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The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flows origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of Americas aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

Impulsivity is a trait characteristic that is associated with sexual risk behavior. We examined correlates of impulsivity among 602 female sex workers (FSWs) enrolled in a sexual risk reduction intervention in Mexico (2016-2020). Impulsivity was positively associated with condomless sex with clients. Higher levels of impulsivity were associated with greater use of alcohol and heavy drugs, use of illicit drugs with clients, sexual/physical abuse history, and clinical depression. Global public health policy that supports free substance abuse treatment in combination with psychotherapeutic treatments (e.g. regulation management skills) and behavioral-focused therapy may help to reduce HIV/STI incidence in this vulnerable population.

HIV transmission in Ukraine is driven in part by unsafe injection drug use and sexual risk behaviors among people who inject drugs. We performed a random-intercept latent transition analysis on responses to 9 binary injection drug use and sexual behavior items from 1195 people who inject drugs with negative HIV status enrolled in a clustered randomized clinical trial of a social network intervention in Odessa, Donetsk, and Nikolayev, Ukraine. We identified 5 baseline classes: "Social injection/equipment-sharing" (11.7%), "Social injection" (25.9%), "High-risk collective preparation/splitting" (17.0%), "Collective preparation/splitting" (11.3%), and "Dealer-facilitated injection" (34.1%). After 12 months, intervention participants were more likely to transition to the "Collective preparation/splitting" class, which featured the fewest risk behaviors. Transitioning from the "Collective preparation/splitting" to the "Social injection/equipment-sharing" class was associated with HIV acquisition for control participants. Research to illuminate the stability of these patterns and how they may benefit from uniquely tailored programming to reduce unsafe behaviors is needed.

BackgroundWe evaluated the impact of a brief peer-led intervention on COVID-19 vaccination among people who inject drugs (PWID) presenting at syringe services program (SSP) locations in San Diego County, California.MethodsBetween March and July 2022, PWID aged ≥18 years without recent voluntary COVID-19 testing who were not up to date on COVID-19 vaccinations received a single-session motivational interviewing intervention (LinkUP) or an attention-matched didactic control condition from trained peer counselors at SSP sites randomized by week. Following either 30-minute session, counselors offered referrals to local vaccination services. Multivariable log binomial regression via generalized estimating equations assessed LinkUP effects on (1) acceptance of COVID-19 vaccination referrals immediately postintervention and (2) COVID-19 vaccine uptake at 6-month follow-up.ResultsCOVID-19 vaccination outcomes were obtained on 135 (90.6%) of 149 participants. In multivariable analysis, participants receiving LinkUP had greater acceptance of COVID-19 vaccination referrals than controls (adjusted relative risk, 3.50; 95% CI, 1.01-12.2) and were marginally more likely to report receiving a new COVID-19 vaccine dose (adjusted relative risk, 1.57; 95% CI, .99-2.48). After 6 months, 20% reported receiving a new vaccine dose; however, if COVID-19 vaccine had been available at SSPs, this proportion could have been as high as 34.3% (45.3% LinkUP vs 24.3% control; P = .01).ConclusionsA brief peer-led SSP-based intervention significantly improved COVID-19 vaccination among PWID. Further improvements could likely be obtained by supporting SSPs to offer COVID-19 vaccination on-site instead of relying on referrals.Clinical trials registrationClinicalTrials.gov NCT05181657.

BackgroundIn North America, overdose rates have steeply risen over the past five years, largely due to the ubiquity of illicitly manufactured fentanyls in the drug supply. Drug checking services (DCS) represent a promising harm reduction strategy and characterizing experiences of use and interest among people who inject drugs (PWID) is a priority.MethodsBetween February-October 2022, PWID participating in a cohort study in San Diego, CA and Tijuana, Mexico completed structured surveys including questions about DCS, socio-demographics and substance use behaviors. We used Poisson regression to assess factors associated with lifetime DCS use and characterized experiences with DCS and interest in free access to DCS.ResultsOf 426 PWID, 72% were male, 59% Latinx, 79% were experiencing homelessness and 56% ever experienced a nonfatal overdose. One third had heard of DCS, of whom 57% had ever used them. Among the latter, most (98%) reported using fentanyl test strips (FTS) the last time they used DCS; 66% did so less than once per month. In the last six months, respondents used FTS to check methamphetamine (48%), heroin (30%) or fentanyl (29%). Relative to White/non-Latinx PWID, those who were non-White/Latinx were significantly less likely to have used DCS [adjusted risk ratio (aRR): 0.22; 95% CI: 0.10, 0.47), as were PWID experiencing homelessness (aRR:0.45; 95% CI: 0.28, 0.72). However, a significant interaction indicated that non-White/Latinx syringe service program (SSP) clients were more likely to have used DCS than non-SSP clients (aRR: 2.79; CI: 1.09, 7.2). Among all PWID, 44% expressed interest in free access to FTS, while 84% (of 196 PWID) expressed interest in advanced spectrometry DCS to identify and quantify multiple substances.ConclusionsOur findings highlight low rates of DCS awareness and utilization, inequities by race/ethnicity and housing situation, high interest in advanced spectrometry DCS versus FTS, and the potential role of SSPs in improving access to DCS, especially among racial/ethnic minorities.

