Genetic and nongenetic drivers of platelet reactivity in healthy Tanzanian individuals.

BACKGROUND: Platelets play a key role in hemostasis, inflammation, and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown. OBJECTIVES: We aimed to investigate the nongenetic and genetic determinants of platelet reactivity in healthy adults living in a rapidly urbanizing area in Northern Tanzania. METHODS: Platelet activation and reactivity were measured by platelet P-selectin expression and the binding of fibrinogen in unstimulated blood and after ex vivo stimulation with adenosine diphosphate and PAR-1 and PAR-4 ligands. We then analyzed the associations of platelet parameters with host genetic and nongenetic factors, environmental factors, plasma inflammatory markers, and plasma metabolites. RESULTS: Only a few associations were found between platelet reactivity parameters and plasma inflammatory markers and nongenetic host and environmental factors. In contrast, untargeted plasma metabolomics revealed a large number of associations with food-derived metabolites, including phytochemicals that were previously reported to inhibit platelet reactivity. Genome-wide single-nucleotide polymorphism genotyping identified 2 novel single-nucleotide polymorphisms (rs903650 and rs4789332) that were associated with platelet reactivity at the genome-wide level (P < 5 × 10-8) as well as a number of variants in the PAR4 gene (F2RL3) that were associated with PAR4-induced reactivity. CONCLUSION: Our study uncovered factors that determine variation in platelet reactivity in a population in East Africa that is rapidly transitioning to an urban lifestyle, including the importance of genetic ancestry and the gradual abandoning of the traditional East African diet.

Idiopathic fibrosing mediastinitis with esophageal varices: A case report.

Fibrosing mediastinitis (FM) is a rare cause of lung fibrosis with multiple etiologies ranging from infectious to autoimmune to idiopathic. Common causes of FM include histoplasmosis and a relatively new cause of IgG4-related disease. We present a 55-year-old male with symptoms of esophageal varices, intractable hiccups, and progressive difficulty in breathing. A chest X-ray showed right lung fibrosis with pleural effusion and loss of lung volume, which was originally thought to be the sequelae of SARS-CoV-2 or metastasis, but computed tomography of the chest revealed FM. His variceal bleeding was controlled, and he was discharged home. However, treatment for FM was not pursued because the cause was not identified. Using corticosteroids may not cease the progression of the disease, and surgical options are available when symptoms persist. Idiopathic FM requires laboratory and radiological findings to exclude relevant differential diagnoses.

Chronic purulent pericarditis: case report.

Purulent pericarditis is an infection of the pericardial space that produces pus that is found on gross examination of the pericardial sac or on the tissue microscopy. In this case report, we will discuss a 31-year-old male who presented with a chief complaint of low-grade fevers, dry cough and difficulty breathing for about two weeks which preceded after removing of dental also two weeks prior. He was admitted and treated as COVID-19 in the isolation ward, he later developed cardiac tamponade and during pericardiocentesis thick pus was discharged. Pus culture and Gene Xpert tests were all negative. After his condition improved, the patient was transferred to the general ward with the pericardial window still discharging pus. Pericardiectomy was chosen as definitive management. The key takeaway in this report is that Empirical treatment with RHZE (rifampin, isoniazid, pyrazinamide, and ethambutol) in resource-limited settings is recommended due to difficulty in identifying the exact cause at a required moment.

Facility-based disease surveillance and Bayesian hierarchical modeling to estimate endemic typhoid fever incidence, Kilimanjaro Region, Tanzania, 2007-2018.

