Improvement of a mouse infection model to capture Pseudomonas aeruginosa chronic physiology in cystic fibrosis.

Laboratory models are central to microbiology research, advancing the understanding of bacterial physiology by mimicking natural environments, from soil to the human microbiome. When studying host-bacteria interactions, animal models enable investigators to examine bacterial dynamics associated with a host, and in the case of human infections, animal models are necessary to translate basic research into clinical treatments. Efforts toward improving animal infection models are typically based on reproducing host genotypes/phenotypes and disease manifestations, leaving a gap in how well the physiology of microbes reflects their behavior in a human host. Understanding bacterial physiology is vital because it dictates host response and bacterial interactions with antimicrobials. Thus, our goal was to develop an animal model that accurately recapitulates bacterial physiology in human infection. The system we chose to model was a chronic Pseudomonas aeruginosa respiratory infection in cystic fibrosis (CF). To accomplish this goal, we leveraged a framework that we recently developed to evaluate model accuracy by calculating the percentage of bacterial genes that are expressed similarly in a model to how they are expressed in their infection environment. We combined two complementary models of P. aeruginosa infection-an in vitro synthetic CF sputum model (SCFM2) and a mouse acute pneumonia model. This combined model captured the chronic physiology of P. aeruginosa in CF better than the standard mouse infection model, showing the power of a data-driven approach to refining animal models. In addition, the results of this work challenge the assumption that a chronic infection model requires long-term colonization.

The constitutively active form of a key cholesterol synthesis enzyme is lipid droplet-localized and upregulated in endometrial cancer tissues.

Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we examined its lipid droplet-localized pool using complementary immunofluorescence and cell fractionation approaches and found that it exclusively comprises the truncated enzyme. This partitioning is facilitated by the loss of an endoplasmic reticulum-embedded region at the SM N terminus, whereas the catalytic domain containing membrane-associated C-terminal helices is spared. Moreover, we determined multiple amphipathic helices contribute to the lipid droplet localization of truncated SM. Taken together, our results expand on the striking differences between the two forms of SM and suggest upregulated truncation may contribute to SM-related oncogenesis.

Cognitive Behavioral Program for the Prevention of Depression in At-Risk Adolescents: Isolating the Effects of Dose.

The current study estimated effects of intervention dose (attendance) of a cognitive behavioral prevention (CBP) program on depression-free days (DFD) in adolescent offspring of parents with a history of depression. As part of secondary analyses of a multi-site randomized controlled trial, we analyzed the complete intention-to-treat sample of 316 at-risk adolescents ages 13-17. Youth were randomly assigned to the CBP program plus usual care (n=159) or to usual care alone (n=157). The CBP program involved 8 weekly acute sessions and 6 monthly continuation sessions. Results showed that higher CBP program dose predicted more DFDs, with a key threshold of approximately 75% of a full dose in analyses employing instrumental variable methodology to control multiple channels of bias. Specifically, attending at more than 75% of acute phase sessions led to 45.3 more DFDs over the 9-month period post randomization, which accounted for over 12% of the total follow-up days. Instrument sets were informed by study variables and external data including weather and travel burden. In contrast, conventional analysis methods failed to find a significant dose-outcome relation. Application of the instrumental variable approach, which better controls the influence of confounding, demonstrated that higher CBP program dose resulted in more DFDs.

Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice.

Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects.

Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents.

Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC50 of 2.60 µM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.

Variation in completeness of coding external cause of injuries under ICD-10-CM.

INTRODUCTION: Information about causes of injury is key for injury prevention efforts. Historically, cause-of-injury coding in clinical practice has been incomplete due to the need for extra diagnosis codes in the International Classification of Diseases-Ninth Revision-Clinical Modification (ICD-9-CM) coding. The transition to ICD-10-CM and increased use of clinical support software for diagnosis coding is expected to improve completeness of cause-of-injury coding. This paper assesses the recording of external cause-of-injury codes specifically for those diagnoses where an additional code is still required. METHODS: We used electronic health record and claims data from 10 health systems from October 2015 to December 2021 to identify all inpatient and emergency encounters with a primary diagnosis of injury. The proportion of encounters that also included a valid external cause-of-injury code is presented. RESULTS: Most health systems had high rates of cause-of-injury coding: over 85% in emergency departments and over 75% in inpatient encounters with primary injury diagnoses. However, several sites had lower rates in both settings. State mandates were associated with consistently high external cause recording. CONCLUSIONS: Completeness of cause-of-injury coding improved since the adoption of ICD-10-CM coding and increased slightly over the study period at most sites. However, significant variation remained, and completeness of cause-of-injury coding in any diagnosis data used for injury prevention planning should be empirically determined.

