M. tuberculosis Infection Attributable to Exposure in Social Networks of Tuberculosis Cases in an Urban African Community.

Background: The persistence of tuberculosis today and its global disparity send a powerful message that effective tuberculosis control must respond to its regional epidemiology. Active case finding through contact investigation is a standard protocol used for tuberculosis control, but its effectiveness has not been established, especially in endemic areas. Methods: To quantify the potential effectiveness of contact investigation in Kampala, Uganda, we used a cross-sectional design to evaluate the social networks of 123 tuberculosis index cases and 124 controls without tuberculosis. Results: Tuberculous infection was present in 515 of 989 tuberculosis case contacts (52.1%) and 396 of 1026 control contacts (38.6%; adjusted prevalence ratio, 1.4; 95% CI, 1.3-1.6). The proportion of infected participants with known exposure within the social network of the tuberculosis case was 35%. The population-attributable fraction was 11.1% for any known exposure, with 7.3% attributable to household exposure and 3.4% attributable to extrahousehold exposure. Conclusions: This low population-attributable fraction indicates that contact tracing in the social networks of index cases will have only a modest effect in reducing tuberculous infection in a community. New approaches to community-level active case finding are needed.

Implementation challenges in preeclampsia care: perspectives from health care professionals in urban Uganda.

BACKGROUND: Sub-Saharan Africa bears the burden of 70% of maternal deaths worldwide, of which ∼10% are attributable to hypertensive disorders of pregnancy, primarily complications of preeclampsia. In other global settings, outcomes of pregnancies affected by preeclampsia are improved with timely and effective medical care. OBJECTIVE: This study aimed to explore the perspectives of local health care professionals on how preeclampsia care is currently delivered in the study setting and what challenges they experience in providing prompt and safe care. We identified specific objectives of exploring stakeholder perceptions of (1) recognizing preeclampsia and (2) timely intervention when preeclampsia is diagnosed. We also explored the wider system factors (eg, cultural, financial, and logistic challenges) that health care professionals perceived as affecting their ability to deliver optimal preeclampsia care. STUDY DESIGN: Individual semistructured interviews were conducted with health care professionals and stakeholders. The findings were analyzed using thematic analysis. RESULTS: Thirty-three participants contributed to the study, including doctors and midwives with varying degrees of clinical experience and external stakeholders. The following 5 key themes emerged: delayed patient presentation, recognizing the unwell patient with preeclampsia, the challenges of the existing triage system, stakeholder disconnect, and ways of learning from each other. Health care professionals referenced an important psychosocial perspective associated with preeclampsia in the study setting, which may influence the likelihood of seeking care through traditional healers rather than hospital-based routes. CONCLUSION: We identify the key barriers to improving maternal and neonatal outcomes of preeclampsia, described at both the institutional level and within the wider setting. The study provides invaluable contextual information that suggests that a systems-based approach to health care quality improvement may be effective in reducing rates of maternal and neonatal morbidity and mortality.

COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase.

Little is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we profile the peripheral blood proteome and transcriptome to characterize the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 is distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity.

Comparison of 3 optimized delivery strategies for completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: A single-center randomized trial.

BACKGROUND: Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies. METHODS AND FINDINGS: In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings. CONCLUSIONS: Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers. TRIAL REGISTRATION: ClinicalTrials.gov NCT03934931.

Effectiveness of intensive adherence counselling in achieving an undetectable viral load among people on antiretroviral therapy with low-level viraemia in Uganda.

