Potential Utility of C-reactive Protein for Tuberculosis Risk Stratification Among Patients With Non-Meningitic Symptoms at HIV Diagnosis in Low- and Middle-income Countries.

Background: The World Health Organization recommends initiating same-day antiretroviral therapy (ART) while tuberculosis (TB) testing is under way for patients with non-meningitic symptoms at HIV diagnosis, though safety data are limited. C-reactive protein (CRP) testing may improve TB risk stratification in this population. Methods: In this baseline analysis of 498 adults (>18 years) with TB symptoms at HIV diagnosis who were enrolled in a trial of rapid ART initiation in Haiti, we describe test characteristics of varying CRP thresholds in the diagnosis of TB. We also assessed predictors of high CRP as a continuous variable using generalized linear models. Results: Eighty-seven (17.5%) participants were diagnosed with baseline TB. The median CRP was 33.0 mg/L (interquartile range: 5.1, 85.5) in those with TB, and 2.6 mg/L (interquartile range: 0.8, 11.7) in those without TB. As the CRP threshold increased from ≥1 mg/L to ≥10 mg/L, the positive predictive value for TB increased from 22.4% to 35.4% and negative predictive value decreased from 96.9% to 92.3%. With CRP thresholds varying from <1 to <10 mg/L, a range from 25.5% to 64.9% of the cohort would have been eligible for same-day ART and 0.8% to 5.0% would have untreated TB at ART initiation. Conclusions: CRP concentrations can be used to improve TB risk stratification, facilitating same-day decisions about ART initiation. Depending on the CRP threshold, one-quarter to two-thirds of patients could be eligible for same-day ART, with a reduction of 3- to 20-fold in the proportion with untreated TB, compared with a strategy of same-day ART while awaiting TB test results.

Circulating CD4+ T cells in people with HIV and history of pulmonary tuberculosis have more intact HIV DNA.

Background: The primary barrier to curing HIV infection is the pool of intact HIV proviruses integrated into host cell DNA throughout the bodies of people living with HIV (PLHIV), called the HIV reservoir. Reservoir size is impacted by the duration of HIV infection, delay in starting antiretroviral therapy (ART), and breakthrough viremia during ART. The leading infectious cause of death worldwide for PLHIV is TB, but we don't know how TB impacts the HIV reservoir. Methods: We designed a case-control study to compare HIV provirus-containing CD4 in PLHIV with vs. without a history of active TB disease. Study participants in the pilot and confirmatory cohort were enrolled at GHESKIO Centers in Port au Prince, Haiti. Intact and non-intact proviral DNA were quantified using droplet digital PCR of PBMC-derived CD4 cells. For a subset, Th1 and Th2 cytokines were assayed in plasma. Kruskal-Wallis tests were used to compare medians with tobit regression for censoring. Results: In the pilot cohort, we found that PLHIV with history of active pulmonary TB (n=20) had higher intact provirus than PLHIV without history of active TB (n=47) (794 vs 117 copies per million CD4, respectively; p<0.0001). In the confirmatory cohort, the quantity of intact provirus was higher in the TB group (n=13) compared with the non-TB group (n=18) (median 102 vs. 0 intact provirus per million CD4, respectively p=0.03). Additionally, we found that the frequencies of CD4+ T cells with any detectable proviral fragment was directly proportional to the levels of IL1B (p= 0.0025) and IL2 (p=0.0002). Conclusions: This is the first assessment of HIV provirus using IPDA in a clinical cohort from a resource limited setting, and the finding of larger reservoir in PLHIV with history of TB has significant implications for our understanding of TB-HIV coinfection and HIV cure efforts in TB-endemic settings.

The Many Hosts of Mycobacteria 9 (MHM9): A conference report.

The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes. Various confounders were presented and discussed at MHM9 including those that originate from the host (comorbidities and coinfections) as well as those arising from the environment (e.g., zoonotic exposures), economic inequality (e.g. healthcare disparities), stigma (a confounder of leprosy and TB for millennia), and historical neglect (a confounder in Native American Nations). This conference report summarizes select talks given at MHM9 highlighting recent research advances, as well as talks regarding the historic and ongoing impact of TB and other infectious diseases on Native American Nations, including those in Southwestern Alaska where the regional TB incidence rate is among the highest in the Western hemisphere.