Growing evidence suggests considerable variation in endemic typhoid fever incidence at some locations over time, yet few settings have multi-year incidence estimates to inform typhoid control measures. We sought to describe a decade of typhoid fever incidence in the Kilimanjaro Region of Tanzania. Cases of blood culture confirmed typhoid were identified among febrile patients at two sentinel hospitals during three study periods: 2007-08, 2011-14, and 2016-18. To account for under-ascertainment at sentinel facilities, we derived adjustment multipliers from healthcare utilization surveys done in the hospital catchment area. Incidence estimates and credible intervals (CrI) were derived using a Bayesian hierarchical incidence model that incorporated uncertainty of our observed typhoid fever prevalence, of healthcare seeking adjustment multipliers, and of blood culture diagnostic sensitivity. Among 3,556 total participants, 50 typhoid fever cases were identified. Of typhoid cases, 26 (52%) were male and the median (range) age was 22 (<1-60) years; 4 (8%) were aged <5 years and 10 (20%) were aged 5 to 14 years. Annual typhoid fever incidence was estimated as 61.5 (95% CrI 14.9-181.9), 6.5 (95% CrI 1.4-20.4), and 4.0 (95% CrI 0.6-13.9) per 100,000 persons in 2007-08, 2011-14, and 2016-18, respectively. There were no deaths among typhoid cases. We estimated moderate typhoid incidence (≥10 per 100 000) in 2007-08 and low (<10 per 100 000) incidence during later surveillance periods, but with overlapping credible intervals across study periods. Although consistent with falling typhoid incidence, we interpret this as showing substantial variation over the study periods. Given potential variation, multi-year surveillance may be warranted in locations making decisions about typhoid conjugate vaccine introduction and other control measures.

Opportunities for Improving Antimicrobial Stewardship: Findings From a Prospective, Multi-Center Study in Three Low- or Middle-Income Countries.

Background: To develop effective antimicrobial stewardship programs (ASPs) for low- and middle-income countries (LMICs), it is important to identify key targets for improving antimicrobial use. We sought to systematically describe the prevalence and patterns of antimicrobial use in three LMIC hospitals. Methods: Consecutive patients admitted to the adult medical wards in three tertiary care hospitals in Tanzania, Kenya, and Sri Lanka were enrolled in 2018-2019. The medical record was reviewed for clinical information including type and duration of antimicrobials prescribed, indications for antimicrobial use, and microbiologic testing ordered. Results: A total of 3,149 patients were enrolled during the study period: 1,103 from Tanzania, 750 from Kenya, and 1,296 from Sri Lanka. The majority of patients were male (1,783, 56.6% overall) with a median age of 55 years (IQR 38-68). Of enrolled patients, 1,573 (50.0%) received antimicrobials during their hospital stay: 35.4% in Tanzania, 56.5% in Kenya, and 58.6% in Sri Lanka. At each site, the most common indication for antimicrobial use was lower respiratory tract infection (LRTI; 40.2%). However, 61.0% received antimicrobials for LRTI in the absence of LRTI signs on chest radiography. Among patients receiving antimicrobials, tools to guide antimicrobial use were under-utilized: microbiologic cultures in 12.0% and microbiology consultation in 6.5%. Conclusion: Antimicrobials were used in a substantial proportion of patients at tertiary care hospitals across three LMIC sites. Future ASP efforts should include improving LRTI diagnosis and treatment, developing antibiograms to direct empiric antimicrobial use, and increasing use of microbiologic tests.

Performance of Xpert Ultra nasopharyngeal swab for identification of tuberculosis deaths in northern Tanzania.

