The spectrum of TP53 mutations in Rwandan patients with gastric cancer.

BACKGROUND: Gastric cancer is the sixth most frequently diagnosed cancer and third in causing cancer-related death globally. The most frequently mutated gene in human cancers is TP53, which plays a pivotal role in cancer initiation and progression. In Africa, particularly in Rwanda, data on TP53 mutations are lacking. Therefore, this study intended to obtain TP53 mutation status in Rwandan patients with gastric cancer. RESULTS: Formalin-fixed paraffin-embedded tissue blocks of 95 Rwandan patients with histopathologically proven gastric carcinoma were obtained from the University Teaching Hospital of Kigali. After DNA extraction, all coding regions of the TP53 gene and the exon-intron boundary region of TP53 were sequenced using the Sanger sequencing. Mutated TP53 were observed in 24 (25.3%) of the 95 cases, and a total of 29 mutations were identified. These TP53 mutations were distributed between exon 4 and 8 and most of them were missense mutations (19/29; 65.5%). Immunohistochemical analysis for TP53 revealed that most of the TP53 missense mutations were associated with TP53 protein accumulation. Among the 29 mutations, one was novel (c.459_477delCGGCACCCGCGTCCGCGCC). This 19-bp deletion mutation in exon 5 caused the production of truncated TP53 protein (p.G154Wfs*10). Regarding the spectrum of TP53 mutations, G:C > A:T at CpG sites was the most prevalent (10/29; 34.5%) and G:C > T:A was the second most prevalent (7/29; 24.1%). Interestingly, when the mutation spectrum of TP53 was compared to three previous TP53 mutational studies on non-Rwandan patients with gastric cancer, G:C > T:A mutations were significantly more frequent in this study than in our previous study (p = 0.013), the TCGA database (p = 0.017), and a previous study on patients from Hong Kong (p = 0.006). Even after correcting for false discovery, statistical significance was observed. CONCLUSIONS: Our results suggested that TP53 G:C > T:A transversion mutation in Rwandan patients with gastric cancer is more frequent than in non-Rwandan patients with gastric cancer, indicating at an alternative etiological and carcinogenic progression of gastric cancer in Rwanda.

Clinicopathological Characteristics and Mutational Landscape of APC, HOXB13, and KRAS among Rwandan Patients with Colorectal Cancer.

Cancer research in Rwanda is estimated to be less than 1% of the total African cancer research output with limited research on colorectal cancer (CRC). Rwandan patients with CRC are young, with more females being affected than males, and most patients present with advanced disease. Considering the paucity of oncological genetic studies in this population, we investigated the mutational status of CRC tissues, focusing on the Adenomatous polyposis coli (APC), Kirsten rat sarcoma (KRAS), and Homeobox B13 (HOXB13) genes. Our aim was to determine whether there were any differences between Rwandan patients and other populations. To do so, we performed Sanger sequencing of the DNA extracted from formalin-fixed paraffin-embedded adenocarcinoma samples from 54 patients (mean age: 60 years). Most tumors were located in the rectum (83.3%), and 92.6% of the tumors were low-grade. Most patients (70.4%) reported never smoking, and 61.1% of patients had consumed alcohol. We identified 27 variants of APC, including 3 novel mutations (c.4310_4319delAAACACCTCC, c.4463_4470delinsA, and c.4506_4507delT). All three novel mutations are classified as deleterious by MutationTaster2021. We found four synonymous variants (c.330C>A, c.366C>T, c.513T>C, and c.735G>A) of HOXB13. For KRAS, we found six variants (Asp173, Gly13Asp, Gly12Ala, Gly12Asp, Gly12Val, and Gln61His), the last four of which are pathogenic. In conclusion, here we contribute new genetic variation data and provide clinicopathological information pertinent to CRC in Rwanda.

Sero-prevalence of anti-Leptospira antibodies and associated risk factors in rural Rwanda: A cross-sectional study.

