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.

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.

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.

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.

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.

Adolescents Who Do Not Endorse Risk via the Patient Health Questionnaire Before Self-Harm or Suicide.

Importance: Given that the Patient Health Questionnaire (PHQ) item 9 is commonly used to screen for risk of self-harm and suicide, it is important that clinicians recognize circumstances when at-risk adolescents may go undetected. Objective: To understand characteristics of adolescents with a history of depression who do not endorse the PHQ item 9 before a near-term intentional self-harm event or suicide. Design, Setting, and Participants: This was a retrospective cohort study design using electronic health record and claims data from January 2009 through September 2017. Settings included primary care and mental health specialty clinics across 7 integrated US health care systems. Included in the study were adolescents aged 13 to 17 years with history of depression who completed the PHQ item 9 within 30 or 90 days before self-harm or suicide. Study data were analyzed September 2022 to April 2023. Exposures: Demographic, diagnostic, treatment, and health care utilization characteristics. Main Outcome(s) and Measure(s): Responded "not at all" (score = 0) to PHQ item 9 regarding thoughts of death or self-harm within 30 or 90 days before self-harm or suicide. Results: The study included 691 adolescents (mean [SD] age, 15.3 [1.3] years; 541 female [78.3%]) in the 30-day cohort and 1024 adolescents (mean [SD] age, 15.3 [1.3] years; 791 female [77.2%]) in the 90-day cohort. A total of 197 of 691 adolescents (29%) and 330 of 1024 adolescents (32%), respectively, scored 0 before self-harm or suicide on the PHQ item 9 in the 30- and 90-day cohorts. Adolescents seen in primary care (odds ratio [OR], 1.5; 95% CI, 1.0-2.1; P = .03) and older adolescents (OR, 1.2; 95% CI, 1.0-1.3; P = .02) had increased odds of scoring 0 within 90 days of a self-harm event or suicide, and adolescents with a history of inpatient hospitalization and a mental health diagnosis had twice the odds (OR, 2.0; 95% CI, 1.3-3.0; P = .001) of scoring 0 within 30 days. Conversely, adolescents with diagnoses of eating disorders were significantly less likely to score 0 on item 9 (OR, 0.4; 95% CI, 0.2-0.8; P = .007) within 90 days. Conclusions and Relevance: Study results suggest that older age, history of an inpatient mental health encounter, or being screened in primary care were associated with at-risk adolescents being less likely to endorse having thoughts of death and self-harm on the PHQ item 9 before a self-harm event or suicide death. As use of the PHQ becomes more widespread in practice, additional research is needed for understanding reasons why many at-risk adolescents do not endorse thoughts of death and self-harm.

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.

Bile acids mediate fructose-associated liver tumour growth in mice.

High fructose diets are associated with an increased risk of liver cancer. Previous studies in mice suggest increased lipogenesis is a key mechanism linking high fructose diets to liver tumour growth. However, these studies administered fructose to mice at supraphysiological levels. The aim of this study was to determine whether liver tumour growth and lipogenesis were altered in mice fed fructose at physiological levels. To test this, we injected male C57BL/6 mice with the liver carcinogen diethylnitrosamine and then fed them diets without fructose or fructose ranging from 10 to 20 % total calories. Results showed mice fed diets with ≥15 % fructose had significantly increased liver tumour numbers (2-4-fold) and total tumour burden (∼7-fold) vs mice fed no-fructose diets. However, fructose-associated tumour burden was not associated with lipogenesis. Conversely, unbiased metabolomic analyses revealed bile acids were elevated in the sera of mice fed a 15 % fructose diet vs mice fed a no-fructose diet. Using a syngeneic ectopic liver tumour model, we show that ursodeoxycholic acid, which decreases systemic bile acids, significantly reduced liver tumour growth in mice fed the 15 % fructose diet but not mice fed a no-fructose diet. These results point to a novel role for systemic bile acids in mediating liver tumour growth associated with a high fructose diet. Overall, our study shows fructose intake at or above normal human consumption (≥15 %) is associated with increased liver tumour numbers and growth and that modulating systemic bile acids inhibits fructose-associated liver tumour growth in mice.

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).

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.

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.

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.

Racial-Ethnic Differences in Receipt of Past-Year Health Care Services Among Suicide Decedents: A Case-Control Study.

OBJECTIVE: Suicide remains an urgent public health crisis. Although some sociodemographic characteristics are associated with greater suicide risk in the general population, it is unclear whether individuals utilizing health care in the United States have similar suicide incidence patterns. The authors examined whether race-ethnicity is associated with suicide death among patients seeking health care and investigated health care utilization patterns. METHODS: Data were collected from electronic health records and government mortality records for patients seeking health care across nine health care systems in the United States. Patients who died by suicide (N=1,935) were matched with patients in a control group (N=19,350) within each health care system. RESULTS: Patients who died by suicide were significantly more likely to be White, older, male, living in low-education areas, living in rural areas, or diagnosed as having mental health conditions or were significantly less likely to have commercial insurance (p<0.05). Among most racial-ethnic groups, those who died by suicide had a higher number of past-year mental health, primary care, and total health care visits; for American Indian/Alaska Native patients, the number of health care visits tended to be lower among suicide decedents. CONCLUSIONS: These findings suggest that higher past-year health care utilization was associated with increased likelihood of suicide death across several racial-ethnic groups. This observation underscores the need for identifying and managing suicide risk in health care settings, including outside of mental health visits, among most racial-ethnic groups.

The motivation and process for developing a consortium-wide time and motion study to estimate resource implications of innovations in the use of genome sequencing to inform patient care.

Costs of implementing genomic testing innovations extend beyond the cost of sequencing, affecting personnel and infrastructure for which little data are available. We developed a time and motion (T&M) study within the Clinical Sequencing Evidence-Generating Research (CSER) consortium to address this gap, and herein describe challenges of conducting T&M studies within a research consortium and the approaches we developed to overcome them. CSER investigators created a subgroup to carry out the T&M study (authors). We describe logistical and administrative challenges associated with resource use data collection across heterogeneous projects conducted in real-world clinical settings, and our solutions for completing this study and harmonizing data across projects. We delineate processes for feasible data collection on workflow, personnel, and resources required to deliver genetic testing innovations in each CSER project. A critical early step involved developing detailed project-specific process flow diagrams of innovation implementation in projects' clinical settings. Analyzing diagrams across sites, we identified common process-step themes, used to organize project-specific data collection and cross-project analysis. Given the heterogeneity of innovations, study design, and workflows, which affect resources required to deliver genetic testing innovations, flexibility was necessary to harmonize data collection. Despite its challenges, this heterogeneity provides rich insights about variation in clinical processes and resource implications for implementing genetic testing innovations.

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy.

PURPOSE: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. METHODS: A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [203Pb]Pb-MC1L, was used for [212Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [212Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. RESULTS: Biodistribution analysis identified [212Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [212Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [212Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. CONCLUSION: Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors.

PURPOSE: The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals. METHODS: New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies. RESULTS: The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model. CONCLUSION: Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.

Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice.

Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, 6-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls, without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders.