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Muhamadi Lubega,1–4 Ibrahim A Musenze,3 Gukiina Joshua,2 George Dhafa,2 Rose Badaza,3 Christopher J Bakwesegha,3 Steven J Reynolds41District Health Office, Iganga District Administration, Iganga, Uganda; 2Research Institute, 3School of Graduate Studies and Research, Busoga University, Iganga, Uganda; 4National Institutes of Health/NIAID-ICER American Embassy, Kampala, UgandaBackground: In Iganga, Uganda, 45% of women who tested HIV-positive during antenatal care between 2007 and 2010 were lost to follow-up (LTFU). We explored reasons for LTFU during prevention of mother-to-child transmission (PMTCT) from a client perspective in eastern Uganda, where antiretroviral therapy (ART) awareness is presumably high.Methods: Seven key informant interviews and 20 in-depth interviews, including both clients who had been retained under PMTCT care and those LTFU during PMTCT were held. Ten focus-group discussions involving a total of 112 participants were also conducted with caretakers/relatives of the PMTCT clients. Content analysis was performed to identify recurrent themes.Results: Our findings indicate that LTFU during PMTCT in eastern Uganda was due to sex inequality, high transport costs to access the services, inadequate posttest counseling, lack of HIV status disclosure, and the isolated/exposed location of the ART clinic, which robs the clients of their privacy.Conclusion: There is a need for approaches that empower women with social capital, knowledge, and skills to influence health-seeking practices. There is also a need to train low-ranking staff and take PMTCT services closer to the clients at the lower-level units to make them affordable and accessible to rural clients. Posttest counseling should be improved to enable PMTCT clients to appreciate the importance of PMTCT services through increasing the number of staff in antenatal care to match the client numbers for improved quality. The counseling should emphasize HIV status disclosure to partners and encourage partner escort for antenatal care visits for further counseling. The exposed and isolated ART clinic should be integrated with the other regular outpatient services to reduce the labeling stigma.Keywords: mother-to-child transmission, HIV, Uganda, sex inequality

Biomass-derived indoor air pollution has been associated with increased risks of respiratory diseases; however, relatively few studies have examined the cardiovascular effects of biomass burning. We measured 48-hour indoor fine particulate matter and indoor and personal carbon monoxide (CO) concentrations in 124 households using open-fire cook stoves in Nicaragua. We also examined the cross-sectional relationship of air pollution and health. High air pollutant concentrations with considerable variability were measured. Nonsignificant elevations in systolic blood pressure were associated with increases in CO concentrations. These associations were stronger among obese participants; an 8.51 mmHg (95% confidence interval [CI]: 3.06, 13.96) increase in systolic blood pressure per 24 ppm increase in 48-hour average indoor CO levels was observed. Although the cross-sectional design of this study limits the interpretation, we observed evidence of a relationship between indoor air pollution and blood pressure and heart rate, two indicators of cardiovascular health. [ABSTRACT FROM AUTHOR]

Unlabelled: In Rakai, Uganda, human immunodeficiency virus (HIV)-positive men were randomized to undergo either immediate circumcision (intervention arm) or delayed circumcision (control arm). Penile swab samples were assayed for high-risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and at 24 months (intervention arm, 103 subjects; control arm, 107 subjects). Rate ratios (RRs) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was found in 57 (55.3%) of 103 subjects in the intervention arm and in 77 (71.7%) of 107 subjects in the control arm (RR, 0.77; 95% confidence interval [CI], 0.62-0.97). Multiple HR-HPV infections were found in 19 (22.4%) of 85 subjects in the intervention arm and in 45 (42.5%) of 106 subjects in the control arm (RR, 0.53; 95% CI, 0.33-0.83). New HR-HPV genotypes were acquired by 34 (42.0%) of 81 subjects in the intervention arm and by 53 (57.0%) 85 subjects in the control arm (RR, 0.74; 95% CI, 0.54-1.01; P = .06). Multiple new HR-HPV genotypes were acquired by 8 (9.9%) of 81 subjects in the intervention arm and by 23 (24.7%) of 93 subjects in the control arm (RR, 0.40; 95% CI, 0.19-0.84; P = .01). Circumcision did not affect the acquisition of single HR-HPV infections (RR, 1.00; 95% CI 0.65-1.53) or clearance of HR-HPV infections (RR, 1.09; 95% CI 0.94-1.27). Circumcision of HIV-positive men reduced the prevalence and incidence of multiple HR-HPV infections.Trial Registration: ClinicalTrials.gov identifier: NCT00124878 . [ABSTRACT FROM AUTHOR]

Background: Intrapartum single-dose nevirapine decreases mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but promotes nevirapine resistance. Although resistant viruses fade to undetectable levels in plasma, they may persist as stably integrated proviruses within the latent reservoir in resting CD4(+) T cells, potentially complicating future treatment.Methods: Blood samples were collected from 60 women from South Africa and Uganda >6 months after they had received single-dose nevirapine. To selectively analyze the stable latent form of HIV-1, resting CD4(+) T cells were isolated and activated in the presence of reverse-transcriptase inhibitors and integrase inhibitors, which allows for the specific isolation of viruses produced by cells with stably integrated proviral DNA. These viruses were then analyzed for nevirapine resistance.Results: Although only a small number of latently infected cells were present in each blood sample (mean, 162 cells), nevirapine resistance mutations (K103N and G190A) were detected in the latent reservoir of 4 (8%) of 50 evaluable women.Conclusions: A single dose of nevirapine can establish antiretroviral resistance within the latent reservoir. This results in a potentially lifelong risk of reemergence of nevirapine-resistant virus and highlights the need for strategies to prevent transmission that do not compromise successful future treatment. [ABSTRACT FROM AUTHOR]