Value-Based, Environmentally Sustainable Anterior Cruciate Ligament Surgery.

Orthopedic surgeons are increasingly recognizing the broader societal impact of their clinical decisions, which includes value-based and environmentally sustainable care. Within anterior cruciate ligament reconstruction, value-based care-or most cost-effective care-includes an outpatient surgical setting with regional anesthesia, use of autograft, meniscus repair when indicated, and use of traditional metal implants such as interference screws and staples. Environmentally sustainable care includes slimming down surgical packs and trays to avoid opening unnecessary equipment, avoiding desflurane as an inhaled anesthetic agent, and minimizing waste in the operating room-a priority that addresses both cost and environmental impact.

International Experience of Implementing Cognitive Remediation for People With Psychotic Disorders.

BACKGROUND: Cognitive remediation (CR) is an effective therapy for the cognitive impact of mental illness, especially schizophrenia. Global efforts are being made to implement CR into routine mental health services with the aim of improving functional outcomes for the population of people recovering from mental illness. Implementation and dissemination of CR in heterogeneous settings require knowledge gleaned from formal implementation research and pragmatic experiential learning. This article describes cross-cultural approaches to CR implementation, focusing on initiatives in France, the United States, Australia, and Japan. METHOD: Key leaders in the implementation of CR in France, the United States, Australia, and Japan were asked to describe the implementation and dissemination process in their settings with respect to the categories of context, implementation, outcomes, facilitators, and barriers. RESULTS: All 4 sites noted the role of collaboration to leverage the implementation of CR into mental health rehabilitation services. In France, high-level, government organizational backing enhanced the dissemination of CR. Academic and clinical service partnerships in the United States facilitated the dissemination of programs. The advocacy from service users, families, and carers can aid implementation. The support from international experts in the field can assist in initiating programs but maintenance and dissemination require ongoing training and supervision of staff. CONCLUSIONS: CR is an effective intervention for the cognitive impact of schizophrenia. Programs can be implemented in diverse settings globally. Adaptations of CR centering upon the core components of effective CR therapy enhance outcomes and enable programs to integrate into diverse settings.

Long-term cohort study of patients presenting with hypercapnic respiratory failure.

OBJECTIVE: We sought to describe the long-term prognosis for a population-based cohort of people with hypercapnic respiratory failure (HRF) and the associations between underlying diagnoses and the risks of death and rehospitalisation. METHODS: We performed a historical cohort study of all persons with HRF in the Liverpool local government area in New South Wales, Australia, in the 3-year period from 2013 to 2015. Cohort members were identified using arterial blood gas results from Liverpool Hospital demonstrating pH ≤7.45 and PaCO2 >45 mm Hg within 24 hours of presentation. Linked health data were obtained from statewide registries with a minimum follow-up period of 6 years. The primary outcomes were time to death from any cause and the standardised mortality ratio (SMR) which compares the observed to the expected number of deaths in the same population. Secondary outcomes were time to rehospitalisation and the associations between death and/or hospitalisation and underlying diagnoses. RESULTS: The cohort comprised 590 adults aged between 15 and 101 years. Overall, 415 (70.3%) participants died in the follow-up period. Among those who survived the index admission, the probability of survival at 1, 3 and 5 years was 81%, 59% and 45%, respectively. The overall SMR was 9.2 (95% CI 7.6 to 11.0), indicating a near 10-fold risk of death than otherwise expected for age. Most (91%) survivors experienced rehospitalisation, with median (IQR) time to readmission of 3.9 (1.2-10.6) months. Congestive cardiac failure and neuromuscular disease were associated with an increased risk of death, whereas chronic obstructive pulmonary disease and sleep disordered breathing increased the risk of rehospitalisation. CONCLUSIONS: HRF is associated with poor survival and high risk of rehospitalisation in the 5 years following an index event. The underlying disease appears to have some influence on overall survival and subsequent hospitalisations.

Echocardiographic and electrocardiographic findings in Irish Wolfhounds eating high-pulse or low-pulse diets.