INTRODUCTION: Uganda was using a threshold of 1000 copies/mL to determine viral non-suppression for antiretroviral therapy monitoring among people living with HIV, prior to this study. It was not clear whether people living with HIV with low-level viraemia (LLV, ≥50 to <1000 copies/mL) would benefit from intensive adherence counselling (IAC). The purpose of this study was to determine the effectiveness of IAC among people living with HIV, receiving antiretroviral therapy, and with LLV in Uganda, to guide key policy decisions in HIV care, including the review of the viral load (VL) testing algorithm. METHODS: This cluster-randomized clinical trial comprised adults from eight HIV clinics who were living with HIV, receiving ART, and had recent VL results indicating LLV (tested from July 2022 to October 2022). Participants in the intervention arm clinics received three once-monthly sessions of IAC, and those in the comparison non-intervention arm clinics received the standard of care. At the end of the study, all participants were re-tested for VL to determine the proportions of those who then had an undetectable VL (<50 copies/mL). We assessed the statistical association between cross-tabulated variables using Fisher's exact test and then modified Poisson regression. RESULTS: A total of 136 participants were enrolled into the study at eight HIV clinics. All 68 participants in the intervention arm completed all IAC sessions. Only one participant in the non-intervention arm was lost to follow-up. The average follow-up time was 3.7 months (standard deviation [SD] 0.2) and 3.5 months (SD 0.1) in the intervention and non-intervention arms, respectively. In total, 59 (43.7%) of 135 people living with HIV achieved an undetectable VL during the study follow-up period. The effect of IAC on attaining an undetectable VL among people with LLV was nearly twice as high in the intervention arm (57.4%) than in the non-intervention arm (29.9%): adjusted risk ratio 1.9 (95% confidence interval 1.0-3.5), p = 0.037. CONCLUSION: IAC doubled the likelihood of an undetectable VL among people living with HIV with LLV. Therefore, IAC has been instituted as an intervention to manage people living with HIV with LLV in Uganda, and this should also be adopted in other Sub-Saharan African countries with similar settings. GOV IDENTIFIER: NCT05514418.

Evaluating the effectiveness of Uganda's Supranational TB Reference Laboratory quality management system training program.

BACKGROUND: Achieving the targeted organizational goals through effective training can increase employee satisfaction. Since 2015, the Supranational Reference Laboratory Uganda (SRL Uganda) has trained National Tuberculosis Reference Laboratories (NTRLs) from 21 countries in a variety of areas that cover both technical and programmatic aspects pertinent to TB laboratories. The Laboratory Quality Management System (LQMS) under SRL coordinates actions intended to ensure sustained quality of the laboratory services offered by the National TB Reference Laboratories. In order for laboratory results to be helpful in a clinical or public health setting, they must be accurate, reliable, and timely. The LQMS course aims to provide learners with knowledge on how to attain and maintain this quality. Prior to this study, there was hardly any data available on the effectiveness of LQMS trainings provided by SRL Uganda; using Kirkpatrick model, which is popular among researchers for evaluating the efficacy of the training program, this paper seeks to establish the effectiveness of the LQMS training offered by the SRL Uganda. METHOD: We evaluated the effectiveness of LQMS training within the Uganda's SRL network for courses offered during the period 2017 and 2021 for participants from the Southern and East African sub-Saharan region. RESULTS: In 2017 and 2021, respectively, test results from 10/17 and 9/17 showed overall post-test scores above 80%. Of the 18 labs evaluated, 14 showed improvement; of these, 7 labs were from the Eastern region and the other 7 were from Southern Africa; one facility in this region also maintained its accreditation. In the post-evaluation assessment, attendees of the LQMS course gave feedback of strongly agree and agree variety. CONCLUSION: More SRL Uganda network laboratories in the regions achieved a 5-star SLIPTA level rating and among these, 5 NTRLs got ISO 15189:2012 accredited by the end of 2021, while one maintained its accreditation status. This proves that the Laboratory Quality Management System training program was an effective tool in improving the quality of laboratory services, work practices, and processes.

A user-centred implementation strategy for tuberculosis contact investigation in Uganda: protocol for a stepped-wedge, cluster-randomised trial.

BACKGROUND: Tuberculosis(TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented. METHODS: We are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including (1) a TB-education booklet, (2) a contact-identification algorithm, (3) an instructional sputum-collection video, and (4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including (1) collaborative improvement meetings, (2) regular audit-and-feedback reports, and (3) a digital group-chat application designed to develop a community of practice. Sites will cross-over from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB(#554), the Uganda National Council for Science and Technology(#HS1720ES), and the Yale Institutional Review Board(#2000023199) approved the study and waived informed consent for the main trial implementation-effectiveness outcomes. We will submit results for publication in peer-reviewed journals and disseminate findings to local policymakers and representatives of affected communities. DISCUSSION: This pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden settings using contact investigation. It will also help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustaining evidence-based interventions in low-and-middle-income countries. TRIAL REGISTRATION: The trial was registered(ClinicalTrials.gov Identifier NCT05640648) on 16 November 2022, after the trial launch on 7 March 2022.

