The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.

ObjectivesTo describe heavy alcohol use patterns and correlates in a diverse sample of MSM.MethodsWe used respondent-driven sampling (RDS) to enroll 252 alcohol-using MSM in San Francisco from March 2015-July 2017. We examined heavy alcohol use patterns and conducted RDS-adjusted multivariable analyses to characterize correlates of hazardous alcohol consumption and binge drinking.ResultsRDS-adjusted prevalence of weekly and at least weekly binge drinking was 24.9% and 19.3%, respectively. Hazardous consumption was common; prevalence of mid- and high-levels of hazardous drinking was 11.4% and 29.9%, respectively. In multivariable analyses, identifying as Hispanic/Latino or mixed/other race; being moderately or extremely interested in reducing alcohol use; ever receiving alcohol treatment; using ecstasy; reporting syphilis diagnosis; and having more than 5 male partners were independently associated with hazardous alcohol consumption. Less hazardous consumption was associated with having a bachelor's degree or completing post-graduate studies; and not being in a relationship. Reporting chlamydia infection; being somewhat, moderately or extremely interested in reducing alcohol use; and having multiple male sex partners were associated with higher odds of at least weekly binge drinking. Lower odds of binge drinking were associated with completing post-graduate studies. Moreover, for the outcomes of hazardous alcohol consumption and binge-drinking, we observed significant interaction effects between race/ethnicity and interest in reducing alcohol, past receipt of alcohol treatment, use of ecstasy, syphilis diagnosis, and number of male partners.ConclusionAmong alcohol-using MSM in San Francisco, heavy drinking patterns were common and independently associated with greater number of male sexual partners and sexually transmitted infections (STI). Moreover, significant racial/ethnic and socioeconomic disparities related to heavy alcohol use were observed and race/ethnicity modified the effect of the risk factors associated with these outcomes. These findings underscore the need to develop more MSM-specific interventions that jointly address heavy alcohol use and HIV/STI risk, as well as culturally-tailored and targeted strategies to alleviate health disparities.

Increasing rates of sexually transmitted infections (STIs) in the United States among men who have sex with men (MSM) have raised concerns that pre-exposure prophylaxis (PrEP) has been associated with higher engagement in condomless anal intercourse (CAI). While partnership characteristics have previously been found to influence condom use, the extent to which PrEP use may modify their effect on CAI remains unknown. A secondary analysis of 535 sexual partnerships from a cross-sectional study in San Francisco was conducted to evaluate interactions between PrEP use and partnership characteristics on CAI. Bivariate and multivariate generalized estimating equation (GEE) logistic regression models were used to estimate relative measures of association, adjusted for confounding by seroconcordance and partnership type, as well as account for repeated partnerships per respondent. Partnerships where both partners used biomedical prevention had significantly greater odds of CAI [odds ratio (OR) = 5.19, 95% confidence interval (CI): 2.27-11.9] compared to those where only one partner used biomedical prevention, while those where neither partner used biomedical prevention had significantly lower odds of CAI (OR = 0.61, 95% CI: 0.40-0.93). There was no significant association between meeting place (online vs. offline) and sexual risk taking (OR = 1.03, p = 0.894). Having one partner disclose their HIV status (compared to neither partner having disclosed) was associated with significantly higher odds of CAI among partnerships of PrEP-using MSM [adjusted OR (aOR) = 5.28, 95% CI: 1.91-14.61], while the association was not significant among the partnerships of non-PrEP-using MSM (aOR = 1.29, 95% CI: 0.75-2.21). Differences in condom use among MSM using PrEP may not be well explained by differences in the effect of partnership characteristics. MSM using PrEP appear to commonly practice biomedical matching and high engagement in CAI with other biomedical prevention users, which could indicate relatively concentrated sexual networks and partly explain their disproportionate risk for STIs. Future studies should further investigate biomedical matching to develop interventions that further promote the sexual health of those using PrEP.

Background: Coaches delivering telemental health services as part of an employer-sponsored benefit may increase access to affordable and effective care. We examined the effectiveness of evidence-based telecoaching delivered via videoconferencing to people requesting mental health services during the coronavirus disease 2019 (COVID-19) pandemic. Materials and Methods: We analyzed data from 1,228 employees (mean age = 35 -8 years; 67.2% female) who utilized telecoaching through the Modern Health benefits platform between March 11, 2020 and March 11, 2021. We used paired samples t tests to examine changes in well-being, burnout, absenteeism, and presenteeism before and after telecoaching and moderated regressions to test whether these changes depended on visit utilization. We analyzed rates of clinical improvement for well-being and reduction from entry in symptoms for burnout. We conducted analyses in the full sample and participants presenting with elevated symptoms at baseline. Results: Participants utilized an average of 2.6 visits. Wellbeing (p = 0.02) significantly increased, while both presenteeism (p < 0.001) and absenteeism (p < 0.001) significantly decreased at follow-up in our full sample, but represented negligible effect sizes. Burnout was not found to have significantly changed at follow-up in our full sample (p = 0.69). In participants beginning care with elevated depressive-related symptoms, well-being significantly increased (p < 0.001) and 46.3% experienced a clinically relevant improvement. In par-ticipants beginning care with elevated levels of burnout, burnout significantly decreased (p < 0.001) and 20.9% experienced a reduction in symptoms from entry. Conclusions: Leveraging videoconferencing, telecoaching had positive effects on mental health and workplace outcomes, even during the COVID-19 pandemic. Evidence-based telecoaching represents a promising option for achieving optimal outcomes in people who need mental health services.