Citations

Background: Myxofibrosarcomas are notoriously highly infiltrative soft-tissue sarcomas, making negative surgical margins difficult to obtain. Recently, vacuum-assisted closure (VAC) is used to delay wound closure until a negative margin has been achieved; however, this can delay care and increase costs. Our institution has historically performed single-stage resections with intraoperative frozen margin analysis and reconstruction in these patients. The purpose of this study is to report the outcomes of this technique. Methods: We reviewed 112 patients (62 males, mean age 70 ± 14 years) with superficial myxofibrosarcoma. Eighty-eight patients received preoperative radiation. All patients underwent surgical resection with intraoperative frozen margin analysis, and the planned reconstruction was performed in a single anesthetic. Results: The 10-year local recurrence-free survival was 90%; positive intraoperative frozen section (HR 7.44, p = 0.004) and final permanent margins (HR 8.53, p = 0.007) were associated with local recurrence. Intraoperative margins were negative in 103 (92%) of patients, 1 of which was positive on final permanent section. There were nine cases of microscopically positive margins, of which seven underwent immediate re-excision to a negative margin. The accuracy of frozen margin assessment for myxofibrosarcoma was between 92.92 and 98.23%. All patients underwent reconstruction at the time of resection, with 19% needing an additional procedure, most commonly due to a wound complication (12%). Conclusions: Multidisciplinary single-stage excision with intraoperative frozen margin assessment and soft-tissue reconstruction yields low rates of local recurrence in patients with superficial myxofibrosarcoma.

This Viewpoint discusses care denial for transgender youth forced by law and how health systems will need to invest resources to adjust to the expected emergence of mental health concerns, for which psychiatrists can play a key role in developing and implementing such programs locally.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. METHODS: Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in APOB , LDLR , or PCSK9 . A chart review was performed to collect demographics, personal, and family cardiovascular history. RESULTS: At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 APOB , 298 LDLR , and 5 PCSK9 . Sixty-six percent were female, the mean body mass index was 27.3, with 12.3% reporting a history of diabetes. Hypertriglyceridemia (≥150 mg/dL) was present in 39.5% and reduced HDL (<50 mg/dL) was present in 56.7% of patients. 27.5% of patients were not on cholesterol-lowering medications, and only 10% of FH carriers were at goal low-density lipoprotein cholesterol levels. A history of coronary artery disease was reported in 22.4% of the cohort. Nearly 90% of these participants were newly diagnosed carriers of FH. Only 30.8% of confirmed genetic diagnoses of FH satisfied clinical (Dutch lipid clinic network) criteria for a diagnosis. CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05212428.

Abstract Introduction/Objective Burnout among trainers can lead to increased human-derived laboratory errors (HDLEs), which can negatively affect patient outcomes. Through implemented improvement strategies, trainer burnout and HDLEs were reduced without impacting the trainee burnout by creating a core training group to ensure consistency in training and providing additional training tools. Methods/Case Report Burnout was assessed using a survey from the Burnout Assessment Tool1. This survey indicates burnout as a numerical score and was given to trainers and trainees at 3 intervals. Pre-implementation concluded trainer burnout average score was 2.47. HDLEs were categorized and totaled in conjunction with the burnout surveys. Pre-implementation data for HDLEs showed 14% were associated with a training event and 14% were associated with a process change that did not have a training event. Results: Conclusion Final data showed a decrease in average burnout score for trainers (pre=2.47, post=2.26). Trainee score was not statistically different. Post-implementation data of HDLEs showed 6% were associated with a training event and 0% were associated with a process change that didn’t have a training event. In review of the project, standardization of training, proper communication of process changes decreases average burnout of trainers and reduces the amount of HDLEs associated with training and process changes.

