Citations

Abstract Incretin‐based therapies, including glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) and dual incretin agonists, are increasingly used for the management of diabetes, obesity, and cardiometabolic disease. Although their systemic benefits are well established, uncertainty remains regarding their safety in patients with neuroendocrine neoplasms (NENs), a biologically heterogeneous group of tumors with diverse molecular profiles. Preclinical studies suggest that GLP‐1 receptor activation may promote tumor growth in select receptor‐expressing models, although receptor expression varies widely across NEN subtypes and is often absent in common tumors such as ileal neuroendocrine tumors. Population‐level and retrospective clinical data have not demonstrated a consistent increase in oncologic risk but are limited by methodological constraints. In this expert consensus statement, the authors synthesize current evidence and provide a practical framework for the use of incretin mimetics in patients with NENs. The authors emphasize individualized risk assessment, shared decision‐making, and multi‐disciplinary collaboration, balancing potential but unquantified oncologic risks against substantial cardiometabolic benefits. Until prospective data are available, careful patient selection, dose optimization, and close clinical and radiologic surveillance remain essential to guide safe and effective use of these agents in this population.

Lay Summary Glioblastoma is an aggressive brain cancer, and it can be difficult to tell whether changes seen on scans after radiation treatment represent tumor growth or treatment-related effects. The authors of this study wanted to evaluate whether a specialized imaging test called PSMA PET could help define tumor boundaries for radiation planning and distinguish tumor progression from treatment-related changes. To do this, they performed PSMA PET scans in 27 patients with high-grade gliomas, including patients undergoing radiation planning and patients being evaluated for possible tumor recurrence. They found that tumors showed higher PSMA PET signal than surrounding tissue, that PSMA PET sometimes identified tumor beyond what was visible on standard MRI, and that it correctly distinguished tumor progression from treatment-related changes in most patients.

Despite advances in pharmacogenomics that have led to innovative therapeutic strategies, substantial interindividual variability in drug efficacy and toxicity persists. Both endogenous and exogenous factors contribute to this unexplained variation, resulting in suboptimal treatment effectiveness, unnecessary healthcare costs, preventable mortality, and significant human suffering. The emerging field of exposomics is aimed at addressing the complex exposures that impact human health and offers an opportunity to interrogate how these exposures influence drug actions and outcomes. Here, we introduce pharmacoexposomics as a complementary framework that systematically quantifies the body's metabolic response to drug and environmental exposures using high-resolution mass spectrometry. We then present IndiPHARM (Individualized Pharmacology), a multi-institution, Advanced Research Projects Agency for Health–supported platform designed to integrate population-scale pharmacoexposomics with pharmacogenomics and clinical data to elucidate interindividual variability in drug response, identify adverse reactions, and inform tailored, effective treatment strategies that advance precision medicine.

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Abstract Objectives To systematically evaluate the certainty of evidence for treatment strategies across age groups and mood phases in bipolar disorder, and develop an open access web platform to facilitate shared decision making. Design Living umbrella review, evaluation, analysis, and communication hub (U-REACH) project. Data sources PubMed, PsycInfo, and Cochrane library databases, from inception to 19 November 2024. Eligibility criteria for selecting studies Systematic reviews with network or pairwise meta-analyses of randomised controlled trials of pharmacological, nutraceutical, psychosocial, brain stimulation, or circadian rhythm based treatments, administered as monotherapy (without concurrent interventions), augmentation treatment (interventions added to an ongoing treatment regimen), or combination treatment (simultaneous initiation of two different interventions), examining any age group, bipolar disorder phase (ie, acute bipolar depression, mania or mixed episodes, or maintenance), treatment, control, or outcome. Results 77 studies met the inclusion criteria (21 network meta-analyses and 56 pairwise meta-analyses), including 116 unique pharmacological (n=74), brain stimulation (n=18), nutraceutical (n=13), psychosocial (n=8), and circadian rhythm based (n=3) treatments as monotherapy, augmentation, or combination therapy, along with five control interventions. These studies covered 133 unique outcomes (45 efficacy outcomes and 88 safety outcomes) resulting in 2510 meta-analyses with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) ratings of the certainty of the evidence as high (n=236), moderate (n=827), low (n=986), and very low (n=461). A communication hub, the Evidence Based Interventions for Bipolar Disorder (EBI-BD) platform, was developed and the full results are freely available ( https://ebibd-database.org ), including the preference based tool (12 interventions and 17 safety outcomes). Interventions effective across outcomes varied by phases. For bipolar depression, effective interventions in adults were cariprazine, divalproex or valproate, fluoxetine, ketamine (augmentation), lamotrigine, lumateperone, lurasidone, olanzapine, olanzapine with fluoxetine, and quetiapine, whereas effective interventions in children and adolescents were lurasidone and olanzapine with fluoxetine. For mania episodes, effective interventions in adults were aripiprazole, asenapine, carbamazepine, cariprazine, divalproex or valproate, haloperidol, lithium, olanzapine, paliperidone, quetiapine (also augmentation), risperidone (also as augmentation), tamoxifen, and ziprasidone, whereas effective interventions in children and adolescents were aripiprazole, asenapine, olanzapine, quetiapine, and risperidone. For maintenance, interventions effective across outcomes in adults were aripiprazole (also the long acting injectable formulation), asenapine, divalproex or valproate, lithium, olanzapine, group psychoeducation (augmentation), quetiapine, and risperidone long acting injectable formulation. Interventions effective across phases were aripiprazole (also as augmentation and as a long acting injectable formulation), asenapine, cariprazine, cognitive behavioural therapy (augmentation), divalproex or valproate, lamotrigine, lithium, olanzapine (also as augmentation), paliperidone, quetiapine (also as augmentation), and risperidone (also as augmentation and the long acting injectable formulation) (adults). Treatment effects by neuroscience based nomenclature classes are also reported. Conclusions The EBI-BD tool can help clinicians make evidence based, personalised treatment decisions for bipolar disorder. This resource can inform clinical guidelines and provides a foundation for continuously improving bipolar disorder care as new evidence emerges. Trial registration Open Science Framework https://osf.io/pjmvn/ Readers’ note This is a living systematic review and may be updated in the next two years if additional evidence emerges.