Same-day testing with initiation of antiretroviral therapy or tuberculosis treatment versus standard care for persons presenting with tuberculosis symptoms at HIV diagnosis: A randomized open-label trial from Haiti.

BACKGROUND: Same-day HIV testing and antiretroviral therapy (ART) initiation is being widely implemented. However, the optimal timing of ART among patients with tuberculosis (TB) symptoms is unknown. We hypothesized that same-day treatment (TB treatment for those diagnosed with TB; ART for those not diagnosed with TB) would be superior to standard care in this population. METHODS AND FINDINGS: We conducted an open-label trial among adults with TB symptoms at initial HIV diagnosis at GHESKIO in Haiti; participants were recruited and randomized on the same day. Participants were randomized in a 1:1 ratio to same-day treatment (same-day TB testing with same-day TB treatment if TB diagnosed; same-day ART if TB not diagnosed) versus standard care (initiating TB treatment within 7 days and delaying ART to day 7 if TB not diagnosed). In both groups, ART was initiated 2 weeks after TB treatment. The primary outcome was retention in care with 48-week HIV-1 RNA <200 copies/mL, with intention to treat (ITT) analysis. From November 6, 2017 to January 16, 2020, 500 participants were randomized (250/group); the final study visit occurred on March 1, 2021. Baseline TB was diagnosed in 40 (16.0%) in the standard and 48 (19.2%) in the same-day group; all initiated TB treatment. In the standard group, 245 (98.0%) initiated ART at median of 9 days; 6 (2.4%) died, 15 (6.0%) missed the 48-week visit, and 229 (91.6%) attended the 48-week visit. Among all who were randomized, 220 (88.0%) received 48-week HIV-1 RNA testing; 168 had <200 copies/mL (among randomized: 67.2%; among tested: 76.4%). In the same-day group, 249 (99.6%) initiated ART at median of 0 days; 9 (3.6%) died, 23 (9.2%) missed the 48-week visit, and 218 (87.2%) attended the 48-week visit. Among all who were randomized, 211 (84.4%) received 48-week HIV-1 RNA; 152 had <200 copies/mL (among randomized: 60.8%; among tested: 72.0%). There was no difference between groups in the primary outcome (60.8% versus 67.2%; risk difference: -0.06; 95% CI [-0.15, 0.02]; p = 0.14). Two new grade 3 or 4 events were reported per group; none were judged to be related to the intervention. The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain. CONCLUSIONS: In patients with TB symptoms at HIV diagnosis, we found that same-day treatment was not associated with superior retention and viral suppression. In this study, a short delay in ART initiation did not appear to compromise outcomes. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov NCT03154320.

High Dietary Sodium, Measured Using Spot Urine Samples, is Associated with Higher Blood Pressure among Young Adults in Haiti.

Background: Hypertension (HTN) is the leading cardiovascular disease (CVD) risk factor in Haiti and is likely driven by poverty-related social and dietary factors. Salt consumption in Haiti is hypothesized to be high but has never been rigorously quantified. Methods: We used spot urine samples from a subset of participants in the population-based Haiti Cardiovascular Disease Cohort to estimate population mean daily sodium intake. We compared three previously validated formulas for estimating dietary sodium intake using urine sodium, urine creatinine, age, sex, height, and weight. We explored the association between dietary sodium intake and blood pressure, stratified by age group. Results: A total of 1,240 participants had spot urine samples. Median age was 38 years (range 18-93), and 48% were female. The mean dietary sodium intake was 3.5-5.0 g/day across the three estimation methods, with 94.2%-97.9% of participants consuming above the World Health Organization (WHO) recommended maximum of 2 g/day of sodium. Among young adults aged 18-29, increasing salt intake from the lowest quartile of consumption (<3.73 g/day) to the highest quartile (>5.88 g/day) was associated with a mean 8.71 mmHg higher systolic blood pressure (SBP) (95% confidence interval: 3.35, 14.07; p = 0.001). An association was not seen in older age groups. Among participants under age 40, those with SBP ≥120 mmHg consumed 0.5 g/day more sodium than those with SBP <120 mmHg (95% confidence interval: 0.08, 0.69; p = 0.012). Conclusions: Nine out of 10 Haitian adults in our study population consumed more than the WHO recommended maximum for daily sodium intake. In young adults, higher sodium consumption was associated with higher SBP. This represents an inflection point for increased HTN risk early in the life course and points to dietary salt intake as a potential modifiable risk factor for primordial and primary CVD prevention in young adults.

