Evidence-based guidelines for the interpretation of the 9-item Concise Health Risk Tracking - Self-Report (CHRT-SR9) measure of suicidal risk.

BACKGROUND: The 9-item Concise Health Risk Tracking - Self-Report (CHRT-SR9) is a widely used patient-reported outcome measure of suicidal risk. The goal of this article is to provide an evidence-based interpretation of the CHRT-SR9 total score in terms of four clinically actionable categories of suicidal risk (none, mild, moderate, and severe). METHODS: Data from two large programs involving adolescents and adults were combined in this paper. In these studies, the CHRT-SR9 was anchored against an independent measure of suicidal risk, the suicide item (Item #9) in the Patient Health Questionnaire (PHQ-9), with categories 0 (none), 1 (mild), 2 (moderate), and 3 (severe). In the combined data (n = 1945), we calculated the cumulative percentage of data across these four categories and the percentile score of the CHRT-SR9 total score that corresponded to these percentages; from this, we developed ranges of the CHRT-SR9 total score that corresponded to the four categories of Item #9 of PHQ-9. We also calculated similar ranges for two broad subscales of the CHRT-SR9 total score; Propensity and Suicidal Thoughts. To assess the robustness of our findings, we repeated the analysis at another timepoint across studies. RESULTS: Findings indicated that the CHRT-SR9 total score (range: 0-36) can be categorized as none (0-14), mild (15-21), moderate (22-26), and severe (27-36). Similar categories were calculated for the Propensity and Suicidal Thoughts subscales. The findings were the same when repeated at another timepoint. CONCLUSION: This categorization of the CHRT-SR9 total score can place patients into clinically meaningful and actionable categories of suicidal risk.

PlanoUp!: A pilot program for the identification and treatment of depression for youth in low-income secondary schools.

Rates of depression in youth are continuing to increase at a steady rate, yet these youth often do not receive mental health services (Bertha & Balázs, 2013; Thomas et al., 2011). Schools are an ideal setting to connect youth to mental health services; however, many barriers exist with respect to schools having adequate resources and access to the appropriate levels of services (Duong et al., 2021; Owens & Peltier, 2002). Schools may collaborate with local community providers with available resources to address these gaps. The current article describes the pilot of a school-based mental health promotion program intended to reduce depression in youth by promoting access to care through referrals to community providers. Data were collected, via self-report measures, every 3 months for 12 months from students from three middle and high schools in North Texas. The students (N = 88) enrolled in this program experienced significant reductions in their depression symptoms at the end of 12 months. This program highlights the importance of school-community partnerships to promote access to care to address mental health concerns. The results from our pilot study demonstrate the feasibility and the potential of school-based programs in improving the mental health of youth in schools through community partnership. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Clinical correlates of anxious depression in youth from the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

BACKGROUND: Anxious depression is a prevalent subtype of depression associated with adverse outcomes such as higher depression severity and higher rates of suicidality. This study leveraged a state-wide research registry of depressed and/or suicidal youth to compare the prevalence, clinical correlates, and symptom patterns of those with versus without anxious depression. METHODS: We included baseline data from 797 participants (ages 8-20) with a diagnosis of a depressive disorder. A score on the Generalized Anxiety Disorder Scale (GAD-7) ≥ 10 was used to define individuals with and without anxious depression. A structured battery was used to capture psychiatric diagnostic status, depression/anxiety severity, suicide risk, history of trauma, functioning, and resilience. RESULTS: The prevalence of anxious depression among youth with depressive disorders was 59.5 % (n = 474). Youth with anxious depression had greater depression severity and anxiety symptoms, higher suicidality, and a higher prevalence of comorbid anxiety disorders than those without. Youth with anxious depression had greater impairment in functioning defined as worse pain interference, pain severity, fatigue, and social relationships compared to those without anxious depression. Youth with anxious depression also reported higher rates of depressive symptoms such as irritable mood, feelings of guilt, and psychomotor agitation compared to those without anxious depression. CONCLUSION: Anxious depression is associated with worse depression severity, higher suicidality, and lower functioning. Longitudinal work is needed to examine long-term courses of anxious depression to explore its stability as a diagnostic subcategory.