BACKGROUND: Leptospirosis is a zoonotic disease transmitted through the urine of wild and domestic animals, and is responsible for over 50,000 deaths each year. In East Africa, prevalence varies greatly, from as low as 7% in Kenya to 37% in Somalia. Transmission epidemiology also varies around the world, with research in Nicaragua showing that rodents are the most clinically important, while studies in Egypt and Chile suggest that dogs may play a more important role. There are no published studies of leptospirosis in Rwanda. METHODS & FINDINGS: We performed a cross-sectional survey of asymptomatic adults recruited from five occupational categories. Serum samples were tested using ELISA and Microscopic Agglutination Test (MAT). We found that 40.1% (151/377) of asymptomatic adults had been exposed to Leptospira spp. Almost 36.3% of positive subjects reported contact with rats (137/377) which represent 90.7% among positive leptospira serology compared with 48.2% of negative subjects (182/377) which represent 80.5% among negative leptospira serology (OR 2.37, CI 1.25-4.49) and 1.7 fold on prevalence ratio and 2.37 of odd ratio. Furthermore, being a crop farmer was significantly associated with leptospirosis (OR 2.06, CI 1.29-3.28). We identified 6 asymptomatic subjects (1.6%) who met criteria for acute infection. CONCLUSIONS: This study demonstrates a high prevalence of leptospiral antibodies infection among asymptomatic adults in rural Rwanda, particularly relative to neighboring countries. Although positive subjects were more likely to report rat contact, we found no independent association between rats and leptospirosis infection. Nonetheless, exposure was high among crop farmers, which is supportive of the hypothesis that rats together with domestic livestock might contribute to the transmission. Further studies are needed to understand infecting Leptospira servers and elucidate the transmission epidemiology in Rwanda and identify means of host transmitters.

Challenges in the Recognition and Management of Acute Kidney Injury by Hospitals in Resource-Limited Settings.

INTRODUCTION: Acute kidney injury (AKI) is prevalent in low- and middle-income countries (LMIC) and is associated with significant morbidity and mortality, particularly among hospitalized patients. Successful strategies for the prevention and management of AKI in these countries are dependent on the capacity of primary care centers to provide optimal initial management of patients at risk for this disorder. METHODS: From December 2018 to February 2019, using mixed methods, we assessed hospital capacity and the knowledge of clinicians relevant to the prevention, diagnosis, and management of AKI in Rwanda. A checklist based on Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and clinical vignette-based assessment tool were used to assess hospital capacity and provider knowledge base, respectively. Data were analyzed using stata 13 with findings reported as simple frequencies or means with standard deviation. Multivariate analysis was used to assess factors associated with a higher knowledge score among clinicians. RESULTS: Ten hospitals and 193 health care providers from sites throughout Rwanda participated in the survey. Surveyed hospitals were equipped with basic general medical equipment but were deficient in diagnostic tools and medical supplies that would allow the diagnosis and nondialytic management of AKI. Although 20% of the hospitals could offer hemodialysis services, peritoneal dialysis services were nonexistent. With regard to knowledge base, the health care providers demonstrated significant deficiencies in the diagnosis and management of AKI. The mean knowledge score for all health providers was 6.3 (±1.5) of a maximum of 11, with a mean (±SD) score for doctors, nurses, and midwives of 6.3 ± 2.05, 6.4 ± 1.3, and 6.08 ± 1.2, respectively. On multivariate analysis, the length of clinical experience and age of the respondents were significantly associated with participants' knowledge score. CONCLUSION: This study documents significant barriers to providing optimal management of AKI in primary health care settings in Rwanda, a resource-limited setting. These include lack of specialized medical personnel, significant knowledge gaps among primary health care providers, suboptimal diagnostic capacity, and limited treatment options for detection and management of AKI.

Prevalence and sociodemographic determinants of dyspepsia in the general population of Rwanda.

INTRODUCTION: Dyspepsia accounts for a significant burden of worldwide disease, but there is a relative paucity of data from the sub-Saharan African setting. We undertook to describe the burden, risk factors and severity of dyspepsia across Rwanda. METHODS: We performed a population-based clustered cross-sectional survey between November 2015 and January 2016, nationwide in Rwanda, using the Short Form Leeds Dyspepsia Questionnaire to describe the presence and severity of dyspepsia, and the Short Form Nepean Dyspepsia Index to describe the concomitant quality of life effects. Univariate and multivariate logistic regression models were constructed to correlate measured sociodemographic factors with dyspepsia. RESULTS: The prevalence of clinically significant dyspepsia in the general Rwandan population was 14.2% (283/2000). The univariate factors that significantly predicted severity were gender, profession, socioeconomic status, and non-steroidal anti-inflammatory drug, aspirin and alcohol use, with gender, current smoking, aspirin use both in the past and currently, and alcohol use in the past remaining significant on multivariate modelling. Dyspeptics had a significantly lower gastrointestinal-related quality of life, though the sociodemographic factors measured did not modify the observed quality of life. CONCLUSION: Dyspepsia is prevalent in the Rwandan setting and is associated with a significant burden on quality of life. More work is required to determine the pathological entities involved, and the optimal approach to mitigating this burden.

