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Background In 2018 the World Health Organization recommended a switch to an all oral bedaquiline-based second-line regimen for treatment of drug-resistant tuberculosis (DR-TB). How these new second-line regimens fare in comparison to first-line regimens for treatment of drug-sensitive tuberculosis (DS-TB) is not well known. Methods In this study, we contemporaneously enrolled subjects with DS-TB (n = 31) or DR-TB (n = 23) and assessed their response to therapy with first-line (rifampin, isoniazid, ethambutol, pyrazinamide) or second-line (bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine) regimens, respectively. Results We found that the early bactericidal activity of first- and second-line regimens was similar during the first 2 weeks of therapy as determined by BACTEC MGIT, colony-forming units, and a liquid limiting dilution assay capable of detecting differentially detectable/culturable Mycobacterium tuberculosis. Furthermore, an identical percentage (77.8%) of subjects from the DS-TB and DR-TB cohorts converted to culture negative after 2 months of therapy. Conclusions Despite presenting with more advanced disease at time of treatment, subjects with DR-TB receiving an all oral bedaquiline-based second-line treatment regimen displayed a similar microbiological response to therapy as subjects with DS-TB receiving a first-line treatment regimen. [ABSTRACT FROM AUTHOR]

Background Isoniazid-resistant, rifampin-susceptible tuberculosis (Hr-TB) is associated with poor treatment outcomes and higher rates of acquisition of further drug resistance during treatment. Due to a lack of widespread diagnostics, Hr-TB is frequently undetected and its epidemiology is incompletely understood. Methods We studied the molecular epidemiology of Hr-TB among all patients diagnosed with culture-positive pulmonary tuberculosis between January 1 and June 30, 2017, at an urban referral tuberculosis clinic in Port-au-Prince, Haiti. Demographic and clinical data were extracted from the electronic medical record. Archived diagnostic Mycobacterium tuberculosis isolates were tested for genotypic and phenotypic isoniazid resistance using the Genotype MTBDR plus assay (Hain, Nehren, Germany) and culture-based testing, respectively. All isoniazid-resistant isolates and a randomly selected subset of isoniazid-susceptible isolates underwent whole-genome sequencing to confirm the presence of mutations associated with isoniazid resistance, to validate use of Genotype MTBDR plus in this population, and to identify potential transmission links between isoniazid-resistant isolates. Results and Conclusions Among 845 patients with culture-positive pulmonary tuberculosis in Haiti, 65 (7.7%) had Hr-TB based on the Genotype MTBDR plus molecular assay. Age < 20 years was significantly associated with Hr-TB (odds ratio, 2.39; 95% confidence interval, 1.14, 4.70; P =.015). Thirteen (20%) isoniazid-resistant isolates were found in 5 putative transmission clusters based on a single nucleotide polymorphism distance of ≤ 5. No patients in these transmission clusters were members of the same household. Adolescents are at higher risk for Hr-TB. Strains of isoniazid-resistant M tuberculosis are actively circulating in Haiti and transmission is likely occurring in community settings. [ABSTRACT FROM AUTHOR]

Background Reasons for the high prevalence of Kaposi sarcoma–associated herpesvirus (KSHV) in sub-Saharan Africa, and risk factors leading to viral reactivation and shedding, remain largely undefined. Preliminary studies have suggested that schistosome infection, which has been associated with impaired viral control, is associated with KSHV. In this study we sought to determine the relationship between active Schistosoma mansoni or Schistosoma haematobium infection and KSHV shedding. Methods We quantified KSHV DNA in saliva and cervical swabs from 2 cohorts of women living in northwestern Tanzanian communities endemic for S mansoni or S haematobium by real-time polymerase chain reaction. χ2 and Fisher exact tests were used to determine differences in clinical and demographic factors between those who were and were not shedding KSHV. Results Among 139 total women, 44.6% were KSHV seropositive. Six percent of those with S mansoni and 17.1% of those with S haematobium were actively shedding KSHV in saliva and none in cervical samples. Women from the S mansoni cohort who were shedding virus reported infertility more frequently (80% vs 19.5%, P =.009). There was no difference in frequency of KSHV salivary shedding between schistosome-infected and -uninfected women. Conclusions In an area with high KSHV seroprevalence and endemic schistosome infections, we provide the first report with data demonstrating no association between schistosome infection and salivary or cervical herpesvirus shedding. KSHV salivary shedding was associated with infertility, a known effect of another herpesvirus, human herpesvirus 6. [ABSTRACT FROM AUTHOR]