A Comparison of Depressive Symptom Self-Reported Measures in the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

Objective: To evaluate psychometrically and provide crosswalks between 3 self-report measures of depressive symptomatology in youth in psychiatric care settings. Ratings included the Patient Health Questionnaire for Adolescents (PHQ-A), a widely used 9-item self-report; the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and the 5-item Very Quick Inventory of Depressive Symptomatology-Self-Report (VQIDS-SR5), a recent effort to create a bridge from the QIDS-SR16 to clinical practice.Methods: Data from the Texas Youth Depression and Suicide Research Network Registry (August 26, 2020-May 11, 2022) were included in this work. At first visit, 795 depressed or suicidal adolescent (12-20 years of age) psychiatric outpatients completed the PHQ-A, QIDS-SR16, and VQIDS-SR5. Classical test theory and item-response theory (IRT) analyses were conducted. Crosswalks among total scales were created. Sensitivity to change over 1-month follow-up was assessed for all 3 scales (n = 682).Results: Cronbach alphas were 0.86 (PHQ-A), 0.80 (QIDS-SR16), and 0.76 (VQIDS-SR5). Item total correlations were 0.49-0.72, 0.29-0.64, and 0.43-0.61, respectively. All 3 scales were unidimensional and sensitive to change over a 1-month period. IRT analyses revealed satisfactory item performance. Modest but significant associations were found between baseline to 1-month changes in PHQ-A and VQIDS-SR5 total scores (r = 0.50, P < .0001) and between PHQ-A and QIDS-SR16 total scores (r = 0.56; P < .0001). Categorical thresholds of severity (ie, mild, moderate, severe, and very severe) were comparable between PHQ-A and QIDS-SR16.Conclusions: The PHQ-A, QIDS-SR16, and VQIDS-SR5 are unidimensional, psychometrically acceptable self-reports of depressive prevalence or severity in adolescents and young adults in this sample. Total scale scores on any measure can be converted reliably to those on any other.

Promotore-Led Versus Registered Nurse-Led Diabetes Self-Management Education in Mexican Americans: A Randomized Clinical Trial.

PURPOSE: The purpose of this study is to compare the benefits of a diabetes self-management program led by registered nurses (RNs) versus community health workers (promotores) for Spanish-speaking Mexican Americans with type 2 diabetes (T2DM). METHODS: Three hundred thirty Spanish-speaking Mexican American adults with T2DM were randomly assigned to "Tomando Control de Su Diabetes" delivered for six 2.5-hour sessions either by promotores or RNs. The primary outcome measure was the Summary of Diabetes Self-Care Activities (SDSCA). Evaluations were made at baseline, 6 weeks, and at 3, 6, and 12 months. Mixed-effects regression models were fit to test if participants had differential changes in the SDSCA total score by group over time, controlling for demographic and clinical factors. RESULTS: SDSCA scores were significantly higher at all time points compared to baseline and not statistically different between the 2 groups. Only years of education correlated with improvement in diabetes self-management behaviors. No moderating variables predicted improvement between groups. CONCLUSIONS: Spanish-speaking Mexican American adults with T2DM who participated in a diabetes educational program with promotores or RNs demonstrated similar improvements. Promotores may increase the accessibility of effective diabetes self-management training for this difficult-to-reach population.

Predicting suicidal events: A comparison of the Concise Health Risk Tracking Self-Report (CHRT-SR) and the Columbia Suicide Severity Rating Scale (C-SSRS).

This report examines the predictive capabilities of two scales of suicidality in high-risk adolescents. Charts of adolescents with severe suicidality participating in an intensive outpatient program were reviewed. Self-report data from the 9-item Concise Health Risk Tracking Self-Report (CHRT-SR9) and clinician-completed data from the Columbia Suicide Severity Risk Scale (C-SSRS) were obtained at entry. Scales' performances in predicting suicide attempts and suicidal events were evaluated using logistic regression models and ROC analyses. Of 539 adolescents, 53 had events of which 19 were attempts. The CHRT-SR9 total score predicted events (OR=1.05) and attempts (OR=1.09), as did the C-SSRS Suicide Ideation (SI) Intensity Composite for events (OR=1.10) and attempts (OR=1.16). The CHRT-SR9 AUC was 0.70 (84.2% sensitivity; 41.7% specificity; PPV=5.0%; NPV=98.6%) for attempts. The C-SSRS Intensity Composite AUC was 0.62 (89.5% sensitivity; 24.1% specificity; PPV=4.2%; NPV=98.4%) for attempts. Both the CHRT-SR9 and C-SSRS capture important parameters related to suicidal events or attempts that can help assess suicidal risk in adolescents.