OBJECTIVE: Numerous tuberculosis (TB) deaths remain undetected in low-resource endemic settings. With autopsy-confirmed tuberculosis as our standard, we assessed the diagnostic performance of Xpert MTB/RIF Ultra (Ultra; Cepheid) on nasopharyngeal specimens collected postmortem. METHODS: From October 2016 through May 2019, we enrolled pediatric and adult medical deaths to a prospective autopsy study at two referral hospitals in northern Tanzania with next-of-kin authorization. We swabbed the posterior nasopharynx prior to autopsy and tested the samples later by Ultra. At autopsy we collected lung, liver, and, when possible, cerebrospinal fluid for mycobacterial culture and histopathology. Confirmed tuberculosis was defined as Mycobacterium tuberculosis complex recovery by culture with consistent tissue histopathology findings; decedents with only histopathology findings, including acid-fast staining or immunohistochemistry, were defined as probable tuberculosis. RESULTS: Of 205 decedents, 78 (38.0%) were female and median (range) age was 45 (0,96) years. Twenty-seven (13.2%) were found to have tuberculosis at autopsy, 22 (81.5%) confirmed and 5 (18.5%) probable. Ultra detected M. tuberculosis complex from the nasopharynx in 21 (77.8%) of 27 TB cases (sensitivity 70.4% [95% confidence interval {CI} 49.8-86.2%], specificity 98.9% [95% CI 96.0-99.9%]). Among confirmed TB, the sensitivity increased to 81.8% (95% CI 59.7-94.8%). Tuberculosis was not included as a death certificate diagnosis in 14 (66.7%) of the 21 MTBc detections by Ultra. DISCUSSION: Nasopharyngeal Ultra was highly specific for identifying in-hospital tuberculosis deaths, including unsuspected tuberculosis deaths. This approach may improve tuberculosis death enumeration in high-burden countries.

Performance Assessment of the Universal Vital Assessment Score vs Other Illness Severity Scores for Predicting Risk of In-Hospital Death Among Adult Febrile Inpatients in Northern Tanzania, 2016-2019.

Importance: Severity scores are used to improve triage of hospitalized patients in high-income settings, but the scores may not translate well to low- and middle-income settings such as sub-Saharan Africa. Objective: To assess the performance of the Universal Vital Assessment (UVA) score, derived in 2017, compared with other illness severity scores for predicting in-hospital mortality among adults with febrile illness in northern Tanzania. Design, Setting, and Participants: This prognostic study used clinical data collected for the duration of hospitalization among patients with febrile illness admitted to Kilimanjaro Christian Medical Centre or Mawenzi Regional Referral Hospital in Moshi, Tanzania, from September 2016 through May 2019. All adult and pediatric patients with a history of fever within 72 hours or a tympanic temperature of 38.0 °C or higher at screening were eligible for enrollment. Of 3761 eligible participants, 1132 (30.1%) were enrolled in the parent study; of those, 597 adults 18 years or older were included in this analysis. Data were analyzed from December 2019 to September 2021. Exposures: Modified Early Warning Score (MEWS), National Early Warning Score (NEWS), quick Sequential Organ Failure Assessment (qSOFA), Systemic Inflammatory Response Syndrome (SIRS) assessment, and UVA. Main Outcomes and Measures: The main outcome was in-hospital mortality during the same hospitalization as the participant's enrollment. Crude risk ratios and 95% CIs for in-hospital death were calculated using log-binomial risk regression for proposed score cutoffs for each of the illness severity scores. The area under the receiver operating characteristic curve (AUROC) for estimating the risk of in-hospital death was calculated for each score. Results: Among 597 participants, the median age was 43 years (IQR, 31-56 years); 300 participants (50.3%) were female, 198 (33.2%) were HIV-infected, and in-hospital death occurred in 55 (9.2%). By higher risk score strata for each score, compared with lower risk strata, risk ratios for in-hospital death were 3.7 (95% CI, 2.2-6.2) for a MEWS of 5 or higher; 2.7 (95% CI, 0.9-7.8) for a NEWS of 5 or 6; 9.6 (95% CI, 4.2-22.2) for a NEWS of 7 or higher; 4.8 (95% CI, 1.2-20.2) for a qSOFA score of 1; 15.4 (95% CI, 3.8-63.1) for a qSOFA score of 2 or higher; 2.5 (95% CI, 1.2-5.2) for a SIRS score of 2 or higher; 9.1 (95% CI, 2.7-30.3) for a UVA score of 2 to 4; and 30.6 (95% CI, 9.6-97.8) for a UVA score of 5 or higher. The AUROCs, using all ordinal values, were 0.85 (95% CI, 0.80-0.90) for the UVA score, 0.81 (95% CI, 0.75-0.87) for the NEWS, 0.75 (95% CI, 0.69-0.82) for the MEWS, 0.73 (95% CI, 0.67-0.79) for the qSOFA score, and 0.63 (95% CI, 0.56-0.71) for the SIRS score. The AUROC for the UVA score was significantly greater than that for all other scores (P < .05 for all comparisons) except for NEWS (P = .08). Conclusions and Relevance: This prognostic study found that the NEWS and the UVA score performed favorably compared with other illness severity scores in predicting in-hospital mortality among a hospitalized cohort of adults with febrile illness in northern Tanzania. Given its reliance on readily available clinical data, the UVA score may have utility in the triage and prognostication of patients admitted to the hospital with febrile illness in low- to middle-income settings such as sub-Saharan Africa.