BackgroundPeople who inject drugs (PWID) have low rates of COVID-19 testing yet are vulnerable to severe disease. In partnership with a mobile syringe service program (SSP) in San Diego County, CA, we developed the evidence-, community-, and Social Cognitive Theory-informed "LinkUP" intervention (tailored education, motivational interviewing, problem-solving, and planning) to increase COVID-19 testing uptake among PWID.PurposeTo assess preliminary efficacy of LinkUP in increasing PWID COVID-19 testing in a pilot randomized controlled trial (RCT).MethodsWe referred participants (PWID, ≥18 years old, San Diego County residents who had not recently undergone voluntary COVID-19 testing) to mobile SSP sites that had been randomized (by week) to offer the active LinkUP intervention or didactic attention-control conditions delivered by trained peer counselors. Following either condition, counselors offered on-site rapid COVID-19 antigen testing. Analyses estimated preliminary intervention efficacy and explored potential moderation.ResultsAmong 150 participants, median age was 40.5 years, 33.3% identified as Hispanic/Latinx, 64.7% were male, 73.3% were experiencing homelessness, and 44.7% had prior mandatory COVID-19 testing. The LinkUP intervention was significantly associated with higher COVID-19 testing uptake (p

BackgroundDue to the persistence of COVID-19, it remains important to measure and examine potential barriers to COVID-19 prevention and treatment to avert additional loss of life, particularly among stigmatized populations, such as people who inject drugs (PWID), who are at high risk for contracting and spreading SARS-CoV-2. We assessed the psychometrics of a novel COVID-19 response-related discrimination scale among PWID, and characterized associations between COVID-19 response-related discrimination, resilience to adversity, and endorsement of COVID-19 disinformation.MethodsWe assessed internal reliability, structural validity and construct validity of a 4-item COVID-19 response-related discrimination scale among PWID living in San Diego County, completing interviewer-administered surveys between October 2020 and September 2021. Using negative binomial regression, we assessed the relationship between COVID-19 response-related discrimination and disinformation and the potential moderating role of resilience.ResultsOf 381 PWID, mean age was 42.6 years and the majority were male (75.6 %) and Hispanic (61.9 %). The COVID-19 response-related discrimination scale had modest reliability (α = 0.66, ω = 0.66) as a single construct with acceptable construct validity (all p ≤ 0.05). Among 216 PWID who completed supplemental surveys, a significant association between COVID-19 response-related discrimination and COVID-19 disinformation was observed, which was moderated by resilience (p = 0.044). Specifically, among PWID with high levels of resilience, endorsement of COVID-19 disinformation significantly increased as exposure to COVID-19 response-related discrimination increased (p = 0.011).ConclusionsThese findings suggest that intervening on COVID-19 response-related discrimination may offset the negative outcomes associated with COVID-19 disinformation.

