Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Unintentional ingestion of putative delta-8 tetrahydrocannabinol by two youth requiring critical care: a case report.

BACKGROUND: Delta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid from the cannabis plant that can be synthetically converted from cannabidiol (CBD). Most states permit the full or restricted sale of hemp and hemp-derived CBD products, and therefore, delta-8 THC products are on the rise. Delta-8 THC consumption can cause intoxication. Products are often sold in edible form and occasionally in packaging that appears similar to candy. Clinical presentations for delta-8 THC ingestions are understudied and may differ from those described for delta-9 THC ingestions. CASE PRESENTATION: This case report describes unintentional ingestions of putative delta-8 THC by two pediatric patients that results in admission to the pediatric intensive care unit. The ingestions were of putative delta-8 THC infused product that resembled popular candies. Both patients developed periods of bradypnea with continued intermittent periods of agitation. Medical intervention included observation, noninvasive positive pressure ventilation via high flow nasal cannula, and intubation-but was not needed for both patients. Although family noted ongoing irritability for the patients, both were discharged approximately 45 h after ingestion. Delta-8 THC ingestion is reliant on self-report. CONCLUSIONS: As the availability of delta-8 THC increases, along with associated pediatric exposures, it is imperative for health care providers to quickly recognize and provide adequate treatment. While there is no specific antidote for THC intoxication beyond supportive care, providers can play an important role in prevention by educating parents and guardians on safe cannabis storage and by documenting cases for adverse event monitoring.

In Vitro Testing of Trichomonas vaginalis Drug Susceptibility: Evaluation of Minimal Lethal Concentrations for Metronidazole and Tinidazole That Correspond With Treatment Failure.

BACKGROUND: The only drugs approved by the US Food and Drug Administration for oral treatment of trichomoniasis belong to the 5-nitroimidazole group. Most individuals infected with Trichomonas vaginalis can be cured with a standard treatment of metronidazole or tinidazole, but it is estimated that more than 159,000 people fail treatment each year. Although a minimal lethal concentration (MLC) corresponding to treatment failure has been reported for metronidazole, the MLC for tinidazole associated with treatment failure has not been determined. We conducted a study using T. vaginalis isolates from women with reported treatment success or failure to determine these values. METHODS: We measured MLCs of 47 isolates obtained from women who had failed metronidazole treatment, 33 isolates from women who had failed tinidazole treatment, and 48 isolates from women successfully cured with metronidazole. The cutoff was calculated as the 95th percentile of MLCs of susceptible isolates for each drug. RESULTS: Our data confirmed that the MLC previously associated with metronidazole treatment failure is ≥50 µg/mL and identified the MLC associated with tinidazole treatment failure as ≥6.3 µg/mL. For metronidazole, the agreement between laboratory result and treatment outcome was 93.7%; for tinidazole, this agreement was 88.9%. CONCLUSIONS: The T. vaginalis susceptibility assay is useful for determining whether 5-nitroimidazole treatment failure in persons with trichomoniasis can be attributed to drug resistance. These results are useful for establishing interpretive guidance of test results, and MLC levels can help guide appropriate patient treatment.

Pilot Testing a Brief Partner-Inclusive Hybrid Intervention for Perinatal Mood and Anxiety Disorders.

The necessity of hybrid and more accessible options for perinatal mood and anxiety disorders (PMADs) has taken on increased urgency in the wake of the COVID-19 pandemic and its lasting impacts. In the New Family Wellness Project (NFWP), participants engage in a hybrid in-person and teletherapy six-session intervention for new parents early in their postpartum period. This small, phase 1 clinical research examined early outcomes of the NFWP's cognitive behavioral intervention on adverse mental health outcomes (i.e., perinatal depression and anxiety, overall mental illness symptoms) and adaptive outcomes and protective factors (i.e., relational health, social support, flourishing, self-efficacy). Despite a small sample size (N = 12), paired t-tests yielded significant effects for improvements in mental health symptoms at posttest, as well as marginally significant improvements in postpartum anxiety and self-efficacy. Findings suggest the brief, partner-inclusive, hybrid intervention shows promise for further study. Lessons learned from this small phase 1 clinical study and recommendations for revising the intervention prior to future trials are discussed.

Association of Diagnostic Stewardship for Blood Cultures in Critically Ill Children With Culture Rates, Antibiotic Use, and Patient Outcomes: Results of the Bright STAR Collaborative.