The Keokuk County Rural Health Study is a population-based study of an agricultural community in Iowa. The study includes in-depth evaluations of respiratory disease, injury, and other health outcomes in relation to environmental and occupational exposures. This article reports descriptive findings on pesticide use from among the 1191 participants completing occupational surveys. Fifty-one percent (612) of respondents (farmers and non-farmers) had applied insecticides including lawn and garden chemicals at home during the past year. Thirty-three percent (395) of respondents had personally mixed or applied farm chemicals during their life. One-hundred and four had a current pesticide applicator's license. Information on the specific types of pesticides and protective measures used was obtained for the 144 individuals who had mixed or applied pesticides on farms within the previous year. Of these individuals, 67% worked with fertilizers, 49% used herbicides, 48% used crop insecticides, 28% used crop storage insecticides, 45% applied livestock insecticides, and 9% worked with fungicides. The use of personal protective equipment such as gloves, aprons, and respirators varied depending on the chemical. A substantial proportion did not use gloves even for mixing. Thirty-five percent reported at least one suspected work-related symptom after working with pesticides during the previous year. The lack of differences in protective equipment use between applicators who have completed pesticide applicator training courses and those who have not suggests a need to develop more effective training methods. The increased use of protective equipment when applying odorous agrochemicals suggests that addition of an odorant to more toxic pesticides may be a successful intervention strategy. [ABSTRACT FROM AUTHOR]

Air sampling was completed on the front lawn of 35 homes neighboring swine farms in three different regions in the Upper Midwest of the United States. One region was dominated by large scale, swine confined animal feeding operations (CAFO's) noted as swine confinement area (SCA). The second area was dominated by smaller scale operations utilizing hoop structure facilities (HA). The third area was basically devoid of livestock, dominated by row-crop production, and served as the control area (CA). The time weighted average concentrations of hydrogen sulfide (8.42 ppb) was higher (p = 0.047) in SCA area than the control (3.48 ppb). However, carbon dioxide (449.6 ppm), ammonia (12.78 ppb) and PM10 (42.25 ìg/m3) were higher in the hoop structure area than the other areas. Swine population density, distance between the homes and swine facilities, and wind direction had an interactive effect on the average levels of ammonia (p = 0.04). The contaminant levels at the homes were relatively low compared to typical concentrations inside animal buildings. However, exceedences of federal recommended limits for hydrogen sulfide in outdoor air were observed in the swine CAFO area. Concentration of hydrogen sulfide exceeded the recommended limits of the ATSDR (30 ppb) for chronic exposure at two of the 12 homes in the CAFO area (17%). Average hydrogen sulfide concentration exceeded the EPA recommended community standards (0.7 ppb) in all three areas assessed (SCA, HA, and CA). As chronic exposure to hydrogen sulfide may be present in areas of production agriculture, a potential health risk may be present. Further studies to provide additional information regarding exposures to hydrogen sulfide in rural environments are warranted. [ABSTRACT FROM AUTHOR]

The goals of this study were to define the current methods for training entry-level workers on Colorado dairies, to measure the relationship of training methods to the incidence of work-related injuries on those operations, and to characterize the nature and cause of injuries reported by participating workers. Seventy-two workers from 15 dairies from Weld, Morgan, Larimer and Yuma counties volunteered to be interviewed privately in the language of their choice. Training methods were classified by content (task training versus safety training), method of delivery (on-the-job verbal instruction, on-the-job demonstration, on-the-job supervision, classroom- based, and / or reading materials); and instructor (supervisor and/or co-worker). The majority (84.7%) of interviewed workers were Mexican-born, Spanish-speaking males. Most workers reported the training to be a combination of verbal instruction, demonstration and supervision. Twenty-nine of 72 (40.3%) of all participants suffered at least one work-related injury in the 12 months prior to the interview. Entry-level safety training had no protective effect (P = 0.463) on the reported incidence of injury in dairy workers in the previous year. However, workers that received task-related training were four times less likely to suffer a work-related injury (P = 0.008). Training conducted by a co-worker also had a significant protective effect against work-related injuries (P = 0.028). Dairy workers identified direct contact with livestock or machinery as the main cause for work-related injuries, and most injuries occurred while medicating sick cows and milking. [ABSTRACT FROM AUTHOR]

Although agriculture is one of the most hazardous industries, the costs of agricultural injuries and illnesses are not well known. This study aimed to determine the cost burden from compensated injuries and occupational diseases in Finnish agriculture using workers compensation records. The incidence rates in 1996 were 7.4/100 for injuries and 0.61/100 for occupational diseases. Men had a higher risk of injury (RR = 1.89; 95% CI: 1.81-1.97), but a lower risk of an occupational disease (RR = 0.68; 95% CI: 0.60-0.78), compared to women. The total cost burden was 75 (Euros) per person in 1983, increasing to 215 (Euros) in 1999. The total insurance cost in 1996 was 23.5 million (Euros) consisting of medical care (16%), per diem (lost time compensation within one year from the incident) (37%), pension (lost time compensation after one year from the incident) (23%), survivors pension (3%), impairment allowance (7%), rehabilitation (6%), and other costs (9%). The total cost was 0.7% of the national gross farm income and 2.2% of the net farm income. The mean cost of 1996 cases was 1340 (Euros) for injuries and 6636 (Euros) for occupational diseases. Injuries represented 92% of the claims and 71% of the total costs. Occupational diseases represented 8% of the claims and 29% of the costs. Twenty percent of the most severe claims represented 79.5% of the total insurance costs. Injuries and occupational diseases result in significant costs in agriculture. Lost time was the largest cost item. Overall, injuries were more costly than occupational diseases. This study indicates that the 20%-80% rule applies to agricultural injury and illness costs, and from the cost standpoint, it is important to focus prevention efforts on the most severe incidents. [ABSTRACT FROM AUTHOR]

