Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal.

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.

Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort.

BACKGROUND: There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To investigate clinical laboratory markers of SARS-CoV-2 and PASC. DESIGN: Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). SETTING: 83 enrolling sites. PARTICIPANTS: RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. MEASUREMENTS: Participants completed questionnaires and standard clinical laboratory tests. RESULTS: Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. LIMITATION: Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. CONCLUSION: Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. PRIMARY FUNDING SOURCE: National Institutes of Health.

Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.

Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.

Ibrexafungerp is efficacious in a neutropenic murine model of pulmonary mucormycosis as monotherapy and combined with liposomal amphotericin B.

Ibrexafungerp (formerly SCY-078) is the first member of the triterpenoid class that prevents the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan by inhibiting the enzyme glucan synthase. We evaluated the in vivo efficacy of ibrexafungerp against pulmonary mucormycosis using an established murine model. Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with placebo (diluent control), ibrexafungerp (30 mg/kg, PO BID), liposomal amphotericin B (LAMB 10 mg/kg IV QD), posaconazole (PSC 30 mg/kg PO QD), or a combination of ibrexafungerp plus LAMB or ibrexafungerp plus PSC began 16 h post-infection and continued for 7 days for ibrexafungerp or PSC and through day 4 for LAMB. Ibrexafungerp was as effective as LAMB or PSC in prolonging median survival (range: 15 days to >21 days) and enhancing overall survival (30%-65%) vs placebo (9 days and 0%; P < 0.001) in mice infected with R. delemar. Furthermore, median survival and overall percent survival resulting from the combination of ibrexafungerp plus LAMB were significantly greater compared to all monotherapies (P ≤ 0.03). Similar survival results were observed in mice infected with M. circinelloides. Monotherapies also reduce the lung and brain fungal burden by ~0.5-1.0log10 conidial equivalents (CE)/g of tissue vs placebo in mice infected with R. delemar (P < 0.05), while a combination of ibrexafungerp plus LAMB lowered the fungal burden by ~0.5-1.5log10 CE/g compared to placebo or any of the monotherapy groups (P < 0.03). These results are promising and warrant continued investigation of ibrexafungerp as a novel treatment option against mucormycosis.

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.

BACKGROUND: Severe 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. METHODS: We 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. RESULTS: A 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). CONCLUSIONS: Baricitinib 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.).

Financial Vulnerability and Its Association with HIV Transmission Risk Behaviors Among People Who Inject Drugs in Kyrgyzstan.

The Family Resource Scale (FRS) is a three-factor financial vulnerability (FV) measure. FV may impact HIV transmission risks. Cross-sectional data from 279 people who inject drugs (PWID) in Kyrgyzstan surveyed April-October 2021 was used to validate the FRS and estimate associations between FV on past 6-month injection and sexual HIV risk outcomes. The three-factor FRS reflected housing, essential needs, and fiscal independence, and had good internal reliability and structural validity. Greater cumulative, housing, and essential needs FRS scores were associated with increased relative risk on public injection (adjusted risk ratio [aRR], 95% confidence interval [95% CI]: 1.03 [1.01, 1.04]; aRR [95% CI]: 1.06 [1.02, 1.09]; aRR [95% CI]: 1.06 [1.03, 1.08], respectively, all p < 0.001) and preparing injections with unsafe water sources (aRR [95% CI]: 1.04 [1.02, 1.07]; aRR [95% CI]: 1.09 [1.04, 1.15]; aRR [95% CI]: 1.08 [1.03, 1.14], respectively, all p < 0.001). Results suggest that PWID housing- and essential needs-related FV may exacerbate injection HIV transmission risks. Reducing PWIDs' FV may enhance the HIV response in Kyrgyzstan.