Potential Utility of C-reactive Protein for Tuberculosis Risk Stratification among Patients with Non-Meningitic Symptoms at HIV Diagnosis in Low- and Middle-Income Countries.

Article Summary: We assessed the association between C-reactive protein (CRP) and Mycobacterium tuberculosis (TB) diagnosis in symptomatic patients at HIV diagnosis. We found that CRP concentrations can improve tuberculosis risk stratification, facilitating decision making about whether (specific) tuberculosis testing is indicated before antiretroviral therapy initiation. Background: The World Health Organization recommends initiating same-day ART while tuberculosis testing is underway for patients with non-meningitic symptoms at HIV diagnosis, though safety data are limited. C-reactive protein (CRP) testing may improve tuberculosis risk stratification in this population. Methods: In this baseline analysis of 498 adults (>18 years) with tuberculosis symptoms at HIV diagnosis who were enrolled in a trial of rapid ART initiation in Haiti, we describe test characteristics of varying CRP thresholds in the diagnosis of TB. We also assessed predictors of high CRP (≥3 mg/dL) using generalized linear models. Results: Eighty-seven (17.5%) patients were diagnosed with baseline TB. The median CRP was 33.0 mg/L (IQR: 5.1, 85.5) in those with TB, and 2.6 mg/L (IQR: 0.8, 11.7) in those without TB. As the CRP threshold increased from ≥1 mg/L to ≥10 mg/L, the positive predictive value for TB increased from 22.4% to 35.4%, and negative predictive value decreased from 96.9% to 92.3%. With CRP thresholds varying from <1 to <10 mg/L, a range from 25.5% to 64.9% of the cohort would have been eligible for same-day ART, and 0.8% to 5.0% would have untreated TB at ART initiation. Conclusions: CRP concentrations can be used to improve TB risk stratification, facilitating same-day decisions about ART initiation. Depending on the CRP threshold, one-quarter to two-thirds of patients could be eligible for same-day ART, with a reduction of 3-fold to 20-fold in the proportion with untreated TB, compared with a strategy of same-day ART while awaiting TB test results.

Time to Culture Conversion of Bedaquiline and High-Dose Isoniazid for Drug-Resistant Tuberculosis.

Patients with multidrug-resistant tuberculosis who received regimens containing high-dose isoniazid (INHHD) had similar time to culture conversion and treatment outcomes as patients who received regimens with bedaquiline. INHHD is an inexpensive and safe medication that may contribute additive efficacy in combination regimens.

The Impact of Vitamin A Deficiency on Tuberculosis Progression.

BACKGROUND: Although previous studies have shown that vitamin A deficiency is associated with incident tuberculosis (TB) disease, the direction of the association has not been established. We investigated the impact of vitamin A deficiency on TB disease progression. METHODS: We conducted a longitudinal cohort study nested within a randomized clinical trial among HIV-infected patients in Haiti. We compared serial vitamin A levels in individuals who developed TB disease to controls matched on age, gender, follow-up time, and time to antiretroviral therapy initiation. We also evaluated histopathology, bacterial load, and immune outcomes in TB infection in a guinea pig model of dietary vitamin A deficiency. RESULTS: Among 773 participants, 96 developed incident TB during follow-up, 62.5% (60) of whom had stored serum samples obtained 90-365 days before TB diagnosis. In age- and sex- adjusted and multivariate analyses, respectively, incident TB cases were 3.99 times (95% confidence interval [CI], 2.41 to 6.60) and 3.59 times (95% CI, 2.05 to 6.29) more likely to have been vitamin A deficient than matched controls. Vitamin A-deficient guinea pigs manifested more extensive pulmonary pathology, atypical granuloma morphology, and increased bacterial growth after experimental TB infection. Reintroduction of dietary vitamin A to deficient guinea pigs after established TB disease successfully abrogated severe disease manifestations and altered cellular immune profiles. CONCLUSIONS: Human and animal studies support the role of baseline vitamin A deficiency as a determinant of future TB disease progression.