Use of adenosine deaminase (ADA) to diagnose suspected peritoneal tuberculosis in Rwanda: a cross-sectional study.

BACKGROUND: Peritoneal tuberculosis is the most common cause of low albumin gradient ascites in developing countries, but it can be easily confused with other causes of ascites. Peritoneal tuberculosis requires early recognition of symptoms and signs in order to make a quick diagnosis for appropriate treatment. Measurement of adenosine deaminase (ADA) level > 39 in ascites fluid is an established test to diagnose peritoneal tuberculosis. Many low-income countries do not currently test for adenosine deaminase in ascites fluid, including Rwanda. METHOD: Cross-sectional, descriptive study conducted through the Internal Medicine Department of three university teaching hospitals in Rwanda. Participants were patients older than 16 years presenting to tertiary referral hospitals with ascites of unknown cause. RESULTS: Of 103 ascites fluid samples collected, 52 of them (50.5%) had an elevated ADA, consistent with a presumptive diagnosis of peritoneal TB. Among those 52 subjects diagnosed with peritoneal TB, 39 out of 52 (75%) did not receive anti-TB medications. Among the 17 subjects who were treated with anti-TB medications, 4 of 17 (23.6%) did not have peritoneal TB based on ADA level. Samples with low-albumin gradient ascites were more likely to have high ADA ≥39 IU/L (p = 0.039). CONCLUSION: Our findings suggest that 3out of 4 patients with PTB in Rwanda are not getting TB treatment and 1 in 4 patients who are taking TB medications do not need it. Even if the true number of Rwandans who are being undertreated and overtreated is less than our study suggests, these results should prompt a larger study of peritoneal tuberculosis. Adding adenosine deaminase (ADA) to the diagnostic tools available to clinicians could help achieve the goal of correctly putting every Rwandan with tuberculosis on treatment, while avoiding unnecessary tuberculosis medications in those who do not have the disease.

Efficacy of Helicobacter pylori eradication regimens in Rwanda: a randomized controlled trial.

BACKGROUND: Successful H. pylori treatment requires the knowledge of local antimicrobial resistance. Data on the efficacy of H. pylori eradication regimens available in sub-Saharan Africa are scant, hence the optimal treatment is unknown. Our goals were to determine the efficacy of available regimens in Rwanda as well as evaluate the effect of treatment on health-related quality of life (HRQoL) in patients undergoing esophagogastroduodenoscopy. METHODS: This is a randomized controlled trial conducted from November 2015 to October 2016 at a tertiary hospital in Rwanda. Enrollees were 299 patients (35% male, age 42 ± 16 years (mean ± SD)) who had a positive modified rapid urease test on endoscopic biopsies. After a fecal antigen test (FAT) and HRQoL assessment by the Short Form Nepean Dyspepsia Index (SF-NDI) questionnaire, patients were randomized 1:1:1:1 to either a triple therapy combining omeprazole, amoxicillin and one of clarithromycin/ciprofloxacin/metronidazole or a quadruple therapy combining omeprazole, amoxicillin, ciprofloxacin and doxycycline. All therapies were given for a duration of 10 days. The outcome measures were the persistence of positive FAT (treatment failure) 4 to 6 weeks after treatment and change in HRQoL scores. RESULTS: The treatment success rate was 80% in the total population and 78% in patients with a history of prior triple therapy. Significant improvement in HRQoL in the total group (HRQoL mean scores before and after treatment respectively: 76 ± 11 and 32 ± 11, p < 0.001) and the group with functional dyspepsia (HRQoL mean scores before and after treatment respectively: 73 ± 11 and 30 ± 9, P < 0.001) was observed across all treatment groups. Using clarithromycin based triple therapy (standard of care) as a reference, the group treated with metronidazole had worse HRQoL (p = 0.012) and had a trend towards worse treatment outcome (p = 0.086) compared to the ciprofloxacin based combination therapies. CONCLUSION: Clarithromycin and ciprofloxacin based combination therapies are effective and safe to use alternatively for H. pylori eradication and improve HRQoL. Among the regimens studied, metronidazole based triple therapy is likely to be clinically inferior. TRIAL REGISTRATION: The clinical trial was retrospectively registered ( PACTR201804003257400 ) with the Pan African Clinical Trial Registry database, on April 6th, 2018 in South Africa.

