High variance in quantification of Mycobacterium tuberculosis at low bacterial loads and with differentially detectable mycobacteria.

We examined the correlation between three different methods of Mycobacterium tuberculosis quantification: time to positivity (TTP), log10 CFU, and an assay to detect differentially detectable M. tuberculosis (DD Mtb) from three different prospective studies. Participants with DD Mtb have significantly more variation in the CFU/TTP correlation than participants with no DD Mtb (P < 0.001). This may impact the design of early bactericidal activity studies that use TTP as the primary outcome.

Linkage Case Management and Posthospitalization Outcomes in People With HIV: The Daraja Randomized Clinical Trial.

Importance: Despite the widespread availability of antiretroviral therapy (ART), people with HIV still experience high mortality after hospital admission. Objective: To determine whether a linkage case management intervention (named "Daraja" ["bridge" in Kiswahili]) that was designed to address barriers to HIV care engagement could improve posthospital outcomes. Design, Setting, and Participants: Single-blind, individually randomized clinical trial to evaluate the effectiveness of the Daraja intervention. The study was conducted in 20 hospitals in Northwestern Tanzania. Five hundred people with HIV who were either not treated (ART-naive) or had discontinued ART and were hospitalized for any reason were enrolled between March 2019 and February 2022. Participants were randomly assigned 1:1 to receive either the Daraja intervention or enhanced standard care and were followed up for 12 months through March 2023. Intervention: The Daraja intervention group (n = 250) received up to 5 sessions conducted by a social worker at the hospital, in the home, and in the HIV clinic over a 3-month period. The enhanced standard care group (n = 250) received predischarge HIV counseling and assistance in scheduling an HIV clinic appointment. Main Outcomes and Measures: The primary outcome was all-cause mortality at 12 months after enrollment. Secondary outcomes related to HIV clinic attendance, ART use, and viral load suppression were extracted from HIV medical records. Antiretroviral therapy adherence was self-reported and pharmacy records confirmed perfect adherence. Results: The mean age was 37 (SD, 12) years, 76.8% were female, 35.0% had CD4 cell counts of less than 100/µL, and 80.4% were ART-naive. Intervention fidelity and uptake were high. A total of 85 participants (17.0%) died (43 in the intervention group; 42 in the enhanced standard care group); mortality did not differ by trial group (17.2% with intervention vs 16.8% with standard care; hazard ratio [HR], 1.01; 95% CI, 0.66-1.55; P = .96). The intervention, compared with enhanced standard care, reduced time to HIV clinic linkage (HR, 1.50; 95% CI, 1.24-1.82; P < .001) and ART initiation (HR, 1.56; 95% CI, 1.28-1.89; P < .001). Intervention participants also achieved higher rates of HIV clinic retention (87.4% vs 76.3%; P = .005), ART adherence (81.1% vs 67.6%; P = .002), and HIV viral load suppression (78.6% vs 67.1%; P = .01) at 12 months. The mean cost of the Daraja intervention was about US $22 per participant including startup costs. Conclusions and Relevance: Among hospitalized people with HIV, a linkage case management intervention did not reduce 12-month mortality outcomes. These findings may help inform decisions about the potential role of linkage case management among hospitalized people with HIV. Trial Registration: ClinicalTrials.gov Identifier: NCT03858998.

A bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine second line regimen for tuberculosis displays similar early bactericidal activity as the standard rifampin based first line regimen.

BACKGROUND: In 2018 the World Health Organization (WHO) recommended a switch to an all oral bedaquiline based second line regimen for treatment of drug resistant (DR) tuberculosis (TB). How these new second line regimens fare in comparison to first line regimens for treatment of drug sensitive (DS) tuberculosis is not well known. METHODS: In this study, we contemporaneously enrolled subjects with DS (n = 31) and DR (n = 23) TB 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 two weeks of therapy as determined by BACTEC MGIT, colony forming units (CFU), and a liquid limiting dilution (LD) assays capable of detecting differentially detectable/culturable Mtb (DD Mtb). Further, an identical percentage (77.8%) of subjects from the DS and DR cohorts converted to culture negative after two 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.