IntroductionWe studied characteristics of COVID-19 vaccination uptake among people who inject drugs (PWID).MethodsParticipants aged ≥18 years who injected drugs ≤1 month ago were recruited into a community-based cohort from October 2020 to September 2021 in San Diego, California Poisson regression identified correlates of having had ≥1 COVID-19 vaccine dose based on semi-annual follow-up interviews through March 15, 2022.ResultsOf 360 participants, 74.7% were male, mean age was 42 years; 63.1% were Hispanic/Mexican/Latinx. More than one-third had ≥1 co-morbidity. HIV and HCV seroprevalence were 4.2% and 50.6% respectively; 41.1% lacked health insurance. Only 37.8% reported having ≥1 COVID-19 vaccine dose. None received ≥3 doses. However, of those vaccinated, 37.5% were previously unwilling/unsure about COVID-19 vaccines. Believing COVID-19 vaccines include tracking devices (adjusted incidence rate ratio [aIRR]: 0.62; 95% CI: 0.42,0.92) and lacking health insurance (aIRR: 0.60; 95% CI: 0.40,0.91) were associated with approximately 40% lower COVID-19 vaccination rates). Ever receiving influenza vaccines (aIRR: 2.16; 95%CI: 1.46, 3.20) and testing HIV-seropositive (aIRR: 2.51; 95% CI: 1.03, 6.10) or SARS-CoV-2 RNA-positive (aIRR: 1.82; 95% CI: 1.05, 3.16) independently predicted higher COVID-19 vaccination rates. Older age, knowing more vaccinated people, and recent incarceration were also independently associated with higher COVID-19 vaccination rates.ConclusionsOne year after COVID-19 vaccines became available to U.S. adults, only one third of PWID had received ≥1 COVID-19 vaccine dose. Multi-faceted approaches that dispel disinformation, integrate public health and social services and increase access to free, community-based COVID-19 vaccines are urgently needed.

BackgroundPeople who inject drugs (PWID) are vulnerable to SARS-CoV-2 infection. We examined correlates of COVID-19 testing among PWID in the U.S.-Mexico border region and described encounters with services representing potential opportunities (i.e., 'touchpoints') where COVID-19 testing could have been offered.MethodsBetween October, 2020 and September, 2021, participants aged ≥18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month completed surveys and SARS-CoV-2, HIV, and HCV serologic testing. Logistic regression identified factors associated with COVID-19 testing including potential touchpoints, comorbidities and COVID-19 related misinformation and disinformation.ResultsOf 583 PWID, 30.5% previously had a COVID-19 test. Of 172 PWID who tested SARS-CoV-2 seropositive (30.1%), 50.3% encountered at least one touchpoint where COVID-19 testing could have been offered within the prior six months. Factors independently associated with at least two fold higher odds of COVID-19 testing were living in San Diego, recent incarceration, receiving substance use treatment, and experiencing ≥1 chronic health condition. Homelessness, having received ≥1 dose of COVID-19 vaccine, and having a HIV or HCV test since the COVID-19 epidemic began were also independently associated with having had a prior COVID-19 test.ConclusionWe identified several factors independently associated with COVID-19 testing and multiple touchpoints where COVID-19 testing could be scaled up for PWID, such as SUD treatment programs and syringe service programs. Integrated health services are needed to improve access to rapid, free COVID-19 testing in this vulnerable population.

BackgroundAlong the Mexico-US border, illicitly manufactured fentanyls (fentanyl) have been detected in other illicit drugs, including street opioid formulations known as 'china white.' We studied correlates of recent overdose among people who inject drugs (PWID), focusing on the risk of knowlingly or unknowingly using fentanyl in china white.MethodsFrom October 2020 - September, 2021 we surveyed participants in San Diego, California and Tijuana, Mexico and employed Poisson regression to identify correlates of recent overdose.ResultsOf 612 PWID, most were male (74.0 %), Latinx (71.9 %), US residents (67.0 %). Mean age was 43 years. In the last six months, 15.8 % experienced overdose, 31.0 % knowingly used fentanyl and 11.1 % used china white, of whom 77.9 % did not think it contained fentanyl. After controlling for sex and race, factors independently associated with risk of overdose included knowingly using fentanyl, using china white and not believing it contained fentanyl, recent drug rehabilitation, being stopped/arrested by police, and homelessness. Further, PWID who believed china white contained fentanyl were less likely to use it.ConclusionsBoth intentional fentanyl use and unintentional exposure to fentanyl via china white were associated with overdose risk; however, PWID who believed china white contained fentanyl were less likely to use it. These data suggest that advanced drug checking systems should be implemented to empower PWID to avoid dangerous street formulations or to plan their drug use knowing its contents. Other overdose risk factors such as decreased tolerance following drug treatment, police interactions, and homelessness also require urgent intervention.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

