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Background Myxomatous mitral valve disease (MMVD) is a degenerative disorder marked by excess tissue fibrosis and matrix remodeling, leading to leaflet prolapse. While recent studies linked transforming growth factor beta (TGF-β) activation to MMVD development and progression, upstream regulators of this and other modulatory/causal pathways remain largely unexplored. Objectives In this study, we utilized high-throughput sequencing to conduct unbiased analyses of mRNA and microRNA (miRNA) levels in myxomatous and healthy mitral valve tissues, aiming to uncover novel molecular mechanisms involved in MMVD. Methods We defined differentially expressed mRNAs and miRNAs transcripts displaying a fold-change > 1.5 and P < .05. Pathway analysis was performed using Ingenuity Pathway Analysis and DAVID, with key findings validated via qRT-PCR. A total of 2378 transcripts were differentially expressed between myxomatous and normal valves. Established pathways, including TGF-β signaling, were confirmed as major contributors to MMVD. Additionally, Random Forests with Boruta Feature Selection identified transcripts with a 95% likelihood of importance, and subsequent pathway analysis on this subset of genes revealed unique signaling pathways. Results Most notably, circadian rhythm disruption emerged as a novel, highly ranked pathway in MMVD. Key miRNAs, such as miR-1, miR-133a, and miR-217 were highlighted as highly relevant, with miRNA–mRNA interactions displaying distinct molecular signatures predictive of MMVD. Conclusions Collectively, this study represents the first comprehensive analysis of both miRNA and mRNA expression in MMVD, revealing both established and novel disease-associated pathways. The discovery of circadian rhythm disturbances and new regulatory miRNAs suggests promising directions for further research and potential therapeutic targets for nonsurgical treatment strategies in patients with MMVD.

Objective: To systematically review the existent literature on radiosurgery for treatment of sporadic facial nerve schwannomas (FNS). Databases reviewed: PubMed, SCOPUS, EMBASE, and Web of Science databases. Methods: Systematic review was performed per PRISMA criteria of studies published from 1990 through 2024 on patients diagnosed with sporadic FNS who were treated with radiosurgery. Outcomes included change in facial nerve function, change in hearing class, and radiosurgical treatment failure defined by need for reintervention. Study quality was assessed using the LEGENDS rubric for mixed modality studies. Results: In total, 35 studies encompassing 364 patients were included for data abstraction. Gamma Knife was the most common modality reported. Longitudinal patient-level data on facial nerve function were available for 101 patients, with 8% of patients experiencing worsening facial nerve function and 92% of patients having either stable nerve function or improvement in facial nerve function following treatment over a median follow-up of 36 months. Longitudinal patient-level hearing data were available for 53 patients, including 35 patients with serviceable hearing (AAO-HNS class A or B) at baseline; only 2 patients developed nonserviceable hearing (AAO-HNS class C or D) following treatment over a median follow-up of 36 months. Clinical tumor control data were available for 295 patients, of whom 11 required salvage treatment over a mean follow-up of 49 months. Conclusions: This systematic review demonstrates a relatively low risk of worsening facial nerve function and a high rate of clinical tumor control following radiosurgery for sporadic FNS.

Abstract Toxicology testing for drugs associated with scenarios such as recreational use or substance use disorder can be performed in support of the emergency department (ED) for specific patient populations such as pediatrics and trauma. These compounds were historically referred to as drugs of abuse (DOA); although the word “abuse” is recognized as potentially stigmatizing, no replacement terminology for DOA has emerged in current guidelines. This document refers to these compounds as drugs or substances of misuse, and acknowledges the need for less-stigmatizing language that more fully encompasses the range of uses for these drugs. This literature-driven, consensus guidance document provides recommendations primarily targeted to US hospital-based laboratories performing urine drug testing (UDT) in support of the ED. Indications for ordering UDT and related testing in both pediatric and adult populations are summarized. Further, recommendations are made for testing that should be available at all facilities with rapid turnaround, and how to perform and report testing. The advantages and disadvantages of immunoassays and mass spectrometry, as well as common challenges, are reviewed. Indications for mass-spectrometry assays and more extensive testing (e.g., novel psychoactive substances) are also provided. Future directions for improvements in laboratory technology to improve the utility of this testing are outlined. All laboratories should collaborate with ED leadership, medical toxicologists and poison control centers to optimize and update test menus to reflect local drug use patterns, ensure test methodologies and results meet clinical needs, and educate clinical staff regarding assay limitations and accurate test interpretation.