Abstract BACKGROUND High-grade and recurrent meningiomas frequently demonstrate aggressive behavior and therapeutic resistance, with limited treatment options. Dysregulation of the MAPK and FAK pathways drive meningioma progression, but compensatory activation between these pathways could limit single agent efficacy. Recently, a clinical trial (Alliance A071401) showed encouraging efficacy of single-agent FAK inhibition in recurrent/progressive meningioma (Brastianos et al, JCO 2023). This preclinical study aimed to evaluate the therapeutic potential of dual RAF/MEK (avutometinib) and FAK (VS-4718) inhibition in suppressing tumor growth and improving survival in intracranial meningioma models. METHODS Orthotopic intracranial models were established by injecting IOMM-Lee (Fluc-mCherry) or CH157-MN (eGFP-LUC2) cells into nu/nu mice. Mice were randomized into four groups: vehicle, VS-4718 (murine formulation of defactinib, 50 mg/kg, BID), avutometinib (0.3 mg/kg, QD), or combination therapy. Treatments were administered for a 4-week period. Tumor growth was monitored via bioluminescent imaging (BLI) at baseline, midpoint, and study endpoint. Pharmacokinetic (PK) and pharmacodynamic (PD) effects were assessed by intratumoral drug concentrations and Western blotting for p-ERK and p-AKT, respectively. RESULTS In the NF2-mutant CH157-MN model, avutometinib increased median survival from 12.5 to 20.5 days (p=0.001), while combination therapy extended survival further to 22 days (p&lt;0.0001 vs vehicle). Similarly, in the NF2-wildtype IOMM-Lee model, avutometinib raised survival from 27.5 to 33 days (p=0.0237), with combination therapy reaching 34.5 days (p=0.0057 vs vehicle). VS-4718 monotherapy did not extend survival in both models. BLI demonstrated significant inhibition of tumor growth in both avutometinib and combination groups in both tumor models. PK analysis revealed Kp values of 0.26–0.37 for avutometinib and 0.46–0.50 for VS-4718 in orthotopic tumor tissue. Furthermore, combination therapy lowered p-ERK in tumors (p=0.001) compared to vehicle. CONCLUSION Dual RAF/MEK and FAK inhibitor therapy blocks MAPK activation and enhances survival in orthotopic meningioma models, supporting further clinical evaluation for aggressive meningiomas.

ABSTRACT INTRODUCTION Neighborhood deprivation increases dementia risk, although mechanisms remain unclear. We tested a framework in which modifiable risk factors and cerebral small vessel disease (SVD) mediate the link between neighborhood deprivation and cognition. METHODS In 585 cognitively healthy midlife adults (ages 40–59), neighborhood deprivation was derived from postcodes, cognition was assessed using the COGNITO, lifestyle risk factors were measured using clinical assessments, and SVD (white matter hyperintensities, lacunes, microbleeds, perivascular spaces) was assessed on 3T magnetic resonance imaging. Multivariate analyses examined association pathways among these variables. RESULTS Neighborhood deprivation was associated with poorer cognition ( r = 0.36, p < 0.001), greater prevalence of modifiable risk factors ( r = 0.36, p < 0.001), and greater SVD burden ( β = 0.18, p = 0.008). Serial mediation showed that the effects of deprivation on cognition were indirect, possibly operating via lifestyle risk and SVD, explaining 20% of the total effect, whereas SVD alone explained 28%. DISCUSSION Neighborhood disadvantage relates to poorer cognition, possibly mediated through vascular risk factors and cerebrovascular disease. Highlights Neighborhood deprivation linked to poorer cognition in healthy midlife adults Deprivation linked to small vessel disease (SVD) and modifiable risk factors (chiefly cardiovascular risk) Association between deprivation and cognition mediated by modifiable risk and SVD Mediation was exclusive to hypertensive SVD, but not cerebral amyloid angiopathy (CAA)‐related SVD