Five-year follow-up of phase II trial of stromal cells for bronchopulmonary dysplasia.

BACKGROUND: We previously performed a phase II randomised double-blind clinical trial of mesenchymal stromal cell (MSCs) transplantation to prevent bronchopulmonary dysplasia in extremely premature infants. Subsequently, we followed the infants enrolled in this clinical trial to determine the safety and effectiveness of MSCs against bronchopulmonary dysplasia at 5-year follow-up. METHODS: We evaluated infants at 5 years of age receiving placebo or MSCs in a prospective follow-up study. RESULTS: In terms of the primary end point of composite respiratory morbidities, including respiratory problem-related readmission, emergency department visits or oxygen therapy, the MSC group had a rate of 60.7% for composite morbidities, while the control group showed a tendency of higher rate of 83.9% for the same outcomes without statistical significance. In terms of the secondary outcomes, the MSC group infants showed a tendency of being less likely to visit emergency department (control 67.7% vs MSC 35.7%) and to receive oxygen therapy (control 29.0% vs MSC 3.6%). No difference was observed in the incidence of respiratory problem-related hospital readmission or wheezing episodes between the groups. CONCLUSION: Intratracheally instilled MSCs showed the possibility of potential to decrease respiratory symptom-related emergency department visits and oxygen therapy episodes in infants born extremely preterm during the 5 years after a phase II randomised controlled, double-blind trial of MSCs transplantation for bronchopulmonary dysplasia. This small size study suggests preliminary insights that can be further tested using larger sample sizes. TRIAL REGISTRATION NUMBER: NCT01897987.

A Cluster-Randomized Trial of Traditional Healer-Delivered Counseling and Rapid HIV Testing in Tanzania.

Collaborations with traditional healers have been proposed to improve HIV testing uptake. We hypothesized that healer-delivered HIV testing would improve HIV testing uptake, compared with referral to clinic-based HIV testing. We conducted a cluster randomized trial to determine the effectiveness of traditional healers delivering counseling and HIV testing in Mwanza, Tanzania (ClinicalTrials.gov NCT#04071873). Intervention arm healers provided counseling and offered point-of-care HIV tests to adult clients of unknown HIV serostatus. Control arm healers provided referral for clinic-based testing. Primary outcome was receipt of an HIV test within 90 days of enrollment. Secondary outcomes were new HIV diagnosis and linkage to care. In the intervention, 100 clients (100%) received an HIV test, compared with 73 (73%) of control participants (p < 0.001). Two intervention arm participants (2%) had a new diagnosis compared with zero in the control arm (p = 0.50). Engaging traditional healers might provide a culturally concordant opportunity to improve HIV testing uptake.

Human Immunodeficiency Virus-Associated Myocardial Diastolic Dysfunction and Soluble ST2 Concentration in Tanzanian Adults: A Cross-Sectional Study.

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.

Characterization of Differentially Detectable Mycobacterium tuberculosis in the Sputum of Subjects with Drug-Sensitive or Drug-Resistant Tuberculosis before and after Two Months of Therapy.

Standard methods for enumerating Mycobacterium tuberculosis in patient sputum can miss large populations of viable M. tuberculosis cells that are unable to grow either on solid medium or in liquid medium unless the medium has been extensively diluted. Because these bacteria can be detected in liquid medium after limiting dilution, they have been termed differentially culturable or differentially detectable M. tuberculosis (DD-Mtb). Treatment with isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) (HRZE) for 1 to 2 weeks has been shown to increase the representation of DD-Mtb in the sputum of drug-sensitive (DS) tuberculosis (TB) patients. However, little is known about DD-Mtb after longer periods of treatment with HRZE or in patients with drug-resistant (DR) TB who receive second-line therapies. Here, we measured the proportion of DD-Mtb cells in the sputum of 47 subjects, 29 with DS TB and 18 with DR TB, before initiation of treatment and at 2 weeks and 2 months thereafter. Prior to treatment, DD-Mtb cells represented the majority of M. tuberculosis cells in the sputum of 21% of subjects with DS TB, and this proportion rose to 65% after 2 weeks of treatment with first-line drugs. In subjects with DR TB, DD-Mtb cells were found in the sputum of 29% of subjects prior to treatment initiation, and this proportion remained steady at 31% after 2 weeks of treatment with second-line drugs. By 2 months, DD-Mtb cells were detected in the sputum of only 2/15 (13.3%) subjects with DS TB and in 0/15 of subjects with DR TB. One of the DS subjects whose sputum was positive for DD-Mtb at month 2 later experienced treatment failure.