Schistosoma mansoni infection may impair genital mucosal antiviral immunity, but immune cell populations have not been well characterized. We characterized mononuclear cells from cervical brushings of women with and without S mansoni infection. We observed lower frequencies of natural killer T cells and higher frequencies of CD14+ monocytes in infected women. [ABSTRACT FROM AUTHOR]

We evaluated sex-related differences in symptoms and risk factors for mortality in 4798 patients hospitalized with coronavirus disease 2019 in New York City. When adjusted for age and comorbidities, being male was an independent predictor of death with mortality significantly higher than females, even with low severe acute respiratory syndrome coronavirus 2 viral load at admission. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were (1) to compare the prevalence of myocardial diastolic dysfunction (DD) in antiretroviral therapy (ART)-naive people living with human immunodeficiency virus (PLWH) to human immunodeficiency virus (HIV)-uninfected adults in East Africa and (2) to determine the association between serum concentration of the cardiac biomarkers ST2 and DD.Methods: In this cross-sectional study, we enrolled PLWH and uninfected adults at a referral HIV clinic in Mwanza, Tanzania. Standardized history, echocardiography, and serum were obtained. Regression models were used to quantify associations.Results: We enrolled 388 ART-naive PLWH and 461 HIV-uninfected adults with an average age of 36.0 ± 10.2 years. Of PLWH in the third, fourth, and fifth decades of life, 5.0%, 12.5%, and 32.7%, respectively, had DD. PLWH had a higher prevalence of DD (adjusted odds ratio, 2.71 [95% confidence interval, 1.62-4.55]; P < .0001). PLWH also had a higher probability of dysfunction with one or fewer traditional risk factors present. Serum ST2 concentration was associated with dysfunction in PLWH but not uninfected participants (P = .04 and P = .90, respectively).Conclusions: In a large population of young adults in sub-Saharan Africa, DD prevalence increased starting in the third decade of life. HIV was independently associated with dysfunction. Serum ST2 concentration was associated with DD in PLWH but not HIV-uninfected participants. This pathway may provide insight into the mechanisms of HIV-associated dysfunction. [ABSTRACT FROM AUTHOR]

BACKGROUND Hypertensive urgency is associated with a high risk for cardiovascular events and mortality in the United States and Europe, but data from low-income countries and interventions to improve outcomes are lacking. METHODS We conducted a 1-year prospective study of the prevalence and outcomes of hypertensive urgency (blood pressure (BP) ≥180 mm Hg/120 mm Hg without end-organ damage) in a busy outpatient clinic in Tanzania. RESULTS Of 7,600 consecutive adult outpatients screened with 3 unattended automated BP measurements according to standard protocol, the prevalence of hypertensive crisis was 199/7,600 (2.6%) (BP ≥180 mm Hg/120 mm Hg) and the prevalence of hypertensive urgency was 164/7,600 (2.2%). Among 150 enrolled patients with hypertensive urgency, median age was 62 years (54–68), 101 (67.3%) were women, and 53 (35%) were either hospitalized or died within 1 year. In a multivariate model, the strongest predictor of hospitalization/death was self-reported medication adherence on a 3 question scale (hazard ratio: 0.06, P < 0.001); 90% of participants with poor adherence were hospitalized or died within 1 year. CONCLUSIONS Patients with hypertensive urgency in Africa are at high risk of poor outcomes. Clinicians can identify the patients at highest risk for poor outcomes with simple questions related treatment adherence. New interventions are needed to improve medication adherence in patients with hypertensive urgency. [ABSTRACT FROM AUTHOR]

Background: Schistosomiasis increases the risk of human immunodeficiency virus (HIV) acquisition in women by mechanisms that are incompletely defined. Our objective was to determine how the cervical environment is impacted by Schistosoma haematobium or Schistosoma mansoni infection by quantifying gene expression in the cervical mucosa and cytokine levels in cervicovaginal lavage fluid.Methods: We recruited women with and those without S. haematobium infection and women with and those without S. mansoni infection from separate villages in rural Tanzania with high prevalences of S. haematobium and S. mansoni, respectively. Infection status was determined by urine and stool microscopy and testing for serum circulating anodic antigen. RNA was extracted from cervical cytobrush samples for transcriptome analysis. Cytokine levels were measured by magnetic bead immunoassay.Results: In the village where S. haematobium was prevalent, 110 genes were differentially expressed in the cervical mucosa of 18 women with versus 39 without S. haematobium infection. Among the 27 cytokines analyzed in cervicovaginal lavage fluid from women in this village, the level of interleukin 15 was lower in the S. haematobium-infected group (62.8 vs 102.9 pg/mL; adjusted P = .0013). Differences were not observed in the S. mansoni-prevalent villages between 11 women with and 29 without S. mansoni infection.Conclusions: We demonstrate altered cervical mucosal gene expression and lower interleukin 15 levels in women with S. haematobium infection as compared to those with S. mansoni infection, which may influence HIV acquisition and cancer risks. Studies to determine the effects of antischistosome treatment on these mucosal alterations are needed. [ABSTRACT FROM AUTHOR]