Schistosoma mansoni infection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses.

Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine responses revealed significant upregulation of CCL19, CXCL9 and CCL17 known to be involved in T cell activation and recruitment, in higher CAA individuals, and CCL17 correlated negatively with HepB titers at month 12 post-vaccination. We show that HepB-specific CD4+ T cell memory responses correlated positively with HepB titers at M7. We further established that those participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination, but higher regulatory T cells (Tregs) post-vaccination, suggesting changes in the immune microenvironment in high CAA could favor Treg recruitment and activation. Additionally, we found that changes in the levels of innate-related cytokines/chemokines CXCL10, IL-1ß, and CCL26, involved in driving T helper responses, were associated with increasing CAA concentration. This study provides further insight on pre-vaccination host responses to Schistosoma worm burden which will support our understanding of vaccine responses altered by pathogenic host immune mechanisms and memory function and explain abrogated vaccine responses in communities with endemic infections.

A user-centred implementation strategy for tuberculosis contact investigation in Uganda: Protocol for a stepped-wedge, cluster-randomised trial.

Background Tuberculosis (TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented. Methods We are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including 1) a TB-education booklet, 2) a contact-identification algorithm, 3) an instructional sputum-collection video, and 4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including 1) collaborative improvement meetings, 2) regular audit-and-feedback reports, and 3) a digital group-chat application designed to develop a community of practice. Sites will cross from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB (#554), the Uganda National Council for Science and Technology (#HS1720ES), and the Yale Institutional Review Board (#2000023199) approved the study with a waiver of informed consent for the main trial implementation-effectiveness outcomes. We will submit trial results for publication in a peer-reviewed journal and disseminate findings to local shareholders, including policymakers and representatives of affected communities. Discussion This pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden setting using contact investigation. It will help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustain evidence-based interventions in low-and-middle-income countries. Trial registration number ClinicalTrials.gov Identifier: NCT05640648.

Uvula infections and traditional uvulectomy: Beliefs and practices in Luwero district, central Uganda.

Uvulitis is the inflammation and swelling of the uvula, usually associated with infection of nearby structures. Uvulitis can be treated symptomatically, using medication or in some cases with uvulectomy, the uvula surgical removal or shortening. Traditional uvulectomy by traditional practitioners has been practiced in Africa for ages, associated with adverse outcomes. Although there is no empirical evidence for the association between adverse outcomes and traditional uvulectomy in Uganda, anecdotal findings showed incidents of uvula infections following uvulectomy in central Uganda. While these findings also indicate that traditional uvulectomy is common, the community understanding of uvulitis, the beliefs and practices are not well understood. This qualitative study sought to understand beliefs and practices using interviews with community health workers, traditional uvulectomy clients, and traditional surgeons, and focus group discussions with community members. Transcribed data were analysed in Atlas.ti 9 using thematic analysis steps. The findings show that uvula infection, locally known as "Akamiro" and the associated traditional uvulectomy are common in Luwero and beyond. "Akamiro" was described as larger than the normal, the size of a chicken heart or a big pimple, visible when a child cries, with unknown causes. Symptoms included persistent cough, diarrhoea, vomiting, loss of appetite, inability to swallow and ultimately weight loss, swollen stomach, saliva overflow, fever, breathing and speech difficulty. Diagnosis was confirmed after seeking care from health workers or in consultation with significant others and finally the traditional surgeon; in a hierarchical pattern. Uvulectomy was conducted by traditional surgeons, with surgery lasting a few minutes, in the morning or after sun-set. Tools used were razor blades, reeds, strings, wires, sickle knives and spoons. Payment was flexible; cash or in-kind. Surgeons had immense community trust, including community health workers. Interventions to support persons with uvula infections need to address the health system weaknesses, and health education.

