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Introduction Despite growing evidence to characterise cancer-associated cognitive decline (CACD) in women with breast cancer, interventions to mitigate CACD are limited. Emerging evidence suggests aerobic exercise may enhance cognition after breast cancer diagnosis and treatment; yet, CACD remains an understudied outcome of exercise, and few high-quality studies have been conducted. In addition to knowledge gaps in effectiveness, the translation of exercise interventions to community settings remains challenging. The Breast cancer Reasoning and Activity INtervention (BRAIN) investigates the effectiveness of aerobic exercise training, delivered in a community-based setting, for improving cognitive function in women with breast cancer and gathers information on the implementation success of the intervention. Methods and analysis This Hybrid Type I effectiveness–implementation study is conducted at an academic medical centre in the southwestern United States in partnership with a non-profit, community health and wellness organisation. The study enrols 160 women diagnosed with stage I–IIIa breast cancer and within 3–36 months of treatment completion into a 1:1 randomised controlled trial. Individuals randomised to the exercise group receive a 6-month, individually tailored aerobic exercise programme delivered by exercise trainers employed at local community fitness centres. The programme is progressive in nature and designed to help participants achieve aerobic exercise levels consistent with guidelines for cancer survivors. Individuals randomise to the control group receive a 6-month health education control intervention delivered virtually by hospital-based health educators. Cognitive performance (primary), self-reported cognition, patient-reported outcomes, physical activity and cardiorespiratory fitness are measured at baseline, 6 months (postintervention) and 12 months (follow-up). Brain structure and function are measured via magnetic resonance imaging (MRI) at baseline and 6 months. Implementation outcomes are defined by the RE-AIM framework, which includes reach, effectiveness, adoption, implementation and maintenance. RE-AIM outcomes are measured at baseline, 6 months, 12 months and ongoing during the study. Ethics and dissemination This study was approved by the Mayo Clinic Institutional Review Board (#23-000020). All participants provide informed consent prior to participation. Findings will be disseminated to scientific, clinical and community audiences through manuscripts, presentations and newsletters. Trial registration number NCT04816006.

Abstract Purpose: Navtemadlin is a potent small-molecule inhibitor of MDM2, which has completed a phase 0 window-of-opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient-derived xenografts (PDX). Experimental Design: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53–wild-type GBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX compared with 100 mg/kg in a non-amplified PDX. Central nervous system distribution was limited by blood–brain barrier efflux (Kp_brain = 0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood–brain barrier efflux (Rag−/−Abcb1a−/−Abcg2−/−), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in three (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusions: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of patients with GBM.

Lay Summary Oral vancomycin shows promise in treating pouchitis in patients with primary sclerosing cholangitis and ulcerative colitis. In this study, vancomycin helped reduce stool frequency, urgency, and incontinence. More research is needed to confirm its long-term benefits and best treatment practices.

Abstract Background Medical chaperones are authorized individuals present during physical examinations involving the genitals, breasts/chest, or anal areas. The use of medical chaperones may provide an opportunity to improve transgender and gender diverse (TGD) patients’ experiences with sensitive examinations. Aim To examine TGD adult patients’ preferences and comfort for having a medical chaperone and whether TGD-specific characteristics, social anxiety symptoms, and feelings of medical mistrust are associated with preference for having a medical chaperone present during a sensitive physical examination. Methods This study used a cross-sectional survey that randomly sampled adult patients from a gender clinic in the Midwest region of the U.S. A total of 420 surveys were mailed. Sixty-two surveys were returned undeliverable, 358 reached recipients; 151 were returned (42.1% response rate). The survey included items related to demographics, gender-related anatomical dysphoria, social anxiety symptoms, feelings of medical mistrust, and preference and comfort towards medical chaperones. Results Among 149 respondents, 74 (49.7%) reported comfort for the idea of having a medical chaperone present during a sensitive physical examination, 50 (33.6%) reported neutral comfort, and 25 (16.8%) reported discomfort. Among 147 respondents, 89 (60.5%) endorsed a preference for a female medical chaperone. We found no associations between gender-related anatomical dysphoria or social anxiety symptoms and comfort for having a medical chaperone, or the gender preference for a medical chaperone. Medical mistrust was associated with lower comfort with having a medical chaperone present during a sensitive physical examination. Clinical Implications Routinely offering medical chaperones, especially female chaperones, is like to be generally acceptable to most TGD patients. These findings may inform clinic policies on providing medical chaperones during sensitive examinations. Strengths and Limitations This study is the first to examine TGD preferences for medical chaperones. Findings are limited by a single site, homogeneous sample, cross-sectional design, and reliance on hypothetical rather than observed examinations. Conclusion TGD adults report comfort with the concept of having a medical chaperone during sensitive examinations and most would prefer the chaperone to be female. Preference for having a medical chaperone present during a sensitive physical exam is not likely influenced by gender dysphoria or social anxiety.