We consider how many components to retain in principal component analysis when the dimension is much higher than the number of observations. To estimate the number of components, we propose to sequentially test skewness of the squared lengths of residual scores that are obtained by removing leading principal components. The residual lengths are asymptotically left-skewed if all principal components with diverging variances are removed, and right-skewed otherwise. The proposed estimator is shown to be consistent, performs well in high-dimensional simulation studies, and provides reasonable estimates in examples. [ABSTRACT FROM AUTHOR]

Background Adequate control of the global tuberculosis (TB) burden is limited by a lack of accurate measures of treatment efficacy. Current gold standard relies on sputum cultures, which often lag weeks behind time of sample collection. Previous studies have identified urinary N 1 ,N 12 -diacetylspermine (DiAcSpm) as a potential biomarker of active pulmonary TB (ATB). We aimed to quantify urinary DiAcSpm in participants being treated for ATB and identify its relationship to treatment response. Methods Longitudinal urine samples were obtained from two separate cohorts of participants treated for ATB. Cohort one consisted of 34 successfully treated ATB cases with urine collected at weeks 0, 2, 4, 8, 17, 26, and 52. Cohort two consisted of 35 ATB cases under two treatment arms: one arm was successfully treated with the standard therapy of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE), and the other arm received an experimental drug, which was later found to be ineffective against ATB. Urine from cohort two was collected at days 0, 2, 4, and 14. All samples were blinded, randomized, normalized to osmolality and urinary creatinine, and analyzed using high-performance liquid chromatography-mass spectrometry. DiAcSpm concentrations were further tested using ELISA. Results Using linear-mixed modeling that adjusted for age, sex, and participant weight, we found that urinary DiAcSpm significantly decreased by week 2 of successful treatment in both cohorts (P < 0.0001). DiAcSpm levels remained unchanged in the ineffective experimental drug group (cohort two), significantly differentiating treatment success and failure by day 14 (P < 0.0001). Additionally, concentrations of urinary DiAcSpm positively correlate with sputum mycobacterial burden (P = 0.0002).These findings were consistent across both methods of detection. Conclusion Our results suggest that urinary concentrations of DiAcSpm correlate with TB treatment outcome and mycobacterial disease burden, and have the potential to serve as an early biomarker of TB treatment efficacy. Disclosures All Authors: No reported Disclosures. [ABSTRACT FROM AUTHOR]

Objectives: Obtaining clinical samples that contain RNA of sufficient quality and quantity for next-generation sequencing is costly and challenging in resource-poor areas, in part due to the complexity of transporting whole blood samples which require dry ice. In this study, our aim was to optimize messenger RNA extraction from dried blood spots (DBS) and to determine whether this RNA was comparable to whole blood RNA preserved in Tempus tubes (Applied Biosystems, Foster City, CA). Methods: We collected single phlebotomy samples from eight adults in rural Tanzania. Blood was placed immediately into Tempus tubes and spotted onto Whatman Protein Saver 903 cards (GE Healthcare Life Sciences, Buckinghamshire, UK). We varied methods of RNA extraction from DBS and assessed the resulting quality and concentration of RNA. We then compared transcriptomes generated from our optimized DBS extraction technique with those from Tempus tubes. We used R to analyze the mapped transcripts and DESeq2 to normalize the count data. Then we compared log2 normalized gene expression between paired DBS and whole blood using Spearman correlation coefficients and MA plots. Results: The optimal DBS RNA extraction used eight 3 mm DBS punches, bead beater disruption at maximum speed for 60 seconds, extraction by Illustra RNAspin Mini RNA Isolation Kit (GE Healthcare Life Sciences), and purification with Zymo RNA Concentrator kit (Zymo Research, Irvine, CA). Spearman correlations of optimal DBS extraction vs whole blood transcriptomes showed that the results were similar with each method, ranging from 0.887 to 0.941. Conclusion: We demonstrated that RNA of sufficient quality and quantity for transcriptome generation can be extracted from DBS, and correlates highly with transcriptomes generated from Tempus tubes. To our knowledge, this is the first study to demonstrate the feasibility of using DBS for transcriptome analysis, which has less burdensome requirements for sample procurement and transportation. [ABSTRACT FROM AUTHOR]