BackgroundPeople who inject drugs (PWID) are vulnerable to acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We examined correlates of coronavirus disease 2019 (COVID-19) vaccine hesitancy among PWID in the US-Mexico border region, of whom only 7.6% had received ≥ 1 COVID-19 vaccine dose by September 2021.MethodsBetween October 2020 and September 2021, participants aged ≥ 18 years from San Diego, California, USA, and Tijuana, Baja California, Mexico, who injected drugs within the last month completed surveys and SARS-CoV-2, human immunodeficiency virus (HIV), and hepatitis C virus (HCV) serologic testing. Logistic regressions with robust standard error estimation via generalized estimating equations identified factors associated with being unsure or unwilling to receive COVID-19 vaccines.ResultsOf 393 participants, 266 (67.7%) were willing to receive COVID-19 vaccines and 127 (32.3%) were hesitant (23.4% unwilling and 8.9% unsure). Older participants, those with greater food insecurity, and those with greater concern about acquiring SARS-CoV-2 were more willing to be vaccinated. Higher numbers of chronic health conditions, having access to a smart phone or computer, and citing social media as one's most important source of COVID-19 information were independently associated with vaccine hesitancy. COVID-19-related disinformation was independently associated with vaccine hesitancy (adjusted odds ratio: 1.51 per additional conspiracy theory endorsed; 95% confidence interval: 1.31-1.74).ConclusionsNearly one third of people injecting drugs in the US-Mexico border region were COVID-19 vaccine hesitant, which was significantly associated with exposure to social media, disinformation and co-morbidities and inversely associated with food security and high perceived threat of COVID-19. Interventions that improve accurate knowledge of and trust in COVID-19 vaccines are needed in this vulnerable population.

Invasive fungal infections continue to increase as at-risk populations expand. The high associated morbidity and mortality with fungal diseases mandate the continued investigation of novel antifungal agents and diagnostic strategies that include surrogate biomarkers. Biologic markers of disease are useful prognostic indicators during clinical care, and their use in place of traditional survival end points may allow for more rapid conduct of clinical trials requiring fewer participants, decreased trial expense, and limited need for long-term follow-up. A number of fungal biomarkers have been developed and extensively evaluated in prospective clinical trials and small series. We examine the evidence for these surrogate biomarkers in this review and provide recommendations for clinicians and regulatory authorities.

Decriminalization of sex work is increasingly promoted as a structural measure to improve the health of vulnerable groups. In México, sex work is not illegal, but knowledge of policies' street-level impact is limited. This study describes typologies of police violence against female sex workers who inject drugs (FSWID), identifying risk and protective factors for violence exposure to inform policy responses. Survey data were collected during 2008-2010 among HIV-negative FSWID in a behavioral intervention in Tijuana and Ciudad Juarez (N = 584). Latent class analysis identified typologies of police violence in the past 6 months: asked for money, money taken, syringes taken, asked for sex, and sexually assaulted. Structural equation modeling (SEM) predicted latent class membership using sociodemographic, behavioral and risk environment factors, controlling for age, education, marital status, and city. Recent police violence was reported by 68% of FSWID, with three typologies emerging: Low (36.6%); Material (47.8%): having money/syringes taken or being asked for money; and Material/Sexual (15.7%): material violence and being asked for sex or sexually assaulted. In multivariable SEM, Material Violence was associated with: being jailed [adjusted Odds Ratio (aOR) = 4.34], HIV testing (aOR = 2.18), and trading sex indoors (aOR = 1.66). Factors associated with Material/Sexual Violence included: being jailed (aOR = 41.18), injecting with clients (aOR = 3.12), earning more money for sex without a condom (aOR = 2.88), being raped by a client (aOR = 2.13), drinking with clients (aOR = 2.03), receiving substance use treatment (aOR = 1.95), being