The availability of limited funds from international agencies for the purchase of antiretroviral (ARV) treatment in developing countries presents challenges, especially in prioritizing who should receive therapy. Public input and the protection of human rights are crucial in making treatment programs equitable and accountable. By examining historical precedents of resource allocation, we aim to provoke and inform debate about current ARV programs.Through a critical review of the published literature, we evaluate 4 precedents for key lessons: the discovery of insulin for diabetes in 1922, the release of penicillin for civilian use in 1943, the development of chronic hemodialysis programs in 1961, and current allocation of liver transplants. We then describe current rationing mechanisms for ARVs. [ABSTRACT FROM AUTHOR]

Background: Ecological and observational studies suggest that male circumcision reduces the risk of HIV acquisition in men. Our aim was to investigate the effect of male circumcision on HIV incidence in men.Methods: 4996 uncircumcised, HIV-negative men aged 15-49 years who agreed to HIV testing and counselling were enrolled in this randomised trial in rural Rakai district, Uganda. Men were randomly assigned to receive immediate circumcision (n=2474) or circumcision delayed for 24 months (2522). HIV testing, physical examination, and interviews were repeated at 6, 12, and 24 month follow-up visits. The primary outcome was HIV incidence. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00425984.Findings: Baseline characteristics of the men in the intervention and control groups were much the same at enrollment. Retention rates were much the same in the two groups, with 90-92% of participants retained at all time points. In the modified intention-to-treat analysis, HIV incidence over 24 months was 0.66 cases per 100 person-years in the intervention group and 1.33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% CI 16-72; p=0.006). The as-treated efficacy was 55% (95% CI 22-75; p=0.002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30-77; p=0.003). HIV incidence was lower in the intervention group than it was in the control group in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups. Moderate or severe adverse events occurred in 84 (3.6%) circumcisions; all resolved with treatment. Behaviours were much the same in both groups during follow-up.Interpretation: Male circumcision reduced HIV incidence in men without behavioural disinhibition. Circumcision can be recommended for HIV prevention in men. [ABSTRACT FROM AUTHOR]

Sterols are involved in life processes in organisms and are therefore potential biomarkers for assessment of environmental ecosystems. Current data indicate that sterols are persistent in stream sediments, since sterols are not sufficiently soluble in water to be readily detected in water samples. Stream sediment therefore can act as an integrating exposure index of pollution for animal or human waste in streams. The study reported here was conducted in two phases. Phase 1 involved development and validation of a simplified method for the determination of sterols, and Phase 2 involved application of that method to evaluate actual environmental samples. Stream sediment samples from agricultural settings, wastewater-treatment-facility outfalls, and recreational state parks in Iowa and Pennsylvania were analyzed for sterol compounds. Sterol profiles differ considerably among animals, and the study distinguished sterol profiles within stream sediments. Feces from different animal species were also analyzed to provide reference sterol profiles. Individual-sterol and total-sterol concentrations were determined. Sterols were observed in 73.4 percent of environmental sediment samples tested (n = 124) and at 100 percent of the sites (n = 18). Coprostanol, a key indicator of fecal pollution, was observed in 38.7 percent of the environmental sediment samples tested and at 72.2 percent of the sites. Samples were collected from multiple points at selected sites, and duplicate samples were analyzed at a frequency of 16.1 percent. One to five months later, additional samples were collected from the duplicate locations and were analyzed. Data generated by the study provide a basis for stream sediment monitoring that enables the chronological recording of waste impact; this method may be coupled with other measurements to determine the extent and possible source of stream contaminants. [ABSTRACT FROM AUTHOR]