Psychometrics of the Concise Health Risk Tracking Self-Report (CHRT-SR16) Assessment of Suicidality in a Sample of Adults with Moderate to Severe Methamphetamine Use Disorder: Findings from the ADAPT-2 Randomized Trial.

Background: The co-occurrence of suicidality and substance use disorders has been well established, but rating scales to examine suicidal behavior and risk are sparse among participants with substance use disorders. We examined the psychometric properties of the 16-item Concise Health Risk Tracking Scale - Self Report (CHRT-SR16) to measure suicidality among adults with moderate-to-severe methamphetamine use disorder. Methods: Participants (n = 403) with moderate-to-severe methamphetamine use disorder completed the CHRT-SR16 as part of a randomized, double-blind, placebo-controlled pharmacotherapy trial. The CHRT-SR16 factor structure was assessed using confirmatory factor analysis (CFA). Internal consistency was estimated with coefficients alpha (α) and omega (ω), test-retest reliability with intraclass correlation coefficient (ICC) and standard error of measurement, and convergent validity using Spearman's ρ rank order correlation coefficient test between CHRT-SR16 factors and the Patient Health Questionnaire (PHQ-9). The analyses utilized baseline and week 1 data (for test-retest reliability only). Results: CFA revealed a seven-factor model of Pessimism, Helplessness, Social Support, Despair, Impulsivity, Irritability, and Suicidal Thoughts as the best-fitting model. The CHRT-SR16 also exhibited strong internal consistency (α = 0.89; ω = 0.89), test-retest reliability (ICC = 0.78) and convergent validity with the PHQ-9 total score (ρ = 0.62). Conclusion: The CHRT-SR16 showed strong psychometric properties in a sample of participants with primary methamphetamine use disorder. Clinicaltrialsgov Identifier: NCT03078075.

Association Between Disrupted Cerebral Autoregulation and Radiographic Neurologic Injury for Children on Extracorporeal Membrane Oxygenation: A Prospective Pilot Study.

Validation of a real-time monitoring device to evaluate the risk or occurrence of neurologic injury while on extracorporeal membrane oxygenation (ECMO) may aid clinicians in prevention and treatment. Therefore, we performed a pilot prospective cohort study of children under 18 years old on ECMO to analyze the association between cerebral blood pressure autoregulation as measured by diffuse correlation spectroscopy (DCS) and radiographic neurologic injury. DCS measurements of regional cerebral blood flow were collected on enrolled patients and correlated with mean arterial blood pressure to determine the cerebral autoregulation metric termed DCSx. The primary outcome of interest was radiographic neurologic injury on eligible computed tomography (CT) or magnetic resonance imaging (MRI) scored by a blinded pediatric neuroradiologist utilizing a previously validated scale. Higher DCSx scores, which indicate disruption of cerebral autoregulation, were associated with higher radiographic neurologic injury score (slope, 11.0; 95% confidence interval [CI], 0.29-22). Patients with clinically significant neurologic injury scores of 10 or more had higher median DCSx measures than patients with lower neurologic injury scores (0.48 vs . 0.13; p = 0.01). Our study indicates that obtaining noninvasive DCS measures for children on ECMO is feasible and disruption of cerebral autoregulation determined from DCS is associated with higher radiographic neurologic injury score.

The 9-item Concise Health Risk Tracking - Self-Report (CHRT-SR9) measure of suicidal risk: Performance in adult primary care patients.

Purpose: To evaluate the psychometric properties of a 9-item Concise Health Risk Tracking Self-Report (or CHRT-SR9) to assess suicidal risk in adult primary care outpatients. Methods: Overall, 369 adults completed the original 14-item version of CHRT-SR at baseline and within 4 months thereafter, from which the CHRT-SR9 was extracted using multigroup confirmatory factor analysis. Measurement invariance (across age and sex) and classical test theory characteristics of the CHRT-SR9 were evaluated. Concurrent validity was assessed by comparing CHRT-SR9 responses to those of the suicide item in the Patient Health Questionnaire (PHQ-9), both cross-sectionally and as a change measure over time. Results: Confirmatory factor analysis identified the CHRT-SR9 as the optimal solution. Factors included pessimism, helplessness, despair (2 items each) and suicidal thoughts (3 items). Measurement invariance held across sex and age groups, indicating that mean differences among sub-groups were real and not attributable to measurement bias. Classical test theory revealed acceptable item-total correlations overall (0.57-0.79) and internal consistency (Spearman-Brown from 0.76 to 0.90). Concurrent validity analyses revealed that the CHRT-SR9 can measure both improvement and worsening of suicidality over time. A PHQ-9 response of 0, 1, 2, and 3 on the suicide item corresponded to 7.82 (5.53), 16.80 (4.99), 20.71 (5.36), and 25.95 (7.30) (mean and SD) on CHRT-SR9 total score, respectively. Conclusion: The CHRT-SR9 is a brief self-report evaluating suicidality with excellent psychometric properties that is sensitive to change over time.