Shame may increase HIV risk among stigmatized populations. The Personal Feelings Questionnaire-2 (PFQ-2) measures shame, but has not been validated in Spanish-speaking or nonclinical stigmatized populations disproportionately affected by HIV in resource-limited settings. We examined the psychometric properties of the Spanish-translated PFQ-2 shame subscale among female sex workers in two Mexico-U.S. border cities. From 2016 to 2017, 602 HIV-negative female sex workers in Tijuana and Ciudad Juarez participated in an efficacy trial evaluating a behavior change maintenance intervention. Interviewer-administered surveys collected information on shame (10-item PFQ-2 subscale), psychosocial factors, and sociodemographics. Item performance, confirmatory factor analysis, internal consistency, differential item functioning by city, and concurrent validity were assessed. Response options were collapsed to 3-point responses to improve item performance, and one misfit item was removed. The revised 9-item shame subscale supported a single construct and had good internal consistency (Cronbach's α = .86). Notable differential item functioning was found but resulted in a negligible effect on overall scores. Correlations between the revised shame subscale and guilt (r = .79, p < .01), depression (r = .69, p < .01), and emotional support (r = -.28, p < .01) supported concurrent validity. The revised PFQ-2 shame subscale showed good reliability and concurrent validity in our sample, and should be explored in other stigmatized populations.

BackgroundPeople who inject drugs (PWID) have low rates of COVID-19 testing and vaccination and are vulnerable to severe disease. We partnered with a local, community-based syringe service program (SSP) in San Diego County, CA, to develop the single-session theory- and evidence-informed "LinkUP" intervention to increase COVID-19 testing and vaccination. This paper details the protocol for a pilot randomized controlled trial (RCT) of the LinkUP intervention.MethodsWith significant community input into study design considerations, including through our Community and Scientific Advisory Board, the LinkUP pilot RCT leverages an ongoing cohort study with adult (≥ 18 years) PWID in San Diego County to recruit participants who have not recently undergone voluntary COVID-19 testing and are unvaccinated. Eligible participants are referred to SSP locations randomized to offer the active intervention (involving tailored education, motivational interviewing, and problem-solving strategies) or a didactic attention-control condition (information sharing only). Both conditions are delivered by trained peer counselors hired by the SSP and were designed to be delivered at mobile (outdoor) SSP sites in ~ 30 min. Intake data assesses COVID-19 testing and vaccination history, health status, and harm reduction needs (to facilitate SSP referrals). At the end of either intervention condition, peer counselors offer onsite rapid COVID-19 antigen testing and COVID-19 vaccination referrals. Out-take and follow-up data (via SSP and state health department record linkages) confirms whether participants received the intervention, COVID-19 testing (and results) onsite or within six months, and vaccination referrals (and uptake) within six months. Planned analyses, which are not powered to assess efficacy, will provide adequate precision for effect size estimates for primary (COVID-19 testing) and secondary (vaccination) intervention outcomes. Findings will be disseminated widely including to local health authorities, collaborating agencies, and community members.DiscussionLessons from this community-based pilot study include the importance of gathering community input into study design, cultivating research-community partnerships based on mutual respect and trust, and maintaining frequent communication regarding unexpected events (e.g., police sweeps, neighborhood opposition). Findings may support the adoption of COVID-19 testing and vaccination initiatives implemented through SSPs and other community-based organizations serving vulnerable populations of people impacted by substance use and addiction. Trial registration This trial was registered prospectively at ClinicalTrials.gov (identifier NCT05181657).

Shame may increase HIV risk among stigmatized populations. The Personal Feelings Questionnaire–2 (PFQ-2) measures shame, but has not been validated in Spanish-speaking or nonclinical stigmatized populations disproportionately affected by HIV in resource-limited settings. We examined the psychometric properties of the Spanish-translated PFQ-2 shame subscale among female sex workers in two Mexico–U.S. border cities. From 2016 to 2017, 602 HIV-negative female sex workers in Tijuana and Ciudad Juarez participated in an efficacy trial evaluating a behavior change maintenance intervention. Interviewer-administered surveys collected information on shame (10-item PFQ-2 subscale), psychosocial factors, and sociodemographics. Item performance, confirmatory factor analysis, internal consistency, differential item functioning by city, and concurrent validity were assessed. Response options were collapsed to 3-point responses to improve item performance, and one misfit item was removed. The revised 9-item shame subscale supported a single construct and had good internal consistency (Cronbach’s α =.86). Notable differential item functioning was found but resulted in a negligible effect on overall scores. Correlations between the revised shame subscale and guilt (r =.79, p

Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19-associated fungal infections.

BackgroundFunctional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.MethodsWe did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.FindingsBetween Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.InterpretationInterferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.FundingThe National Institute of Allergy and Infectious Diseases (USA).

