Qualitative Assessment of Barriers and Facilitators of PrEP Use Before and After Rollout of a PrEP Program for Priority Populations in South-central Uganda.

Uganda piloted HIV pre-exposure prophylaxis (PrEP) for priority populations (sex workers, fishermen, truck drivers, discordant couples) in 2017. To assess facilitators and barriers to PrEP uptake and adherence, we explored perceptions of PrEP before and experiences after rollout among community members and providers in south-central Uganda. We conducted 75 in-depth interviews and 12 focus group discussions. We analyzed transcripts using a team-based thematic framework approach. Partners, family, peers, and experienced PrEP users provided adherence support. Occupational factors hindered adherence for sex workers and fishermen, particularly related to mobility. Pre-rollout concerns about unskilled/untrained volunteers distributing PrEP and price-gouging were mitigated. After rollout, awareness of high community HIV risk and trust in PrEP effectiveness facilitated uptake. PrEP stigma and unexpected migration persisted as barriers. Community-initiated, tailored communication with successful PrEP users may optimize future engagement by addressing fears and rumors, while flexible delivery and refill models may facilitate PrEP continuation and adherence.

RESUMEN: En 2017, Uganda introdujo profilaxis pre-exposición (PrEP), dirigida a las populaciones con alto riesgo de contraer al VIH (trabajadoras sexuales, pescadores, camioneros, parejas sero-discordantes). Para investigar facilitadores y barreras para la adopción y la adherencia a la PrEP, exploramos percepciones de PrEP antes y después de su introducción en Uganda. Realizamos 75 entrevistas y 12 grupos focales con miembros de la comunidad y trabajadores de salud. Analizamos las transcripciones temáticamente usando un marco de referencia. Parejas, familias, compañeros, y clientes usando PrEP apoyaron a los demás mantener adherencia. Movilidad fue una barrera para la adherencia a la PrEP para trabajadoras sexuales y pescadores. Preocupaciones sobre el entrenamiento de los distribuidores de PrEP y la especulación de precios no fueron realizadas. Percepciones del riesgo del VIH y confianza en la eficacia de PrEP facilitaron su adopción. Estigma y migración inesperada persistieron como barreras para la adopción de PrEP. Comunicaciones manejadas por clientes usando PrEP pueden motivar interés en PrEP y abordar rumores. Sistemas flexibles del entrego y la recarga de medicinas pueden permitir continuación de, y adherencia a, la PrEP.

Mixed Methods, Implementation Science Evaluation of a Community Health Worker Strategy for HIV Service Engagement in Uganda.

BACKGROUND: A trial found that a community health worker (CHW) strategy using "Health Scouts" improved HIV care uptake and ART coverage. To better understand outcomes and areas for improvement, we conducted an implementation science evaluation. METHODS: Using the RE-AIM framework, quantitative methods included analyses of a community-wide survey (n = 1903), CHW log books, and phone application data. Qualitative methods included in-depth interviews (n = 72) with CHWs, clients, staff, and community leaders. RESULTS: Thirteen Health Scouts logged 11,221 counseling sessions; 2532 unique clients were counseled. 95.7% (1789 of 1891) of residents reported awareness of the Health Scouts. Overall, reach (self-reported receipt of counseling) was 30.7% (580 of 1891). Unreached residents were more likely to be male and HIV seronegative ( P < 0.05). Qualitative themes included the following: (1) reach was promoted by perceived usefulness but deterred by busy client lifestyles and stigma, (2) effectiveness was enabled through good acceptability and consistency with the conceptual framework, (3) adoption was facilitated by positive impacts on HIV service engagement, and (4) implementation fidelity was initially promoted by the CHW phone application but deterred by mobility. Maintenance showed consistent counseling sessions over time. The findings suggested the strategy was fundamentally sound but had suboptimal reach. Future iterations could consider adaptations to improve reach to priority populations, testing the need for mobile health support, and additional community sensitization to reduce stigma. CONCLUSIONS: A CHW strategy to promote HIV services was implemented with moderate success in an HIV hyperendemic setting and should be considered for adoption and scale-up in other communities as part of comprehensive HIV epidemic control efforts. TRIAL REGISTRATION: ClinicalTrials.gov Trial Number NCT02556957.

