Real-Time Observation of Frustrated Ultrafast Recovery from Ionization in Nanostructured SiO_{2} Using Laser-Driven Accelerators.

Ionizing radiation interactions in matter can trigger a cascade of processes that underpin long-lived damage in the medium. To date, however, a lack of suitable methodologies has precluded our ability to understand the role that material nanostructure plays in this cascade. Here, we use transient photoabsorption to track the lifetime of free electrons (τ_{c}) in bulk and nanostructured SiO_{2} (aerogel) irradiated by picosecond-scale (10^{-12} s) bursts of x rays and protons from a laser-driven accelerator. Optical streaking reveals a sharp increase in τ_{c} from <1 ps to >50 ps over a narrow average density (ρ_{av}) range spanning the expected phonon-fracton crossover in aerogels. Numerical modeling suggests that this discontinuity can be understood by a quenching of rapid, phonon-assisted recovery in irradiated nanostructured SiO_{2}. This is shown to lead to an extended period of enhanced energy density in the excited electron population. Overall, these results open a direct route to tracking how low-level processes in complex systems can underpin macroscopically observed phenomena and, importantly, the conditions that permit them to emerge.

Seminal plasma uterine priming alters uterine transcriptomics and negatively impacts embryo growth and uterine artery resistance but not offspring liver transcriptomics in beef cattle.

Seminal plasma uterine priming is important for pregnancy and offspring phenotype in mice and swine; however, impacts on the uterus of the dam and her offspring in cattle are unknown. We sought to determine the effects of seminal plasma uterine priming at estrus on uterine transcriptomics, early gestation (d 35, 40, and 45) embryo morphometrics, mid- to late-gestation (d 140 to 220) uterine artery hemodynamics, birth morphometrics, and liver transcriptomics in offspring at 30 d of age. Multiparous Angus-based commercial beef cows were randomly assigned to receive treatment at estrus: 0.5 mL pooled seminal plasma in the uterine body (n = 31, seminal plasma primed) or no treatment (n = 31, control). Seven d later a subset of cows (n = 4/treatment) underwent uterine biopsies, and the remaining cows underwent embryo transfer. Embryo crown-rump length and uterine artery hemodynamics were measured during gestation using ultrasonography. Morphometrics of the calf were collected within 24 h of parturition. Liver biopsies were collected at 30 d of age. Data were analyzed by ANOVA in a completely randomized design for the effect of treatment. Myosin heavy chain I (JSP.1) was downregulated [Benjamin-Hochberg adj P (BH) <= 0.05] and ABO alpha 1-3-N-acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase (ABO) was upregulated (BH adj P <= 0.05) in the uterus of seminal plasma primed cows 7 d after treatment. Embryo crown-rump length was less (P < 0.05) in seminal plasma primed cows. Mid- to late-gestation (d 140 to 220) uterine artery resistance was increased (P < 0.05) in seminal plasma primed cows. Seminal plasma priming did not alter birth weights or curve-crown-rump length, but heart girth was increased (P < 0.05) in offspring from seminal plasma primed cows. There were no differentially expressed genes (BH adj P <= 0.05) in offspring liver at 30 d of age; however, myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF) was absent in all liver samples from calves from seminal plasma primed cows. In contrast, vomeronasal 1 receptor bosTauV1R414 (BOSTAUV1R414) was present in 6 of the 7 liver samples from calves from seminal plasma primed cows. Seminal plasma uterine priming alters uterine transcriptomics, negatively impacts early gestation embryo growth and mid- to late-gestation uterine artery resistance suggesting downstream vascular anomalies. However, these in utero conditions did not impact offspring from birth to 30 d of age.

The conservation value of small population remnants: variability in inbreeding depression and heterosis of a perennial herb, the narrow-leaved purple coneflower (Echinacea angustifolia).