Tijuana, Mexico, has a concentrated HIV epidemic among overlapping key populations (KPs) including people who inject drugs (PWID), female sex workers (FSW), their male clients, and men who have sex with men (MSM). We developed a dynamic HIV transmission model among these KPs to determine the extent to which their unmet prevention and treatment needs is driving HIV transmission. Over 2020-2029 we estimated the proportion of new infections acquired in each KP, and the proportion due to their unprotected risk behaviours. We estimate that 43.7% and 55.3% of new infections are among MSM and PWID, respectively, with FSW and their clients making-up

BackgroundEvolutionary analyses of well-annotated human immunodeficiency virus (HIV) sequence data can provide insights into viral transmission patterns and associated factors. Here, we explored the transmission dynamics of the HIV-1 subtype B epidemic across the San Diego (US) and Tijuana (Mexico) border region to identify factors that could help guide public health policy.MethodsHIV pol sequences were collected from people with HIV in San Diego County and Tijuana between 1996-2018. A multistep phylogenetic approach was used to characterize the dynamics of spread. The contributions of geospatial factors and HIV risk group to the local dynamics were evaluated.ResultsPhylogeographic analyses of the 2034 sequences revealed an important contribution of local transmission in sustaining the epidemic, as well as a complex viral migration network across the region. Geospatial viral dispersal between San Diego communities occurred predominantly among men who have sex with men, with central San Diego being the main source (34.9%) and recipient (39.5%) of migration events. HIV migration was more frequent from San Diego county towards Tijuana than vice versa. Migrations were best explained by the driving time between locations.ConclusionsThe US-Mexico border may not be a major barrier to the spread of HIV, which may stimulate coordinated transnational intervention approaches. Whereas a focus on central San Diego has the potential to avert most spread, the substantial viral migration independent of central San Diego shows that county-wide efforts will be more effective. Combined, this work shows that epidemiological information gleaned from pathogen genomes can uncover mechanisms that underlie sustained spread and, in turn, can be a building block of public health decision-making.

INTRODUCTION: Performance-based assessments of social skills have detected impairments in people with severe mental illness and are correlated with functional outcomes in people with schizophrenia and bipolar disorder. The most common of these assessments, the Social Skills Performance Assessment (SSPA), has two communication scenarios and items measuring both social competence and appropriateness. As real-world competence and appropriateness appear to have different correlates, we hypothesized that SSPA Items measuring competence and appropriateness would be distinct and have different correlations with other outcomes. METHODS: We aggregated data from 557 people with schizophrenia, 106 with bipolar disorder, and 378 well controls from 4 separate research studies. All participants were assessed with both SSPA scenarios and other performance based and clinician-rated measures. A single expert rated the SSPA interactions for competence and appropriateness while blind to participant diagnoses. RESULTS: Participants with bipolar disorder and schizophrenia performed more poorly on every item of the SSPA than healthy controls. Items measuring social competence and appropriateness in communication were intercorrelated across scenarios, as were elements of socially competent communication, although the items measuring competence did not correlate substantially with appropriateness. Items assessing social competence, but not social appropriateness, correlated with better cognitive and functional performance and residential and financial independence. DISCUSSION: Social competence and social appropriateness were distinct elements of performance-based social skills with potential differences in their functional correlates. As both social competence and appropriateness impact functional outcomes, improvement in the measurement and treatment of appropriate communication seems to be an important goal.

BackgroundMediated and moderated processes that lead to intervention efficacy may underlie results of trials ruled as nonefficacious. The overall purpose of this study was to examine such processes to explain the findings of one of the largest, rigorously conducted behavioral intervention randomized controlled trials, EXPLORE.MethodsFour thousand two hundred ninety-five HIV-negative men who have sex with men (MSM) in the United States were randomized in a 2-armed trial. Participants completed follow-up and an HIV test every 6 months up to 48 months. We used multiple and causal mediation analyses to test 5 mediators, including safer sex self-efficacy and condomless receptive anal sex with HIV-positive or status-unknown partners on our primary outcome (HIV seroconversion). We also examined whether intervention effects on the mediators would be moderated by robust correlates of HIV among MSM, including stimulant use.ResultsThere were significant effects of the intervention on all hypothesized mediators. Stimulant use moderated the effect on condomless receptive anal sex In stratified multiple mediation models, we found that among MSM with low stimulant use, the intervention significantly prevented HIV by reducing condomless receptive anal sex with HIV-positive or status-unknown partners. Among MSM with higher stimulant use, there were no indirect effects of the intervention on HIV through any of the hypothesized mediators.ConclusionThe results suggest that the null effect found in the original EXPLORE trial might have occurred as a function of previously unexplored mediated and moderated processes. This study illustrates the value of testing mediated and moderated pathways in randomized trials, even in trials ruled out as nonefficacious.

Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.

There is increased concern that the quality, generalizability and reproducibility of biomedical research can be influenced by the sex of animals used. We studied the differences between male and female mice in response to invasive pulmonary mucormycosis including susceptibility to infection, host immune reaction and responses to antifungal therapy. We used diabetic ketoacidotic (DKA) or neutropenic mice infected with either Rhizopus delemar or Mucor circinelloides. The only difference detected was that when DKA mice were infected with M. circinelloides, female mice were more resistant to infection than male mice (median survival time of 5 vs. 2 days for female and male mice, respectively). However, a 100% lethality was detected among infected animals of both sexes. Treatment with either liposomal amphotericin B (L-AMB) or posaconazole (POSA) protected mice from infection and eliminated the difference seen between infected but untreated female and male mice. Treatment with L-AMB consistently outperformed POSA in prolonging survival and reducing tissue fungal burden of DKA and neutropenic mice infected with R. delemar or M. circinelloides, in both mouse sexes. While little difference was detected in cytokine levels among both sexes, mucormycosis infection in the DKA mouse model induced more inflammatory cytokines/chemokines involved in neutrophil (CXCL1) and macrophage (CXCL2) recruitment vs. uninfected mice. As expected, this inflammatory response was reduced in the neutropenic mouse model. Our studies show that there are few differences between female and male DKA or neutropenic mice infected with mucormycosis with no effect on the outcome of treatment or host immune response.

Objective: At a time of unprecedented attention to the public health impact of policing, it is imperative to understand the role of occupational safety in shaping officer behaviours. We assessed the longitudinal impact of police training in a quasi-experimental hybrid type-1 trial to reduce syringe-related occupational risk, while realigning police practices with public health prevention among people who inject drugs (PWID). Setting: Tijuana, Mexico. Participants: Of 1806 Tijuana municipal police trainees, 771 reporting previous exposure to syringes were randomly selected for follow-up. All participants completed at least one follow-up visit; attrition at 24 months was 8%. Intervention: Between 2015 and 2016, officers received a training intervention (Safety and Health Integration in the Enforcement of Laws on Drugs, SHIELD) bundling occupational needle stick injury (NSI) prevention with health promotion among PWID. Outcome measures: Longitudinal analysis with generalised linear mixed models to evaluate training impact on occupational NSI risk via NSI incidence and prevalidated Syringe Threat and Injury Correlates (STIC) score. This composite indicator integrates five self-reported risky syringe-handling practices (eg, syringe confiscation, breaking) and was used as a proxy for NSI risk due to reporting bias and concerns about reliability of NSI incidence reports. Results: No change in self-reported NSI incidence was observed, but significant reductions in risk (16.2% decrease in STIC score) occurred at 3 months, with a sustained decrease of 17.8% through 24 months, compared with pretraining (p

We analyzed the relationship between itraconazole (ITZ) and hydroxy-itraconazole (OH-ITZ) levels in 1,223 human samples. Overall, there was a statistically significant correlation between ITZ and OH-ITZ levels (Pearson's r, 0.7838), and OH-ITZ levels were generally higher than ITZ levels (median OH-ITZ:ITZ ratio, 1.73; range, 0.13 to 8.96). However, marked variability was observed throughout the range of ITZ concentrations. Thus, it is difficult to predict OH-ITZ concentrations based solely on ITZ levels.

BackgroundSevere coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.MethodsWe conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.ResultsA total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).ConclusionsBaricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