Prevalence of HTLV-I Infection and Its Association with Tuberculosis among Patients at an Urban Clinic in Haiti.

This retrospective case-control study examined the prevalence of HTLV-I and its association with tuberculosis among urban clinic patients in Haiti. Prevalence of HTLV-I among tuberculosis cases was 2.1% and among controls was 2.4%. Prevalence of HLTV-I was higher in females than males (odds ratio [OR] 2.45, P = 0.020). HTLV-I prevalence in those ≥ 50 years was 8.4% compared with 1.3% in those < 50 (OR 6.74, P < 0.001). We found no association between HTLV-I and tuberculosis in this population.

Long-term mortality after tuberculosis treatment among persons living with HIV in Haiti.

INTRODUCTION: Long-term mortality among TB survivors appears to be higher than control populations without TB in many settings. However, data are limited among persons with HIV (PWH). We assessed the association between cured TB and long-term mortality among persons with PWH in Haiti. METHODS: A prospective cohort of PWH from the CIPRA HT-001 trial was followed from study enrolment (August 2005 to July 2008) to study closure (December 2018) to compare mortality between participants with and without TB. The index date for the survival analysis was defined as 240 days after TB diagnosis or randomization date. Time to death was described using Kaplan-Meier curves, and log-rank tests were used to compare time to death between the TB and no-TB cohorts. The association between TB and long-term mortality was estimated with multivariable Cox models. RESULTS: Of the 816 participants in the CIPRA HT-001 trial, 77 were excluded for a history of TB prior to study enrolment and 31 were excluded due to death or attrition prior to the index date, leaving 574 in the no-TB and 134 in the TB cohort. Twenty-four (17.9%) participants in the TB and 48 (8.4%) in the no-TB cohort died during follow-up. Five and 10-year mortality rates were 14.2% and 17.9% respectively, in the TB cohort, and 6.1% and 8.4% in the no-TB cohort. In Kaplan-Meier analysis, participants in the TB cohort had a significantly shorter time to death (log-rank p < 0.001). In multivariable analysis, TB treatment was the only predictor of mortality (HR: 2.78; 95% CI: 1.61, 4.79). Sensitivity analyses, which included only baseline TB cases, an index date of two years after TB diagnosis, and study enrolment and case-control matching yielded results that were consistent with primary analyses. CONCLUSIONS: PWH who are successfully treated for TB have higher long-term mortality than those who are never diagnosed with TB, even after accounting for acute TB-related mortality. A better understanding of the underlying mechanisms associated with TB sequelae is critically needed to guide specific interventions. Until then, more aggressive measures for health promotion and disease prevention are essential to improve long-term survival for PWH after TB treatment.

Urinary biomarkers of mycobacterial load and treatment response in pulmonary tuberculosis.

BACKGROUNDControl of the tuberculosis (TB) pandemic remains hindered in part by a lack of simple and accurate measures of treatment efficacy, as current gold standard markers rely on sputum-based assays that are slow and challenging to implement. However, previous work identified urinary N1, N12-diacetylspermine (DiAcSpm), neopterin, hydroxykynurenine, N-acetylhexosamine, ureidopropionic acid, sialic acid, and mass-to-charge ratio (m/z) 241.0903 as potential biomarkers of active pulmonary TB (ATB). Here, we evaluated their ability to serve as biomarkers of TB treatment response and mycobacterial load.METHODSWe analyzed urine samples prospectively collected from 2 cohorts with ATB. A total of 34 study participants from African countries treated with first-line TB therapy rifampin, isoniazid, pyrazinamide, and ethambutol (HRZE) were followed for 1 year, and 35 participants from Haiti treated with either HRZE or an experimental drug were followed for 14 days. Blinded samples were analyzed by untargeted HPLC-coupled high-resolution TOF-mass spectrometry.RESULTSUrinary levels of all 7 molecules significantly decreased by week 26 of successful treatment (P = 0.01 to P < 0.0001) and positively correlated with sputum mycobacterial load (P < 0.0001). Urinary DiAcSpm levels decreased significantly in participants treated with HRZE as early as 14 days (P < 0.0001) but remained unchanged in cases of ineffective therapy (P = 0.14).CONCLUSIONUrinary DiAcSpm, neopterin, hydroxykynurenine, N-acetylhexosamine, ureidopropionic acid, sialic acid, and m/z 241.0903 reductions correlated with successful anti-TB treatment and sputum mycobacterial load. Urinary DiAcSpm levels exhibited reductions capable of differentiating treatment success from failure as early as 2 weeks after the initiation of chemotherapy, advocating its further development as a potentially simple, noninvasive biomarker for assessing treatment response and bacterial load.FUNDINGThis work was supported by the Clinical and Translational Science Center at Weill Cornell College of Medicine (NIH/NCATS 1 UL1 TR002384-02 and KL2TR000458), the Department of Defense (PR170782), the National Institute of Allergy and Infectious Disease grants (NIAID T32AI007613-16, K24 AI098627, and K23 AI131913), the NIH Fogarty International Center grants (R24 TW007988 and TW010062), NIH grant (R01 GM135926), the Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine, and the Tuberculosis Research Units Networks (TBRU-N, AI111143).