BACKGROUND: Apparently healthy dogs of various breeds eating nontraditional, high-pulse diets can have larger left ventricular diameter, lower systolic function, and more ventricular premature complexes (VPCs) compared with dogs eating traditional, low-pulse diets. It is unknown whether Irish Wolfhounds eating high-pulse diets have similar cardiac abnormalities. HYPOTHESIS/OBJECTIVES: To compare electrocardiographic and echocardiographic findings between Irish Wolfhounds eating high- or low-pulse diets. ANIMALS: Ninety-seven Irish Wolfhounds. METHODS: Retrospective study of Irish Wolfhounds that had echocardiography performed at dog shows between October 2018 and May 2021. Demographic information, echocardiographic measurements, cardiac rhythm (1-minute lead II rhythm strip), and main diet were recorded retrospectively. Diets were classified as high-pulse or low-pulse based on the presence and location of pulses (peas, lentils, chickpeas, or dry beans) on the ingredient list. RESULTS: Thirty-five of 97 Irish Wolfhounds (36%) were eating high-pulse diets and 62 of 97 (64%) were eating low-pulse diets. There were no significant differences between diet groups in echocardiographic measurements. A significantly higher percentage of dogs in the high-pulse diet group (6/35 [17%]) had VPCs compared with those in the low-pulse diet group (1/62 [2%]; effect size = 0.15 [95% confidence interval: 0.004-0.31]; P = .005). CONCLUSIONS AND CLINICAL IMPORTANCE: In this retrospective study of apparently healthy Irish Wolfhounds, high-pulse diets were associated with a higher prevalence of VPCs which could represent early cardiac abnormalities.

Patient and carer transition outcomes and experiences at the Westmead Centre for Adolescent and Young Adult Health, Westmead, Australia: protocol for a longitudinal cohort study.

INTRODUCTION: The Westmead Centre for Adolescent and Young Adult Health is a purpose-built facility supporting integrated care for young patients with a variety of long-term health conditions transitioning from paediatric services at the Children's Hospital at Westmead to adult services at Westmead Hospital, Australia. METHODS AND ANALYSIS: This protocol outlines a prospective, within-subjects, repeated-measures longitudinal cohort study to measure self-reported experiences and outcomes of patients (12-25 years) and carers accessing transition care at the Centre for Adolescent and Young Adult Health. Longitudinal self-report data will be collected using Research Electronic Data Capture surveys at the date of service entry (recruitment baseline), with follow-ups occurring at 6 months, 12 months, 18 months and after transfer to adult services. Surveys include validated demographic, general health and psychosocial questionnaires. Participant survey responses will be linked to routinely recorded data from hospital medical records. Hospital medical records data will be extracted for the 12 months prior to service entry up to 18 months post service entry. All young people accessing services at the Centre for Adolescent and Young Adult Health that meet inclusion criteria will be invited to join the study with research processes to be embedded into routine practices at the site. We expect a sample of approximately 225 patients with a minimum sample of 65 paired responses required to examine pre-post changes in patient distress. Data analysis will include standard descriptive statistics and paired-sample tests. Regression models and Kaplan-Meier method for time-to-event outcomes will be used to analyse data once sample size and test requirements are satisfied. ETHICS AND DISSEMINATION: The study has ethics approval through the Sydney Children's Hospitals Network Human Research Ethics Committee (2021/ETH11125) and site-specific approvals from the Western Sydney Local Health District (2021/STE03184) and the Sydney Children's Hospitals Network (2039/STE00977). Patients under the age of 18 will require parental/carer consent to participate in the study. Patients over 18 years can provide informed consent for their participation in the research. Dissemination of research will occur through publication of peer-reviewed journal reports and conference presentations using aggregated data that precludes the identification of individuals. Through this work, we hope to develop a digital common that can be shared with other researchers and clinicians wanting to develop a standardised and shared approach to the measurement of patient outcomes and experiences in transition care.

Short report: Transition to International Classification of Diseases, 10th Revision and the prevalence of autism in a cohort of healthcare systems.

LAY ABSTRACT: Currently, the prevalence of autism spectrum disorder (henceforth "autism") is 1 in 36, an increasing trend from previous estimates. In 2015, the United States adopted a new version (International Classification of Diseases, 10th Revision) of the World Health Organization coding system, a standard for classifying medical conditions. Our goal was to examine how the transition to this new coding system impacted autism diagnoses in 10 healthcare systems. We obtained information from electronic medical records and insurance claims data from July 2014 through December 2016 for each healthcare system. We used member enrollment data for 30 consecutive months to observe changes 15 months before and after adoption of the new coding system. Overall, the rates of autism per 1000 enrolled members was increasing for 0- to 5-year-olds before transition to International Classification of Diseases, 10th Revision and did not substantively change after the new coding was in place. There was variation observed in autism diagnoses before and after transition to International Classification of Diseases, 10th Revision for other age groups. The change to the new coding system did not meaningfully affect autism rates at the participating healthcare systems. The increase observed among 0- to 5-year-olds is likely indicative of an ongoing trend related to increases in screening for autism rather than a shift associated with the new coding.

Predicting suicide death after emergency department visits with mental health or self-harm diagnoses.

OBJECTIVE: Use health records data to predict suicide death following emergency department visits. METHODS: Electronic health records and insurance claims from seven health systems were used to: identify emergency department visits with mental health or self-harm diagnoses by members aged 11 or older; extract approximately 2500 potential predictors including demographic, historical, and baseline clinical characteristics; and ascertain subsequent deaths by self-harm. Logistic regression with lasso and random forest models predicted self-harm death over 90 days after each visit. RESULTS: Records identified 2,069,170 eligible visits, 899 followed by suicide death within 90 days. The best-fitting logistic regression with lasso model yielded an area under the receiver operating curve of 0.823 (95% CI 0.810-0.836). Visits above the 95th percentile of predicted risk included 34.8% (95% CI 31.1-38.7) of subsequent suicide deaths and had a 0.303% (95% CI 0.261-0.346) suicide death rate over the following 90 days. Model performance was similar across subgroups defined by age, sex, race, and ethnicity. CONCLUSIONS: Machine learning models using coded data from health records have moderate performance in predicting suicide death following emergency department visits for mental health or self-harm diagnosis and could be used to identify patients needing more systematic follow-up.

Impact of trauma exposure and depression comorbidity on response to transdiagnostic behavioral therapy for pediatric anxiety and depression.

By adolescence, two-thirds of youth report exposure to at least one traumatic event, yet the impact of trauma history is not routinely considered when evaluating the effect of psychotherapeutic interventions. Trauma may be a particularly important moderator of the effects of transdiagnostic therapies for emotional disorders, as trauma exposure is associated with risk for the development of comorbid depression and anxiety. The current study examined the history of trauma exposure and the presence of clinically significant depression as moderators of treatment outcomes in the Brief Behavioral Therapy (BBT) trial, the largest study of transdiagnostic psychotherapy for youth. Youths (age 8-16 years) were randomized to BBT (n = 89) based in pediatric primary care or assisted referral to outpatient community care (ARC; n = 86). Clinical response, functioning, anxiety symptoms, and depression symptoms were assessed at post-treatment (Week 16) and at follow-up (Week 32). A significant three-way interaction emerged between the treatment group, comorbid depression, and trauma exposure. BBT was broadly effective for 3/4 of the sample, but, for anxious-depressed youth with trauma exposure, BBT never significantly separated from ARC. Differences in outcome were not accounted for by other participant characteristics or by therapist-rated measures of alliance, youth engagement, or homework completion. Implications for models of learning and for intervention theory and development are discussed.

Impact of preanalytical factors on liquid biopsy in the canine cancer model.

While liquid biopsy has potential to transform cancer diagnostics through minimally-invasive detection and monitoring of tumors, the impact of preanalytical factors such as the timing and anatomical location of blood draw is not well understood. To address this gap, we leveraged pet dogs with spontaneous cancer as a model system, as their compressed disease timeline facilitates rapid diagnostic benchmarking. Key liquid biopsy metrics from dogs were consistent with existing reports from human patients. The tumor content of samples was higher from venipuncture sites closer to the tumor and from a central vein. Metrics also differed between lymphoma and non-hematopoietic cancers, urging cancer-type-specific interpretation. Liquid biopsy was highly sensitive to disease status, with changes identified soon after post chemotherapy administration, and trends of increased tumor fraction and other metrics observed prior to clinical relapse in dogs with lymphoma or osteosarcoma. These data support the utility of pet dogs with cancer as a relevant system for advancing liquid biopsy platforms.

Beneficial effects of MGL-3196 and BAM15 combination in a mouse model of fatty liver disease.

BACKGROUND AND AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)-ß agonist resmetirom/MGL-3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH. METHODS: C57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair-fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses. RESULTS: MGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis. CONCLUSIONS: MGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR-ß agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance.

The role of perceived parent drinking motives on alcohol use among adolescents with and without childhood attention-deficit/hyperactivity disorder.