Gut microbiome-mediated metabolism effects on immunity in rural and urban African populations.

The human gut microbiota is increasingly recognized as an important factor in modulating innate and adaptive immunity through release of ligands and metabolites that translocate into circulation. Urbanizing African populations harbor large intestinal diversity due to a range of lifestyles, providing the necessary variation to gauge immunomodulatory factors. Here, we uncover a gradient of intestinal microbial compositions from rural through urban Tanzanian, towards European samples, manifested both in relative abundance and genomic variation observed in stool metagenomics. The rural population shows increased Bacteroidetes, led by Prevotella copri, but also presence of fungi. Measured ex vivo cytokine responses were significantly associated with 34 immunomodulatory microbes, which have a larger impact on circulating metabolites than non-significant microbes. Pathway effects on cytokines, notably TNF-α and IFN-γ, differential metabolome analysis and enzyme copy number enrichment converge on histidine and arginine metabolism as potential immunomodulatory pathways mediated by Bifidobacterium longum and Akkermansia muciniphila.

Barriers to implementing antimicrobial stewardship programs in three low- and middle-income country tertiary care settings: findings from a multi-site qualitative study.

BACKGROUND: Antimicrobial resistance has been named as one of the top ten threats to public health in the world. Hospital-based antimicrobial stewardship programs (ASPs) can help reduce antimicrobial resistance. The purpose of this study was to determine perceived barriers to the development and implementation of ASPs in tertiary care centers in three low- and middle-income countries (LMICs). METHODS: Interviews were conducted with 45 physicians at tertiary care hospitals in Sri Lanka (n = 22), Kenya (12), and Tanzania (11). Interviews assessed knowledge of antimicrobial resistance and ASPs, current antimicrobial prescribing practices, access to diagnostics that inform antimicrobial use, receptiveness to ASPs, and perceived barriers to implementing ASPs. Two independent reviewers coded the interviews using principles of applied thematic analysis, and comparisons of themes were made across the three sites. RESULTS: Barriers to improving antimicrobial prescribing included prohibitively expensive antimicrobials, limited antimicrobial availability, resistance to changing current practices regarding antimicrobial prescribing, and limited diagnostic capabilities. The most frequent of these barriers in all three locations was limited drug availability. Many physicians in all three sites had not heard of ASPs before the interviews. Improved education was a suggested component of ASPs at all three sites. The creation of guidelines was also recommended, without prompting, by interviewees at all three sites. Although most participants felt microbiological results were helpful in tailoring antibiotic courses, some expressed distrust of laboratory culture results. Biomarkers like erythrocyte sedimentation rate and c-reactive protein were not felt to be specific enough to guide antimicrobial therapy. Despite limited or no prior knowledge of ASPs, most interviewees were receptive to implementing protocols that would include documentation and consultation with ASPs regarding antimicrobial prescribing. CONCLUSIONS: Our study highlighted several important barriers to implementing ASPs that were shared between three tertiary care centers in LMICs. Improving drug availability, enhancing availability of and trust in microbiologic data, creating local guidelines, and providing education to physicians regarding antimicrobial prescribing are important steps that could be taken by ASPs in these facilities.

Urban living in healthy Tanzanians is associated with an inflammatory status driven by dietary and metabolic changes.

Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries.