Soluble Programmed Death-Ligand 1 (sPD-L1) is Elevated in Aggressive Prostate Cancer Disease Among African Men.

INTRODUCTION: Programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1)-targeted immunotherapies have become a new mode of treatment for several tumours; however, there is limited evidence on the expression and prognostic value of PD-1/PD-L1 in prostate cancer, especially in African men. METHODS: Plasma concentrations of PD-L1/PD-1 were assessed using enzyme-linked immunosorbent assay in patients with prostate cancer and normal healthy controls at the Uganda Cancer Institute. The associations between plasma PD-L1/PD-1 concentration levels and serum prostate-specific antigen (PSA) levels, Gleason scores, age, and body mass index (BMI) were determined. RESULTS: We found significant differences in the median plasma concentrations of PD-L1 and PD-1 immune checkpoint molecules between prostate cancer cases and normal healthy controls of 0.285 vs 0.035 (p = 0.001) and 0.596 vs 0.355 (p = 0.017), respectively. We found no significant association between age, serum PSA levels, BMI and Gleason scores, and PD-1 among patients with prostate cancer and controls. However, elevated levels of PD-L1 were significantly associated with higher Gleason scores among patients with prostate cancer (p = 0.014). CONCLUSIONS: Elevated PD-L1 levels were statistically significantly linked to high Gleason scores. These results may guide clinicians in assessing the prognosis of patients individually and selecting patients who will be suitable candidates for anti-PD-L1 immunotherapy.

Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation.

OBJECTIVE: Procalcitonin may be associated with reduced antibiotic usage compared to usual care. However, individual randomized controlled trials testing this hypothesis were too small to rule out harm, and the full cost-benefit of this strategy has not been evaluated. The purpose of this analysis was to evaluate the effect of a procalcitonin-guided antibiotic strategy on clinical and economic outcomes. INTERVENTIONS: The use of procalcitonin-guided antibiotic therapy. METHODS AND MAIN RESULTS: We searched computerized databases, reference lists of pertinent articles, and personal files. We included randomized controlled trials conducted in the intensive care unit that compared a procalcitonin-guided strategy to usual care and reported on antibiotic utilization and clinically important outcomes. Results were qualitatively and quantitatively summarized. On the basis of no effect in hospital mortality or hospital length of stay, a cost or cost-minimization analysis was conducted using the costs of procalcitonin testing and antibiotic acquisition and administration. Costs were determined from the literature and are reported in 2009 Canadian dollars. Five articles met the inclusion criteria. Procalcitonin-guided strategies were associated with a significant reduction in antibiotic use (weighted mean difference -2.14 days, 95% confidence interval -2.51 to -1.78, p < .00001). No effect was seen of a procalcitonin-guided strategy on hospital mortality (risk ratio 1.06, 95% confidence interval 0.86-1.30, p = .59; risk difference 0.01, 95% confidence interval -0.04 to +0.07, p = .61) and intensive care unit and hospital lengths of stay. The cost model revealed that, for the base case scenario (daily price of procalcitonin Can$49.42, 6 days of procalcitonin measurement, and 2-day difference in antibiotic treatment between procalcitonin-guided therapy and usual care), the point at which the cost of testing equals the cost of antibiotics saved is when daily antibiotics cost Can$148.26 (ranging between Can$59.30 and Can$296.52 on the basis of different assumptions in sensitivity analyses). CONCLUSIONS: Procalcitonin-guided antibiotic therapy is associated with a reduction in antibiotic usage that, under certain assumptions, may reduce overall costs of care. However, the overall estimate cannot rule out a 7% increase in hospital mortality.

Diaphragm neurostimulation during mechanical ventilation reduces atelectasis and transpulmonary plateau pressure, preserving lung homogeneity and [Formula: see text]/[Formula: see text].