Implementation, feasibility, and acceptability of 99DOTS-based supervision of treatment for drug-susceptible TB in Uganda.

99DOTS is a low-cost digital adherence technology that allows people with tuberculosis (TB) to self-report treatment adherence. There are limited data on its implementation, feasibility, and acceptability from sub-Saharan Africa. We conducted a longitudinal analysis and cross-sectional surveys nested within a stepped-wedge randomized trial at 18 health facilities in Uganda between December 2018 and January 2020. The longitudinal analysis assessed implementation of key components of a 99DOTS-based intervention, including self-reporting of TB medication adherence via toll-free phone calls, automated text message reminders and support actions by health workers monitoring adherence data. Cross-sectional surveys administered to a subset of people with TB and health workers assessed 99DOTS feasibility and acceptability. Composite scores for capability, opportunity, and motivation to use 99DOTS were estimated as mean Likert scale responses. Among 462 people with pulmonary TB enrolled on 99DOTS, median adherence was 58.4% (inter-quartile range [IQR] 38.7-75.6) as confirmed by self-reporting dosing via phone calls and 99.4% (IQR 96.4-100) when also including doses confirmed by health workers. Phone call-confirmed adherence declined over the treatment period and was lower among people with HIV (median 50.6% vs. 63.7%, p<0.001). People with TB received SMS dosing reminders on 90.5% of treatment days. Health worker support actions were documented for 261/409 (63.8%) people with TB who missed >3 consecutive doses. Surveys were completed by 83 people with TB and 22 health workers. Composite scores for capability, opportunity, and motivation were high; among people with TB, composite scores did not differ by gender or HIV status. Barriers to using 99DOTS included technical issues (phone access, charging, and network connection) and concerns regarding disclosure. 99DOTS was feasible to implement and highly acceptable to people with TB and their health workers. National TB Programs should offer 99DOTS as an option for TB treatment supervision.

Evaluating the impact of cash transfers on tuberculosis (ExaCT TB): a stepped wedge cluster randomised controlled trial.

Background: Mitigating financial barriers to tuberculosis (TB) diagnosis and treatment is a core priority of the global TB agenda. We evaluated the impact of a cash transfer intervention on completion of TB testing and treatment initiation in Uganda. Methods: We conducted a pragmatic complete stepped wedge randomised trial of a one-time unconditional cash transfer at 10 health centres between September 2019 and March 2020. People referred for sputum-based TB testing were enrolled to receive UGX 20 000 (∼USD 5.39) upon sputum submission. The primary outcome was the number initiating treatment for micro-bacteriologically confirmed TB within 2 weeks of initial evaluation. The primary analysis included cluster-level intent-to-treat and per-protocol analyses using negative binomial regression. Results: 4288 people were eligible. The number diagnosed with TB initiating treatment was higher in the intervention period versus the pre-intervention period (adjusted rate ratio (aRR)=1.34) with a 95% CI of 0.62-2.91 (p=0.46), indicating a wide range of plausible true intervention effects. More were referred for TB testing (aRR=2.60, 95% CI 1.86-3.62; p<0.001) and completed TB testing (aRR=3.22, 95% CI 1.37-7.60; p=0.007) per National Guidelines. Results were similar but attenuated in per-protocol analyses. Surveys revealed that while the cash transfer supported testing completion, it was insufficient to address long-term underlying social/economic barriers. Interpretation: While it is uncertain whether a single unconditional cash transfer increased the number of people diagnosed and treated for TB, it did support higher completion of diagnostic evaluation in a programmatic setting. A one-time cash transfer may offset some but not all of the social/economic barriers to improving TB diagnosis outcomes.

Hopes, joys and fears: Meaning and perceptions of viral load testing and low-level viraemia among people on antiretroviral therapy in Uganda: A qualitative study.