Mycobacterium tuberculosis protease MarP activates a peptidoglycan hydrolase during acid stress.

Mycobacterium tuberculosis (Mtb) can persist in the human host in a latent state for decades, in part because it has the ability to withstand numerous stresses imposed by host immunity. Prior studies have established the essentiality of the periplasmic protease MarP for Mtb to survive in acidified phagosomes and establish and maintain infection in mice. However, the proteolytic substrates of MarP that mediate these phenotypes were unknown. Here, we used biochemical methods coupled with supravital chemical probes that facilitate imaging of nascent peptidoglycan to demonstrate that during acid stress MarP cleaves the peptidoglycan hydrolase RipA, a process required for RipA's activation. Failure of RipA processing in MarP-deficient cells leads to cell elongation and chain formation, a hallmark of progeny cell separation arrest. Our results suggest that sustaining peptidoglycan hydrolysis, a process required for cell elongation, separation of progeny cells, and cell wall homeostasis in growing cells, may also be essential for Mtb's survival in acidic conditions.

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.

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.

High accumulation of γ-linolenic acid and Stearidonic acid in transgenic Perilla (Perilla frutescens var. frutescens) seeds.

BACKGROUND: Polyunsaturated fatty acids such as linoleic acid (LA) and α-linolenic acid (ALA) are abundant in vegetable oils and are important for human health. In the body, LA and ALA are respectively converted to the omega-6 fatty acid γ-linolenic acid (GLA) and the omega-3 fatty acid stearidonic acid (SDA) by Δ6 desaturase (D6DES). Currently, dietary GLA and SDA are mainly obtained from marine organisms, but given their benefits to human health, many studies have aimed to enhance their accumulation in transgenic crops. Perilla frutescens (perilla) accumulates more ALA in its seed oil compared to other oilseed crops, making it a good candidate for the production of fatty acids via the fatty acid desaturase D6DES. RESULTS: In this study, we cloned the D6DES gene from Phytophthora citrophthora and confirmed its function in budding yeast. We then transformed the functional D6DES gene under the control of the seed-specific vicilin promoter into the perilla cultivar Yeobsil. The resulting transgenic perilla seeds accumulated significant levels of GLA and SDA, as well as putative C18:2Δ6,9 at minor levels. Developing seeds and leaves also accumulated GLA and SDA, although PcD6DES expression and GLA and SDA levels were much lower in leaves compared to developing seeds. GLA and SDA accumulated in both polar lipids and neutral lipids in mature perilla seeds expressing PcD6DES, especially in neutral lipids. Although the seed weight in PcD6DES perilla was 87-96% that of wild type, the total oil content per seed weight was similar between lines. The PcD6DES perilla plants contained very high content (over 45%) of both GLA and SDA in seed oil. CONCLUSIONS: Thus, PcD6DES perilla plants may represent a feasible alternative to traditional marine sources for the production of omega-3 oil capsules and to evening primrose seed oil for GLA as health food. In addition, these plants can be used to create other transgenic lines harboring additional genes to produce other desirable fish-oil like oils.

Educating religious leaders to promote uptake of male circumcision in Tanzania: a cluster randomised trial.