Clinical Profile and Outcome of Patients with Acute Kidney Injury Requiring Hemodialysis: Two Years' Experience at a Tertiary Hospital in Rwanda.

INTRODUCTION: Acute kidney injury (AKI) requiring renal replacement therapy is associated with high mortality. The study assessed the impact of the introduction of hemodialysis (HD) on outcomes of patients with AKI in Rwanda. METHODS: A single center retrospective study that evaluated the clinical profile and survival outcomes of patients with AKI requiring HD [AKI-D] at a tertiary hospital in Rwanda. Data was collected on patients who received HD for AKI from September 2014 to December 2016. Patient demographics, comorbidities, clinical presentation, laboratory tests, and mortality were reviewed and analyzed. Predictors of mortality were assessed using age and gender adjusted multivariate analyses. RESULTS: Of the 82 eligible patients, median age was 38 years (IQR 28-57 years). Males comprised 51% of the cohort. Infectious diseases including malaria, pneumonia, and sepsis (35.1%) and pregnancy-related conditions (26.9%) were the most frequent comorbidities. Pulmonary oedema (54.9%) and uremic encephalopathy (50%) were top indications for HD. Mortality was 34.1%. On multivariate analysis, receipt of <5 sessions of HD (OR = 4.01, 95% CI 1.185-13.61, P = 0.026) and hyperkalemia (OR = 3.23, 95% CI 1.040-10.065, P = 0.043) were associated with mortality. CONCLUSION: The availability of acute hemodialysis in Rwanda has resulted in improved patient survival and persistent hyperkalemia predicted higher mortality.

Prevalence of Strongyloides stercoralis infection and other soil-transmitted helminths by cross-sectional survey in a rural community in Gisagara District, Southern Province, Rwanda.

Background: Strongyloides stercoralis is one of the most neglected tropical diseases. Sparse, dated central African and Rwandan data on seroprevalence are available to guide public health efforts and clinical care. Methods: In February 2016 we conducted a community-based cross-sectional study among 539 asymptomatic participants in a rural area in the Gisagara District, Southern Province, Rwanda. Direct faecal smear (DFS) and modified Koga agar plate culture (APC) were used to detect S. stercoralis infection in a single stool sample. Data on other soil-transmitted helminths diagnosed by DFS were also recorded. Results: Four intestinal helminth infections were diagnosed, with S. stercoralis (17.4%) and hookworms (8.2%) seen most often. APC, compared with DFS, increased the diagnosis rate for S. stercoralis from 1.9% to 17.4% (p<0.01). The prevalence was higher in farmers and those with lower socio-economic status. Females were less often infected than males (odds ratio 0.6 [95% confidence interval 0.3 to 0.9], p=0.02). Conclusions: S. stercoralis is highly prevalent among the general population in a rural area of Gisagara District, Southern Province, Rwanda. Access to effective diagnosis and treatment is needed for this neglected disease.

Health Professional Training and Capacity Strengthening Through International Academic Partnerships: The First Five Years of the Human Resources for Health Program in Rwanda.