Psychometric evaluation of the 9-item Concise Health Risk Tracking - Self-Report (CHRT-SR9) (a measure of suicidal risk) in adolescent psychiatric outpatients in the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

BACKGROUND: This study evaluated the psychometric properties of the 9-item Concise Health Risk Tracking Self-Report (CHRT-SR9), a measure of suicidality, in adolescent psychiatric outpatients. METHODS: Altogether, 933 depressed or suicidal adolescents (12-20 years of age), receiving treatment at psychiatric outpatient clinics in Texas, completed the 16-item CHRT-SR at baseline and one month later. CHRT-SR9 was extracted from CHRT-SR16 using multigroup confirmatory factor analysis. Sex and age measurement invariance, classical test theory, item response theory (IRT), and concurrent validity analyses (against the suicidal ideation Item 9 of Patient Health Questionnaire-Adolescent (PHQ-A)) were conducted. RESULTS: The CHRT-SR9 demonstrated excellent model fit with four factors (pessimism, helplessness, despair, and suicidal thoughts). Measurement invariance was upheld. Acceptable item-total correlations (0.56-0.80) and internal consistency (Spearman-Brown 0.78-0.89) were revealed. IRT analyses showed a unidimensional instrument with excellent item performance. Using the CHRT-SR9 total score as a measure of overall suicidality and comparing it against levels of PHQ-A Item 9, the mean (standard deviation) of CHRT-SR9 total score was 8.64 (SD = 5.97) for no-risk (0 on Item 9), 17.05 (SD = 5.00) for mild, 23.16 (SD = 5.05) for moderate, and 26.96 (SD = 5.24) for severe-risk (3 on Item 9). Significant differences (p-value<0.0001) indicated that CHRT-SR9 total score distinguished between levels of suicidal risk. Furthermore, CHRT-SR9 was sensitive to change over a one-month period. LIMITATIONS: Whether CHRT-SR9 predicts actual suicidal attempts in adolescents is not well defined. CONCLUSION: The CHRT-SR9 is an easy-to-administer, user-friendly self-report with good psychometric qualities which makes it an excellent screening measure of suicidal risk in adolescent psychiatric outpatients.

Improving Self-management of Type 2 Diabetes in Latinx Patients: Protocol for a Sequential Multiple Assignment Randomized Trial Involving Community Health Workers, Registered Nurses, and Family Members.

BACKGROUND: The rate of Type 2 diabetes mellitus (T2DM) among Mexican American individuals is 16.3%, about twice that of non-Hispanic White individuals. While a number of education approaches have been developed and shown to improve diabetes self-management behaviors and glycemic control for Spanish-speaking Latinx patients with T2DM, there is little research to guide health practitioners regarding which interventions to apply and when so that resources are used efficiently, and treatment outcomes are maximized. OBJECTIVE: This study aimed to describe an adaptive intervention that integrates community mental health workers, diabetes nurse educators, family members, and patients as partners in care while promoting diabetes self-management for Mexican American individuals with T2DM. The project incorporates four evidence-based, culturally tailored treatments to determine what sequence of intervention strategies work most efficiently and for whom. Given the increasing prevalence of T2DM, achieving better control of diabetes and lowering the associated medical complications experienced disproportionally by Mexican American individuals is a public health priority. METHODS: Funded by the National Institute of Nursing Research (National Institutes of Health grant R01 NR015809), this project used a sequential multiple assignment randomized trial and included 330 Spanish-speaking Latinx patients with T2DM. In the first phase of the study, subjects were randomly assigned to an evidence-based diabetes self-management educational program called Tomando Control delivered in a group format for 6, biweekly 1.5-hour sessions, led either by a community health worker or a diabetes nurse educator. In the second phase of the study, those subjects who did not improve their diabetes self-management behaviors were rerandomized to receive either an augmented version of Tomando Control or a multifamily group treatment focused on problem-solving. The primary outcome measure was the "Summary of Diabetes Self-Care Activities." Evaluations were made at baseline and at 3, 6, and 12 months. RESULTS: This study was funded in June 2016 for a period of 5 years. Institutional review board approval was obtained in November 2016. Between March 2017 and September 2020, a total of 330 patients were recruited from the outpatient primary care clinics of Olive View-UCLA Medical Center, with a brief hiatus between May 2020 and July 2020 due to COVID-19 restrictions. The study interventions were completed in December 2020. Data collection began in March 2017 and was completed in December 2021. Data analysis is expected to be completed in Spring 2023, and results will be published in Fall 2023. CONCLUSIONS: The results of this trial should help practitioners in selecting the optimal approach for improving diabetes self-management in Spanish-speaking, Latinx patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov NCT03092063; https://clinicaltrials.gov/ct2/show/NCT03092063. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44793.