OBJECTIVE: Parent history of alcohol-related problems and antisocial behaviors contribute to adolescent alcohol use and are associated with offspring attention-deficit/hyperactivity disorder (ADHD). Youth with ADHD may be susceptible to intergenerational transmission of alcohol-related cognitions, which may model drinking motives that enhance risk for adolescent alcohol use. We examined whether childhood ADHD and parent history of alcohol use disorder, with or without antisociality, were associated with adolescents' perceptions of their parents' drinking motives and whether these perceptions predicted their alcohol use behaviors. METHOD: Adolescents (N = 199; 56% with ADHD; Mage = 15.73) completed the Drinking Motives Questionnaire regarding perceptions of their parents' drinking motives. Participants subsequently reported their past-year alcohol use behaviors (Mage = 16.95). Parents reported their history of alcohol-related problems and antisocial symptoms. Covariates included adolescent gender (7% girls), race (9% self-identified Black), and parental education and marital status. RESULTS: Perceived parent drinking motives were highest for social and lowest for conformity motives, consistent with adult self-reports in the literature. Parent alcohol use and antisociality history predicted perceptions of parent drinking motives, and child ADHD only predicted perceptions of parent social drinking motives. Perceived parent drinking motives predicted adolescent alcohol use, but only among youth without ADHD. CONCLUSION: Findings reflect the potential importance of assessing adolescent perceptions of parent drinking motives for adolescents without ADHD and a possible need for supporting parents in communicating about their own alcohol use. Future research should consider alternative strategies (e.g., assessing implicit cognitions) for studying the link between alcohol-related cognitions and behaviors for adolescents with ADHD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Head-to-head comparison of BAM15, semaglutide, rosiglitazone, NEN, and calorie restriction on metabolic physiology in female db/db mice.

Metabolic disorders such as type 2 diabetes, fatty liver disease, hyperlipidemia, and obesity commonly co-occur but clinical treatment options do not effectively target all disorders. Calorie restriction, semaglutide, rosiglitazone, and mitochondrial uncouplers have all demonstrated efficacy against one or more obesity-related metabolic disorders, but it currently remains unclear which therapeutic strategy best targets the combination of hyperglycaemia, liver fat, hypertriglyceridemia, and adiposity. Herein we performed a head-to-head comparison of 5 treatment interventions in the female db/db mouse model of severe metabolic disease. Treatments included ∼60 % calorie restriction (CR), semaglutide, rosiglitazone, BAM15, and niclosamide ethanolamine (NEN). Results showed that BAM15 and CR improved body weight and liver steatosis to levels superior to semaglutide, NEN, and rosiglitazone, while BAM15, semaglutide, and rosiglitazone improved glucose tolerance better than CR and NEN. BAM15, CR, semaglutide, and rosiglitazone all had efficacy against hypertriglyceridaemia. These data provide a comprehensive head-to-head comparison of several key treatment strategies for metabolic disease and highlight the efficacy of mitochondrial uncoupling to correct multiple facets of the metabolic disease milieu in female db/db mice.

Clozapine Use Among People With Psychotic Disorders Who Experience Specific Indications for Clozapine.

Objective: To examine rates of clozapine use among people with psychotic disorders who experience specific indications for clozapine.Methods: Records data from 11 integrated health systems identified patients aged 18 years or older with recorded International Classification of Diseases, Tenth Revision, Clinical Modification, diagnoses of schizophrenia, schizoaffective disorder, or other psychotic disorder who experienced any of the 3 events between January 1, 2019, and December 31, 2019, suggesting indications for clozapine: a diagnosis of self-harm injury or poisoning, suicidal ideation diagnosed or in response to standardized assessments, and hospitalization or emergency department (ED) care for psychotic disorder despite treatment with 2 or more antipsychotic medications. Prescription dispensing data identified all clozapine use prior to or in the 12 months following each indication event. Analyses were conducted with aggregate data from each health system; no individual data were shared.Results: A total of 7,648 patients with psychotic disorder diagnoses experienced at least 1 indication event. Among 1,097 experiencing a self-harm event, 32 (2.9%) had any prior clozapine use, and 10 (0.9%) initiated clozapine during the following 12 months. Among 6,396 with significant suicidal ideation, 238 (3.7%) had any prior clozapine use, and 70 (1.1%) initiated clozapine over 12 months. Among 881 with hospitalization or ED visit despite pharmacotherapy, 77 (8.7%) had any prior clozapine treatment, and 41 (4.7%) initiated clozapine over 12 months. Among those with significant suicidal ideation, rates of both prior clozapine treatment and subsequent initiation varied significantly by race and ethnicity, with rates among Hispanic and non-Hispanic Black patients lower than among non Hispanic White patients.Conclusions: Initiating clozapine treatment is uncommon among people with psychotic disorders who experience events suggesting clozapine is indicated, with even lower rates among Black and Hispanic patients.