Tidal volume delivered by mechanical ventilation to a sedated patient is distributed in a nonphysiological pattern, causing atelectasis (underinflation) and overdistension (overinflation). Activation of the diaphragm during controlled mechanical ventilation in these sedated patients may provide a method to reduce atelectasis and alveolar inhomogeneity, protecting the lungs from ventilator-induced lung injury while also protecting the diaphragm by preventing ventilator-induced diaphragm dysfunction. We studied the hypothesis that diaphragm contractions elicited by transvenous phrenic nerve stimulation, delivered in synchrony with volume-control ventilation, would reduce atelectasis and lung inhomogeneity in a healthy, normal lung pig model. Twenty-five large pigs were ventilated for 50 h with lung-protective volume-control ventilation combined with synchronous transvenous phrenic-nerve neurostimulation on every breath, or every second breath. This was compared to lung-protective ventilation alone. Lung mechanics and ventilation pressures were measured using esophageal pressure manometry and electrical impedance tomography. Alveolar homogeneity was measured using alveolar chord length of preserved lung tissue. Lung injury was measured using inflammatory cytokine concentration in bronchoalveolar lavage fluid and serum. We found that diaphragm neurostimulation on every breath preserved [Formula: see text]/[Formula: see text] and significantly reduced the loss of end-expiratory lung volume after 50 h of mechanical ventilation. Neurostimulation on every breath reduced plateau and driving pressures, improved both static and dynamic compliance and resulted in less alveolar inhomogeneity. These findings support that temporary transvenous diaphragm neurostimulation during volume-controlled, lung-protective ventilation may offer a potential method to provide both lung- and diaphragm-protective ventilation.NEW & NOTEWORTHY Temporary transvenous diaphragm neurostimulation has been shown to mitigate diaphragm atrophy in a preclinical model. This study contributes to this work by demonstrating that diaphragm neurostimulation can also offer lung protection from ventilator injury, providing a potential solution to the dilemma of lung- versus diaphragm-protective ventilation. Our findings show that neurostimulation on every breath preserved [Formula: see text]/[Formula: see text], end-expiratory lung volume, alveolar homogeneity, and required lower pressures than lung-protective ventilation over 50 h in healthy pigs.

Setting the stage: current state of affairs and major challenges.

The global human immunodeficiency virus (HIV) pandemic reached staggering proportions over the past 2 decades, particularly in areas of sub-Saharan Africa and other developing countries. Tremendous increases in donor resources over the past decade have allowed for a rapid scale-up of antiretroviral treatment and greater access to basic care and prevention programs in countries worst affected by HIV infection and AIDS. These programs have had a tremendous impact on the lives of millions of individuals and have also created optimism and hope where previously there was despair. Major challenges remain in combating the current HIV pandemic with regard to access to treatment; efficiency, quality, and sustainability of current programs; and the scale-up of evidence-based, effective prevention strategies. The global health community and political leaders will need to overcome these challenges if a long-term effective response to the HIV pandemic is to be achieved.

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) randomised clinical trial: study protocol.

INTRODUCTION: Bloodstream infections are a leading cause of mortality and morbidity; the duration of treatment for these infections is understudied. METHODS AND ANALYSIS: We will conduct an international, multicentre randomised clinical trial of shorter (7 days) versus longer (14 days) antibiotic treatment among hospitalised patients with bloodstream infections. The trial will include 3626 patients across 60 hospitals and 6 countries. We will include patients with blood cultures confirming a pathogenic bacterium after hospital admission. Exclusion criteria will include patient factors (severe immunosuppression), infection site factors (endocarditis, osteomyelitis, undrained abscesses, infected prosthetic material) and pathogen factors (Staphylococcus aureus, Staphylococcus lugdunensis, Candida and contaminant organisms). We will leave the selection of specific antibiotics, doses and route of delivery to the discretion of treating physicians; no placebo control will be used given the diversity of pathogens and sources of bacteraemia. The intervention will be assignment of treatment duration to be 7 versus 14 days. We will minimise selection bias via central randomisation with variable block sizes, with concealed allocation until day 7 of adequate antibiotic treatment. The primary outcome is 90-day survival; we will test whether 7 days is non-inferior to 14 days of treatment, with a non-inferiority margin of 4% absolute mortality. Secondary outcomes include hospital and intensive care unit (ICU) mortality, relapse rates of bacteraemia, hospital and ICU length of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile infection, antibiotic allergy and adverse events and colonisation/infection with antibiotic-resistant organisms. ETHICS AND DISSEMINATION: The study has been approved by the ethics review board at each participating site. Sunnybrook Health Sciences Centre is the central ethics committee. We will disseminate study results via the Canadian Critical Care Trials Group and other collaborating networks to set the global paradigm for antibiotic treatment duration for non-staphylococcal Gram-positive, Gram-negative and anaerobic bacteraemia, among patients admitted to hospital. TRIAL REGISTRATION NUMBER: The BALANCE (Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness) trial was registered at www.clinicaltrials.gov (registration number: NCT03005145).