BACKGROUND: Although diabetes is a known driver of heart failure with preserved ejection fraction, whether antecedent hyperinsulinemia drives preclinical diastolic dysfunction (DD) progression before overt hyperglycemia remains unknown. Therefore, we investigated whether elevated endogenous insulin and insulin resistance independently predict longitudinal DD progression and adverse cardiovascular outcomes. METHODS: In a community-based cohort study, we evaluated 1191 participants from the Olmsted County Heart Function Study (median age, 58.7 [interquartile range, 52.4–66.6 years]) who underwent echocardiography at baseline and after 4 years. Fasting insulin and homeostatic model assessment of insulin resistance were assessed. The primary end point was DD progression. Secondary outcomes (mortality, heart failure) were assessed in 2030 participants followed for a median of 10.97 (95% CI, 10.90–11.05) years for heart failure and a median of 18.1 (95% CI, 18.0–18.2) years for mortality. RESULTS: DD progression occurred in 7.5% of participants. Baseline fasting insulin and homeostatic model assessment of insulin resistance strongly predicted progression ( P <0.001). In multivariable analysis, every 1-SD increase in log-transformed insulin was associated with 65% increased odds of progression (odds ratio, 1.65 [95% CI, 1.33–2.07]; P <0.001), adjusting for age, creatinine, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Similar results were observed for homeostatic model assessment of insulin resistance (odds ratio, 1.66 [95% CI, 1.34–2.08]; P <0.001). In secondary analyses, elevated insulin independently predicted all-cause (hazard ratio, 1.11 per 1-SD [95% CI, 1.02–1.21]) and cardiovascular mortality (hazard ratio, 1.16 [95% CI, 1.02–1.33]). Homeostatic model assessment of insulin resistance was similarly predictive of all-cause (hazard ratio, 1.11 [95% CI, 1.03–1.20]) and cardiovascular mortality (hazard ratio, 1.16 [95% CI, 1.02–1.32]). CONCLUSIONS: Elevated endogenous insulin and insulin resistance are predictors of progressive DD and long-term mortality, even after accounting for body mass index. Metabolic dysregulation may drive myocardial stiffening before diabetes onset, identifying a potential early therapeutic window for heart failure with preserved ejection fraction prevention.

Objective To compare perioperative outcomes, complications, imaging utilization, and device management following posterior vault distraction osteogenesis (PVDO) and spring-mediated cranioplasty (SMC) for multisutural craniosynostosis. Design Retrospective cohort study. Setting Single pediatric tertiary care center. Patients, Participants Twenty-three patients with multisutural craniosynostosis treated between 2017 and 2025 (PVDO, n = 18; SMC, n = 5). Interventions PVDO or SMC. Main Outcome Measure(s) Time to device removal, imaging utilization, reoperations, readmissions, device-related complications, revision surgeries, wound infections, and absolute intracranial volume change. Results PVDO was associated with earlier device removal than SMC (78.7 ± 22.1 vs. 133.0 ± 27.4 days; P = .0015) but greater postoperative imaging utilization during the first year (5.33 ± 1.28 vs. 2.80 ± 1.64 studies; P = .01). Rates of reoperation (22.2% vs. 0%), readmission (22.2% vs. 40.0%), device-related complications (11.1% vs. 0%), revision surgery (16.7% vs. 0%), and wound infection (22.2% vs. 20.0%) did not differ significantly (all P ≥ .50). Preoperative imaging utilization and postoperative intracranial volume gain were comparable between groups. Conclusions PVDO and SMC demonstrated similar safety profiles and intracranial volume expansion in patients with multisutural craniosynostosis. Compared with SMC, PVDO enabled earlier device removal but required increased postoperative imaging. These findings may inform operative planning, postoperative surveillance, and family counseling. Larger, multicenter studies with longer follow-up are needed to evaluate long-term outcomes.