BackgroundEfforts to increase HIV testing, diagnosis and care are critical to curbing HIV epidemics among cisgender men who have sex with men (MSM) and transgender women (TW) in low- and middle-income countries (LMIC). We compared the effectiveness of respondent-driven sampling (RDS) and venue-based sampling (VBS) for identifying previously undiagnosed HIV infection among MSM and TW in Tijuana, Mexico.MethodsBetween March 2015 and December 2018, we conducted RDS within the social networks of MSM and TW and VBS at venues frequented by MSM and TW to socialize and meet sexual partners. Those reached by RDS/VBS who reported at least 18 years of age, anal sex with MSM or TW, and no previous HIV diagnosis were eligible for HIV testing.ResultsOf those screened following recruitment via RDS (N = 1232; 98.6% MSM; 1.3% TW), 60.8% (749/1232) were eligible for HIV testing and 97.5% (730/749) were tested for HIV infection, which led to the identification of 36 newly diagnosed HIV infections (4.9%). Of those screened following recruitment via VBS (N = 2560; 95.2% MSM; 4.6% TW), 56.5% (1446/2560) were eligible for HIV testing and 92.8% (1342/1446) were tested for HIV infection, which led to the identification of 82 newly diagnosed HIV infections (6.1%). The proportion of new HIV diagnoses did not differ by recruitment method (ratio = 0.81, 95% confidence interval: 0.55 to 1.18). Compared to those recruited via RDS, those tested following recruitment via VBS were younger, more likely to identify as gay, and more likely to identify as TW. Compared to those recruited via VBS, those newly diagnosed with HIV infection following recruitment via RDS reported higher levels of internalized stigma and were more likely to report injection drug use and a history of deportation from the United States.ConclusionsDespite RDS and VBS being equally effective for identifying undiagnosed HIV infection, each recruitment method reached different subgroups of MSM and TW in Tijuana. Our findings suggest that there may be benefits to using both RDS and VBS to increase the identification of previously undiagnosed HIV infection and ultimately support HIV care engagement among MSM and TW in Mexico and other similar LMIC.

BackgroundPeople who inject drugs may be at elevated SARS-CoV-2 risk due to their living conditions and/or exposures when seeking or using drugs. No study to date has reported upon risk factors for SARS-CoV-2 infection among people who inject drugs.Methods and findingsBetween October, 2020 and June, 2021, participants aged ≥18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month underwent interviews and testing for SARS-CoV-2 RNA and antibodies. Binomial regressions identified correlates of SARS-CoV-2 seropositivity.ResultsOf 386 participants, SARS-CoV-2 seroprevalence was 36.3% (95% CI: 31.5%-41.1%); 92.1% had detectable IgM antibodies. Only 37.5% had previously been tested. Seroprevalence did not differ by country of residence. None tested RNA-positive. Most (89.5%) reported engaging in ≥1 protective behavior [e.g., facemasks (73.5%), social distancing (46.5%), or increasing handwashing/sanitizers (22.8%)]. In a multivariate model controlling for sex, older age, and Hispanic/Latinx/Mexican ethnicity were independently associated with SARS-CoV-2 seropositivity, as was engaging in sex work (AdjRR: 1.63; 95% CI: 1.18-2.27) and having been incarcerated in the past six months (AdjRR: 1.49; 95% CI: 0.97-2.27). Comorbidities and substance using behaviors were not associated with SARS-CoV-2 seropositivity.ConclusionsIn this community-based study of people who inject drugs in the San Diego-Tijuana border region, over one third were SARS-CoV-2 seropositive, exceeding estimates from the general population in either city. We found no evidence that substance use behaviors were associated with an elevated risk of SARS-CoV-2 infection, but observed that circumstances in the risk environment, notably sex work and incarceration, were independently associated with higher SARS-CoV-2 seroprevalence. Our findings suggest that a binational policy response to COVID-19 mitigation is warranted beyond the closure of the U.S.-Mexico border. Furthermore, decriminalizing sex work and drug use could reduce the burden of COVID-19 among people who inject drugs.

Mobile phone technology may help sustain reductions in HIV/STI transmission risk behaviors among female sex workers (FSWs). We examined the efficacy of a text messaging intervention designed to maintain behavioral improvements in safer sex practices among 602 FSWs in Tijuana and Ciudad Juarez, Mexico. We hypothesized that FSWs who received brief risk reduction counseling and theory-based safer sex maintenance text messages over a 24-month period would have fewer incident HIV/STIs and report greater maintenance of safer sex practices compared to FSWs who received counseling and texts on maintaining general health. Theory-based texts did not change the odds of becoming infected with HIV/STIs in either study site. However, they did lead to significant, sustained protected sex in Tijuana. Theory-based text messaging interventions may help sustain reductions in sexual risk behavior among FSWs.Trial Registration Clinical Trials.gov. Identifier: NCT02447484.