Introduction: In Africa, migrants are more likely to be living with HIV and HIV viremic than nonmigrants, but less is known about HIV outcomes among nonmigrants living in households with migrants. We compared HIV outcomes in nonmigrating persons in households with and without migration., Methods: We analyzed cross-sectional data collected between August 2016 and May 2018 from nonmigrating participants aged 15-49 years in the Rakai Community Cohort Study in Uganda. Migrant households were classified as those reporting ≥1 member moving into or out of the household since the prior survey. HIV serostatus was determined using a validated testing algorithm, and viremia defined as >1000 copies/mL. Modified Poisson regression was used to estimate prevalence ratios between household migration and HIV outcomes. Analyses were stratified by gender, direction of migration (into/out of household), and relationship between nonmigrants and migrants (eg, spouse)., Results: There were 14,599 nonmigrants (52% women) and 4415 (30%) lived in a household with ≥1 migrant. Of these, 972 (22%) had migrant spouses, 1102 (25%) migrant children, and 875 (20%) migrant siblings. Overall, HIV prevalence and viremia did not differ between nonmigrants in households with and without migration. However, in stratified analyses, nonmigrant women with migrant spouses were significantly more likely to be HIV seropositive compared with nonmigrant women with nonmigrant spouses [adjusted prevalence ratio: 1.44, 95% confidence interval: 1.21 to 1.71]. Conversely, nonmigrant mothers living with HIV who had migrant children were less likely to be viremic (adjusted prevalence ratio: 0.34, 95% confidence interval: 0.13 to 0.86)., Conclusions: Nonmigrating women with migrating spouses are more likely be living with HIV, and may benefit from additional HIV support services., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Preventing HIV infections among adolescents and young adults (AYA) is crucial for curtailing the epidemic. Oral pre-exposure prophylaxis (PrEP) is a highly effective prevention method increasingly available to this age group in sub-Saharan Africa but population-based data on awareness and use of PrEP among AYA remains limited., Methods: Analyzing survey data from two rounds of the Rakai Community Cohort Study, an open, population-based cohort, we estimated prevalence ratios associating various sociodemographic characteristics with PrEP awareness and ever-use among 15- to 24-year-olds in south-central Uganda between 2018 and 2023., Results: Most (62.4%, N=3,308/5,301) participants were aware of PrEP as an HIV prevention method but only 1.7% (N=133/7,999) of AYA had ever used it. Among the 35.5% (N=2,838/7,999) of participants meeting PrEP eligibility criteria, ever-use was similarly rare (2.6%, N=75/2,838). Compared to 20 to 24-year-olds, 15 to 19-year-olds were less likely to report awareness (fullyadjPR=0.82, 95%CI 0.78, 0.86) or ever-use (fullyadjPR=0.35, 95%CI 0.21, 0.58). Participants from fishing communities were more likely to be PrEP-aware (fullyadjPR=1.22, 95%CI 1.16, 1.29) or have ever used the prevention method (fullyadjPR=6.07, 95%CI 4.10, 8.98) than those from non-fishing communities., Conclusion: In this cross-sectional study of AYA in Uganda, awareness of PrEP was common but ever-use was rare, even among the third of respondents who were likely PrEP-eligible. This suggests that prevention policies and barriers besides unawareness of the method impede PrEP initiation. Efforts that target those barriers, particularly for adolescents, are critical for reducing HIV incidence among this priority population., Competing Interests: Conflicts of Interest: Authors have no conflicts of interest to report., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Migration is associated with increased risk of HIV infection in Africa, but evidence about non-HIV sexually transmitted infection (STI) burden among African migrants is limited., Methods: We used data from the Sexually Transmitted Infection Prevalence Study, a cross-sectional population-based study of chlamydia, gonorrhoea, trichomoniasis, syphilis and herpes simplex virus type 2 prevalence in southern Uganda, to compare STI prevalence between adults aged 18 and 49 years with and without a recent history of migration. Migration status was determined using household census data, with a recent migration history defined as having moved into one's community of current residence within the last ~18 months. Unadjusted and adjusted modified Poisson regression models were used to compare individual STI prevalence risk by recent migration status with associations reported as adjusted prevalence risk ratios (adjPRRs) with 95% CIs. Adjusted models included participants' sex, age, community type, education, occupation and marital status., Results: Among 1825 participants, 358 (19.6%) had a recent migration history. Overall, migrants exhibited a significantly higher combined prevalence of curable STIs (gonorrhoea, chlamydia, high-titre syphilis (rapid plasma regain ≥1:8) and trichomoniasis) as compared with long-term residents (34.4% vs 24.2%; adjPRR=1.23; 95% CI 1.03 to 1.47). Significant differences in curable STI prevalence by migration status were concentrated among persons living with HIV (49.4% prevalence in migrants vs 32.6% in long-term residents; adjPRR=1.42; 95% CI 1.10 to 1.85) and among women (38.8% in migrants vs 27.8% in long-term residents; adjPRR=1.26; 95% CI 1.01 to 1.58). High-titre syphilis prevalence was especially elevated among male migrants (11.2% in migrants vs 4.9% in long-term residents; adjPRR=1.82; 95% CI 1.06 to 3.13)., Conclusions: The prevalence of non-HIV STIs is higher among migrants. Tailored outreach and service delivery approaches that address the needs of mobile populations are crucial for integrated HIV and STI epidemic control in Uganda to optimise resources and reduce transmission risks., Competing Interests: Competing interests: YCM has received grant support to Johns Hopkins University from Hologic, Cepheid, Roche, ChemBio, Becton Dickinson and miDiagnostics, and has provided consultative support to Abbot., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Recent declines in HIV incidence among adolescent girls and young women (AGYW) in Africa are often attributed to the expansion of biomedical interventions such as antiretroviral therapy and voluntary medical male circumcision. However, changes in sexual behaviour may also play a critical role. Understanding the relative contributions of these factors is essential for developing strategies to sustain and further reduce HIV transmission., Methods: We conducted a mathematical modelling study of data from the Rakai Community Cohort Study (RCCS), an open, population-based cohort of 15- to 49-year-olds in 30 communities in Rakai, Uganda, to investigate the biomedical and behavioural drivers of HIV incidence decline in AGYW (15-24 years of age). We estimated changes in the HIV incidence rate between 2000-2019 using retrospective cohort data to validate our modelled incidence estimates. We ran modelled counterfactual scenarios to quantify the independent and combined effects (cumulative infections averted and difference in incidence rates) of antiretroviral therapy (ART), voluntary medical male circumcision (VMMC), and delays in age of first sex (AFS) over historical (between 2000-2020) and projected (between 2000-2050) time horizons., Findings: Incidence in women 15-24 years of age declined by 83% between 2000-2019 (from 1.72 per 100 person-years in 2000 to 0.30 per 100 person-years in 2019), the largest reduction in incidence of all age groups of women. Increasing AFS over the last two decades (by 3 years in women and 2 years in men) was the largest contributor to incidence decline in women 15-19 years of age, averting 17% of cumulative infections between 2000-2020 and 37% between 2000-2050. Incidence in 15-19-year-old women was 69% lower in 2020 and 75% lower in 2050 compared to counterfactual scenarios without changes in AFS. ART scale-up contributed the most to incidence declines among women 20-24 years of age, averting 13% of infections between 2000-2020 and 43% of infections between 2000-2050. VMMC averted < 5% of infections in 15-24-year-olds to-date, with larger reductions in incidence between 2000-2050 in both 15-19 year-olds (13% reduction in cumulative infections) and 20-24 year-olds (22% of cumulative infections). ART, VMMC, and increasing AFS acted additively to reduce HIV incidence in AGYW, with little redundancy when combined., Interpretation: Our results provide strong support for maintaining both the protective changes in sexual behaviours and effective biomedical interventions to sustain continued reductions in HIV incidence among AGYW.