Uganda applies the World Health Organization threshold of 1,000 copies/ml to determine HIV viral non-suppression. While there is an emerging concern of low-level viraemia (≥50 to <1,000 copies/ml), there is limited understanding of how people on antiretroviral therapy perceive viral load testing and low-level viremia in resource-limited settings. This qualitative study used the health belief model to explore the meaning that people living with HIV attach to viral load testing and low-level viraemia in Uganda. We used stratified purposive sampling to select people on antiretroviral therapy from eight high volume health facilities from the Central, Eastern, Northern and Western regions of Uganda. We used an interview guide, based on the health belief model, to conduct 32 in-depth interviews, which were audio-recorded and transcribed verbatim. Thematic analysis technique was used to analyze the data with the help of ATLAS.ti 6. The descriptions of viral load testing used by the participants nearly matched the medical meaning, and many people living with HIV understood what viral load testing was. Perceived benefits for viral load testing were the ability to show; the amount of HIV in the body, how the people living with HIV take their drugs, whether the drugs are working, and also guide the next treatments steps for the patients. Participants reported HIV stigma, lack of transport, lack of awareness for viral load testing, delayed and missing viral load results and few health workers as the main barriers to viral load testing. On the contrary, most participants did not know what low-level viraemia meant, while several perceived it as having a reduced viral load that is suppressed. Many people living with HIV are unaware about low-level viraemia, and hence do not understand its associated risks. Likewise, some people living with HIV are still not aware about viral load testing. Lack of transport, HIV stigma and delayed viral load results are major barriers to viral load testing. Hence, there is an imminent need to institute more strategies to create awareness about both low-level viraemia and viral load testing, manage HIV related stigma, and improve turnaround time for viral load results.

Safety and feasibility of autologous adipose-derived stromal vascular fraction in the treatment of keloids: a phase one randomized controlled pilot trial.

INTRODUCTION: Autologous adipose-derived stromal vascular fraction (SVF) has been described to have therapeutic benefits in the treatment of keloids. However, most of the evidence on its efficacy is based on observational studies the majority of which are conducted in high-income countries and yet the highest burden of keloids is in low- and middle-income countries (LMICs). OBJECTIVES: We set out to determine the safety and feasibility of using autologous adipose derived stromal vascular fraction in the treatment of keloids in LMICs. METHODS: In this phase II randomized controlled pilot clinical trial conducted in the Plastic Surgery Unit of Kirruddu National Referral Hospital in Kampala Uganda, 8 patients were assigned a 1:1 ratio to either SVF or triamcinolone acetonide (TAC) arms. In the SVF arm, a median (Inter quartile range) amount of stromal cell infiltration of 2.7×106 (11×106) was administered, while the controls received 10 mg/ml TAC at a ratio of 1:1 TAC to keloid volume. Primary endpoints were adverse event development based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 tool and feasibility assessment based on ≥ 70% recruitment feasibility and ≥ 80% interventional feasibility rates. RESULTS: The participants' mean age was 27.9 (±6.5) years, with a female predilection of 5 (63%). Overall, no adverse events were reported in the SVF arm, while ulceration in a single patient in the TAC arm, which was a grade II adverse event, was reported. Recruitment feasibility of 80% and interventional feasibility with 100% completion were reported. CONCLUSION: Based on our findings, an autologous adipose-derived stromal vascular fraction is feasible and safe for the treatment of keloids in LMICs.

Schistosoma mansoni infection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses.

The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence of Schistosoma mansoni infection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that negatively associated with HepB titers. Additionally, alterations in pre-vaccination monocyte function correlated with HepB titers, and changes in innate-related cytokines/chemokine production were associated with increasing CAA concentration. We report, that by influencing the immune landscape, schistosomiasis has the potential to modulate immune responses to HepB vaccination. These findings highlight multiple Schistosoma -related immune associations that could explain abrogated vaccine responses in communities with endemic infections. Author Summary: Schistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact of Schistosoma mansoni ( S. mansoni ) infection on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that high schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination. We show higher pre-vaccination levels of cellular and soluble factors in instances of high CAA that are negatively associated with HepB antibody titers post-vaccination, which coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and that high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis creates and sustains an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.

Prevalence and factors associated with reported adverse-events among patients on multi-drug-resistant tuberculosis treatment in two referral hospitals in Uganda.