Importance: Blood culture overuse in the pediatric intensive care unit (PICU) can lead to unnecessary antibiotic use and contribute to antibiotic resistance. Optimizing blood culture practices through diagnostic stewardship may reduce unnecessary blood cultures and antibiotics. Objective: To evaluate the association of a 14-site multidisciplinary PICU blood culture collaborative with culture rates, antibiotic use, and patient outcomes. Design, Setting, and Participants: This prospective quality improvement (QI) collaborative involved 14 PICUs across the United States from 2017 to 2020 for the Bright STAR (Testing Stewardship for Antibiotic Reduction) collaborative. Data were collected from each participating PICU and from the Children's Hospital Association Pediatric Health Information System for prespecified primary and secondary outcomes. Exposures: A local QI program focusing on blood culture practices in the PICU (facilitated by a larger QI collaborative). Main Outcomes and Measures: The primary outcome was blood culture rates (per 1000 patient-days/mo). Secondary outcomes included broad-spectrum antibiotic use (total days of therapy and new initiations of broad-spectrum antibiotics ≥3 days after PICU admission) and PICU rates of central line-associated bloodstream infection (CLABSI), Clostridioides difficile infection, mortality, readmission, length of stay, sepsis, and severe sepsis/septic shock. Results: Across the 14 PICUs, the blood culture rate was 149.4 per 1000 patient-days/mo preimplementation and 100.5 per 1000 patient-days/mo postimplementation, for a 33% relative reduction (95% CI, 26%-39%). Comparing the periods before and after implementation, the rate of broad-spectrum antibiotic use decreased from 506 days to 440 days per 1000 patient-days/mo, respectively, a 13% relative reduction (95% CI, 7%-19%). The broad-spectrum antibiotic initiation rate decreased from 58.1 to 53.6 initiations/1000 patient-days/mo, an 8% relative reduction (95% CI, 4%-11%). Rates of CLABSI decreased from 1.8 to 1.1 per 1000 central venous line days/mo, a 36% relative reduction (95% CI, 20%-49%). Mortality, length of stay, readmission, sepsis, and severe sepsis/septic shock were similar before and after implementation. Conclusions and Relevance: Multidisciplinary diagnostic stewardship interventions can reduce blood culture and antibiotic use in the PICU. Future work will determine optimal strategies for wider-scale dissemination of diagnostic stewardship in this setting while monitoring patient safety and balancing measures.

Health Equity Morbidity and Mortality Conferences in Obstetrics and Gynecology.

Maternal mortality and morbidity continue to occur at unacceptably high levels in the United States, with communities of color experiencing significantly higher rates than their White counterparts, even after adjustment for confounding factors such as socioeconomic status. Many obstetrics and gynecology departments across the country have begun to incorporate routine discussion and analysis of health equity into peer review and educational processes, including grand rounds and morbidity and mortality conferences. Despite the desire and drive, there is little published guidance on best practices for incorporation of an equity component into these conferences. This document outlines the current processes at four academic institutions to highlight the variety of ways in which health equity and social justice can be incorporated when analyzing patient experiences and health outcomes. This commentary also provides a list of specific recommendations based on the combined experiences at these institutions so that others across the country can incorporate principles of health equity into their peer-review processes.

Administering Labor Analgesia Under General Anesthesia in an Intellectually Disabled Patient.

Maternal intellectual disability presents anesthetic challenges.1 A 19-year-old primigravida with significant intellectual disability presented with preterm premature rupture of membranes at 31 4/7 weeks of gestation and underwent induction of labor for chorioamnionitis. She was unable to tolerate bedside epidural placement. Intrapartum general anesthesia allowed for epidural catheter placement that provided adequate labor analgesia for a vaginal delivery. This report describes a unique approach to providing labor analgesia in the intellectually disabled patient.

Horizons and Group Motivational Enhancement Therapy: HIV Prevention for Alcohol-Using Young Black Women, a Randomized Experiment.

