Yeast pex1 cells contain peroxisomal ghosts that import matrix proteins upon reintroduction of Pex1

Pex1 and Pex6 are two AAA-ATPases that play a crucial role in peroxisome biogenesis. We have characterized the ultrastructure of the Saccharomyces cerevisiae peroxisome-deficient mutants pex1 and pex6 by various high-resolution electron microscopy techniques. We observed that the cells contained peroxisomal membrane remnants, which in ultrathin cross sections generally appeared as double membrane rings. Electron tomography revealed that these structures consisted of one continuous membrane, representing an empty, flattened vesicle, which folds into a cup shape. Immunocytochemistry revealed that these structures lack peroxisomal matrix proteins but are the sole sites of the major peroxisomal membrane proteins Pex2, Pex10, Pex11, Pex13, and Pex14. Upon reintroduction of Pex1 in Pex1-deficient cells, these peroxisomal membrane remnants (ghosts) rapidly incorporated peroxisomal matrix proteins and developed into peroxisomes. Our data support earlier views that Pex1 and Pex6 play a role in peroxisomal matrix protein import

Early access to antiretroviral therapy versus standard of care among HIV-positive participants in Eswatini in the public health sector : the MaxART stepped-wedge randomized controlled trial

Introduction The WHO recommends antiretroviral treatment (ART) for all HIV-positive patients regardless of CD4 count or disease stage, referred to as "Early Access to ART for All" (EAAA). The health systems effects of EAAA implementation are unknown. This trial was implemented in a government-managed public health system with the aim to examine the "real world" impact of EAAA on care retention and viral suppression. Methods In this stepped-wedge randomized controlled trial, 14 public sector health facilities in Eswatini were paired and randomly assigned to stepwise transition from standard of care (SoC) to EAAA. ART-naive participants >= 18 years who were not pregnant or breastfeeding were eligible for enrolment. We used Cox proportional hazard models with censoring at clinic transition to estimate the effects of EAAA on retention in care and retention and viral suppression combined. Results Between September 2014 and August 2017, 3405 participants were enrolled. In SoC and EAAA respectively, 12-month HIV care retention rates were 80% (95% CI: 77 to 83) and 86% (95% CI: 83 to 88). The 12-month combined retention and viral suppression endpoint rates were 44% (95% CI: 40 to 48) under SoC compared to 80% (95% CI: 77 to 83) under EAAA. EAAA increased both retention (HR: 1 center dot 60, 95% CI: 1 center dot 15 to 2 center dot 21,p = 0.005) and retention and viral suppression combined (HR: 4.88, 95% CI: 2.96 to 8.05,p < 0.001). We also identified significant gaps in current health systems ability to provide viral load (VL) monitoring with 80% participants in SoC and 66% in EAAA having a missing VL at last contact. Conclusions The observed improvement in retention in care and on the combined retention and viral suppression provides an important co-benefit of EAAA to HIV-positive adults themselves, at least in the short term. Our results from this "real world" health systems trial strongly support EAAA for Eswatini and countries with similar HIV epidemics and health systems. VL monitoring needs to be scaled up for appropriate care management

PrEP uptake and delivery setting preferences among clients visiting six healthcare facilities in Eswatini

Due to the high HIV incidence among the general population of Eswatini, pre-exposure prophylaxis (PrEP) for HIV-exposed individuals is recommended. However, little is known about PrEP uptake and preferences in PrEP delivery healthcare setting among the general population. We conducted a secondary analysis of a randomized trial that aimed to increase PrEP uptake. All clients eligible for PrEP in one of six public-sector healthcare facilities in Eswatini were included. PrEP uptake was stratified by initial reason for visit (e.g. outpatient). Preferences in PrEP delivery setting were collected among those clients who initiated PrEP. A total of 1782 clients had their HIV acquisition risk assessed. Of these, 72% (1277/1782) were considered at risk by healthcare providers and, among them, 40% (517/1277) initiated PrEP. Uptake was higher among clients visiting specifically to initiate PrEP (93%), followed by HIV testing visits (45.8%) and outpatient visits (40%). Among those who initiated PrEP, preferred delivery settings were outpatient services (31%), HIV testing services (26%), family planning (21%) and antenatal services (14%). Men or those at high risk of HIV acquisition were more likely to prefer HIV testing and outpatient services, while young women were more likely to visit and express a preference for antenatal and family planning services. Outpatient services and HIV testing services could be preferable choices for PrEP delivery integration, due to the high PrEP uptake and delivery setting preferences of the populations who use these services. Antenatal and family planning could also be considered with a view to targeting the youngest women

Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data

BACKGROUND: Previous WHO guidance on tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis (PrEP) suggests measuring creatinine levels at PrEP initiation and regularly afterwards, which might represent barriers to PrEP implementation and uptake. We aimed to systematically review published literature on kidney toxicity among tenofovir disoproxil fumarate-based oral PrEP users and conducted an individual participant data meta-analysis (IPDMA) on kidney function among PrEP users in a global implementation project dataset. METHODS: In this systematic review and meta-analysis we searched PubMed up to June 30, 2021, for randomised controlled trials (RCTs) or cohort studies that reported on graded kidney-related adverse events among oral PrEP users (tenofovir disoproxil fumarate-based PrEP alone or in combination with emtricitabine or lamivudine). We extracted summary data and conducted meta-analyses with random-effects models to estimate relative risks of grade 1 and higher and grade 2 and higher kidney-related adverse events, measured by elevated serum creatinine or decline in estimated creatinine clearance or estimated glomerular filtration rate. The IPDMA included (largely unpublished) individual participant data from 17 PrEP implementation projects and two RCTs. Estimated baseline creatinine clearance and creatinine clearance change after initiation were described by age, gender, and comorbidities. We used random-effects regressions to estimate the risk in decline of creatinine clearance to less than 60 mL/min. FINDINGS: We identified 62 unique records and included 17 articles reporting on 11 RCTs with 13 523 participants in meta-analyses. PrEP use was associated with increased risk of grade 1 and higher kidney adverse events (pooled odds ratio [OR] 1·49, 95% CI 1·22-1·81; I2=25%) and grade 2 and higher events (OR 1·75, 0·68-4·49; I2=0%), although the grade 2 and higher association was not statistically significant and events were rare (13 out of 6764 in the intervention group vs six out of 6782 in the control group). The IPDMA included 18 676 individuals from 15 countries (1453 [7·8%] from RCTs) and 79 (0·42%) had a baseline estimated creatinine clearance of less than 60 mL/min (increasing proportions with increasing age). Longitudinal analyses included 14 368 PrEP users and 349 (2·43%) individuals had a decline to less than 60 mL/min creatinine clearance, with higher risks associated with increasing age and baseline creatinine clearance of 60·00-89·99 mL/min (adjusted hazard ratio [aHR] 8·49, 95% CI 6·44-11·20) and less than 60 mL/min (aHR 20·83, 12·83-33·82). INTERPRETATION: RCTs suggest that risks of kidney-related adverse events among tenofovir disoproxil fumarate-based oral PrEP users are increased but generally mild and small. Our global PrEP user analysis found varying risks by age and baseline creatinine clearance. Kidney function screening and monitoring might focus on older individuals, those with baseline creatinine clearance of less than 90 mL/min, and those with kidney-related comorbidities. Less frequent or optional screening among younger individuals without kidney-related comorbidities may reduce barriers to PrEP implementation and use. FUNDING: Unitaid, Bill & Melinda Gates Foundation, WHO

Casting a Wide Net: HIV Drug Resistance Monitoring in Pre-Exposure Prophylaxis Seroconverters in the Global Evaluation of Microbicide Sensitivity Project.

BACKGROUND: Evidence of HIV drug resistance (HIVDR) in individuals using oral pre-exposure prophylaxis (PrEP) who acquire HIV is limited to clinical trials and case studies. More data are needed to understand the risk of HIVDR with oral PrEP during PrEP rollout. Mechanisms to collect these data vary, and are dependent on cost, scale of PrEP distribution, and in-country infrastructure for the identification, collection, and testing of samples from PrEP seroconverters. METHODS: The Global Evaluation of Microbicide Sensitivity (GEMS) project, in collaboration with country stakeholders, initiated HIVDR monitoring among new HIV seroconverters with prior PrEP use in Eswatini, Kenya, South Africa, and Zimbabwe. Standalone protocols were developed to assess HIVDR among a national sample of PrEP users. In addition, HIVDR testing was incorporated into existing demonstration projects for key populations. LESSONS LEARNED: Countries are supportive of conducting a time-limited evaluation of HIVDR during the early stages of PrEP rollout. As PrEP rollout expands, the need for long-term HIVDR monitoring with PrEP will need to be balanced with maintaining national HIV drug resistance surveillance for pretreatment and acquired drug resistance. Laboratory capacity is a common obstacle to setting up a monitoring system. CONCLUSIONS: Establishing HIV resistance monitoring within PrEP programs is feasible. Approaches to drug resistance monitoring may evolve as the PrEP programs mature and expand. The methods and implementation support offered by GEMS assisted countries in developing methods to monitor for drug resistance that best fit their PrEP program needs and resources

ENIGMA-anxiety working group : Rationale for and organization of large-scale neuroimaging studies of anxiety disorders

Altres ajuts: Anxiety Disorders Research Network European College of Neuropsychopharmacology; Claude Leon Postdoctoral Fellowship; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 44541416-TRR58); EU7th Frame Work Marie Curie Actions International Staff Exchange Scheme grant 'European and South African Research Network in Anxiety Disorders' (EUSARNAD); Geestkracht programme of the Netherlands Organization for Health Research and Development (ZonMw, 10-000-1002); Intramural Research Training Award (IRTA) program within the National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, MH002781); National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, ZIA-MH-002782); SA Medical Research Council; U.S. National Institutes of Health grants (P01 AG026572, P01 AG055367, P41 EB015922, R01 AG060610, R56 AG058854, RF1 AG051710, U54 EB020403).Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders

The Costs of Creatinine Testing in the Context of a HIV Pre-Exposure Prophylaxis Demonstration Project in Eswatini

HIV treatment and prevention as well as other chronic disease care can require regular kidney function assessment based on a creatinine test. To assess the costs of creatinine testing in a public health care system, we conducted activity-based costing during a HIV pre-exposure prophylaxis (PrEP) demonstration project in the Hhohho region of Eswatini. Resource use was assessed by a laboratory technician and valued with government procurement prices, public sector salaries, and own cost estimates. Obtaining a blood sample in a clinic and performing a creatinine test in a high-throughput referral laboratory (&amp;gt; 660,000 blood tests, including &amp;gt; 120,000 creatinine tests, in 2018) were estimated to have cost, on average, $1.98 in 2018. Per test,$1.95 were variable costs ($1.38 personnel, ¢39 consumables, and ¢18 other costs) and ¢2.6 were allocated semi-fixed costs (¢1.1 laboratory equipment, ¢0.85 other, ¢0.45 consumables, and ¢1.3 personnel costs). Simulating different utilization of the laboratory indicated that semi-fixed costs of the laboratory (e.g., equipment purchase or daily calibration of the chemistry analyzer) contributed less than variable costs (e.g., per-test personnel time and test reagents) to the average creatinine test cost when certain minimum test numbers can be maintained. Our findings suggest, first, lower creatinine testing costs than previously used in cost and cost-effectiveness analyses of HIV services and, second, that investment in laboratory equipment imposed a relatively small additional cost on each performed test in the high-throughput referral laboratory

PrEP uptake and delivery setting preferences among clients visiting six healthcare facilities in Eswatini.

Due to the high HIV incidence among the general population of Eswatini, pre-exposure prophylaxis (PrEP) for HIV-exposed individuals is recommended. However, little is known about PrEP uptake and preferences in PrEP delivery healthcare setting among the general population. We conducted a secondary analysis of a randomized trial that aimed to increase PrEP uptake. All clients eligible for PrEP in one of six public-sector healthcare facilities in Eswatini were included. PrEP uptake was stratified by initial reason for visit (e.g. outpatient). Preferences in PrEP delivery setting were collected among those clients who initiated PrEP. A total of 1782 clients had their HIV acquisition risk assessed. Of these, 72% (1277/1782) were considered at risk by healthcare providers and, among them, 40% (517/1277) initiated PrEP. Uptake was higher among clients visiting specifically to initiate PrEP (93%), followed by HIV testing visits (45.8%) and outpatient visits (40%). Among those who initiated PrEP, preferred delivery settings were outpatient services (31%), HIV testing services (26%), family planning (21%) and antenatal services (14%). Men or those at high risk of HIV acquisition were more likely to prefer HIV testing and outpatient services, while young women were more likely to visit and express a preference for antenatal and family planning services. Outpatient services and HIV testing services could be preferable choices for PrEP delivery integration, due to the high PrEP uptake and delivery setting preferences of the populations who use these services. Antenatal and family planning could also be considered with a view to targeting the youngest women

Client and healthcare worker experiences with differentiated HIV treatment models in Eswatini.

IntroductionUniversal access to antiretroviral therapy (ART) is a cornerstone of Eswatini's national HIV strategy, and the number of people on ART in the country more than tripled between 2010 and 2019. Building on these achievements, the Ministry of Health (MOH) is scaling up differentiated service delivery, including less-intensive differentiated ART (DART) models for people doing well on treatment. We conducted a mixed-methods study to explore client and health care worker (HCW) perceptions of DART in Eswatini.MethodsThe study included structured site assessments at 39 purposively selected health facilities (HF), key informant interviews with 20 HCW, a provider satisfaction survey with 172 HCW and a client satisfaction survey with 270 adults.ResultsAll clients had been on ART for more than a year; 69% were on ART for ≥ 5 years. The most common DART models were Fast-Track (44%), Outreach (26%) and Community ART Groups (20%). HCW and clients appreciated DART, noting that the models often decrease provider workload and client wait time. Clients also reported that DART models helped them to adhere to ART, 96% said they were "very satisfied" with their current model, and 90% said they would recommend their model to others, highlighting convenience, efficiency and cost savings. The majority of HCW (52%) noted that implementation of DART reduced their workload, although some models, such as Outreach, were more labor-intensive. Each model had advantages and disadvantages; for example, clients concerned about stigma and inadvertent disclosure of HIV status were less interested in group models.ConclusionsClients in DART models were very satisfied with their care. HCW were also supportive of the new approach to HIV treatment delivery, noting its advantages to HF, HCW and to clients. Given the heterogeneous needs of people living with HIV, no single DART model will suit every client; a diverse portfolio of DART models is likely the best strategy