Returning of antiretroviral medication dispensed over a period of 8 months suggests non-adherence despite full adherence according to real time medication monitoring.

Real-time medication monitoring (RTMM) may potentially enhance adherence to antiretroviral treatment (ART). We describe a participant in an ongoing trial who, shortly after completing trial participation, died of cryptococcal meningitis despite high levels of adherence according to self-report, pill-counts and RTMM (> 99%). However, she evidenced consistently high HIV viral load throughout the 48-week study follow-up. Subsequently, her relatives unsolicitedly returned eight months' dispensed ART medication that she was supposed to have taken. This brief report illustrates the challenges of adherence measurements including RTMM, and reinforces the need to combine adherence assessments with viral load monitoring in HIV care.

Technical and Psychosocial Challenges of mHealth Usage for Antiretroviral Therapy Adherence Among People Living With HIV in a Resource-Limited Setting: Case Series.

BACKGROUND: Mobile communication has been found to improve antiretroviral therapy (ART) adherence among people living with HIV. In an ongoing randomized clinical trial, 2 mobile communication strategies (ie, sending SMS text messages and real-time medication monitoring [RTMM]) were used to improve adherence to ART among people living with HIV in Tanzania. We noticed remarkable discrepancies between self-reported adherence and adherence recorded by SMS text messaging or RTMM among some of the first trial participants. OBJECTIVE: Our objective was to describe these cases and the observed discrepancies in more detail, to serve as a useful illustration of some of the challenges in using mobile health in resource-limited settings. METHODS: In an ongoing randomized trial, adults living with HIV from two HIV treatment centers in Tanzania who were suspected of low levels of adherence were randomly assigned in a 1:1:1 ratio to receive (1) SMS text message reminders, (2) an RTMM device, or (3) no additional intervention to standard HIV care. During bimonthly study visits, the participants self-reported their level of adherence, received feedback about their level of adherence based on SMS text messaging or RTMM, and discussed strategies to overcome adherence problems with nurses providing HIV care. For the purpose of this report, we selected people living with HIV who had completed 5 follow-up visits and consistently reported more than 95% adherence, while SMS text messaging or RTMM recorded lower than 75% adherence. The participants were invited for a short, face-to-face in-depth interview to explore reasons for this discrepancy. RESULTS: At the time of this analysis, 26 participants had completed follow-up. Six of these evidenced the above-mentioned discrepancies, with an average adherence of 46% based on SMS text messaging or RTMM, while self-reported adherence was 98%. Five of these 6 participants insisted that their adherence to ART was good, with 4 reporting that their adherence to properly using the monitoring device was low. Three participants mentioned concerns about involuntary disclosure of HIV status as a main reason for low adherence to using the device. Two participants were still depending on other reminder cues despite receiving SMS text message or RTMM reminders. Poor network coverage caused low adherence in 1 participant. CONCLUSIONS: Psychosocial barriers were reported as importantly contributing to low adherence, both with respect to use of ART and proper use of the adherence-monitoring device. This case series illustrates that when introducing new digital adherence monitoring technology, researchers should consider psychosocial barriers and distinguish between adherence to device use and adherence to treatment. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201712002844286; https://tinyurl.com/y98q4p3l.

Predictors of Treatment Outcomes among Multidrug Resistant Tuberculosis Patients in Tanzania.