INTRODUCTION: Black women are at disproportionately greater risk for HIV and sexually transmitted infections than women of other ethnic/racial backgrounds. Alcohol use may further elevate the risk of HIV/sexually transmitted infection acquisition and transmission. STUDY DESIGN: A random-assignment parallel-group comparative treatment efficacy trial was conducted with random assignment to 1 of 3 conditions. SETTING/PARTICIPANTS: The sample comprised 560 Black or African American women aged 18-24 years who reported recent unprotected vaginal or anal sex and recent alcohol use. Participants were recruited from community settings in Atlanta, Georgia, from January 2012 to February 2014. INTERVENTION: A Group Motivational Enhancement Therapy module was designed to complement a Centers for Disease Control and Prevention-designated evidence-based intervention (Horizons) to reduce sexual risk behaviors, alcohol use, and sexually transmitted infections, with 3 comparison groups: (1) Horizons + Group Motivational Enhancement Therapy intervention, (2) Horizons + General Health Promotion intervention, and (3) enhanced standard of care. MAIN OUTCOME MEASURES: Outcome measures included safe sex (abstinence or 100% condom use); condom nonuse; proportion of condom use during sexual episodes; incident chlamydia, gonorrhea, and trichomonas infections; and problematic alcohol use measured by Alcohol Use Disorders Identification Test score. Treatment effects were estimated using an intention-to-treat protocol‒generalized estimating equations with logistic regression for binomial outcomes and Poisson regression for count outcomes. Analyses were conducted between October 2018 and October 2019. RESULTS: Participants assigned to Horizons + Group Motivational Enhancement Therapy had greater odds of safe sex (AOR=1.45, 95% CI=1.04, 2.02, p=0.03), greater proportion of condom use (AOR=1.68, 95% CI=1.18, 2.41, p=0.004), and lower odds of condom nonuse (AOR=0.57, 95% CI=0.38, 0.83, p=0.004). Both interventions had lower odds of problematic alcohol use (Horizons: AOR=0.57, 95% CI=0.39, 0.85, p=0.006; Horizons + Group Motivational Enhancement Therapy: AOR=0.61, 95% CI=0.41, 0.90, p=0.01). CONCLUSIONS: Complementing an evidence-based HIV prevention intervention with Group Motivational Enhancement Therapy may increase safer sexual behaviors and concomitantly reduce alcohol use among young Black women who consume alcohol. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01553682.

Pathophysiology for the Pediatric Critical Care Fellow: Three Representative Simulation Cases.

Introduction: During the course of fellowship training, pediatric critical care fellows are expected to develop a broad and in-depth understanding of the pathophysiology of multiple disease processes. The simulation-based pediatric critical care pathophysiology curriculum we present uses scenarios created by pediatric critical care fellows to teach complex pathophysiology. Methods: Each of the three representative cases presented covered a specific pathophysiologic process and required participants to acutely manage (1) an 18-year-old patient with altered mental status in the setting of hepatic encephalopathy; (2) an 8-year-old patient with sepsis, coagulopathy, and acute kidney injury; or (3) a 12-year-old patient with status epilepticus. Each case could be conducted in a simulation suite or an acute care unit bed. We assessed learners' knowledge and attitudes at the end of these simulations with a structured debriefing session and via completion of an evaluation form. The simulations were then followed by a 30-minute interactive didactic session on the topic. Results: Each scenario had six fellow participants who completed evaluations. After completing each of the three case scenarios presented, the majority of participating pediatric critical care fellows indicated that the content was relevant and sufficiently challenging. They also indicated that these simulation scenarios would improve their clinical practice. Discussion: This fellow-developed simulation curriculum is novel, highlighting the relevance for critical care fellows' understanding of realistic clinical scenarios while promoting advanced management skills with a pathophysiology focus.

Exploring Changes in Racial/Ethnic Disparities of HIV Diagnosis Rates Under the "Ending the HIV Epidemic: A Plan for America" Initiative.

OBJECTIVES: Racial/ethnic disparities in HIV diagnosis rates remain despite the availability of effective treatment and prevention tools in the United States. In 2019, President Trump announced the "Ending the HIV Epidemic: A Plan for America" (EHE) initiative to reduce new HIV infections in the United States at least 75% by 2025 and at least 90% by 2030. The objective of this study was to show the potential effect of the EHE initiative on racial/ethnic disparities in HIV diagnosis rates at the national level. METHODS: We used 2017 HIV diagnoses data from the Centers for Disease Control and Prevention National HIV Surveillance System. We developed a counterfactual scenario to determine changes in racial/ethnic disparities if the 2017 HIV diagnosis rates were reduced by 75% in the geographic regions targeted by the EHE initiative. We used 4 measures to calculate results: rate ratio, population-attributable proportion (PAP), Gini coefficient, and Index of Disparity. RESULTS: The relative measures of racial/ethnic disparity decreased by 9%-21% in the EHE scenario compared with the 2017 HIV diagnoses data. The largest decrease was in the Hispanic/Latino:white rate ratio (-20.6%) and in the black:white rate ratio (-18.2%). The PAP measure decreased by 11.5%. The absolute versions of the Index of Disparity (unweighted and weighted) were approximately 50% lower in the EHE scenario than in the 2017 HIV diagnoses data. CONCLUSIONS: EHE efforts could reduce but will not eliminate racial/ethnic disparities in HIV diagnosis rates. Efforts to address racial/ethnic disparities should continue, and innovative approaches, specifically those that focus on social and structural factors, should be developed and implemented for populations that are disproportionately affected by HIV in the United States.