Anthropogenically fragmented populations may have reduced fitness due to loss of genetic diversity and inbreeding. The extent of such fitness losses due to fragmentation and potential gains from conservation actions are infrequently assessed together empirically. Controlled crosses within and among populations can identify whether populations are at risk of inbreeding depression and whether interpopulation crossing alleviates fitness loss. Because fitness depends on environment and life stage, studies quantifying cumulative fitness over a large portion of the lifecycle in conditions that mimic natural environments are most informative. To assess fitness consequences of habitat fragmentation, we leveraged controlled within-family, within-population, and between-population crosses to quantify inbreeding depression and heterosis in seven populations of Echinacea angustifolia within a 6400-hectare area. We then assessed cumulative offspring fitness after 14 years of growth in a natural experimental plot (N = 1136). Mean fitness of progeny from within-population crosses varied considerably, indicating genetic differentiation among source populations, even though these sites are all less than 9 km apart. The fitness consequences of within-family and between-population crosses varied in magnitude and direction. Only one of the seven populations showed inbreeding depression of high effect, while four populations showed substantial heterosis. Outbreeding depression was rare and slight. Our findings indicate that local crossings between isolated populations yield unpredictable fitness consequences ranging from slight decreases to substantial increases. Interestingly, inbreeding depression and heterosis did not relate closely to population size, suggesting that all fragmented populations could contribute to conservation goals as either pollen recipients or donors.

Cross sectional analysis of an addiction consultation service, substance co-use patterns, and receipt of medications for opioid use disorder during hospitalization.

INTRODUCTION: Despite effective medications for opioid use disorder (MOUD), treatment engagement remains low. As the overdose crisis is increasingly characterized by opioids co-used with other substances, it is important to understand whether existing models effectively support treatment for patients who use multiple substances. Hospital-based addiction consultation services (ACS) have shown promise at increasing MOUD initiation and treatment engagement, but the effectiveness for patients with specific co-use patterns remains unknown. METHODS: Using 2016-2023 admissions data from a large safety net hospital, we estimated a random-effects logistic regression model to determine whether specific co-use (methamphetamine, cocaine, alcohol, sedative, and other) moderated the effect of being seen by ACS on the receipt of MOUD. Adjusting for patient sociodemographic, health, and admission characteristics we estimated the proportion of patients who received MOUD across specific co-use groups. RESULTS: Of 7679 total admissions indicating opioid use, of which 5266 (68.6 %) indicated co-use of one or more substances and 2387 (31.1 %) were seen by the ACS. Among admissions not seen by the ACS, a smaller proportion of admissions with any co-use received MOUD (23.5 %; 95 % CI: 21.9-25.1) compared to admissions with opioid use alone (34.0 %; 95 % CI: 31.9-36.1). However, among admissions seen by the ACS a similar proportion of admissions with any co-use received MOUD (57.8 %; 95 % CI: 55.5-60.1) as admissions with opioid use alone (56.2 %; 95 % CI: 52.2-60.2). The increase in proportion of admissions receiving MOUD associated with being seen by the ACS was larger for admissions with methamphetamine (38.6 percentage points; 95 % CI: 34.6-42.6) or cannabis co-use (39.0 percentage points; 95 % CI: 32.9-45.1) compared to admissions without methamphetamine (25.7 percentage points; 95 % CI: 22.2-29.2) or cannabis co-use (29.1 percentage points; 95 % CI: 26.1-32.1). CONCLUSIONS: The ACS is an effective hospital-based treatment model for increasing the proportion of admissions which receive MOUD. This study shows that ACSs are also able to support increased receipt of MOUD for patients who use other substances in addition to opioids. Future research is needed to further understand what transition strategies best support treatment linkage for patients who use multiple substances.

Very High Warfarin Dosing Requirements in a Patient With Tuberculosis and a Pulmonary Embolism: A Case Report.

Purpose: To describe a case of significantly increased warfarin requirements in a patient receiving rifampin for the management of tuberculosis. Summary: A 76-year-old male was admitted due to altered mentation, cough, and weight loss. He was diagnosed concurrently with tuberculosis and a pulmonary embolism. Given the profound effect of rifampin on CYP450 enzymes, direct oral anticoagulants were avoided and warfarin therapy was selected. Management was further complicated by a gastrointestinal bleed during admission, history of cancer, and low body weight. After several weeks of daily international normalized ratio monitoring, a stable regimen of 14 mg of warfarin daily was established, allowing for the patient's safe discharge. Practice Implications: This report underscores the significance of tailored treatment plans, vigilant monitoring, and interdisciplinary collaboration which are necessary to navigate the complexities associated with these medications and optimize patient outcomes.