BACKGROUND: Male circumcision is being widely deployed as an HIV prevention strategy in countries with high HIV incidence, but its uptake in sub-Saharan Africa has been below targets. We did a study to establish whether educating religious leaders about male circumcision would increase uptake in their village. METHODS: In this cluster randomised trial in northwest Tanzania, eligible villages were paired by proximity (<60 km) and the time that a free male circumcision outreach campaign from the Tanzanian Ministry of Health became available in their village. All villages received the standard male circumcision outreach activities provided by the Ministry of Health. Within the village pairs, villages were randomly assigned by coin toss to receive either additional education for Christian church leaders on scientific, religious, and cultural aspects of male circumcision (intervention group), or standard outreach only (control group). Church leaders or their congregations were not masked to random assignment. The educational intervention consisted of a 1-day seminar co-taught by a Tanzanian pastor and a Tanzanian clinician who worked with the Ministry of Health, and meetings with the study team every 2 weeks thereafter, for the duration of the circumcision campaign. The primary outcome was the proportion of male individuals in a village who were circumcised during the campaign, using an intention-to-treat analysis that included all men in the village. This trial is registered with ClinicalTrials.gov, number NCT 02167776. FINDINGS: Between June 15, 2014, and Dec 10, 2015, we provided education for church leaders in eight intervention villages and compared the outcomes with those in eight control villages. In the intervention villages, 52·8% (30 889 of 58 536) of men were circumcised compared with 29·5% (25 484 of 86 492) of men in the eight control villages (odds ratio 3·2 [95% CI, 1·4-7·3]; p=0·006). INTERPRETATION: Education of religious leaders had a substantial effect on uptake of male circumcision, and should be considered as part of male circumcision programmes in other sub-Saharan African countries. This study was conducted in one region in Tanzania; however, we believe that our intervention is generalisable. We equipped church leaders with knowledge and tools, and ultimately each leader established the most culturally-appropriate way to promote male circumcision. Therefore, we think that the process of working through religious leaders can serve as an innovative model to promote healthy behaviour, leading to HIV prevention and other clinically relevant outcomes, in a variety of settings. FUNDING: Bill & Melinda Gates Foundation, National Institutes of Health, and the Mulago Foundation.

Fifteen years of HIV and syphilis outcomes among a prevention of mother-to-child transmission program in Haiti: from monotherapy to Option B.

OBJECTIVE: To evaluate mother and infant outcomes in the largest prevention of mother-to-child-transmission (PMTCT) programme in Haiti in order to identify gaps towards elimination of HIV and syphilis. METHODS: Based on retrospective data from HIV+ pregnant women and their infants enrolled in PMTCT care from 1999 to 2014, we assessed maternal enrolment in PMTCT, receipt of antiretrovirals before delivery, maternal retention through delivery as well as infant enrolment in PMTCT, HIV testing and HIV infection. Four PMTCT programme periods were compared: period 1 (1999-2004, mono ARV), period 2 (2005-2009, dual ARV), period 3 (2010-2012, Option B) and period 4 (Oct 2012-2014, Option B+). Kaplan-Meier methods were used to assess retention in PMTCT care. RESULTS: Among 4665 pregnancies, median age was 27 years and median CD4+ was 494 cells/µl (IQR 328-691). A total of 75% of women received antiretrovirals before delivery, and 73% were retained in care through delivery. Twenty-two percent of women were lost before delivery, <1% died and 6% had stillbirths or abortions. Ninety-four percent of infants who were born alive enrolled in PMTCT, of whom 92% had complete HIV testing. One hundred and sixty-one infants were HIV+, giving a 5.4% HIV transmission rate (9.8%, 4.6%, 5.8% and 3.6% in periods 1-4). Retention among women through 12 months after PMTCT enrolment did not significantly differ across periods. However, among women who received antiretrovirals at the time of enrolment, retention 12 months later was lower in the Option B+ period (83%) than in periods 2 and 3 (94% and 93%) (P < 0.001). Syphilis infection among women decreased from 16% in period 1 to 8% in period 4, whereas syphilis testing of infants increased from 17% to 91%. CONCLUSION: Despite dramatic reductions in MTCT in Haiti, interventions are needed to improve retention to achieve MTCT elimination of HIV and syphilis.