BACKGROUND: The Rwanda Human Resources for Health Program (HRH Program) is a 7-year (2012-2019) health professional training initiative led by the Government of Rwanda with the goals of training a large, diverse, and competent health workforce and strengthening the capacity of academic institutions in Rwanda. METHODS: The data for this organizational case study was collected through official reports from the Rwanda Ministry of Health (MoH) and 22 participating US academic institutions, databases from the MoH and the College of Medicine and Health Sciences (CMHS) in Rwanda, and surveys completed by the co-authors. RESULTS: In the first 5 years of the HRH Program, a consortium of US academic institutions has deployed an average of 99 visiting faculty per year to support 22 training programs, which are on track to graduate almost 4600 students by 2019. The HRH Program has also built capacity within the CMHS by promoting the recruitment of Rwandan faculty and the establishment of additional partnerships and collaborations with the US academic institutions. CONCLUSION: The milestones achieved by the HRH Program have been substantial although some challenges persist. These challenges include adequately supporting the visiting faculty; pairing them with Rwandan faculty (twinning); ensuring strong communication and coordination among stakeholders; addressing mismatches in priorities between donors and implementers; the execution of a sustainability strategy; and the decision by one of the donors not to renew funding beyond March 2017. Over the next 2 academic years, it is critical for the sustainability of the 22 training programs supported by the HRH Program that the health-related Schools at the CMHS significantly scale up recruitment of new Rwandan faculty. The HRH Program can serve as a model for other training initiatives implemented in countries affected by a severe shortage of health professionals.

An International Collaboration for the Training of Medical Chief Residents in Rwanda.

BACKGROUND: The year-long position of chief medical resident is a time-honored tradition in the United States that serves to provide the trainee with an opportunity to gain further skills as a clinician, leader, teacher, liaison, and administrator. However, in most training programs in the developing world, this role does not exist. OBJECTIVES: We sought to develop a collaborative program to train the first medical chief residents for the University of Rwanda and to assess the impact of the new chief residency on residency training, using questionnaires and qualitative interviews with Rwandan faculty, chief residents, and residents. METHODS: The educational context and the process leading up to the appointment of Rwandan chief residents, including selection, job description, and necessary training (in the United States and Rwanda), are described. One year after implementation, we used a parallel, mixed methods approach to evaluate the new chief medical resident program through resident surveys as well as semistructured interviews with key informants, including site chief residents, chief residents, and faculty. We also observed chief residents and site chief residents at work and convened focus groups with postgraduate residents to yield additional qualitative information. RESULTS: Rwandan faculty and residents generally felt that the new position had improved the educational and administrative structure of the teaching program while providing a training ground for future academicians. CONCLUSIONS: A collaborative training program between developing and developed world academic institutions provides an efficient model for the development of a new chief residency program in the developing world.

Effects of a lifestyle education program on glycemic control among patients with diabetes at Kigali University Hospital, Rwanda: A randomized controlled trial.

AIM: Evidence to show whether lifestyle intervention programs are beneficial for patients with diabetes in resource-limited countries is lacking. The present study assessed the additional efficacy of a structured lifestyle education program, as compared to the current standard of diabetic care in Rwanda. METHODS: 251 consecutive adult patients attending a tertiary diabetic care practice were randomly assigned to either an intervention group (standard of care plus monthly lifestyle group education sessions of 45min duration) or to a control group. The primary outcome was between-groups difference in glycated hemoglobin (HbA1c) observed after 12-months follow up. Outcome measures in the intervention and control groups were compared using the ANCOVA test with a two-sided significance of 5%. RESULTS: Of the 251 subjects recruited, 223 were included in the analysis; of whom 115 were assigned to the intervention group, and 108 to the control group. After 12-months, the median HbA1c levels reduced by 1.70 (95% CI: -2.09 to -1.31; p<0.001) in the intervention group; and by 0.52 (95% CI: -0.95 to -0.10; p=0.01) in the control group. The difference in HbA1c reduction between the intervention and control groups was statistically significant (p<0.001) after adjustment for subjects' age, sex, education level, BMI, diabetes duration and diabetic medications. CONCLUSIONS: This study demonstrated that a structured lifestyle group education program for people with diabetes is an attractive option in a resource-limited setting, as it showed significant benefits in improved glycemic control over a 12-month period. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02032108.

Enabling Access to Medical and Health Education in Rwanda Using Mobile Technology: Needs Assessment for the Development of Mobile Medical Educator Apps.