Uptake and retention on HIV pre-exposure prophylaxis among key and priority populations in South-Central Uganda.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) programmes have been initiated in sub-Saharan Africa to prevent HIV acquisition in key populations at increased risk. However, data on PrEP uptake and retention in high-risk African communities are limited. We evaluated PrEP uptake and retention in HIV hyperendemic fishing villages and trading centres in south-central Uganda between April 2018 and March 2019. METHODS: PrEP eligibility was assessed using a national risk screening tool. Programme data were used to evaluate uptake and retention over 12 months. Multivariable modified Poisson regression estimated adjusted prevalence ratios (aPR) and 95% Confidence intervals (CIs) of uptake associated with covariates. We used Kaplan-Meier analysis to estimate retention and multivariable Cox regression to estimate adjusted relative hazards (aRH) and 95% CIs of discontinuation associated with covariates. RESULTS AND DISCUSSION: Of the 2985 HIV-negative individuals screened; 2750 (92.1 %) were eligible; of whom 2,536 (92.2%) accepted PrEP. Male (aPR = 0.91, 95% CI = 0.85 to 0.97) and female (aPR = 0.85, 95% CI = 0.77 to 0.94) fisher folk were less likely to accept compared to HIV-discordant couples. Median retention was 45.4 days for both men and women, whereas retention was higher among women (log rank, p < 0.001) overall. PrEP discontinuation was higher among female sex workers (aRH = 1.42, 95% CI = 1.09 to 1.83) and female fisher folk (aRH = 1.99, 95% CI = 1.46 to 2.72), compared to women in discordant couples. Male fisher folk (aRH = 1.37, 95% CI = 1.07 to 1.76) and male truck drivers (aRH = 1.49, 95% CI = 1.14 to 1.94) were more likely to discontinue compared to men in discordant couples. Women 30 to 34 years tended to have lower discontinuation rates compared to adolescents 15 to 19 years (RH = 0.78 [95% CI = 0.63 to 0.96]). CONCLUSIONS: PrEP uptake was high, but retention was very low especially among those at the highest risk of HIV: fisher folk, sex workers and truck drivers and adolescent girls. Research on reasons for PrEP discontinuation could help optimize retention.

Meta-analysis of nitrogen removal in riparian buffers.

Riparian buffers, the vegetated region adjacent to streams and wetlands, are thought to be effective at intercepting and reducing nitrogen loads entering water bodies. Riparian buffer width is thought to be positively related to nitrogen removal effectiveness by influencing nitrogen retention or removal. We surveyed the scientific literature containing data on riparian buffers and nitrogen concentration in streams and groundwater to identify trends between nitrogen removal effectiveness and buffer width, hydrological flow path, and vegetative cover. Nitrogen removal effectiveness varied widely. Wide buffers (>50 m) more consistently removed significant portions of nitrogen entering a riparian zone than narrow buffers (0-25 m). Buffers of various vegetation types were equally effective at removing nitrogen but buffers composed of herbaceous and forest/herbaceous vegetation were more effective when wider. Subsurface removal of nitrogen was efficient, but did not appear to be related to buffer width, while surface removal of nitrogen was partly related to buffer width. The mass of nitrate nitrogen removed per unit length of buffer did not differ by buffer width, flow path, or buffer vegetation type. Our meta-analysis suggests that buffer width is an important consideration in managing nitrogen in watersheds. However, the inconsistent effects of buffer width and vegetation on nitrogen removal suggest that soil type, subsurface hydrology (e.g., soil saturation, groundwater flow paths), and subsurface biogeochemistry (organic carbon supply, nitrate inputs) also are important factors governing nitrogen removal in buffers.