Introduction: Autoantibodies (AAbs) directed against interferon alpha (aIFNα), nuclear antigens (ANAs), anti-cardiolipin (aCL), and anti-beta 2 glycoprotein 1 (aβ2GP1), have been demonstrated to significantly correlate with the severity of acute Coronavirus Disease 2019 (COVID-19). However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces these AAbs and whether they are associated with long COVID remains unclear., Methods: The potential induction of aIFNα, ANAs, aCL, and aβ2GP1 by SARS-CoV-2 was assessed by measuring these AAbs in 224 pre- and post-infection paired serum samples from the Johns Hopkins Hospital Emergency Department (JHHED). The relationship between these AAbs and long COVID was assessed using 60 serum samples from participants in the Outpatient SARS-CoV-2 Mild and Asymptomatic Infection Response and Transmission study., Results: We found no evidence that these AAbs were induced in the JHHED cohort and no significant difference in their prevalence between patients with (n = 30) and without (n = 30) long COVID in the OutSMART cohort., Conclusion: These findings do not support the hypotheses that SARS-CoV-2 induces these AAbs or that they are related to long COVID., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Published by Elsevier Ltd.)

Globally, people with HIV (PWH) experience a broad spectrum of cognitive impairment that can be noted both before and after initiation of antiretroviral therapy (ART). Sex differences in immune function have been implicated in differential cognitive outcomes. Here, we report sex differences in cerebrospinal fluid (CSF) markers in relation to cognitive performance in a subset of ART-naïve PWH participating in the Rakai Neurology Cohort Study. Participants (55 % male, 45 % female, overall mean age 36.5 years, SD = 8.7) underwent a lumbar puncture and a cognitive battery prior to ART initiation. CSF was collected, and 14 inflammatory markers were analyzed. Individual cognitive test z-scores were generated based on local normative data. We used a series of least absolute shrinkage and selection operator (lasso) regressions to examine associations between CSF inflammatory markers and cognitive outcomes. CSF inflammatory levels did not differ significantly between sexes except for IL-8 being higher in men. In women with HIV, there were more significant associations between inflammatory markers and cognitive performance than men with HIV. Additionally, inflammatory markers were associated with a broader range of cognitive domains in women compared to men with HIV. Patterns of association differed by sex in this young, ART-naïve Ugandan cohort, and several associations in a particular sex persisted or shifted when compared to a post-ART timepoint. Further study into sex-specific patterns of inflammation is warranted to improve cognitive outcomes in PWH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most "latency reversal" agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5-20 years on stable cART, HLP could target CD4 + T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.

Rationale: The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV co-infection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined., Objectives: To identify dominant pathobiological signatures of sepsis in sub-Saharan Africa and their relationship to clinical phenotypes, patient outcomes, and biological classifications of sepsis identified in high-income-countries (HICs)., Methods: We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with qSOFA score≥1) at disparate settings in Uganda (discovery cohort [Entebbe,urban], N=242; validation cohort [Tororo,rural], N=253). To identify pathobiological signatures in the discovery cohort, we applied unsupervised clustering to 173 soluble proteins reflecting key domains of the host response to severe infection. A random forest-derived classifier was used to predict signature assignment in the validation cohort., Measurements and Main Results: Two signatures (Uganda Sepsis Signature [USS]-1 and USS-2) were identified in the discovery cohort, distinguished by expression of proteins involved in myeloid cell and inflammasome activation, T cell co-stimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (AUROC 0.97) reproduced two signatures in the validation cohort with similar biological profiles. In both cohorts, USS-2 mapped to a more severe clinical phenotype associated with HIV and related immunosuppression, severe tuberculosis, and increased risk of 30-day mortality. Substantial biological overlap was observed between USS-2 and hyperinflammatory and reactive sepsis phenotypes identified in HICs., Conclusions: We identified prognostically-enriched pathobiological signatures among sepsis patients with diverse infections and high HIV prevalence in Uganda. Globally inclusive investigations are needed to define generalizable and context-specific mechanisms of sepsis pathobiology, with the goal of improving access to precision medicine treatment strategies.