BACKGROUND: Lack of access to health and medical education resources for doctors in the developing world is a serious global health problem. In Rwanda, with a population of 11 million, there is only one medical school, hence a shortage in well-trained medical staff. The growth of interactive health technologies has played a role in the improvement of health care in developed countries and has offered alternative ways to offer continuous medical education while improving patient's care. However, low and middle-income countries (LMIC) like Rwanda have struggled to implement medical education technologies adapted to local settings in medical practice and continuing education. Developing a user-centered mobile computing approach for medical and health education programs has potential to bring continuous medical education to doctors in rural and urban areas of Rwanda and influence patient care outcomes. OBJECTIVE: The aim of this study is to determine user requirements, currently available resources, and perspectives for potential medical education technologies in Rwanda. METHODS: Information baseline and needs assessments data collection were conducted in all 44 district hospitals (DHs) throughout Rwanda. The research team collected qualitative data through interviews with 16 general practitioners working across Rwanda and 97 self-administered online questionnaires for rural areas. Data were collected and analyzed to address two key questions: (1) what are the currently available tools for the use of mobile-based technology for medical education in Rwanda, and (2) what are user's requirements for the creation of a mobile medical education technology in Rwanda? RESULTS: General practitioners from different hospitals highlighted that none of the available technologies avail local resources such as the Ministry of Health (MOH) clinical treatment guidelines. Considering the number of patients that doctors see in Rwanda, an average of 32 patients per day, there is need for a locally adapted mobile education app that utilizes specific Rwandan medical education resources. Based on our results, we propose a mobile medical education app that could provide many benefits such as rapid decision making with lower error rates, increasing the quality of data management and accessibility, and improving practice efficiency and knowledge. In areas where Internet access is limited, the proposed mobile medical education app would need to run on a mobile device without Internet access. CONCLUSIONS: A user-centered design approach was adopted, starting with a needs assessment with representative end users, which provided recommendations for the development of a mobile medical education app specific to Rwanda. Specific app features were identified through the needs assessment and it was evident that there will be future benefits to ongoing incorporation of user-centered design methods to better inform the software development and improve its usability. Results of the user-centered design reported here can inform other medical education technology developments in LMIC to ensure that technologies developed are usable by all stakeholders.

Validation of the Kinyarwanda-version Short-Form Leeds Dyspepsia Questionnaire and Short-Form Nepean Dyspepsia Index to assess dyspepsia prevalence and quality-of-life impact in Rwanda.

OBJECTIVES: We aimed to develop and validate Kinyarwanda versions of Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) and Short-Form Nepean Dyspepsia Index (SF-NDI) to measure the frequency and severity of dyspepsia and associated quality-of-life impact in Rwanda. SETTING: A single, tertiary care centre in Rwanda. PARTICIPANTS: 200 consecutive Kinyarwanda-speaking patients referred to endoscopy (100 patients) or medical outpatients (100 patients). INTERVENTIONS: Kinyarwanda versions of the SF-LDQ and SF-NDI were developed from English versions by translation, with back translation, crosschecking and pilot testing. Study participants completed these questionnaires at enrolment (time 1), and then completed the surveys again with blinded phone interviewers 3 days later (time 2). 20 randomly selected participants, diagnosed with a peptic ulcer on index endoscopy, completed a third survey by phone at day 30 (time 3), after therapy. PRIMARY OUTCOME MEASURES: Internal consistency at time 1 (by Cronbach's α) and test-retest reliability between time 1 and time 2 (Spearman's correlation coefficient) for translated SF-LDQ and SF-NDI; validity versus clinical diagnosis (by receiver operating characteristic (ROC) curve) and responsiveness to treatment for SF-LDQ (by change in mean score). All outcomes were measured as per protocol. RESULTS: Cronbach's α of the translated SF-LDQ was 0.93, showing high internal consistency. Spearman's correlation coefficient comparing time 1 and time 2 was 0.978 (p<0.001), demonstrating high reliability. Cronbach's α for the translated SF-NDI was 0.92. A cut-off score of 16 on the SF-LDQ showed a sensitivity of 97% and a specificity of 71% for the diagnosis of dyspepsia, correctly classifying 89% of patients. In the responsiveness analysis, the mean SF-LDQ score was reduced from 20.1 prior to treatment to 13.9 after 30 days of treatment (p=0.003). CONCLUSIONS: The Kinyarwanda versions of the SF-LDQ and SF-NDI were valid, reliable and responsive to treatment.