Abstract Background and Objectives Research has established that unpaid family members, friends, or others who care for persons with dementia (ie, caregivers) may encounter socioemotional and physical health concerns as a consequence of providing extensive assistance. Similarly, caregivers for people living with traumatic brain injury (TBI) often experience a range of stressors and negative mental health outcomes due to care demands. Individuals with TBI often develop Alzheimer’s disease and Alzheimer’s disease-related dementia (AD/ADRD). This history of TBI may introduce complications to AD/ADRD caregiving. A comprehensive intervention grounded in the understanding of the complex caregiving context of both diagnoses is warranted to address the unique needs and concerns of TBI-AD/ADRD caregivers. Research Design and Methods This study evaluated the feasibility of the TBI-AD/ADRD Caregiver Support Intervention (TACSI) psychoeducational program, designed to support the unique subset of caregivers facing the challenge of assisting relatives with AD/ADRD and a history of TBI. TACSI, a 6-session telehealth intervention, provides tailored psychosocial and psychoeducational coaching. In partnership with the 2 national healthcare centers, 15 caregivers enrolled in the 3-month feasibility study evaluating the design and subsequent refinement of TACSI. Mixed methods data were collected from 3-month follow-up surveys and qualitative data from postintervention interviews. Results The feasibility, utility, and acceptance of TACSI were established. Caregivers liked the telehealth delivery and the personalized nature of TACSI, yet some expressed it would have been more beneficial earlier in their caregiving journey. Discussion and Implications Caregivers valued the TACSI program. Their feedback has been applied to improve TACSI content and delivery for a larger pilot randomized controlled trial that is currently underway.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Importance: Lung cancer and pulmonary metastases remain the leading cause of cancer-related mortality. While surgery is the gold standard, local tissue-ablative therapies are increasingly used in unresectable disease or inoperable patients. Minimally invasive local control presents a safe, repeatable approach to slow disease progression and prolong survival. Observations: Ablative techniques (radiofrequency, microwave, cryoablation, pulsed electric field) utilize extreme heat, cold, or energy to induce cancer cell death. Traditionally, ablation occurred percutaneously with image guidance, but transbronchial approaches are gaining popularity due to a potentially improved complication profile with reduced tumoral seeding. Stereotactic body radiotherapy utilizes non-invasive, precise radiation with a steep dose fall-off to protect peritumoral tissue. Transarterial infusions via transarterial chemoembolization and intraarterial chemoperfusion are emerging approaches that exploit tumor vasculature to provide focal cytotoxicity and ischemia. Intratumoral injectables (chemotherapy, immunotherapy, radiosensitization, oncolytic viruses, adoptive cell therapy, and chimeric antigen receptor T-cell therapy) directly target the tumor microenvironment, potentially increasing efficacy whilst minimizing systemic adverse effects. Conclusions and relevance: In the age of individualized cancer therapy, a multidisciplinary approach with concurrent modalities can achieve local control. This review provides a comprehensive discussion regarding the role and types of local control, safety, efficacy, and survival outcomes in assessing percutaneous, transbronchial, intraarterial, and intratumoral approaches in nonsurgical patients.

12005 Background: Young adults (YAs) diagnosed with cancer between the ages of 18 and 39 face unique psychosocial challenges and are at risk of experiencing significant emotional distress and poor health-related quality of life (HRQOL). This randomized trial evaluated the efficacy of Bright IDEAS-YA, a problem-solving skills training intervention, on reducing distress and improving HRQOL of YAs newly diagnosed with cancer. A secondary aim examined change in problem-solving ability as a potential mediator of treatment effects. Methods: A three-site randomized trial of Bright IDEAS-YA compared with enhanced usual care (EUC) enrolled YA survivors within four months of a first diagnosis of cancer. Participants were randomized 1:1 to Bright IDEAS-YA or EUC (NCT04585269). Bright IDEAS-YA is a 6-session, one-on-one intervention that teaches a systematic approach to overcome personal challenges across any life domain. EUC involved usual psychosocial care plus AYA resources. Participants completed surveys at 0 (baseline), 3, 6, 12, and 24 months, with 6 months as the primary endpoint. Validated measures included the PROMIS Depression Short Form and Anxiety Short Form (primary outcomes), the Functional Assessment of Cancer Therapy – General (FACT-G; primary outcome), and Social Problem-Solving Inventory-Revised Short Form (SPSI-R; mediator). Efficacy was tested using linear mixed effects models, run in R, examining the group x time interaction effects. Mediation was tested using the R multiple mediation analysis. Results: 344 YA (34.2% acceptance rate, M age = 30.3 years, SD = 6.3; 63% female, 37% male, < 1% non-binary) participated (100% planned enrollment), with 86% and 81% completing surveys at 3 and 6 months, respectively. Compared to baseline, the intervention arm showed statistically significant improvements in depression, anxiety, and HRQOL relative to the control group at 6 months. The intervention arm demonstrated an average reduction of 3.2 T-score points reduction in depression (95% CI [-4.9, -1.5], p < 0.001), 2.4 T-score points in anxiety (95% CI [-4.0, -0.81], p = 0.003), and 3.4 points improvement in total FACT-G (95% CI [0.34, 6.5], p = 0.029) relative to the control. These differences reflect clinically meaningful changes per published reports. Across all three models, change in total problem-solving ability (SPSI-R) was shown to mediate treatment effects, primarily due to change in the negative problem-orientation subscale. Conclusions: Bright IDEAS-YA was efficacious in reducing symptoms of depression and anxiety and improving HRQOL compared with enhanced usual care among YAs with cancer. Improvements are attributable to increased problem-solving ability, particularly by reducing the tendency to view problems as significant threats and doubt one’s ability to successfully solve problems. Clinical trial information: NCT04585269 .