Achieving Independence in Toileting: Self-Catheterization Efficacy and the Role of the School Nurse.

The school nurse is the most consistent healthcare provider for students who require scheduled intermittent self-catheterization; however, there is little literature regarding the role of the school nurse for educating and promoting self-catheterization independence for pediatric populations in the school setting. School nurses are dependent on research to identify best practices when implementing teaching strategies with young students who are ready to start catheterizing independently. The intent of this article is to contribute relevant information that is both useful and evidence based, so the school nurse is equipped with information to support the assessment, planning, and implementation of independent self-catheterization of school-age children. Additionally, this article will examine how to determine candidates for independent self-catheterization, product information and procedure guidelines, and coordination with caregivers and other members of the school health team to provide best outcomes for students diagnosed with neurogenic bladder in the school setting.

Social and Structural Factors Associated with Sustained Viral Suppression Among Heterosexual Black Men with Diagnosed HIV in the United States, 2015-2017.

This paper describes sociodemographic, sexual risk behavior, and clinical care factors associated with sustained viral suppression (SVS) among heterosexual Black men with diagnosed HIV in the US. Sample was 968 men, 2015-2017 cycles of Medical Monitoring Project. We used prevalence ratios and a multivariable logistic regression model to identify independent predictors of SVS. About 9% of sexually active men had sex that carries a risk of HIV transmission. Nearly 2/3 lived at or below the poverty level, 13% were under or uninsured, 1/4 experienced food insecurity and 15% reported recent homelessness. About 26% were not engaged in HIV care, 8% not currently taking antiretroviral therapy (ART) and 59% had SVS. Among men taking ART, care engagement and adherence were the only significant independent predictors of SVS. Efforts to increase VS should focus on increasing ART use, care engagement, and ART adherence, and include strategies that address the social and structural factors that influence them.

Successfully Recruiting Black and Hispanic/Latino Adolescents for Sexually Transmitted Infection and HIV Prevention Research.

Disparities in rates of sexually transmitted infections (STIs) and HIV between Black/African American and Hispanic/Latino adolescents and their white counterparts are well documented. Researchers may encounter notable challenges recruiting Black/African American and Hispanic/Latino adolescents for sexual risk reduction studies. In this article, we present information to assist with planning, implementing, and evaluating recruitment and retention strategies. We also provide practical examples of challenges and solutions from three STI/HIV epidemiologic or prevention intervention studies with different study purposes and populations. Researchers can use this information to aid proposal development, create or refine a recruitment/retention protocol before implementation, and troubleshoot challenges during implementation.

US Regional Changes in Racial/Ethnic Disparities in HIV Diagnoses Among Women in the United States, 2012 and 2017.

Racial/ethnic and geographic disparities in HIV diagnosis rates exist among women in the United States. Black/African American women are disproportionately affected; rates are highest in the South and Northeast. Monitoring progress towards eliminating disparities in HIV diagnosis rates among women is a national HIV prevention goal. To illustrate the performance of different measures of disparities, we compared 2012 and 2017 HIV diagnosis rates among adult and adolescent females by race/ethnicity and geographic region. We used HIV surveillance data for diagnoses and five absolute and three relative measures of disparity. The absolute disparity decreased in each region; the relative disparity decreased with the exception of one measure in the Northeast and South. Despite progress, disparities in HIV diagnosis rates among women remain. Appropriate strategies to measure progress and contextualize findings are needed.

Factors Affecting Pre-Exposure Prophylaxis Implementation for Women in the United States: A Systematic Review.