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a negative-sense RNA virus spread by Hyalomma genus ticks across Europe, Asia, and Africa. CCHF disease begins as a non-specific febrile illness which may progress into a severe hemorrhagic disease with no widely approved or highly efficacious interventions currently available. Recently, we reported a self-replicating, alphavirus-based RNA vaccine that expresses the CCHFV nucleoprotein and is protective against lethal CCHFV disease in mice. This vaccine induces high titers of non-neutralizing anti-NP antibodies and we show here that protection does not require Fc-gamma receptors or complement. Instead, vaccinated mice deficient in the intracellular Fc-receptor TRIM21 were unable to control the infection despite mounting robust CCHFV-specific immunity. We also show that passive transfer of NP-immune sera confers significant TRIM21-dependent protection against lethal CCHFV challenge. Together our data identifies TRIM21-mediated mechanisms as the Fc effector function of protective antibodies against the CCHFV NP and provides mechanistic insight into how vaccines against the CCHFV NP confer protection., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: HIV treatment programs in Africa have implemented centralized testing for routine viral load monitoring (VLM), which may result in specimen processing delays inhibiting timely return of viral load results. Decentralized, point-of-care (PoC) VLM is a promising tool for expediting HIV clinical decision-making but remains unavailable in most African settings. We qualitatively explored the perceived feasibility and appropriateness of PoC VLM to address gaps along the viral load monitoring continuum in rural Uganda., Methods: Between May and September 2022, we conducted 15 in-depth interviews with HIV clinicians (facility in-charges, clinical officers, nurses, counselors) and six focus group discussions with 47 peer health workers from three south-central Ugandan districts. Topics explored centralized VLM implementation and opportunities/challenges to optimizing routine VLM implementation with PoC testing platforms. We explored perspectives on PoC VLM suitability and feasibility using iterative thematic analysis. Applying the Framework Method, we then mapped salient constraints and enablers of PoC VLM to constructs from the Consolidated Framework for Implementation Research., Results: Clinicians and peers alike emphasized centralized viral load monitoring's resource-intensiveness and susceptibility to procedural/infrastructural bottlenecks (e.g., supply stockouts, testing backlogs, community tracing of clients with delayed VLM results), inhibiting timely clinical decision-making. Participants reacted enthusiastically to the prospect of PoC VLM, anticipating accelerated turnarounds in specimen processing, shorter and/or fewer client encounters with treatment services, and streamlined efficiencies in HIV care provision (including expedited VLM-driven clinical decision-making). Anticipated constraints to PoC VLM implementation included human resource requirements for processing large quantities of specimens (especially when machinery require repair), procurement and maintenance costs, training needs in the existing health workforce for operating point-of-care technology, and insufficient space in lower-tier health facilities to accommodate installation of new laboratory equipment., Conclusions: Anticipated implementation challenges, primarily clustering around resource requirements, did not diminish enthusiasm for PoC VLM monitoring among rural Ugandan clinicians and peer health workers, who perceived PoC platforms as potential solutions to existing inefficiencies within the centralized VLM ecosystem. Prioritizing PoC VLM rollout in facilities with available resources for optimal implementation (e.g., adequate physical and fiscal infrastructure, capacity to manage high specimen volumes) could help overcome anticipated barriers to decentralizing viral load monitoring., (© 2024. The Author(s).)

Background: Understanding the impact of natural disasters on the HIV epidemic in populations with high HIV burden is critical for the effective delivery of HIV control efforts. We assessed HIV risk behaviors, seroprevalence, and viral suppression in a high HIV prevalence Lake Victoria fishing community before and after COVID-19 emergence and lockdown and a severe lake flooding event, both of which occurred in 2020., Methods: We used data from the largest Lake Victoria fishing community in the Rakai Community Cohort Study, an open population-based HIV surveillance cohort in south-central Uganda. The data were collected both prior to (September-December 2018) and after (October-December 2021) COVID-19 emergence and a severe flooding event. Households impacted by flooding were identified via drone data and through consulting village community health workers. The entire study population was subject to extensive COVID-19-related lockdowns in the first half of 2020. Differences in HIV-related outcomes before and after COVID, and between residents of flooded and non-flooded households, were assessed using a difference-in-differences statistical modeling approach., Findings: A total of 1,226 people participated in the pre- and post-COVID surveys, of whom 506 (41%) were affected by flooding. HIV seroprevalence in the initial period was 37% in flooded and 36.8% in non-flooded households. After the COVID-19 pandemic and lockdown, we observed a decline in HIV-associated risk behaviors: transactional sex declined from 29.4% to 24.8% (p = 0.011), and inconsistent condom use with non-marital partners declined from 41.6% to 37% (p = 0.021). ART coverage increased from 91.6% to 97.2% (p<0.001). There was 17% decline in transactional sex (aPR = 0.83, 95% CI: 0.75-0.92) and 28% decline in the overall HIV risk score (aPR = 0.83, 95% CI: 0.75-0.92) among HIV-seronegative participants. We observed no statistically significant differences in changes of HIV risk behavior, seroprevalence, or viral suppression outcomes when comparing those affected by floods to those not affected by floods, in the periods before and after COVID-19, based on difference-in-differences analyses., Interpretation: Despite a high background burden of HIV, the COVID-19 pandemic, and severe flooding, we observed no adverse impact on HIV risk behaviors, seroprevalence, or virologic outcomes. This may be attributed to innovative HIV programming during the period and/or population resilience. Understanding exactly what HIV programs and personal or community-level strategies worked to maintain good public health outcomes despite extreme environmental and pandemic conditions may help improve HIV epidemic control during future natural disaster events., Competing Interests: The authors declare no competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Clinical studies have reported rising pre-treatment HIV drug resistance during antiretroviral treatment (ART) scale-up in Africa, but representative data are limited. We estimated population-level drug resistance trends during ART expansion in Uganda., Methods: We analyzed data from the population-based open Rakai Community Cohort Study conducted at agrarian, trading, and fishing communities in southern Uganda between 2012 and 2019. Consenting participants aged 15-49 were HIV tested and completed questionnaires. Persons living with HIV (PLHIV) provided samples for viral load quantification and virus deep-sequencing. Sequence data were used to predict resistance. Population prevalence of class-specific resistance and resistance-conferring substitutions were estimated using robust log-Poisson regression., Findings: Data from 93,622 participant-visits, including 4,702 deep-sequencing measurements, showed that the prevalence of NNRTI resistance among pre-treatment viremic PLHIV doubled between 2012 and 2017 (PR:1.98, 95%CI:1.34-2.91), rising to 9.61% (7.27-12.7%). The overall population prevalence of pre-treatment viremic NNRTI and NRTI resistance among all participants decreased during the same period, reaching 0.25% (0.18% - 0.33%) and 0.05% (0.02% - 0.10%), respectively ( p- values for trend = 0.00015, 0.002), coincident with increasing treatment coverage and viral suppression. By the final survey, population prevalence of resistance contributed by treatment-experienced PLHIV exceeded that from pre-treatment PLHIV, with NNRTI resistance at 0.54% (0.44%-0.66%) and NRTI resistance at 0.42% (0.33%-0.53%). Overall, NNRTI and NRTI resistance was predominantly attributable to rtK103N and rtM184V. While 10.52% (7.97%-13.87%) and 9.95% (6.41%-15.43%) of viremic pre-treatment and treatment-experienced PLHIV harbored the inT97A mutation, no major dolutegravir resistance mutations were observed., Interpretation: Despite rising NNRTI resistance among pre-treatment PLHIV, overall population prevalence of pre-treatment resistance decreased due to treatment uptake. Most NNRTI and NRTI resistance is now contributed by treatment-experienced PLHIV. The high prevalence of mutations conferring resistance to components of current first-line ART regimens among PLHIV with viremia is potentially concerning., Competing Interests: Declaration of interests We declare no competing interests.