Perinatal substance use treatment and criminal legal system referral trends.

INTRODUCTION: To guide improvements in treatment for pregnant persons with substance use disorders within the criminal legal system, treatment programs must first determine the primary substances of concern for this population. The objective of this study is to compare trends in specific substance use upon admission to treatment in pregnancy, based upon whether referrals originated from the criminal legal system or from another referral source. METHODS: This research accessed data on perinatal substance use (1995-2021) and referral sources from the Treatment Episode Data Set-Admissions (TEDS-A). Analyses use multiple logistic regressions to evaluate trends in primary substance use leading to treatment admission during pregnancy. RESULTS: Approximately 1 % (N = 536,948) of all substance use treatment admissions in TEDS-A were for pregnant people. Between 1995 and 2021, the percentage of treatment admissions increased for primary methamphetamine use (10 % to 27 %), primary opioid use (21 % to 38 %), and primary cannabis use (9 % to 18 %), and decreased for primary cocaine use (32 % to 6 %) and primary alcohol use (26 % to 11 %). By 2021, treatment admissions referred from criminal legal agencies were more likely to primarily be for primary methamphetamine use (33 % vs 25 %) and less likely to be for primary opioid use (22 % vs 42 %) compared to other referral sources. CONCLUSIONS: Trends in substance use treatment during pregnancy have changed substantially over the past few decades and emphasize the unique needs of patients referred to treatment by the criminal legal system. Treatment programs must therefore adapt to fluctuating trends in perinatal substance use. In particular, it is important to expand programs that prioritize treatment of methamphetamine use disorder for pregnant people referred through criminal legal agencies.

Comparison of peer, self, and faculty objective structured clinical examination evaluations in a PharmD nonprescription therapeutics course.

PURPOSE: Objective structured clinical examinations (OSCE) are a valuable assessment within healthcare education, as they provide the opportunity for students to demonstrate clinical competency, but can be resource intensive to provide faculty graders. The purpose of this study was to determine how overall OSCE scores compared between faculty, peer, and self-evaluations within a Doctor of Pharmacy (PharmD) curriculum. METHODS: This study was conducted during the required nonprescription therapeutics course. Seventy-seven first-year PharmD students were included in the study, with 6 faculty members grading 10-15 students each. Students were evaluated by 3 graders: self, peer, and faculty. All evaluators utilized the same rubric. The primary endpoint of the study was to compare the overall scores between groups. Secondary endpoints included interrater reliability and quantification of feedback type based on the evaluator group. RESULTS: The maximum possible score for the OSCE was 50 points; the mean scores for self, peer, and faculty evaluations were 43.3, 43.5, and 41.7 points, respectively. No statistically significant difference was found between the self and peer raters. However, statistical significance was found in the comparison of self versus faculty (p = 0.005) and in peer versus faculty (p < 0.001). When these scores were correlated to a letter grade (A, B, C or less), higher grades had greater similarity among raters compared to lower scores. Despite differences in scoring, the interrater reliability, or W score, on overall letter grade was 0.79, which is considered strong agreement. CONCLUSIONS: This study successfully demonstrated how peer and self-evaluation of an OSCE provides a comparable alternative to traditional faculty grading, especially in higher performing students. However, due to differences in overall grades, this strategy should be reserved for low-stakes assessments and basic skill evaluations.

Juvenile survival increases with dispersal distance and varies across years: 15 years of evidence in a prairie perennial.

Juvenile survival is critical to population persistence and evolutionary change. However, the survival of juvenile plants from emergence to reproductive maturity is rarely quantified. This is especially true for long-lived perennials with extended pre-reproductive periods. Furthermore, studies rarely have the replication necessary to account for variation among populations and cohorts. We estimated juvenile survival and its relationship to population size, density of conspecifics, distance to the maternal plant, age, year, and cohort for Echinacea angustifolia, a long-lived herbaceous perennial. In 14 remnant prairie populations over seven sampling years, 2007-2013, we identified 886 seedlings. We then monitored these individuals annually until 2021 (8-15 years). Overall, juvenile mortality was very high; for almost all cohorts fewer than 10% of seedlings survived to age 8 or to year 2021. Only two of the seedlings reached reproductive maturity within the study period. Juvenile survival increased with distance from the maternal plant and varied more among the study years than it did by age or cohort. Juvenile survival did not vary with population size or local density of conspecific neighbors. Our results suggest that low juvenile survival could contribute to projected population declines.