10512 Background: Polygenic risk scores (PRSs) combine information from single-nucleotide polymorphisms (SNPs) across the genome to explain substantial genetic breast cancer (BC) susceptibility. Previous studies have demonstrated that a multiple-ancestry PRS (MA-385) based on 56 ancestry-informative and 329 BC-associated SNPs is accurate for diverse populations and ranks among the most important known factors affecting the risk of BC development. However, medical guidelines call for more evidence before endorsing the clinical use of PRS, including studies to evaluate possible interactions of SNPs with environmental and hormonal risk factors. Here, we use longitudinal outcomes from the UK Biobank (UKB) to explore interactions of MA-385 and the five most informative individual BC-associated SNPs with the widely used Tyrer-Cuzick (TC) risk model and individual TC risk factors. Methods: The study cohort included 197,509 female UKB participants with no history of cancer at the time of study enrollment. We used Cox proportional hazards models to test associations of MA-385, individual BC SNPs, TC, and individual TC risk factors with BC outcomes. Effect modification of MA-385 and individual SNPs by clinical risk factors was evaluated by including interaction terms in the models. All models were adjusted for age at UKB enrollment and 10 principal components. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported per standard deviation, and significance tests were performed using two-sided p-values based on likelihood-ratio test statistics. Results: After a median follow-up of 11.8 years, 7,419 (3.8%) participants were diagnosed with BC.In a model including both MA-385 and TC, MA-385 was a significantly better predictor of BC development (HR = 1.56; 95% CI 1.53-1.60, p = 3.2 x 10 -329 ) over the TC model (HR = 1.21; 95% CI 1.18-1.23; p = 5.4 x 10 -69 ). We found no evidence of interaction between MA-385 and TC ( p = 0.31) , nor between individual SNPs and TC. After Bonferroni adjustment for multiple testing (102 tests), we found no evidence of interaction between MA-385 or individual SNPs with clinical TC factors. The strongest evidence for interaction was found between a BC SNP on chromosome 2 (rs13387042) and age at UKB enrollment (unadjusted p = 0.002; Bonferroni adjusted p = 0.23). Conclusions: In a longitudinal analysis of UKB, MA-385 was a highly significant predictor of BC risk and substantially improved prediction over TC. In contrast, interactions of MA-385, and individual BC SNPs, with TC and individual clinical factors in the TC model were not statistically significant. Clinical TC factors have minimal, if any, impact on the strength of the association between MA-385 and BC. These results may help to alleviate concerns expressed in guidelines that SNPs interact with environmental or hormonal risk factors.

INTRODUCTION: Cardiovascular disease is a leading cause of maternal mortality. Our aim was to evaluate the feasibility and quality of artificial intelligence (AI)-guided focused cardiac ultrasound (FoCUS) by novice scanners to screen for left ventricular (LV) systolic dysfunction in pregnant individuals. METHODS: Patients were prospectively enrolled during routine obstetric appointments. FoCUS images were acquired by individuals without scanning or clinical experience using AI-guided image acquisition software (UltraSight) on a Philips Lumify device. Standard two-dimensional imaging views were attempted: parasternal long axis (PSLA), parasternal short axis mid-level (PSSA Mid), apical four chamber (A4C), three chamber (A3C), and two chamber (A2C). Two experienced cardiologists reviewed all images and graded diagnostic quality: poor, adequate, good, excellent. RESULTS: A total of 101 pregnant participants were enrolled; median age was 32 (interquartile range [IQR], 29, 35) years. The median gestational age was 23 (IQR, 16, 31) weeks; 16% first trimester, 45% second, and 39% third. The most feasible views were the PSLA and PSSA Mid, 98% and 97% with adequate or greater image quality, respectively. A3C and A2C were least feasible, acquired in 34% and 40% with adequate or greater image quality in 28% and 35%, respectively. Average scan time was 6 minutes, 46 seconds ± 0.2. The LV ejection fraction could be determined for the entire cohort and was normal (50–75%) for all. CONCLUSIONS/IMPLICATIONS: Implementation of AI-guided FoCUS in pregnant individuals is feasible, even in the absence of an experienced sonographer. This approach could allow for low-cost screening and early diagnosis of LV systolic dysfunction during pregnancy.