Traditional healer support to improve HIV viral suppression in rural Uganda (Omuyambi): study protocol for a cluster randomized hybrid effectiveness-implementation trial.

BACKGROUND: Rural African people living with HIV face significant challenges in entering and remaining in HIV care. In rural Uganda, for example, there is a threefold higher prevalence of HIV compared to the national average and lower engagement throughout the HIV continuum of care. There is an urgent need for appropriate interventions to improve entry and retention in HIV care for rural Ugandans with HIV. Though many adults living with HIV in rural areas prioritize seeking care services from traditional healers over formal clinical services, healers have not been integrated into HIV care programs. The Omuyambi trial is investigating the effectiveness of psychosocial support delivered by traditional healers as an adjunct to standard HIV care versus standard clinic-based HIV care alone. Additionally, we are evaluating the implementation process and outcomes, following the Consolidated Framework for Implementation Research. METHODS: This cluster randomized hybrid type 1 effectiveness-implementation trial will be conducted among 44 traditional healers in two districts of southwestern Uganda. Healers were randomized 1:1 into study arms, where healers in the intervention arm will provide 12 months of psychosocial support to adults with unsuppressed HIV viral loads receiving care at their practices. A total of 650 adults with unsuppressed HIV viral loads will be recruited from healer clusters in the Mbarara and Rwampara districts. The primary study outcome is HIV viral load measured at 12 months after enrollment, which will be analyzed by intention-to-treat. Secondary clinical outcome measures include (re)initiation of HIV care, antiretroviral therapy adherence, and retention in care. The implementation outcomes of adoption, fidelity, appropriateness, and acceptability will be evaluated through key informant interviews and structured surveys at baseline, 3, 9, 12, and 24 months. Sustainability will be measured through HIV viral load measurements at 24 months following enrollment. DISCUSSION: The Omuyambi trial is evaluating an approach that could improve HIV outcomes by incorporating previously overlooked community lay supporters into the HIV cascade of care. These findings could provide effectiveness and implementation evidence to guide the development of policies and programs aimed at improving HIV outcomes in rural Uganda and other countries where healers play an essential role in community health. TRIAL REGISTRATION: ClinicalTrials.gov NCT05943548. Registered on July 5, 2023. The current protocol version is 4.0 (September 29, 2023).

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.

Neighborhood Social Vulnerability and Premature Cardiovascular Disease in Haiti.

Importance: Higher social vulnerability is associated with premature cardiovascular disease (CVD) and mortality but is understudied in low-income countries that have both the highest magnitude of social vulnerability and a growing CVD epidemic. Objective: To evaluate the association between social vulnerability and hypertension, CVD, and CVD subtypes in Haiti as a model for similar low-income countries. Design, Setting, and Participants: This population-based cohort study used enrollment data from adults participating in the Haiti Cardiovascular Disease Cohort Study. Recruitment occurred via multistage random sampling throughout slum and urban neighborhoods in Port-au-Prince, Haiti, from March 2019 to August 2021. Data were analyzed from May 2022 to December 2023. Exposures: A modified Haitian Social Vulnerability Index (SVI-H) was created following the US Centers for Disease Control and Prevention Social Vulnerability Index method. Twelve variables across the domains of socioeconomic status, household characteristics, and social and community context were included. The SVI-H was calculated for each study neighborhood block and then stratified into SVI-H quartiles (quartile 1 was the least vulnerable; quartile 4, the most vulnerable). Main Outcomes and Measures: Prevalent hypertension and total CVD, defined as heart failure (HF), stroke, transient ischemic attack (TIA), angina, or myocardial infarction (MI). Age-adjusted Poisson regression analysis yielded prevalence ratios (PRs) comparing the prevalence of hypertension, total CVD, and CVD subtypes across SVI-H quartiles. Results: Among 2925 adults (1704 [58.3%] female; mean [SD] age, 41.9 [15.9] years), the prevalence of hypertension was 32.8% (95% CI, 31.1%-34.5%) and the prevalence of CVD was 14.7% (95% CI, 13.5%-16.0%). Hypertension prevalence ranged from 26.2% (95% CI, 23.1%-29.3%) to 38.4% (95% CI, 34.8%-42.0%) between quartiles 1 and 4, while CVD prevalence ranged from 11.1% (95% CI, 8.8%-13.3%) to 19.7% (95% CI, 16.8%-22.6%). SVI-H quartile 4 vs 1 was associated with a greater prevalence of hypertension (PR, 1.17; 95% CI, 1.02-1.34) and CVD (PR, 1.48; 95% CI, 1.16-1.89). Among CVD subtypes, SVI-H was significantly associated with HF (PR, 1.64; 95% CI, 1.23-2.18) but not with combined stroke and TIA or combined angina and MI. Conclusions and Relevance: In urban Haiti, individuals living in neighborhoods with the highest social vulnerability had greater prevalence of hypertension and HF. Understanding CVD disparities in low-income countries is essential for targeting prevention and treatment interventions toward populations at highest risk globally.