RESUMEN: La Escala de Recursos Familiares (FRS, por sus siglas en inglés) es una medida de vulnerabilidad financiera (FV, por sus siglas en inglés) de tres factores. La FV puede afectar los riesgos de transmisión del VIH. Se utilizaron datos transversales de 279 personas que se inyectan drogas (PWID, por sus siglas en inglés) en Kirguistán encuestadas de abril a octubre de 2021 para validar la FRS y estimar las asociaciones entre la FV en la inyección y los resultados de riesgo sexual del VIH en los últimos seis meses. La FRS de tres factores reflejaba la vivienda, las necesidades esenciales y la independencia fiscal, y presentaba una buena confiabilidad interna y validez estructural. Mayores puntajes acumulativos de la FRS en vivienda y necesidades esenciales se asociaron con un mayor riesgo relativo en la inyección pública (Riesgo relativo ajustada [aRR], Intervalo de Confianza del 95% [IC95%]: 1.03 [1.01, 1.04]; aRR [IC95%]: 1.06 [1.02, 1.09]; aRR [IC95%]: 1.06 [1.03, 1.08], respectivamente, todos p < 0.001) y la preparación de inyección con fuentes de agua no seguras (aRR [IC95%]: 1.04 [1.02, 1.07]; aRR [IC95%]: 1.09 [1.04, 1.15]; aRR [IC95%]: 1.08 [1.03, 1.14], respectivamente, todos p < 0.001). Los resultados sugieren que la FV relacionada con la vivienda y las necesidades esenciales de las PWID puede exacerbar los riesgos de transmisión del VIH por la inyección. Reducir la FV de las PWID puede mejorar la respuesta al VIH en Kirguistán.

Safe Injection Self-Efficacy is Associated with HCV and HIV Seropositivity Among People Who Inject Drugs in the San Diego-Tijuana Border Region.

Safe injection self-efficacy (SISE) is negatively associated with injection risk behaviors among people who inject drugs (PWID) but has not been examined in differing risk environments. We compared responses to a validated SISE scale between PWID in San Diego, California and Tijuana, Mexico, and examine correlates of SISE among PWID in Tijuana. PWID were recruited via street outreach for a longitudinal cohort study from October 2020-September 2021. We compared SISE scale items by city. Due to low variability in SISE scores among San Diego residents, we restricted analysis of factors associated with SISE to Tijuana residents and identified correlates of SISE score levels (low, medium, high) using ordinal logistic regression. Of 474 participants, most were male (74%), Latinx (78%) and Tijuana residents (73%). Mean age was 44. Mean SISE scores among San Diego residents were high (3.46 of 4 maximum) relative to Tijuana residents (mean: 1.93). Among Tijuana residents, White race and having previously resided in San Diego were associated with higher SISE scores. HCV and HIV seropositivity, homelessness, fentanyl use, polysubstance co-injection, and greater injection frequency were associated with lower SISE scores. We found profound inequalities between Tijuana and San Diego SISE, likely attributable to differential risk environments. Associations with fentanyl and polysubstance co-injection, injection frequency, and both HIV and HCV seropositivity suggest that SISE contribute to blood-borne infection transmission risks in Tijuana. SISE reflects an actionable intervention target to reduce injection risk behaviors, but structural interventions are required to change the risk environment.

RESUMEN: La autoeficacia de inyección segura (SISE, por sus siglas en inglés) se asocia negativamente con conductas de riesgo de inyección entre las personas que se inyectan drogas (PWID, por sus siglas en inglés), pero no se ha examinado en diferentes entornos de riesgo. Comparamos las respuestas a una escala validada de SISE entre PWID en San Diego, California, y Tijuana, México, y examinamos los correlatos de SISE entre PWID en Tijuana. Participantes fueron reclutados por medio de alcance callejero para un estudio de cohorte longitudinal entre octubre 2020 ­septiembre de 2021. Comparamos los ítems de la escala SISE por ciudad. Debido a la baja variabilidad en los puntajes SISE entre los residentes de San Diego, restringimos el análisis de factores asociados con SISE a los residentes de Tijuana e identificamos factores correlacionados con niveles de SISE (bajo, medio, alto) mediante regresión logística ordinal. De 474 participantes, la mayoría eran hombres (74%), latinx (78%) y residentes de Tijuana (73%). La edad promedio fue de 44 años. Los puntajes medios de SISE entre los residentes de San Diego fueron altos (3.46 de un máximo de 4) en comparación con los residentes de Tijuana (media: 1.93). Entre los residentes de Tijuana, la raza blanca y haber residido previamente en San Diego se asociaron con puntajes más altos de SISE. La seropositividad para HCV y VIH, la falta de vivienda, el uso de fentanilo, la co-inyección de múltiples sustancias y una mayor frecuencia de inyecciónes se asociaron con puntajes más bajos de SISE. Encontramos profundas desigualdades entre SISE en Tijuana y San Diego, probablemente atribuibles a diferentes entornos de riesgo. Las asociaciones con fentanilo y la co-inyección de múltiples sustancias, la frecuencia de inyección y la seropositividad tanto para VIH como para HCV sugieren que SISE contribuye a los riesgos de transmisión de infecciones transmitidas por la sangre en Tijuana. SISE refleja un objetivo de intervención accionable para reducir las conductas de riesgo de inyección, pero se requieren intervenciones estructurales para cambiar el entorno de riesgo.