High Juvenile Mortality Overwhelms Benefits of Mating Potential for Reproductive Fitness.

AbstractAn individual's access to mates (i.e., its "mating potential") can constrain its reproduction but may also influence its fitness through effects on offspring survival. For instance, mate proximity may correspond with relatedness and lead to inbreeding depression in offspring. While offspring production and survival might respond differently to mating potential, previous studies have not considered the simultaneous effects of mating potential on these fitness components. We investigated the relationship of mating potential with both production and survival of offspring in populations of a long-lived herbaceous perennial, Echinacea angustifolia. Across 7 years and 14 sites, we quantified the mating potential of maternal plants in 1,278 mating bouts and followed the offspring from these bouts over 8 years. We used aster models to evaluate the relationship of mating potential with the number of offspring that emerged and that were alive after 8 years. Seedling emergence increased with mating potential. Despite this, the number of offspring surviving after 8 years showed no relationship to mating potential. Our results support the broader conclusion that the effect of mating potential on fitness erodes over time because of demographic stochasticity at the maternal level.

Spatial and Temporal Resolution of Cyanobacterial Bloom Chemistry Reveals an Open-Ocean Trichodesmium thiebautii as a Talented Producer of Specialized Metabolites.

While the ecological role that Trichodesmium sp. play in nitrogen fixation has been widely studied, little information is available on potential specialized metabolites that are associated with blooms and standing stock Trichodesmium colonies. While a collection of biological material from a T. thiebautii bloom event from North Padre Island, Texas, in 2014 indicated that this species was a prolific producer of chlorinated specialized metabolites, additional spatial and temporal resolution was needed. We have completed these metabolite comparison studies, detailed in the current report, utilizing LC-MS/MS-based molecular networking to visualize and annotate the specialized metabolite composition of these Trichodesmium blooms and colonies in the Gulf of Mexico (GoM) and other waters. Our results showed that T. thiebautii blooms and colonies found in the GoM have a remarkably consistent specialized metabolome. Additionally, we isolated and characterized one new macrocyclic compound from T. thiebautii, trichothilone A (1), which was also detected in three independent cultures of T. erythraeum. Genome mining identified genes predicted to synthesize certain functional groups in the T. thiebautii metabolites. These results provoke intriguing questions of how these specialized metabolites affect Trichodesmium ecophysiology, symbioses with marine invertebrates, and niche development in the global oligotrophic ocean.

Characteristics and co-morbidities associated with hospital discharges for opioid and methamphetamine co-use, United States 2016-2019.

Introduction: The US overdose crisis is increasingly characterized by opioid and methamphetamine co-use. Hospitalization is an important opportunity to engage patients in substance use treatment. Understanding characteristics of co-use-related hospital stays can inform the development of services to better support this growing patient population. Methods: We used 2016-2019 National Inpatient Sample data to conduct a cross sectional analysis of hospitalizations involving use of opioids, methamphetamine, or both. We used bivariate analysis to compare patient demographics. We then used multinomial logistic regressions to compare the proportion of hospital stays which indicated co-morbid diagnosis. To account for correlated data, we used generalized linear models to compare outcomes in hospital mortality, patient-directed discharge, and length of stay. Results: Co-use-related stays had a higher proportion of co-morbid mental health (60.7%; 95% CI: 59.9-61.4%) and infectious diseases (41.5%; 95% CI: 40.8-42.2%), than opioid- or methamphetamine-related stays. Co-use-related stays increased between 2016 and 2019 and were associated with a higher proportion of patient directed discharge (10.7%; 95% CI: 10.4-11.0%) and longer length of stay (6.3 days; 95% CI: 6.2-6.4 days) compared to opioid (8.1%; 95% CI: 7.9-8.3% and 5.8 days; 95% CI: 5.8-5.9 days) and methamphetamine-related stays (6.5%; 95% CI: 6.3-6.6% and 5.5 days; 95% CI: 5.4-5.5 days). Conclusion: Patients discharged with co-use differ from patients with opioid or methamphetamine use alone, representing a range of challenges and opportunities. In addition to offering treatment for both substance use disorders, hospital-based services that address co-occurring conditions may better support patients with co-use through targeted and tailored approaches.

Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state.

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted.

SH2 domain protein E and ABL signaling regulate blood vessel size.

Blood vessels in different vascular beds vary in size, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vessel size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow, eventually leading to the DA collapse. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA size in she mutants correlated with an increased endothelial expression of claudin 5a (cldn5a), which encodes a protein enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates vessel and lumen size during vascular tubulogenesis.

Racial and Ethnic Differences in Heroin, Methamphetamine, and Cocaine Use, Treatment, and Mortality Trends in 3 National Data Sources-United States, 2010-2019.

BACKGROUND: As overdose deaths continue to rise, public health officials need comprehensive surveillance data to design effective prevention, harm reduction, and treatment strategies. Disparities across race and ethnicity groups, as well as trends in substance use, treatment, or overdose deaths, have been examined individually, but reports rarely compare findings across multiple substances or data sources. OBJECTIVE: To provide a broad assessment of the overdose crisis, we describe trends in substance use, treatment, and overdose mortality across racial and ethnic groups for multiple substances. RESEARCH DESIGN: We conducted a longitudinal, cross-sectional analysis comparing trends. SUBJECTS: We identified self-reported use from the National Survey on Drug Use and Health, substance use treatment admissions from the Treatment Episode Data Set-Admissions, and overdose deaths from the CDC's Multiple Cause of Death files. MEASURES: We measured rates of substance use, treatment, and deaths involving heroin, methamphetamine, and cocaine among United States adults from 2010 to 2019. RESULTS: Heroin, methamphetamine, and cocaine use increased, though not all changes were statistically significant. Treatment admissions indicating heroin and methamphetamine increased while admissions indicating cocaine decreased. Overdose deaths increased among all groups: methamphetamine (257%-1,115%), heroin (211%-577%), and cocaine (88%-259%). Changes in rates of use, treatment, and death for specific substances varied by racial and ethnic group. CONCLUSIONS: Substance use, treatment, and overdose mortality changed considerably, though not always equivalently. Identifying diverging trends in substance-related measures for specific substances and racial and ethnic groups can inform targeted investment in treatment to reduce disparities and respond to emerging changes in the overdose crisis.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Providers' Experiences and Perspectives in Treating Patients With Co-Occurring Opioid and Stimulant Use Disorders in the Hospital.

BACKGROUND: The overdose crisis is increasingly characterized by opioid and stimulant co-use. Despite effective pharmacologic treatment for both opioid use disorder (OUD) and contingency management for stimulant use disorders, most individuals with these co-occurring conditions are not engaged in treatment. Hospitalization is an important opportunity to engage patients and initiate treatment, however existing hospital addiction care is not tailored for patients with co-use and may not meet the needs of this population. METHODS: Semi-structured interviews were conducted with hospital providers about their experiences and perspectives treating patients with opioid and stimulant co-use. We used directed content analysis to identify common experiences and opportunities to improve hospital-based treatment for patients with co-use. RESULTS: From qualitative interviews with 20 providers, we identified 4 themes describing how co-use complicated hospital-based substance use treatment: (1) patients' unstable circumstances impacting the treatment plan, (2) co-occurring withdrawals are difficult to identify and treat, (3) providers holding more stigmatizing views of patients with co-use, and (4) stimulant use is often "ignored" in the treatment plans. Participants also described a range of potential opportunities to improve hospital-based treatment of co-use that fall into 3 categories: (1) provider practice changes, (2) healthcare system changes, and (3) development and validation of clinical tools and treatment approaches. CONCLUSIONS: We identified unique challenges providing hospital addiction medicine care to patients who use both opioids and stimulants. These findings inform the development, implementation, and testing of hospital-based interventions for patients with co-use.

Understanding Regional Patterns of Overdose Deaths Related to Opioids and Psychostimulants.