Oral HIV pre-exposure prophylaxis (PrEP) is a highly effective pill that HIV-negative individuals can take once daily to prevent HIV infection. Although PrEP is a private, user-controlled method that empowers women to protect themselves without relying on a partner's behavior, women's PrEP use has been extremely low. We systematically reviewed the literature to identify and summarize factors that may be affecting PrEP implementation for women in the United States. We conducted a search of the Centers for Disease Control and Prevention HIV/AIDS Prevention Research Synthesis Project database (MEDLINE, EMBASE, and CINAHL) and PubMed to identify peer-reviewed studies published between January 2000 and April 2018 that reported U.S. women's or health care providers' PrEP knowledge or awareness, willingness to use or prescribe, attitudes, barriers and facilitators to use or prescription, or PrEP adherence and discontinuation influences. Thirty-nine studies (26 women, 13 providers) met the eligibility criteria. In these studies, 0%-33% of women had heard of PrEP. Between 51% and 97% of women were willing to try PrEP, and 60%-92% of providers were willing to prescribe PrEP to women. Implementation barriers included access, cost, stigma, and medical distrust. Three studies addressed adherence or discontinuation. PrEP knowledge is low among women and providers. However, women and providers generally have positive views when aware of PrEP, including a willingness to use or prescribe PrEP to women. Most of the implementation barriers highlighted in studies were social or structural factors (e.g., access). Additional studies are needed to address research gaps, including studies of PrEP adherence and discontinuation.

Disparities in Incidence of Human Immunodeficiency Virus Infection Among Black and White Women - United States, 2010-2016.

Incident human immunodeficiency virus (HIV) infections among adolescent females and women declined during 2010-2016, with the largest decrease (21%) occurring among black women (1). However, in 2016, although black women accounted for 13% of the U.S. female population, 60% of new HIV infections among women were in black women, indicating persisting disparities (1). CDC used the population attributable proportion (PAP) disparity measure to describe the proportional decrease in HIV infection among black and white women combined that would be realized if the group with the higher rate (blacks) had the same rate as did the group with the lower rate (whites) (2). Analyses indicated that an estimated 3,900 of 4,200 (93%) incident HIV infections among black women in 2016 would not have occurred if rates were the same for black and white women. The PAP disparity measure decreased from 0.75 in 2010 to 0.70 in 2016, suggesting that if incidence rates for black women were the same as those for white women, the annual number of incident HIV infections among black and white women would have been 75% lower in 2010 and 70% lower in 2016. Continued efforts are needed to identify and address social and structural determinants associated with HIV-related disparities to eliminate these disparities and decrease HIV incidence among black women.

Psychological and social determinants of health, antiretroviral therapy (ART) adherence, and viral suppression among HIV-positive black women in care.

Black women are disproportionately affected by HIV, accounting for 61% of women diagnosed in 2016. Black women with HIV are less likely to be adherent to antiretroviral therapy (ART) and virally suppressed compared to women of other racial/ethnic groups. We analyzed 2013-2014 data from 1703 black women patients in the Centers for Disease Control and Prevention's Medical Monitoring Project to examine whether select psychological and social determinants of health (SDH) factors were associated with ART adherence and viral suppression. We calculated weighted estimates and used multivariable logistic regression with adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) to examine correlates of ART adherence and viral suppression. Women who had not been incarcerated in the past 12 months (aPR = 1.24; CI: 1.04-1.48) and had not experienced discrimination in a health care setting since their HIV diagnosis (aPR = 1.06; 1.00-1.11) were slightly more likely to be adherent to ART. Women who lived above the federal poverty level were more likely to be virally suppressed during the past 12 months (aPR = 1.09; CI: 1.01-1.18). More research is warranted to identify the best strategies to create health care settings that encourage black women's HIV care engagement, and to address other key SDH and/or psychological factors.

Parents' Strategies to Support Mealtime Participation of Their Children With Autism Spectrum Disorder.

OBJECTIVE: We identified and described the strategies parents use to support the mealtime participation of their child with autism spectrum disorder (ASD). METHOD: Twelve families with children with ASD (ages 2-7 yr) participated in videotaped mealtime observations. Qualitative content analysis was used to identify strategies families used to facilitate participation. RESULTS: Six categories were identified: (1) parent intervening and ignoring, (2) meal preparation and adaptability, (3) play and imagination, (4) distractions, (5) positive reinforcements, and (6) modeling. Props-common child objects that support the child's mealtime participation-were used in the context of multiple strategies. In addition, increased parental vigilance emerged as an important component of all family mealtimes. CONCLUSION: Families used multiple strategies within and across mealtimes, highlighting the individualistic nature of feeding challenges. Understanding parent mealtime strategies allows for further investigation into the efficacy and development of intervention strategies to promote mealtime participation of children with ASD.