Relationship Between Valence and Arousal for Subjective Experience in a Real-life Setting for Supportive Housing Residents: Results From an Ecological Momentary Assessment Study.

BACKGROUND: The circumplex model of affect posits that valence and arousal are the principal dimensions of affect. The center of the 2D space represents a neutral state of valence and a medium state of arousal. The role of valence and arousal in human emotion has been studied extensively. However, no consistent relationship between valence and arousal has been established. Most of the prior studies investigating the relationship have been conducted in relatively controlled laboratory settings. OBJECTIVE: Ecological momentary assessment (EMA) of affect from participants residing in permanent supportive housing was used to study the relationship between valence and arousal in real-life settings. The goal of this study was to explore the relationship between valence and arousal in a person's natural environment. METHODS: Participants were recruited from housing agencies in Fort Worth, Texas, United States. All participants had a history of chronic homelessness and reported at least one mental health condition. A subset of participants completed daily (morning) EMAs of emotions and other behaviors. The sample comprised 78 women and 77 men, and the average age was 52 (SD 8) years. From the circumplex model of affect, the EMA included 9 questions related to the participant's current emotional state (happy, frustrated, sad, worried, restless, excited, calm, bored, and sluggish). The responses were used to calculate 2 composite scores for valence and arousal. RESULTS: Statistical models uniformly showed a dominant linear relation between valence and arousal and a significant difference in the slopes among races. None of the other effects were statistically significant. Compared with previous studies, the effects were quite robust. CONCLUSIONS: Our findings may provide a window to the fundamental structure of affect. We found a strong positive linear relationship between valence and arousal at the nomothetic level, which may provide insight into a universal structure of affect. However, the study needs to be replicated for different populations to determine whether our findings can be generalized beyond the population studied here.

Effects of Intersectionality Along the Pathway to Diagnosis for Autistic Children With and Without Co-occurring Attention Deficit Hyperactivity Disorder in a Nationally-Representative Sample.

Children with complex behavioral profiles (e.g., ASD + ADHD) may experience delays in obtaining a final diagnosis. Low-resource or underrepresented groups may be at even greater risk for delayed diagnosis. We assessed the effect of sociodemographic factors, symptom complexity and co-occurring conditions, and identifier of first symptoms on diagnostic trajectories among children aged 3-17 years diagnosed with ASD (n = 52) or ASD + ADHD (n = 352) from a nationally-representative sample. Race/ethnicity and gender disparities were evident in both groups. Race, symptom complexity, and co-occuring conditions predicted age of final diagnosis and wait time between first concern and final diagnosis, both of which were staggeringly high. Results suggest a complex influence of sociodemographic factors on the diagnostic pathway, and risk of health disparities as a function of intersectionality.

The Concise Health Risk Tracking - Self-Report (CHRT-SR)-A measure of suicidal risk: Performance in adolescent outpatients.