Clinical and Demographic Factors Associated With Kaposi Sarcoma-Associated Herpesvirus Shedding in Saliva or Cervical Secretions in a Cohort of Tanzanian Women.

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.

Spectrum of prevalent cardiovascular diseases in urban Port-au-Prince, Haiti: a population-based cross-sectional study.

Background: Eighty percent of global cardiovascular disease (CVD) is projected to occur in low- and middle -income countries (LMICs), yet local epidemiological data are scarce. We provide the first population-based, adjudicated CVD prevalence estimates in Port-au-Prince, Haiti to describe the spectrum of heart disease and investigate associated risk factors. Methods: Demographic, medical history, clinical, imaging and laboratory data were collected among adults recruited using multistage random sampling from 2019 to 2021. Prevalent CVD (heart failure, stroke, ischemic disease) were adjudicated using epidemiological criteria similar to international cohorts. Multivariable Poisson regressions assessed relationships between risk factors and prevalent CVD. Findings: Among 3003 participants, median age was 40 years, 58.1% were female, 70.2% reported income <1 USD/day, and all identified as Black Haitian. CVD age-adjusted prevalence was 14.7% (95% CI 13.3%, 16.5%), including heart failure (11.9% [95% CI 10.5%, 13.5%]), stroke (2.4% [95% CI 1.9%, 3.3%]), angina (2.1% [95% CI 1.6%, 2.9%]), myocardial infarction (1.0% [95% CI 0.6%, 1.8%]), and transient ischemic attack (0.4% [95% CI 0.2%, 1.0%]). Among participants with heart failure, median age was 57 years and 68.5% of cases were among women. The most common subtype was heart failure with preserved ejection fraction (80.4%). Heart failure was associated with hypertension, obesity, chronic kidney disease, depression, and stress. Interpretation: Early-onset heart failure prevalence is alarmingly high in urban Haiti and challenge modelling assumptions that ischemic heart disease and stroke dominate CVDs in LMICs. These data underscore the importance of local population-based epidemiologic data within LMICs to expedite the selection and implementation of evidence-based cardiovascular health policies targeting each country's spectrum of heart disease. Funding: This study was funded by NIH grants R01HL143788, D43TW011972, and K24HL163393, clinicaltrials.govNCT03892265.

Kernel Continuum Regression.

The continuum regression technique provides an appealing regression framework connecting ordinary least squares, partial least squares and principal component regression in one family. It offers some insight on the underlying regression model for a given application. Moreover, it helps to provide deep understanding of various regression techniques. Despite the useful framework, however, the current development on continuum regression is only for linear regression. In many applications, nonlinear regression is necessary. The extension of continuum regression from linear models to nonlinear models using kernel learning is considered. The proposed kernel continuum regression technique is quite general and can handle very flexible regression model estimation. An efficient algorithm is developed for fast implementation. Numerical examples have demonstrated the usefulness of the proposed technique.