions with robust variance estimation were used to assess factors associated with operative duration (linear) and AEs (logistic). RESULTS: Six physicians and eight COs conducted 1934 and 3218 MCs, respectively; there were 2471 dorsal slit and 2681 sleeve MC procedures. The overall mean operative duration was 33 min for newly trained providers, which decreased to ≈20 min after ≈100 MCs. The adjusted mean operative duration for dorsal slit MC was significantly shorter than that for the sleeve MC method (Δ - 2.7 min, P < 0.001). The operative duration was longer for COs than physicians for the sleeve procedure, but not the dorsal slit procedure; however this difference reduced with increasing numbers of MCs completed. The unadjusted AE rates were 0.6% for dorsal slit MC and 1.4% for the sleeve method (P = 0.006) and 1.5% for physicians and 0.68% for COs (P = 0.003); however, there were no significant differences after multivariate adjustment. Use of bipolar cautery significantly reduced operative duration (Δ - 4.0 min, P = 0.008), but was associated with higher AE rates (adjusted odds ratio 2.13, 95% confidence interval 1.26-3.61, P = 0.005). CONCLUSION: The dorsal slit MC method is faster than sleeve resection, and can be safely performed by non-physicians; however, use of bipolar cautery may be inadvisable in this setting.

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

PURPOSE: In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS: We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS: Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2 and NBN genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSIONS: Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

Intra-abdominal hypertension; prevalence, incidence and outcomes in a low resource setting; a prospective observational study.

BACKGROUND: Intra-abdominal hypertension (IAH) is defined as a sustained elevation in intra-abdominal pressure (IAP) greater than or equal to 12 mmHg. IAH has been shown to cause organ derangements and dysfunction in the body. Objective screening of IAH is neither done early enough nor at all thus leading to significant morbidity and mortality among surgical patients. The epidemiology and outcome of IAH among surgical patients has not been documented in Uganda. The aim of this study was to determine the prevalence, incidence and outcome of intra-abdominal hypertension among patients undergoing emergency laparotomy. METHODOLOGY: Prospective observational study, conducted from January to April 2015 among patients undergoing emergency laparotomy. Inclusion criteria was; age >7 yrs, scheduled for emergency laparotomy, able to lie supine. EXCLUSION CRITERIA: pregnant, failed urethral catheterization, known cardiac, renal and respiratory disorders. Consecutive sampling was used. IAP, blood pressure, heart rate, respiratory rate, Sp02, Serum creatinine, Serum urea, and Urine output were measured preoperatively and postoperatively at 0, 6, 24 and 48 h. IAH was defined as IAP > 12 mmHg on three consecutive readings 3 min apart. RESULTS: In total 192 patients were enrolled. Mean age ± SD was 14.25 (±3.16) yrs in the paediatrics and 34.4(±13.72) yrs in the adults with male preponderance 65 and 80.7 % respectively. The prevalence of IAH was 25 % paediatrics and 17.4 % adults and the cumulative incidence after surgery was 20 % paediatrics and 21 % adults. In paediatrics, IAH was associated with mortality at 0 h postoperatively, RRR = 1:24, 95 % CI (1.371-560.178), p-value 0.048. In adults, the statistically significant outcomes associated with IAH were respiratory system dysfunction RRR1:2.783, p-value 0.023, 95 % CI (1.148-6.744) preoperatively and mortality RRR 1:2.933, p-value 0.034, 95 % CI (1.017-8.464) at 6 h, RRR 1:3.769, p-value 0.033, 95 % CI (1.113-12.760) at 24 h postoperatively. CONCLUSION: The prevalence and incidence of IAH in the paediatrics and adults group in our study population were high. IAH was associated with mortality in both adult and paediatrics groups and respiratory system dysfunction in adult group. This calls for objective monitoring of intraabdominal pressure in patients undergoing emergency laparotomy with the aim of reducing associated mortality.

The safety and acceptance of the PrePex device for non-surgical adult male circumcision in Rakai, Uganda. A non-randomized observational study.

OBJECTIVES: To assess the safety and acceptance of the PrePex device for medical male circumcision (MMC) in rural Uganda. METHODS: In an observational study, HIV-uninfected, uncircumcised men aged 18 and older who requested elective MMC were informed about the PrePex and dorsal slit methods and offered a free choice of their preferred procedure. 100 men received PrePex to assess preliminary safety (aim 1). An additional 329 men, 250 chose PrePex and 79 chose Dorsal slit, were enrolled following approval by the Safety Monitoring Committee (aim 2). Men were followed up at 7 days to assess adverse events (AEs) and to remove the PrePex device. Wound healing was assessed at 4 weeks, with subsequent weekly follow up until completed healing. RESULTS: The PrePex device was contraindicated in 5.7% of men due to a tight prepuce or phimosis/adhesions. Among 429 enrolled men 350 (82.0%) got the PrePex device and 79 (18.0%) the dorsal slit procedure. 250 of 329 men (76.0%) who were invited to choose between the 2 procedures chose Prepex. There were 9 AEs (2.6%) with the PrePex, of which 5 (1.4%) were severe complications, 4 due to patient self-removal of the device leading to edema and urinary obstruction requiring emergency surgical circumcision, and one due to wound dehiscence following device removal. 71.8% of men reported an unpleasant odor prior to PrePex removal. Cumulative rates of completed wound healing with the PrePex were 56.7% at week 4, 84.8% week 5, 97.6% week 6 and 98.6% week 7, compared to 98.7% at week 4 with dorsal slit (p<0.0001). CONCLUSION: The PrePex device was well accepted, but healing was slower than with dorsal slit surgery. Severe complications, primarily following PrePex self-removal, required rapid access to emergency surgical facilities. The need to return for removal and delayed healing may increase Program cost and client burden.