Update on Outbreak of Fungal Meningitis among U.S. Residents who Received Epidural Anesthesia at Two Clinics in Matamoros, Mexico.

BACKGROUND: Public health officials are responding to an outbreak of fungal meningitis among patients who received procedures under epidural anesthesia at two clinics (River Side Surgical Center and Clinica K-3) in Matamoros, Mexico, during January 1-May 13, 2023. This report describes outbreak epidemiology and outlines interim diagnostic and treatment recommendations. METHODS: Interim recommendations for diagnosis and management were developed by the Mycoses Study Group Research Education and Consortium (MSGERC) based on the clinical experience of clinicians caring for patients during the current outbreak or during previous outbreaks of healthcare-associated fungal meningitis in Durango, Mexico, and the United States. RESULTS: As of July 7, 2023, the situation has evolved into a multistate and multinational fungal meningitis outbreak. A total of 185 residents in 22 U.S. states and jurisdictions have been identified who might be at risk of fungal meningitis because they received epidural anesthesia at the clinics of interest in 2023. Among these patients, 11 suspected, 10 probable, and 10 confirmed U.S. cases have been diagnosed, with severe vascular complications and eight deaths occurring. Fusarium solani species complex has been identified as the causative agent, with antifungal susceptibility testing of a single isolate demonstrating poor in vitro activity for most available antifungals. Currently, triple therapy with intravenous voriconazole, liposomal amphotericin B, and fosmanogepix is recommended. CONCLUSIONS: Efforts to understand the source of this outbreak and optimal treatment approaches are ongoing, but infectious diseases physicians should be aware of available treatment recommendations. New information will be available on CDC's website.

Remdesivir for the Treatment of Covid-19 - Final Report.

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).

Preliminary Efficacy of a Theory-Informed Intervention to Increase COVID-19 Testing Uptake Among People Who Inject Drugs in San Diego County: Findings From a Pilot Randomized Controlled Trial.

BACKGROUND: People 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. PURPOSE: To assess preliminary efficacy of LinkUP in increasing PWID COVID-19 testing in a pilot randomized controlled trial (RCT). METHODS: We 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. RESULTS: Among 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 < .0001). Homelessness moderated intervention effects; LinkUP increased COVID-19 testing uptake more among participants experiencing homelessness (adjusted risk ratio [aRR]: 1.80; 95% CI: 1.56-2.09; p < .0001) than those not experiencing homelessness (aRR: 1.20; 95% CI: 1.01-1.43; p = .04). CONCLUSIONS: Findings from this pilot RCT support the preliminary efficacy of the "LinkUP" intervention to increase COVID-19 testing among PWID and underscore the importance of academic-community partnerships and prevention service delivery through SSPs and other community-based organizations serving vulnerable populations.

People who inject drugs (PWID) are vulnerable to severe COVID-19 disease yet have low rates of COVID-19 testing. We partnered with a syringe service program (SSP) in San Diego County, CA, to develop "LinkUP," an evidence- and community-informed intervention. Specifically, LinkUP used tailored education, motivational interviewing, and problem-solving and planning strategies to increase COVID-19 testing uptake among PWID. This study was a pilot randomized controlled trial (RCT) designed to assess the preliminary efficacy of LinkUP in increasing PWID COVID-19 testing. We referred participants (PWID, ≥18 years old, San Diego residents without recent voluntary COVID-19 testing) to mobile SSP sites that had been randomized (by week). Trained peer counselors then offered LinkUP or an educational control condition lasting the same length (~30 minutes). After either condition, counselors offered on-site rapid COVID-19 antigen testing. Among 150 participants, our analyses found that the LinkUP intervention was associated with higher COVID-19 testing uptake, especially for participants experiencing homelessness. In summary, our findings from this pilot RCT support the preliminary efficacy of the "LinkUP" intervention in increasing COVID-19 testing among PWID. This study also underscores the importance of academic-community partnerships and prevention service delivery through SSPs and other community-based organizations serving vulnerable populations.