The Many Hosts of Mycobacteria 8 (MHM8): A conference report.

Mycobacteria are important causes of disease in human and animal hosts. Diseases caused by mycobacteria include leprosy, tuberculosis (TB), nontuberculous mycobacteria (NTM) infections and Buruli Ulcer. To better understand and treat mycobacterial disease, clinicians, veterinarians and scientists use a range of discipline-specific approaches to conduct basic and applied research, including conducting epidemiological surveys, patient studies, wildlife sampling, animal models, genetic studies and computational simulations. To foster the exchange of knowledge and collaboration across disciplines, the Many Hosts of Mycobacteria (MHM) conference series brings together clinical, veterinary and basic scientists who are dedicated to advancing mycobacterial disease research. Started in 2007, the MHM series recently held its 8th conference at the Albert Einstein College of Medicine (Bronx, NY). Here, we review the diseases discussed at MHM8 and summarize the presentations on research advances in leprosy, NTM and Buruli Ulcer, human and animal TB, mycobacterial disease comorbidities, mycobacterial genetics and 'omics, and animal models. A mouse models workshop, which was held immediately after MHM8, is also summarized. In addition to being a resource for those who were unable to attend MHM8, we anticipate this review will provide a benchmark to gauge the progress of future research concerning mycobacteria and their many hosts.

Plasma Endotoxin Levels Are Not Increased in Schistosoma mansoni-Infected Women without Signs or Symptoms of Hepatosplenic Disease.

Elevated circulating endotoxin levels in the plasma of patients with advanced hepatosplenic schistosomiasis caused by Schistosoma mansoni have been reported, possibly caused by parasite egg-induced intestinal mucosal breaches facilitating bacterial access to the bloodstream. Neither endotoxin levels in people with S. mansoni but without hepatosplenic disease nor the impact of treatment on endotoxin levels have been described. We used a methodically optimized Limulus amebocyte lysate assay to measure plasma endotoxin in community-dwelling women from an S. mansoni-endemic area without clinical hepatosplenic disease. We found no difference in baseline mean plasma endotoxin levels between those with (n = 22) and without (n = 31) infection (1.001 versus 0.949 EU/mL, P = 0.61). Endotoxin levels did not change in schistosome-infected women after successful treatment (1.001 versus 1.093 EU/mL, P = 0.45) and were not correlated with circulating anodic antigen or stool egg burden. Our findings do not support the hypothesis that translocating eggs in S. mansoni infection introduce bacterial sources of endotoxin to the circulation.

Differential immunoglobulin and complement levels in leprosy prior to development of reversal reaction and erythema nodosum leprosum.