Abstract: Background: Understanding of immune cell phenotypes associated with inflammatory and immunosuppressive host responses in sepsis is imprecise, particularly in low- and middle-income countries, where the global sepsis burden is concentrated. In these settings, elucidation of clinically relevant immunophenotypes is necessary to determine the relevance of emerging therapeutics and refine mechanistic investigations of sepsis immunopathology. Methods: In a prospective cohort of adults hospitalized with suspected sepsis in Uganda (N = 43; median age 46 years [IQR 36-59], 24 [55.8%] living with HIV, 16 [37.2%] deceased at 60 days), we combined high-dimensional flow cytometry with unsupervised machine learning and manual gating to define peripheral immunophenotypes associated with increased risk of 60-day mortality. Results: Patients who died showed heterogeneous expansion of polymorphonuclear myeloid-derived suppressor cells, with increased and decreased abundance of CD16 - PD-L1 dim and CD16 bright PD-L1 bright subsets, respectively, significantly associated with mortality. While differences between CD16 - PD-L1 dim cell abundance and mortality risk appeared consistent throughout the course of illness, those for the CD16 bright PD-L1 bright subset were more pronounced early after illness onset. Independent of HIV co-infection, depletion of CD4 + T cells, dendritic cells, and CD56 - CD16 bright NK cells were significantly associated with mortality risk, as was expansion of immature, CD56 + CD16 - CD11c + NK cells. Abundance of T cells expressing inhibitory checkpoint proteins (PD-1, CTLA-4, LAG-3) was similar between patients who died versus those who survived. Conclusions: This is the first study to define high-risk immunophenotypes among adults with sepsis in sub-Saharan Africa, an immunologically distinct region where biologically informed treatment strategies are needed. More broadly, our findings highlight the clinical importance and complexity of myeloid derived suppressor cell expansion during sepsis and support emerging data that suggest a host-protective role for PD-L1 myeloid checkpoints in acute critical illness., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

There is limited data on human immunodeficiency virus (HIV) evolutionary trends in African populations. We evaluated changes in HIV viral diversity and genetic divergence in southern Uganda over a 24-year period spanning the introduction and scale-up of HIV prevention and treatment programs using HIV sequence and survey data from the Rakai Community Cohort Study, an open longitudinal population-based HIV surveillance cohort. Gag (p24) and env (gp41) HIV data were generated from people living with HIV (PLHIV) in 31 inland semi-urban trading and agrarian communities (1994-2018) and four hyperendemic Lake Victoria fishing communities (2011-2018) under continuous surveillance. HIV subtype was assigned using the Recombination Identification Program with phylogenetic confirmation. Inter-subtype diversity was evaluated using the Shannon diversity index, and intra-subtype diversity with the nucleotide diversity and pairwise TN93 genetic distance. Genetic divergence was measured using root-to-tip distance and pairwise TN93 genetic distance analyses. Demographic history of HIV was inferred using a coalescent-based Bayesian Skygrid model. Evolutionary dynamics were assessed among demographic and behavioral population subgroups, including by migration status. 9931 HIV sequences were available from 4999 PLHIV, including 3060 and 1939 persons residing in inland and fishing communities, respectively. In inland communities, subtype A1 viruses proportionately increased from 14.3% in 1995 to 25.9% in 2017 ( P  < .001), while those of subtype D declined from 73.2% in 1995 to 28.2% in 2017 ( P  < .001). The proportion of viruses classified as recombinants significantly increased by nearly four-fold from 12.2% in 1995 to 44.8% in 2017. Inter-subtype HIV diversity has generally increased. While intra-subtype p24 genetic diversity and divergence leveled off after 2014, intra-subtype gp41 diversity, effective population size, and divergence increased through 2017. Intra- and inter-subtype viral diversity increased across all demographic and behavioral population subgroups, including among individuals with no recent migration history or extra-community sexual partners. This study provides insights into population-level HIV evolutionary dynamics following the scale-up of HIV prevention and treatment programs. Continued molecular surveillance may provide a better understanding of the dynamics driving population HIV evolution and yield important insights for epidemic control and vaccine development., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The impact of migration on HIV risk among non-migrating household members is poorly understood. We measured HIV incidence among non-migrants living in households with and without migrants in Uganda., Methods: We used four survey rounds of data collected from July 2011 to May 2018 from non-migrant participants aged 15-49 years in the Rakai Community Cohort Study. Non-migrants were individuals with no-migration between surveys or at the prior survey. Household migration was defined as ≥1 household member migrating into or out of the house from another community between surveys (∼18 months). Incident HIV was defined as testing HIV seropositive following a negative result. Incidence rate ratios (IRRs) were estimated using Poisson regression with generalized estimating equations. Analyses were stratified by gender, migration into or out of the household and the relationship between non-migrants and migrants (e.g. spouse, child)., Results: About 11 318 non-migrants (5674 women) were followed for 37 320 person-years. Twenty-eight percent (6059/21 370) of non-migrant person-visits had recent migration into or out of the household, and 240 HIV incident cases were identified. Overall, non-migrants in migrant households were not at greater risk of acquiring HIV than non-migrants in households without any migration. However, men were significantly more likely to acquire HIV if their spouse had recently migrated in [adjusted IRR: 2.12; 95% confidence interval (CI): 1.05-4.27] or out (adjusted IRR: 4.01; 95% CI, 2.16-7.44) compared with men with no spousal migration., Conclusions: HIV incidence is higher among non-migrant men with migrant spouses. Targeted HIV testing and prevention interventions like pre-exposure prophylaxis could be considered for men with migrant spouses., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: Public sharing of de-identified biomedical data promotes collaboration between researchers and accelerates the development of disease prevention and treatment strategies. However, open-access data sharing presents challenges to researchers who need to protect the privacy of study participants, ensure that data are used appropriately, and acknowledge the inputs of all involved researchers. This article presents an approach to data sharing which addresses the above challenges by using a publicly available dashboard with de-identified, aggregated participant data from a large HIV surveillance cohort., Materials and Methods: Data in this study originated from the Rakai Community Cohort Study (RCCS), which was integrated into a centralized data mart as part of a larger data management strategy for the Rakai Health Sciences Program in Uganda. These data were used to build a publicly available, protected health information (PHI)-secured visualization dashboard for general research use., Results: Using two unique case studies, we demonstrate the capability of the dashboard to generate the following hypotheses: firstly, that HIV prevention strategies ART and circumcision have differing levels of impact depending on the marital status of investigated communities; secondly, that ART is very successful in comparison to circumcision as an interventional strategy in certain communities., Discussion: The democratization of large-scale anonymized epidemiological data using public-facing dashboards has multiple benefits, including facilitated exploration of research data and increased reproducibility of research findings., Conclusion: By allowing the public to explore data in depth and form new hypotheses, public-facing dashboard platforms have significant potential to generate new relationships and collaborations and further scientific discovery and reproducibility., Competing Interests: None declared., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2024.)