OBJECTIVES: The Concise Health Risk Tracking Self-Report (CHRT-SR) assesses the risk of suicidal behavior. We report its psychometric properties in a representative sample of adolescent outpatients. METHODS: A sample (n = 657) of adolescents (<18 years of age) in primary or psychiatric care completed the 14-item version of CHRT-SR at both baseline and within 3 months. To identify an optimal brief solution for the scale, we evaluated the factor structure of CHRT-SR using multigroup confirmatory factor analysis, and testing measurement invariance across age and gender. The item response theory and classical test theory characteristics of the optimal solution were evaluated. Concurrent validity (both cross-sectional and as a change measure over time) of the optimal solution was assessed by comparing it to another suicide measure. RESULTS: Confirmatory factor analysis identified the 9-item CHRT-SR (CHRT-SR9 ) as the optimal solution. Classical test theory and item response theory indicated excellent fit. Concurrent validity analyses revealed that it can measure both improvement/worsening of suicidality over time. CONCLUSION: The CHRT-SR9 is a brief self-report with excellent psychometric properties in a sample of adolescents that is sensitive to changes in suicidality over time. Its performance in other populations and ability to predict future suicidal events deserves study.

Youth Aware of Mental Health (YAM) Program With Texas Adolescents: Depression, Anxiety, and Substance Use Outcomes.

Objective: To determine the state of mental health problems among a general youth population and assess whether the Youth Aware of Mental Health (YAM) intervention can improve symptoms of depression and anxiety.Methods: We implemented YAM with a cluster quasi-experimental study design from August 2017 through June 2019 in 29 middle schools and high schools in North Texas. Students completed the Quick Inventory of Depressive Symptomatology, Adolescent version; the Generalized Anxiety Disorder Screener; and additional substance use questionnaires before YAM delivery and 3-6 months after implementation. Multilevel models, with students nested within schools, were used to model difference scores of depression and anxiety, controlling for various student-level and school-level characteristics. Missing data were imputed during analysis. Sensitivity analyses were performed on non-imputed data.Results: Among 3,302 adolescents at pre-test, 27% had moderate-to-severe depression, 22% had moderate-to-severe anxiety, and 4% expressed suicidal ideation. We found that on average, compared to those who had no depression at pre-test, depression decreased at post-test by (a) 4.62 units (P < .05) for those who had severe to very severe depression at pre-test, (b) 2.92 units (P < .0001) for those who had moderate depression at pre-test, and (c) 1.5 units (P < .001) for those who had mild depression at pre-test, controlling for all other factors in the model. Similar significant decreases were observed in anxiety, controlling for student-level characteristics.Conclusions: These findings demonstrate the effectiveness of YAM in reducing symptoms of depression and anxiety among adolescents in North Texas.

Outcomes of Patients with Bacillus Calmette-Guérin (BCG)-Unresponsive Non-Muscle Invasive Bladder Cancer as Defined by the U.S. Food and Drug Administration.

BACKGROUND: Limited data are available on the outcomes of patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical bacillus Calmette-Guérin (BCG), as defined by the United States Food and Drug Administration. OBJECTIVE: To define the outcomes of patients with BCG-unresponsive NMIBC. METHODS: This was a retrospective, single-institution observational cohort study. Records of patients managed at our institution for BCG-unresponsive NMIBC between 2005 and 2020 were reviewed and clinical outcomes evaluated. RESULTS: The study included 149 patients. Management was with initial radical cystectomy in 60 patients (40%) and initial bladder-sparing therapy (BST) in 89 patients (60%). Overall survival was greater among patients undergoing RC than BST (HR 1.83, 95% CI 1.04-3.22, p = 0.036), potentially due to patient selection, as no significant difference was noted for metastasis-free or cancer-specific survival. Patients opting for initial BST had high rates of treatment failure, with estimated 5-year cystectomy-free survival of only 42%. Patients who received additional lines of BST after a subsequent failure were at increased risk of having ≥pT3 or pN+ disease at cystectomy (42% for ≥2 lines BST, versus 18% for 1 line BST and 15% for initial cystectomy, p = 0.038). CONCLUSION: Among patients who underwent initial BST for BCG-unresponsive NMIBC, rates of treatment failure were very high. Patients who underwent delayed cystectomy after ≥2 lines of BST had elevated rates of extravesical disease. Our observations emphasize the importance of recent and ongoing clinical trials in this clinical space.

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.

OBJECTIVE: The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. METHODS: We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice. RESULTS: LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2-119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet. CONCLUSIONS: LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion. LEAP2 deletion increases body weight in females chronically fed a high-fat diet as a result of lowered energy expenditure, reduced locomotor activity, and increased food intake. Furthermore, in female mice, LEAP2 deletion increases body length and exaggerates the hepatic fat accumulation normally associated with chronic high-fat diet feeding.