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BackgroundInjectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study.MethodsThe HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094.FindingsOf the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation.InterpretationLong-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance.FundingDivision of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Abstract Salmonella utilizes a type 3 secretion system to translocate virulence proteins (effectors) into host cells during infection1. The effectors modulate host cell machinery to drive uptake of the bacteria into vacuoles, where they can establish an intracellular replicative niche. A remarkable feature of Salmonella invasion is the formation of actin-rich protuberances (ruffles) on the host cell surface that contribute to bacterial uptake. However, the membrane source for ruffle formation and how these bacteria regulate membrane mobilization within host cells remains unclear. Here, we show that Salmonella exploits membrane reservoirs for the generation of invasion ruffles. The reservoirs are pre-existing tubular compartments associated with the plasma membrane (PM) and are formed through the activity of RAB10 GTPase. Under normal growth conditions, membrane reservoirs contribute to PM homeostasis and are preloaded with the exocyst subunit EXOC2. During Salmonella invasion, the bacterial effectors SipC, SopE2, and SopB recruit exocyst subunits from membrane reservoirs and other cellular compartments, thereby allowing exocyst complex assembly and membrane delivery required for bacterial uptake. Our findings reveal an important role for RAB10 in the establishment of membrane reservoirs and the mechanisms by which Salmonella can exploit these compartments during host cell invasion.

IntroductionInsulin pumps and continuous glucose monitors (CGM) have many benefits in the management of type 1 diabetes. Unfortunately disparities in technology access occur in groups with increased risk for adverse effects (eg, low socioeconomic status [SES], public insurance).Research design & methodsUsing 2015 to 2016 data from 4,895 participants from the T1D Exchange Registry, a structural equation model (SEM) was fit to explore the hypothesized direct and indirect relationships between SES, insurance features, access to diabetes technology, and adverse clinical outcomes (diabetic ketoacidosis, hypoglycemia). SEM was estimated using the maximum likelihood method and standardized path coefficients are presented.ResultsHigher SES and more generous insurance coverage were directly associated with CGM use (β = 1.52, SE = 0.12, P < .0001 and β = 1.21, SE = 0.14, P < .0001, respectively). Though SES displayed a small inverse association with pump use (β = -0.11, SE = 0.04, P = .0097), more generous insurance coverage displayed a stronger direct association with pump use (β = 0.88, SE = 0.10, P < .0001). CGM use and pump use were both directly associated with fewer adverse outcomes (β = -0.23, SE = 0.06, P = .0002 and β = -0.15, SE = 0.04, P = .0002, respectively). Both SES and insurance coverage demonstrated significant indirect effects on adverse outcomes that operated through access to diabetes technology (β = -0.33, SE = 0.09, P = .0002 and β = -0.40, SE = 0.09, P < .0001, respectively).ConclusionsThe association between SES and insurance coverage and adverse outcomes was primarily mediated through diabetes technology use, suggesting that disparities in diabetes outcomes have the potential to be mitigated by addressing the upstream disparities in technology use.

O principal objetivo desse artigo é avaliar os indicadores de qualidade de vida no trabalho (QVT) para os professores universitários, e comparar os indicadores de QVT em universidades públicas no Brasil e no Canadá. A amostra deste estudo é constituída por 205 professores de Minas Gerais e 269 do Quebec. Os dados foram coletados através de um questionário online aplicado em fevereiro e março de 2013. Três diferenças significativas foram encontradas entre as duas amostras: sentido no trabalho, comprometimento afetivo e comprometimento de continuidade. Os professores brasileiros parecem encontrar mais sentido no trabalho do que os canadenses e têm mais comprometimento afetivo com suas instituições.