BACKGROUND: Leprosy is a treatable infectious disease caused by Mycobacterium leprae. However, there is additional morbidity from leprosy-associated pathologic immune reactions, reversal reaction (RR) and erythema nodosum leprosum (ENL), which occur in 1 in 3 people with leprosy, even with effective treatment of M. leprae. There is currently no predictive marker in use to indicate which people with leprosy will develop these debilitating immune reactions. Our peripheral blood mononuclear cell (PBMC) transcriptome analysis revealed that activation of the classical complement pathway is common to both RR and ENL. Additionally, differential expression of immunoglobulin receptors and B cell receptors during RR and ENL support a role for the antibody-mediated immune response during both RR and ENL. In this study, we investigated B-cell immunophenotypes, total and M. leprae-specific antibodies, and complement levels in leprosy patients with and without RR or ENL. The objective was to determine the role of these immune mediators in pathogenesis and assess their potential as biomarkers of risk for immune reactions in people with leprosy. METHODOLOGY/FINDINGS: We followed newly diagnosed leprosy cases (n = 96) for two years for development of RR or ENL. They were compared with active RR (n = 35), active ENL (n = 29), and healthy household contacts (n = 14). People with leprosy who subsequently developed ENL had increased IgM, IgG1, and C3d-associated immune complexes with decreased complement 4 (C4) at leprosy diagnosis. People who developed RR also had decreased C4 at leprosy diagnosis. Additionally, elevated anti-M. leprae antibody levels were associated with subsequent RR or ENL. CONCLUSIONS: Differential co-receptor expression and immunoglobulin levels before and during immune reactions intimate a central role for humoral immunity in RR and ENL. Decreased C4 and elevated anti-M. leprae antibodies in people with new diagnosis of leprosy may be risk factors for subsequent development of leprosy immune reactions.

Gene Expression Differences in Host Response to Schistosoma haematobium Infection.

Schistosome worms infect over 200 million people worldwide. They live in the host's bloodstream and alter host immunity. Epidemiological data suggest that males and females have different responses to schistosome infection, but the effect of sex on systemic response is undetermined. Our objective was to characterize differences in peripheral blood transcriptional profiles in people with or without active Schistosoma haematobium infection and to determine whether this signature differs between males and females. mRNA was isolated using poly(A) selection and sequenced on an Illumina Hi-Seq4000 platform. Transcripts were aligned to the human hg19 reference genome and counted with the HTSeq package. Genes were compared for differential expression using DESeq2. Ingenuity Pathway Analysis (IPA) was used to identify gene networks altered in the presence of S. haematobium We enrolled 33 participants from villages in rural Tanzania where S. haematobium is endemic. After correction for multiple comparisons, we observed 383 differentially expressed genes between those with or without S. haematobium infection when sex was included as a covariate. Heat-mapping of the genes with >1.5-fold differences in gene expression revealed clustering by S. haematobium infection status. The top networks included development, cell death and survival, cell signaling, and immunologic disease pathways. We observed a distinct whole blood transcriptional profile, as well as differences in men and women, with S. haematobium infection. Additional studies are needed to determine the clinical effects of these divergent responses. Attention to sex-based differences should be included in studies of human schistosome infection.

Altered Cervical Mucosal Gene Expression and Lower Interleukin 15 Levels in Women With Schistosoma haematobium Infection but Not in Women With Schistosoma mansoni Infection.

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.

Blood pressure and mortality in a prospective cohort of HIV-infected adults in Port-au-Prince, Haiti.

OBJECTIVE: The objective of this study was to determine how baseline blood pressure and incident hypertension related to antiretroviral therapy (ART) initiation, HIV-related inflammation and mortality in HIV-infected adults in a low-income country. METHODS: We conducted long-term follow-up of HIV-infected adults who had participated in a trial of early vs. delayed initiation of ART in Port-au-Prince, Haiti. Between 2005 and 2008, 816 HIV-infected adults were randomized to early (N = 408) vs. delayed ART (when CD4 cell count <200 cells/µl or AIDS-defining condition; N = 408). Blood pressure was measured every 3 months. Hypertension was diagnosed according to the Joint National Committee (JNC-7) guidelines. Biomarkers of inflammation and coagulation were measured from banked enrolment plasma samples. Survival analyses were performed using Stata 14. RESULTS: The median age at enrolment was 39 years. The median follow-up time was 7.3 years. The hypertension incidence rate was 3.41 per 100 person-years, and was similar in early and delayed ART groups. In multivariable models, independent predictors of incident hypertension were older age, higher BMI and plasma interleukin (IL)-6 levels (adjusted hazard ratio, aHR = 1.23, P < 0.001). Systolic pressure more than 140 mmHg at enrolment was associated with increased mortality (aHR = 2.47, P = 0.03) as was systolic pressure less than 90 mmHg (aHR = 2.25, P = 0.04). Prevalent and incident hypertension were also significantly associated with mortality. CONCLUSION: In a large prospective study of HIV-infected adults, we found a high incidence of hypertension associated with HIV-related inflammation. Baseline hypertension conferred a more than two-fold increased risk of death. Among HIV-infected adults in low-income countries, hypertension should be considered a serious threat to long-term survival.