Injection Drug Use and Sexual Risk Behaviors Among People who Inject Drugs in Ukraine: A Random-Intercept Latent Transition Analysis.

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.

Effects of a social network intervention on HIV seroconversion among people who inject drugs in Ukraine: moderation by network gender composition.

BACKGROUND: Women who inject drugs in Ukraine are disproportionately burdened by HIV. To help address the needs of this population, a greater understanding of how interventions may uniquely benefit women who inject drugs is needed. METHODS: Data come from a randomized controlled trial of a social network intervention targeting people who inject drugs in Ukraine (N = 1195). Indexes, plus two of their injection network members, received HIV testing and counseling (control arm) or HIV testing and counseling plus a social network intervention (intervention arm), in which indexes were trained to influence network members' risk behaviors. We used Cox regressions with interaction terms to assess differences in time to HIV seroconversion between arms by network gender composition and gender of the index. For significant interaction terms, we calculated simple effects, generated survival functions using Kaplan-Meier methods, and compared survival curves using log-rank tests. RESULTS: At 12 months, there were 45 seroconversions among women (40.0 [28.3, 51.7] per 100 person years) and 111 among men (28.4 [23.1, 33.6] per 100 person years) in the control arm; there were 27 seroconversions among women (17.1 [10.7, 23.6] per 100 person years) and 77 among men (18.7 [14.5, 22.9] per 100 person years) in the intervention arm. Network gender composition (but not gender of the index) moderated the intervention effect on HIV incidence (p < 0.05). Specifically, the intervention appeared to be even more protective against HIV acquisition as female gender composition increased. In the intervention arm, the HIV seroconversion hazard rate was 44% lower with 1 network female; 61% lower with 2 network females; and 72% lower with 3 network females. CONCLUSIONS: A greater number of women in an injection network, coupled with the provision of risk-reduction strategies, is associated with HIV risk-mitigation, though the mechanisms through which this occurs remain unclear. Findings can support new research and practice directions that prioritize women who inject drugs and more thoughtfully support their health and wellbeing.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Correlates of impulsivity among female sex workers in Mexico.

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.

Correlates of Coronavirus Disease 2019 (COVID-19) Vaccine Hesitancy Among People Who Inject Drugs in the San Diego-Tijuana Border Region.

BACKGROUND: People 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. METHODS: Between 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. RESULTS: Of 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). CONCLUSIONS: Nearly 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.

The Antifungal and Anti-Pneumocystis Activities of the Novel Compound A3IS (Mycosinate).

A3IS (Mycosinate) is a synthetic product which only contains ingredients found naturally within honey. A3IS is a broad-spectrum antimicrobial product which produces a sustained release of hydrogen peroxide at low but therapeutic levels. The product elicits this release through an enzymatic reaction between glucose oxidase and the substrate glucose once the product is hydrated. As medical uses for different honeys are being re-evaluated, the purpose of this study was to evaluate the in vitro effects of A3IS against a comprehensive panel of human pathogens, including Pneumocystis species, providing a unique assessment against a panel of eukaryotic pathogens. Without exception, A3IS exhibited significant efficacy at 50% and 100% inhibitory concentrations against a broad spectrum of human pathogens including yeasts, molds (both hyaline and dematiaceous), and dimorphic fungi. Notably, A3IS was effective against fungal strains with a high level of resistance to fluconazole or voriconazole. The 50% inhibitory concentrations for Pneumocystis carinii and P. murina (surrogates for P. jirovecii) were considered "Marked" and "Moderate" on an established rank scale, and would be considered for in vivo studies, based on an established in vitro-in vivo pipeline. These results indicate that A3IS is a novel anti-fungal agent against an extensive range of human fungal pathogens.

A cross-sectional study of factors associated with COVID-19 testing among people who inject drugs: missed opportunities for reaching those most at risk.

BACKGROUND: People 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. METHODS: Between 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. RESULTS: Of 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. CONCLUSION: We 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.

Sexual minority status modifies the association between HIV risk behavior and prevalent mood or anxiety disorders in British Columbia, Canada.