Effect of Community Support Agents on Retention of People Living With HIV in Pre-antiretroviral Care: A Randomized Controlled Trial in Eastern Uganda.

BACKGROUND: Over 50% of people living with HIV (PLHIV) in sub-Saharan Africa are lost to follow-up between diagnosis and initiation of antiretroviral treatment during pre-antiretroviral (pre-ARV) care. The effect of providing home counseling visits by community support agents on 2-year retention in pre-ARV care was evaluated through a randomized controlled trial in eastern Uganda. METHODS: Four hundred newly screened HIV-positive patients were randomly assigned to receive posttest counseling alone (routine arm) or posttest counseling and monthly home counseling visits by community support agents to encourage them go back for routine pre-ARV care (intervention arm). The outcome measure was the proportion of new PLHIV in either arm who attended their scheduled pre-ARV care visits for at least 6 of the anticipated 8 visits in the first 24 months after HIV diagnosis. The difference between the 2 study arms was assessed using the χ and T tests. Mantel-Haenszel Risk Ratios and multivariate logistic models were used to assess the adjusted effect of the intervention on the outcome. RESULTS: In all models generated, participants receiving monthly home counseling visits were 2.5 times more likely to be retained in pre-ARV compared with those in standard care over a period of 24 months (adjusted risk ratio, 2.5; 95% confidence interval: 2.0 to 3.0). CONCLUSION: Monthly follow-up home visits by community workers more than doubled the retention of PLHIV in pre-ARV care in rural Uganda and can be applicable in similar resource-poor settings.

Examining advocacy and comprehensive cancer control.

The effectiveness of advocacy has been well documented and its use established as a common practice in furthering sound public health policy and practices. Efforts are underway to explain how advocacy has supported, shaped and influenced public policy concerning -- and the growth and development of -- comprehensive cancer control initiatives. The objective of this paper is to assess the history, current role and future of advocacy as a means of articulating the value of, and furthering, comprehensive cancer control practices. Comprehensive cancer control is approaching a critical moment in its development, and a unified approach is necessary to achieve common goals. A call to action for supporting and contributing to the success of a comprehensive approach to cancer control is more important today than it was 11 years ago. Advocacy is an essential strategy in that call to action.

Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda.

OBJECTIVE: The goal of this study was to assess azithromycin and/or benzathine penicillin for treatment of syphilis. METHODS: In a population-based study, participants with serologic syphilis (TRUST with TPHA confirmation) were offered 2.4 MU benzathine penicillin intramuscularly. Intervention arm participants received 1 g presumptive oral azithromycin. We assessed cure rates with penicillin or azithromycin given alone and in combination. Cure assessed after 10 months was defined as seroreversion or a 4-fold decrease in titer. The rate ratio (RR) of cure and 95% confidence intervals (95% CIs) were estimated by log binomial regression. RESULTS: Among 952 cases with syphilis, 18% received penicillin alone, 17% azithromycin only, and 65% dual treatment. The overall cure rate was 61%. Cure rates were lower in males compared with females (RR, 0.89; 95% CI, 0.80-0.99) and in subjects with initial titers > or =1:4 compared with < or =1:2 (RR, 0.77; 95% CI, 0.69-0.86). There was no significant differences in cure rates among HIV-positive and HIV-negative persons. With initial titers < or =1:2, there were no differences in cure rates by treatment regimen. However, with initial titers > or =1:4, significantly higher cure rates were observed with azithromycin alone (adjusted RR, 1.38; 95% CI, 0.97-1.96), and with dual treatment of azithromycin and benzathine penicillin (RR, 1.38; 95% CI, 1.03-1.87) compared with penicillin alone. CONCLUSION: Azithromycin alone or in combination with penicillin achieved higher cure rates than penicillin alone in cases with a high initial TRUST titer. In low-titer infections, the 3 drug combinations were equally effective. HIV status did not affect cure rates.