Dried Blood Spot RNA Transcriptomes Correlate with Transcriptomes Derived from Whole Blood RNA.

Obtaining RNA from clinical samples collected in resource-limited settings can be costly and challenging. The goals of this study were to 1) optimize messenger RNA extraction from dried blood spots (DBS) and 2) determine how transcriptomes generated from DBS RNA compared with RNA isolated from blood collected in Tempus tubes. We studied paired samples collected from eight adults in rural Tanzania. Venous blood was collected on Whatman 903 Protein Saver cards and in tubes with RNA preservation solution. Our optimal DBS RNA extraction used 8 × 3-mm DBS punches as the starting material, bead beater disruption at maximum speed for 60 seconds, extraction with Illustra RNAspin Mini RNA Isolation kit, and purification with Zymo RNA Concentrator kit. Spearman correlations of normalized gene counts in DBS versus whole blood ranged from 0.887 to 0.941. Bland-Altman plots did not show a trend toward over- or under-counting at any gene size. We report a method to obtain sufficient RNA from DBS to generate a transcriptome. The DBS transcriptome gene counts correlated well with whole blood transcriptome gene counts. Dried blood spots for transcriptome studies could be an option when field conditions preclude appropriate collection, storage, or transport of whole blood for RNA studies.

Effects of schistosomiasis on susceptibility to HIV-1 infection and HIV-1 viral load at HIV-1 seroconversion: A nested case-control study.

BACKGROUND: Schistosomiasis affects 218 million people worldwide, with most infections in Africa. Prevalence studies suggest that people with chronic schistosomiasis may have higher risk of HIV-1 acquisition and impaired ability to control HIV-1 replication once infected. We hypothesized that: (1) pre-existing schistosome infection may increase the odds of HIV-1 acquisition and that the effects may differ between men and women, and (2) individuals with active schistosome infection at the time of HIV-1 acquisition may have impaired immune control of HIV-1, resulting in higher HIV-1 viral loads at HIV-1 seroconversion. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a nested case-control study within a large population-based survey of HIV-1 transmission in Tanzania. A population of adults from seven villages was tested for HIV in 2007, 2010, and 2013 and dried blood spots were archived for future studies with participants' consent. Approximately 40% of this population has Schistosoma mansoni infection, and 2% has S. haematobium. We tested for schistosome antigens in the pre- and post-HIV-1-seroconversion blood spots of people who acquired HIV-1. We also tested blood spots of matched controls who did not acquire HIV-1 and calculated the odds that a person with schistosomiasis would become HIV-1-infected compared to these matched controls. Analysis was stratified by gender. We compared 73 HIV-1 seroconverters with 265 controls. Women with schistosome infections had a higher odds of HIV-1 acquisition than those without (adjusted OR = 2.8 [1.2-6.6], p = 0.019). Schistosome-infected men did not have an increased odds of HIV-1 acquisition (adjusted OR = 0.7 [0.3-1.8], p = 0.42). We additionally compared HIV-1 RNA levels in the post-seroconversion blood spots in HIV-1 seroconverters with schistosomiasis versus those without who became HIV-infected in 2010, before antiretroviral therapy was widely available in the region. The median whole blood HIV-1 RNA level in the 15 HIV-1 seroconverters with schistosome infection was significantly higher than in the 22 without schistosomiasis: 4.4 [3.9-4.6] log10 copies/mL versus 3.7 [3.2-4.3], p = 0.017. CONCLUSIONS/SIGNIFICANCE: We confirm, in an area with endemic S. mansoni, that pre-existing schistosome infection increases odds of HIV-1 acquisition in women and raises HIV-1 viral load at the time of HIV-1 seroconversion. This is the first study to demonstrate the effect of schistosome infection on HIV-1 susceptibility and viral control, and to differentiate effects by gender. Validation studies will be needed at additional sites.

It's reticulated: Diabetes, atherosclerosis, and reticulated platelets.

New research describes regulatory pathways for reticulated thrombocytosis in a mouse model of diabetes.