BACKGROUND: Multi-drug-resistant tuberculosis (MDR-TB) treatment involves toxic drugs that cause adverse events (AEs), which are life-threatening and may lead to death if not well managed. In Uganda, the prevalence of MDR-TB is increasingly high, and about 95% of the patients are on treatment. However, little is known about the prevalence of AEs among patients on MDR-TB medicines. We therefore estimated the prevalence of reported adverse events (AEs) of MDR-TB drugs and factors associated with AEs in two health facilities in Uganda. METHODS: A retrospective cohort study of MDR-TB was conducted among patients enrolled at Mulago National Referral and Mbarara Regional Referral hospitals in Uganda. Medical records of MDR-TB patients enrolled between January 2015 and December 2020 were reviewed. Data on AEs, which were defined as irritative reactions to MDR-TB drugs, were extracted and analyzed. To describe reported AEs, descriptive statistics were computed. A modified Poisson regression analysis was used to determine factors associated with reported AEs. RESULTS: Overall, 369 (43.1%) of 856 patients had AEs, and 145 (17%) of 856 had more than one. Joint pain (244/369, or 66%), hearing loss (75/369, or 20%), and vomiting (58/369, or 16%) were the most frequently reported effects. Patients started on the 24-month regimen (adj. PR = 1.4, 95%; 1.07, 1.76) and individualized regimens (adj. PR = 1.5, 95%; 1.11, 1.93) were more likely to suffer from AEs. Lack of transport for clinical monitoring (adj. PR = 1.9, 95%; 1.21, 3.11); alcohol consumption (adj. PR = 1.2, 95%; 1.05, 1.43); and receipt of directly observed therapy from peripheral health facilities (adj. PR = 1.6, 95%; 1.10, 2.41) were significantly associated with experiencing AEs. However, patients who received food supplies (adj. PR = 0.61, 95%; 0.51, 0.71) were less likely to suffer from AEs. CONCLUSION: The frequency of adverse events reported by MDR-TB patients is considerably high, with joint pain being the most common. Interventions such as the provision of food supplies, transportation, and consistent counseling on alcohol consumption to patients at initiation treatment facilities may contribute to a reduction in the rate of occurrence of AEs.

Respiratory Support Techniques for COVID-19-Related ARDS in a Sub-Saharan African Country: A Multicenter Observational Study.

BACKGROUND: Limited data from low-income countries report on respiratory support techniques in COVID-19-associated ARDS. RESEARCH QUESTION: Which respiratory support techniques are used in patients with COVID-19-associated ARDS in Uganda? STUDY DESIGN AND METHODS: A multicenter, prospective, observational study was conducted at 13 Ugandan hospitals during the pandemic and included adults with COVID-19-associated ARDS. Patient characteristics, clinical and laboratory data, initial and most advanced respiratory support techniques, and 28-day mortality were recorded. Standard tests, log-rank tests, and logistic regression analyses were used for statistical analyses. RESULTS: Four hundred ninety-nine patients with COVID-19-associated ARDS (mild, n = 137; moderate, n = 247; and severe, n = 115) were included (ICU admission, 38.9%). Standard oxygen therapy (SOX), high-flow nasal oxygen (HFNO), CPAP, noninvasive ventilation (NIV), and invasive mechanical ventilation (IMV) was used as the first-line (most advanced) respiratory support technique in 37.3% (35.3%), 10% (9.4%), 11.6% (4.8%), 23.4% (14.4%), and 17.6% (36.6%) of patients, respectively. The first-line respiratory support technique was escalated in 19.8% of patients. Twenty-eight-day mortality was 51.9% (mild ARDS, 13.1%; moderate ARDS, 62.3%; severe ARDS, 75.7%; P < .001) and was associated with respiratory support techniques as follows: SOX, 19.9%; HFNO, 31.9%; CPAP, 58.3%; NIV 61.1%; and IMV, 83.9% (P < .001). Proning was used in 79 patients (15.8%; 59 of 79 awake) and was associated with lower mortality (40.5% vs 54%; P = .03). The oxygen saturation to Fio2 ratio (OR, 0.99; 95% CI, 0.98-0.99; P < .001) and respiratory rate (OR, 1.07; 95% CI, 1.03-1.12; P = .002) at admission and NIV (OR, 6.31; 95% CI, 2.29-17.37; P < .001) or IMV (OR, 8.08; 95% CI, 3.52-18.57; P < .001) use were independent risk factors for death. INTERPRETATION: SOX, HFNO, CPAP, NIV, and IMV were used as respiratory support techniques in patients with COVID-19-associated ARDS in Uganda. Although these data are observational, they suggest that the use of SOX and HFNO therapy as well as awake proning are associated with a lower mortality resulting from COVID-19-associated ARDS in a resource-limited setting.

The association between low-level viraemia and subsequent viral non-suppression among people living with HIV/AIDS on antiretroviral therapy in Uganda.

BACKGROUND: Uganda's efforts to end the HIV epidemic by 2030 are threatened by the increasing number of PLHIV with low-level viraemia (LLV). We conducted a study to determine the prevalence of LLV and the association between LLV and subsequent viral non-suppression from 2016 to 2020 among PLHIV on ART in Uganda. METHOD: This was a retrospective cohort study, using the national viral load (VL) program data from 2016 to 2020. LLV was defined as a VL result of at least 50 copies/ml, but less than 1,000 copies/ml. Multivariable logistic regression was used to determine the factors associated with LLV, and cox proportional hazards regression model was used to determine the association between LLV and viral non-suppression. RESULTS: A cohort of 17,783 PLHIV, of which 1,466 PLHIV (8.2%) had LLV and 16,317 (91.8%) had a non-detectable VL was retrospectively followed from 2016 to 2020. There were increasing numbers of PLHIV with LLV from 2.0% in 2016 to 8.6% in 2020; and LLV was associated with male sex, second line ART regimen and being of lower age. 32.5% of the PLHIV with LLV (476 out of 1,466 PLHIV) became non-suppressed, as compared to 7.7% of the PLHIV (1,254 out of 16,317 PLHIV) with a non-detectable viral load who became non-suppressed during the follow-up period. PLHIV with LLV had 4.1 times the hazard rate of developing viral non-suppression, as compared to PLHIV with a non-detectable VL (adjusted hazard ratio was 4.1, 95% CI: 3.7 to 4.7, p < 0.001). CONCLUSION: Our study indicated that PLHIV with LLV increased from 2.0% in 2016 to 8.6% in 2020, and PLHIV with LLV had 4.1 times the hazard rate of developing viral non-suppression, as compared to PLHIV with a non-detectable VL. Hence the need to review the VL testing algorithm and also manage LLV in Uganda.

Autologous adipose-derived stromal vascular fraction (SVF) in scar treatment among patients with keloids and hypertrophic scars: a systematic review and meta-analysis of current practices and outcomes.

BACKGROUND: Keloids and hypertrophic scars are some of the most common skin conditions globally, associated with poor treatment response and high recurrence rates. Autologous adipose-derived stromal vascular fraction (SVF) is increasingly recognized as an emerging therapy albeit limited literature on its outcome in scar treatment. This review aimed to describe the current practices and outcomes of adipose-derived stromal Vascular Fraction in scar treatment. METHODS: This systematic review assessed articles describing the use of SVF in scar treatment published between 2000 and 2023. Article searches of Medline/PubMed, Cochrane Library, and Embase databases using Mesh terms and the Boolean operators ("AND", "OR") by two independent researchers were done whilst following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical studies assessing SVF in scar treatment with a primary outcome measure being an improvement in scar characteristics including the thickness, scar assessment scores were included. RESULTS: Among the 1425 studies identified in the search, 20 studies met the inclusion criteria with a total of 493 patients included. Eight of these were clinical trials with the rest being observational studies. Follow-up ranged from 3 months to 24 months. In all studies, there was an improvement in scar characteristics following single-dose treatment with SVF or its equivalent. All studies reported SVF to be safe. CONCLUSION: The review found that autologous adipose-derived SVF is a clinically effective therapy for keloids and scar treatment.