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Background: Cardiomyopathy occurring during pregnancy or in the postpartum period is a leading case of maternal death in the US. The most commonly described form of pregnancy related cardiomyopathy (PRCM) associated with left ventricular systolic dysfunction is peripartum cardiomyopathy, defined as left ventricular ejection fraction (LVEF) <45% on echocardiography. PRCM symptoms often overlap with those of normal pregnancy and the lack of validated screening tools limits effective recognition, contributing to diagnostic delays. Recently, several artificial intelligence enabled electrocardiogram (AI-ECG) models have been developed and evaluated for PRCM detection. Aim&Hypothesis: We sought to investigate the pooled diagnostic performance of AI-ECG models for detecting PRCM. We hypothesized that AI-ECG models would be effective for detecting PRCM. Methods: A systematic search of PubMed, Scopus, and Cochrane was performed by combining search terms “artificial intelligence”, “machine learning”, “deep learning”, “algorithm”, “ECG”, “EKG”, “electrocardiogram”, “peripartum cardiomyopathy”, “pregnancy”, “pregnancy related cardiomyopathy” , to identify studies investigating the use of AI-ECG models for PRCM detection. Studies included those utilizing standard 12-lead ECGs as well as single lead ECGs from various devices. For inclusion in the meta-analysis, studies had to provide complete confusion matrix data for the AI-ECG model. Inverse variance random effects model meta-analysis was performed. Pooled performance estimates with corresponding 95% CIs are presented in forest plots and a summary receiver operating characteristics (sROC) curve. Results: Our search identified a total of 201 studies (PubMed: 64, Embase: 117, Cochrane: 20) from which 6 studies involving 11 AI-ECG models and 3,006 patients were included in the meta-analysis (Fig. 1) . Following random effect bivariate meta-analysis, the AI-ECG models yielded a pooled sensitivity of 0.721 (95% CI 0.676–0.762); specificity of 0.931 (95% CI 0.932–0.938); diagnostic odds ratio (DOR) of 44.658 (95% CI 23.843–83.644); and AUC of 0.896 (95% CI 0.87–0.91), for PRCM detection (Fig. 2A-C, 3) . Conclusion: AI-ECG models appear to be effective tools for detecting PRCM and may represent a viable solution to reduce diagnostic delays consequently improving maternal outcomes. Additional studies are needed to evaluate its impact on clinical outcomes in pragmatic settings.

Introduction The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer’s disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient’s trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. Thus, we aim to conduct a systematic review assessing the efficacy of palliative care screening in the ED by assessing inpatient length of stay as the primary outcome and quality of life, percentage of hospitalisation and cost of care as secondary outcomes. Methods This study will use Ovid MEDLINE, Embase, EBSCO CINAHL, Web of Science and Cochrane as databases. The study population comprises adults aged 60 years and older, with no focus on any specific clinical specialty or disease. Patients who have not received palliative care screening will serve as the comparator. Only studies with an applicable comparator will be considered. Studies published from 1 January 2000 to 1 July 2025 will be included. All articles will be reviewed independently and in duplicate, and every author will participate in the review, data abstraction and conflict resolution process. Ethics and dissemination Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO registration number CRD42024562389.

Abstract Background Molecular breast imaging (MBI) has shown utility as a supplement to mammography in women with dense breasts. Background parenchymal uptake (BPU), which describes the level of Tc-99m sestamibi in fibroglandular tissue on MBI, varies among women with similar density. Higher BPU is associated with greater breast cancer risk. The goal of this work is to investigate the histological correlations of BPU that may explain this association with risk. Methods We compared histologic features of prospectively collected benign breast tissue biopsies from healthy women who had a region of dense tissue on mammography exhibiting one of the extreme categories of BPU on MBI: either photopenic or marked. Tissue composition of specimens was assessed by measuring area of epithelium, stroma, and fat and counting lobules. Lobular involution status was assessed by an expert pathologist as either none, partial, or complete. Ki-67 index and estrogen receptor-alpha expression were also assessed. Results Biopsies were performed in 48 women (mean age 54.9 years [SD 11.1 years]), including 20 with marked BPU and 28 with photopenic BPU. Women with marked BPU were younger (mean age 49.9 vs. 58.4 years, p = 0.004), had higher body mass index ( p = 0.01), and were more likely premenopausal ( p = 0.005). Marked BPU specimens had a higher proportion of epithelium (14.5% vs. 2.2%, p < 0.001), lower stromal content (44.8% vs. 84.2%, p = 0.005), similar fat (18.9% vs. 12.9%, p = 0.41), and greater lobule counts (15.5 vs. 6.3, p < 0.001) compared to photopenic specimens. Complete lobular involution was less frequent in marked tissue than in photopenic tissue (10.5% vs. 76%, p < 0.001). Ki-67 index was higher in marked BPU tissues (5.4% vs. 1.6%, p = 0.006), though the difference was attenuated after adjustment for epithelial area (p = 0.26). Estrogen receptor-alpha expression did not differ between marked and photopenic groups (25.6% vs. 28.4%, p = 0.12). Conclusions Marked BPU on MBI is associated with greater epithelial content, less lobular involution, and higher proliferative activity—features characteristic of tissue at elevated risk for malignant transformation. These findings suggest that BPU provides functional information beyond mammographic density, supporting its role as an imaging biomarker for breast cancer risk in women with dense breasts. Trial Registration: NCT01240278 and NCT01588834