The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which have been predominantly conducted in males in the United States and Europe living with HIV-1 subtype B, have revealed that most proviruses that persist during antiretroviral therapy (ART) are defective. In contrast, less is known about proviral landscapes in females with non-B subtypes, which represents the largest group of individuals living with HIV-1. Here, we analyze genomic DNA from resting CD4+ T-cells from 16 female and seven male Ugandans with HIV-1 receiving suppressive ART (n = 23). We perform near-full-length proviral sequencing at limiting dilution to examine the proviral genetic landscape, yielding 607 HIV-1 subtype A1, D, and recombinant proviral sequences (mean 26/person). We observe that intact genomes are relatively rare and clonal expansion occurs in both intact and defective genomes. Our modification of the primers and probes of the Intact Proviral DNA Assay (IPDA), developed for subtype B, rescues intact provirus detection in Ugandan samples for which the original IPDA fails. This work will facilitate research on HIV-1 persistence and cure strategies in Africa, where the burden of HIV-1 is heaviest., (© 2024. The Author(s).)

Motor neuron disease (MND) is an uncommon but invariably fatal condition, with a median survival of 24-48 months from symptom onset. Although there is no cure at the moment, early diagnosis is crucial to enable timely access to multidisciplinary care, and enrolment in clinical trials utilising investigational therapies. Unfortunately, diagnostic delays remain common, and the average delay between symptom onset and diagnosis is 12 months. Large numbers of specialist referrals have been suggested as a key contributor to diagnostic delays. We conducted a retrospective review of the medical records of patients diagnosed with MND in Lancashire and South Cumbria, to investigate whether large numbers of specialty referrals are a common occurrence in MND. Our review identified that 35% of patients with MND were seen by two or more specialties before being referred to neurology. This rose to 49% when patients with bulbar onset disease were considered. 9% of cases saw three or more specialists. There was a statistically significant correlation between the number of specialist referrals and delays in neurology referral. We hope our findings will increase awareness of the importance of early neurology referral in the diagnosis of MND and promote the use of the MND Red Flag tool as a means of identifying patients in need of prompt neurological evaluation., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Introduction: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma associated with Plasmodium falciparum and Epstein-Barr virus, both of which affect metabolic pathways. The metabolomic patterns of BL is unknown., Materials and Methods: We measured 627 metabolites in pre-chemotherapy treatment plasma samples from 25 male children (6-11 years) with BL and 25 cancer-free area- and age-frequency-matched male controls from the Epidemiology of Burkitt Lymphoma in East African Children and Minors study in Uganda using liquid chromatography-tandem mass spectrometry. Unconditional, age-adjusted logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the BL association with 1-standard deviation increase in the log-metabolite concentration, adjusting for multiple comparisons using false discovery rate (FDR) thresholds and Bonferroni correction., Results: Compared to controls, levels for 42 metabolite concentrations differed in BL cases (FDR < 0.001), including triacylglyceride (18:0&#95;38:6), alpha-aminobutyric acid (AABA), ceramide (d18:1/20:0), phosphatidylcholine ae C40:6 and phosphatidylcholine C38:6 as the top signals associated with BL (ORs = 6.9 to 14.7, P < 2.4✕10 - 4 ). Two metabolites (triacylglyceride (18:0&#95;38:6) and AABA) selected using stepwise logistic regression discriminated BL cases from controls with an area under the curve of 0.97 (95% CI: 0.94, 1.00)., Conclusion: Our findings warrant further examination of plasma metabolites as potential biomarkers for BL risk/diagnosis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)