BACKGROUND: As overdose rates increase for multiple substances, policymakers need to identify geographic patterns of substance-specific deaths. In this study, we describe county-level opioid and psychostimulant overdose patterns and how they correlate with county-level social vulnerability measures. METHODS: A cross-sectional observational study, we used nationwide 2016-2018 restricted access Centers for Disease Prevention and Control county-level mortality files for 1,024 counties. We estimated quartiles of opioid and psychostimulant overdose mortality and provided estimates of their association with county-level Social Vulnerability Index (SVI) percentile. RESULTS: There was high opioid and psychostimulant overdose mortality in the Middle Atlantic, South Atlantic, East North Central, and Mountain regions. The Central US had the lowest opioid and psychostimulant overdose mortality rates. Counties with higher SVI scores (i.e. higher social vulnerability) were significantly more likely to experience high opioid and high psychostimulant overdose (high-high) mortality. A 10-percentile increase in SVI score was associated with a 3.1 percentage point increase in the likelihood of being a high-high county (p < 0.001) in unadjusted models and a 1.5 percentage point increase (p < 0.05) in models adjusting for region. CONCLUSION: Our results illustrated the heterogenous geographic distribution of the growing concurrent opioid and psychostimulant overdose crisis. The substantial regional variation we identified highlights the need for local data to guide policymaking and treatment planning. The association of opioid-psychostimulant overdose mortality with social vulnerability demonstrates the critical need in impacted counties for tailored treatment that addresses the complex medical and social needs of people who use both opioids and psychostimulants.

Hospital Addiction Medicine Consultation Service Orders and Outcomes by Patient Race and Ethnicity in an Urban, Safety-Net Hospital.

BACKGROUND: Hospital admissions involving substance use disorders are increasing and represent an opportunity to engage patients in substance use treatment. Addiction medicine consultation services improve access to medications for opioid use disorder (MOUD) and patient outcomes. However, as hospitals continue to adopt addiction medicine consultation services it is important to identify where disparities may emerge in the process of care. OBJECTIVE: To describe addiction medicine consultation service use by race and ethnicity as well as substance to identify opportunities to reduce substance use treatment disparities. DESIGN: Retrospective cohort study using 2016-2021 Electronic Health Record data from a large Midwest safety-net hospital. PARTICIPANTS: Hospitalized adults aged 18 or older, with one or more substance use disorders. MAIN MEASURES: Consultation orders placed, patient seen by consult provider, and receipt of MOUD by self-reported race. KEY RESULTS: Between 2016 and 2021, we identified 16,895 hospitalized patients with a substance use disorder. Consultation orders were placed for 6344 patients and 2789 were seen by the consult provider. Black patients were less likely (aOR = 0.58; 95% CI: 0.53-0.63) to have an addiction medicine consultation order placed and, among patients with a consultation order, were less likely (aOR = 0.74; 95% CI: 0.65-0.85) to be seen by the consult provider than White patients. Overall, Black patients with OUD were also less likely to receive MOUD in the hospital (aOR = 0.63; 95% CI: 0.50-0.79) compared to White patients. However, there were no differences in MOUD receipt among Black and White patients seen by the consult provider. CONCLUSIONS: Using Electronic Health Record data, we identified racial and ethnic disparities at multiple points in the inpatient addiction medicine consultation process. Addressing these disparities may support more equitable access to MOUD and other substance use treatment in the hospital setting.

Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening.

CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through a variety of means, including loss of CAR-T cells and antigen escape. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model of B-cell acute lymphoblastic leukemia (B-ALL) utilizing a modular guide RNA library. We identified IFNγR/JAK/STAT signaling and components of antigen processing and presentation pathway as key mediators of resistance to CAR-T therapy in vivo; intriguingly, loss of this pathway yielded the opposite effect in vitro (sensitized leukemia to CAR-T cells). Transcriptional characterization of this model demonstrated upregulation of these pathways in tumors relapsed after CAR-T treatment, and functional studies showed a surprising role for natural killer (NK) cells in engaging this resistance program. Finally, examination of data from B-ALL patients treated with CAR-T revealed an association between poor outcomes and increased expression of JAK/STAT and MHC-I in leukemia cells. Overall, our data identify an unexpected mechanism of resistance to CAR-T therapy in which tumor cell interaction with the in vivo tumor microenvironment, including NK cells, induces expression of an adaptive, therapy-induced, T-cell resistance program in tumor cells.