BACKGROUND: According to World Health Organization (WHO) the final multidrug resistant tuberculosis (MDRTB) treatment outcome is the most important direct measurement of the effectiveness of the MDRTB control program. Literature review has shown marked diversity in predictors of treatment outcomes worldwide even among the same continents. Therefore, findings could also be different in Tanzanian context, where the success rate is still lower than the WHO recommendation. This study sought to determine the predictors of treatment outcomes among MDRTB patients in Tanzania in order to improve the success rate. METHODOLOGY: This was a retrospective cohort study, which was conducted at Kibong'oto Infectious Diseases Hospital (KIDH) in Tanzania. Patients' demographic and clinical parameters were collected from the MDRTB registry and clinical files. Then, a detailed analysis was done to determine the predictors of successful and unsuccessful MDRTB treatment outcomes. RESULTS: Three hundred and thirty-two patients were diagnosed and put on MDRTB treatment during the year 2009 to 2014. Among them, males were 221 (67%), and 317 (95.48%) were above 18 years of age, mean age being 36.9 years. One hundred and sixty-one patients (48.5%) were living in Dar es Salaam. The number of MDRTB patients has increased from 16 in 2009 to 132 in 2014. Majority of patients (75.7%) had successful treatment outcomes. The following predictors were significantly associated with MDRTB cure: presence of cavities in chest X-rays (aOR 1.89, p value 0.002), low BMI (aOR 0.59, p value 0.044), and resistance to streptomycin (aOR 4.67, p value 0.007) and ethambutol (aOR 0.34, p value 0.041). Smoking and presence of cavities in chest X-rays were associated with MDRTB mortality, aOR 2.31, p value 0.043 and aOR 0.55, p value 0.019, respectively. CONCLUSION: The study indicated that overall number of MDRTB patients and the proportion of successful treatment outcomes have been increasing over the years. The study recommends improving nutritional status of MDRTB patients, widespread antismoking campaign, and close follow-up of patients with ethambutol resistance.

Seroprevalence of hepatitis B virus infection and associated factors among healthcare workers in northern Tanzania.

BACKGROUND: Hepatitis B virus infection is a global health problem with the highest prevalence in East Asia and Sub-Saharan Africa. The majority of infected people, including healthcare workers are unaware of their status. This study is aimed to determining seroprevalence of hepatitis B virus infection and associated factors among healthcare workers in northern Tanzania. METHODS: This cross-sectional study included 442 healthcare workers (HCWs) from a tertiary and teaching hospital in Tanzania before the nationwide hepatitis B vaccination campaign in 2004. Questionnaire- based interviews were used to obtain detailed histories of the following: demographic characteristics; occupation risks such splash and needle stick injuries or other invasive procedure such as intravenous, intramuscular or subcutaneous injections; history of blood transfusion and surgeries, as well as HCWs'knowledge of HBV. Serological markers of HBV were done using Laborex HBsAg rapid test. Serology was done at zero months and repeated after six months ( bioscienceinternational.co.ke/rapid-test-laborex.html HBsAg Piazzale-milano-2, Italy [Accessed on November 2017]). Chi-square (χ2) tests were used to compare proportion of HBV infection by different HCWs characteristics. Multivariable logistic regression was used to determine factors associated with HBV infection. RESULTS: A total of 450 surveys were sent out, with a 98.2% response rate. Among the 442 HCWs who answered the questionnaire, the prevalence of chronic hepatitis B virus infection was 5.7% (25/442). Only 50 (11.3%) of HCWs were aware of the HBV status. During the second HBsAg testing which was done after six months one participant sero-converted hence was excluded. Adjusted for other factors, history of blood transfusion significantly increased the odds of HBV infection (OR = 21.44, 95%CI 6.05, 76.01, p < 0.001) while HBV vaccine uptake was protective against HBV infection (OR = 0.06, 95%CI 0.02, 0.26, p < 0.001). The majority of HCWs with chronic HBV infection had poor to fare knowledge about HBV infection but this was not statistically significant when controlled for confounding. CONCLUSIONS: Prevalence of HBV among health care workers was 5.7% which is similar to national prevalence. Although the response rate to take part in the study was good but knowledge on HBV infection among HCWs was unsatisfactory. History of blood transfusion increased risks while vaccine uptake decreased the risk of HBV infection. This study recommends continues vaccinating HCWs together with continues medical education all over the country. We also recommend documentation of vaccination evidence should be asked before employment of HCWs in order to sensitize more uptakes of vaccinations. Although we didn't assess the use of personal protective equipment but we encourage HCWs to abide strictly on universal protections against nosocomial infections.