PURPOSE: This study aimed at determining to what extent sexual minority status modifies the association between HIV risk behavior and prevalent mood or anxiety disorder diagnosis in British Columbia (BC), Canada, using a population-based survey. METHODS: This analysis was based on the cross-sectional 2013-2014 Canadian Community Health Survey. The sample was restricted to respondents in BC with valid responses to the survey items considered. A multivariable logistic model, where the behavioral HIV risk score exposure was nested into the sexual minority status modifier, estimated the odds of having a prevalent mood or an anxiety disorder. The behavioral HIV risk score (0, 1, 2, ≥ 3) included the following five measures: (1) age at first intercourse < 14 years, (2) condom use during last intercourse, (3) history of sexually transmitted infections, (5) number of sexual partners in the past 12 months (< 4, ≥ 4), and substance use in the past 12 months. RESULTS: Of the weighted sample (2,521,252), 97% (95% confidence interval (CI) 97-98) were heterosexual, while 3% (95% CI 2-3) were lesbian, gay, and bisexual (LGB). The prevalence of a mood or anxiety disorder diagnosis was 12% (95% CI 11-13). For every 1-level increment in the behavioral HIV risk score, the adjusted odds ratio of having a prevalent mood or anxiety disorder diagnosis was 1.29 (95% CI 1.03-1.54) for heterosexual respondents and 2.37 (95% CI 1.84-2.90) for LGB respondents. CONCLUSION: Sexual minority status modified the relationship between HIV risk behavior and prevalent mood or anxiety disorders, with a stronger association among LGB respondents. Healthcare providers should prioritize integrated care that addresses the intersectionality between sexual risk, substance use, and mood or anxiety disorders.

Cohort profile: the Kyrgyzstan InterSectional Stigma (KISS) injection drug use cohort study.

BACKGROUND: In Kyrgyzstan and other Eastern European and Central Asian countries, injection drug use and HIV-related intersectional stigma undermines HIV prevention efforts, fueling a rapidly expanding HIV epidemic. The Kyrgyzstan InterSectional Stigma (KISS) Injection Drug Use Cohort is the first study designed to assess the impact of drug use, methadone maintenance treatment (MMT) and HIV stigma experiences among people who inject drugs (PWID) on HIV prevention service utilization. METHODS: Adult PWID were recruited from Bishkek city and the surrounding rural Chuy Oblast region in northern Kyrgyzstan via modified time location sampling and snowball sampling. All participants completed a baseline rapid HIV test and interviewer-administered survey. A subsample of participants were prospectively followed for three months and surveyed to establish retention rates for future work in the region. Internal reliability of three parallel stigma measures (drug use, MMT, HIV) was evaluated. Descriptive statistics characterize baseline experiences across these three stigma types and HIV prevention service utilization, and assess differences in these experiences by urbanicity. RESULTS: The KISS cohort (N = 279, 50.5% Bishkek, 49.5% Chuy Oblast) was mostly male (75.3%), ethnically Russian (53.8%), median age was 40 years old (IQR 35-46). Of the 204 eligible participants, 84.9% were surveyed at month 3. At baseline, 23.6% had a seropositive rapid HIV test. HIV prevention service utilization did not differ by urbanicity. Overall, we found 65.9% ever utilized syringe service programs in the past 6 months, 8.2% were utilizing MMT, and 60.8% met HIV testing guidelines. No participants reported PrEP use, but 18.5% had heard of PrEP. On average participants reported moderate levels of drug use (mean [M] = 3.25; α = 0.80), MMT (M = 3.24; α = 0.80), and HIV stigma (M = 2.94; α = 0.80). Anticipated drug use stigma from healthcare workers and internalized drug use stigma were significantly higher among PWID from Bishkek (p < 0.05), while internalized HIV stigma among PWID living with HIV was significantly greater among PWID from Chuy Oblast (p = 0.03). CONCLUSION: The KISS cohort documents moderate levels of HIV-related intersectional stigma and suboptimal engagement in HIV prevention services among PWID in Kyrgyzstan. Future work will aim identify priority stigma reduction intervention targets to optimize HIV prevention efforts in the region.

Aspergillus Polymerase Chain Reaction-An Update on Technical Recommendations, Clinical Applications, and Justification for Inclusion in the Second Revision of the EORTC/MSGERC Definitions of Invasive Fungal Disease.

Aspergillus polymerase chain reaction testing of blood and respiratory samples has recently been included in the second revision of the EORTC/MSGERC definitions for classifying invasive fungal disease. This is a result of considerable efforts to standardize methodology, the availability of commercial assays and external quality control programs, and additional clinical validation. This supporting article provides both clinical and technical justifications for its inclusion while also summarizing recent advances and likely future developments in the molecular diagnosis of invasive aspergillosis.