The TransMet trial and Norwegian studies have shown excellent outcomes in highly selected patients undergoing liver transplant (LT) for unresectable colorectal liver metastases (uCRLM). Our aim is to provide an updated analysis of the current state of LT for uCRLM in the United States. Adult patients with a diagnosis of uCRLM listed for LT between December 2017 and March 2025 were identified from the United Network for Organ Sharing database and analyzed. An analysis of living donor LT (LDLT) and deceased donor LT (DDLT) was performed. During this period, 222 patients were listed, and 158 received an LT across 33 centers. Of these, 76 (48.1%) underwent LDLT, and 82 patients (51.9%) underwent DDLT. Of the 82 deceased donors, 56 (68.2%) were out-of-sequence offers. Overall, the 3-year survival and disease-free survival rates were 66.7% and 44.0%, respectively. The 3-year survival for LDLT and DDLT was 74.1% and 57.3% ( p =0.04), respectively. While these results have not yet reached the acceptable threshold established for other LT indications, they have improved and are expected to continue improving after the implementation of prioritization points. Given the potential variability of oncologic selection criteria and graft quality, we call for the standardization of nationally accepted selection criteria for listing patients for LT with uCRLM and for providing early access to high-quality organs. To achieve this, it is imperative to create, update, and maintain national databases that allow for the collection of more granular oncological variables.

Purpose: To present a case of a dislocated posterior lamellar graft into the vitreous cavity in an eye that was postpars plana vitrectomy. Methods: Retrospective case report. Results: A middle-aged man underwent pars plana vitrectomy, pars plana lensectomy, and scleral-sutured intraocular lens fixation after a traumatic eye injury. The patient required subsequent Descemet stripping automated endothelial keratoplasty for corneal edema, and the posterior lamellar graft was lost intraoperatively into the posterior segment. The graft was surgically retrieved 1 week later, followed by a successful placement of a new posterior lamellar graft. Histopathologic examination of the retrieved graft after 1 week in the vitreous cavity revealed viable endothelial cells, a novel finding in a posteriorly dislocated Descemet stripping automated endothelial keratoplasty graft. The newly placed graft remained attached and healed well, with the patient achieving a visual acuity of 20/80 at 3 months postoperatively. Conclusion: Posteriorly dislocated grafts may be suitable for transplantation to the corneal stroma after prompt retrieval from the vitreous cavity. Prompt retrieval and appropriate surgical techniques are critical for optimizing outcomes in such clinical scenarios.

IDH1/2 mutations (IDH mut ) increase methylation of DNA and histones in gliomas. IDH mut inhibitors are effective against low-grade IDH mut gliomas, but new strategies against high-grade IDH mut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDH wt glioblastoma (GBM), their potential in IDH mut gliomas has not been extensively studied. We previously established that IDH mut gliomas are more sensitive to HDACi than IDH wt GBM. Here we show that IDH mut is associated with greater sensitivity to HDACi only in glioma, not in IDH mut chondrosarcoma or cholangiocarcinoma. While HDACi induced more histone acetylation and gene regulation in IDH mut glioma than in IDH wt GBM, such acetylation was mostly within gene deserts, whereas IDH mut glioma promoters paradoxically lost histone acetylation. Two mediators of HDACi resistance, YAP and TAZ, were methylated and suppressed in IDH mut gliomas but not in other IDH mut cancers. Inducing YAP or TAZ expression in IDH mut gliomas conferred resistance to HDACi. Finally, belinostat extended in vivo survival only in IDH mut glioma models, not in IDH mut GBM models. Our findings provide a mechanistic rationale for further studies of HDACi in patients with IDH mut glioma, as well as the potential use of YAP/TAZ as a biomarker of HDACi sensitivity in cancers.

Background Sinonasal pathology, such as chronic inflammatory disease or neoplasm, can cause secondary nasolacrimal duct obstruction (sNLDO). There is a paucity of data on dacryocystorhinostomy (DCR) techniques and outcomes for NLDO secondary to known sinonasal pathologies. Objective To describe case characteristics, management, and surgical outcomes of sNLDO at a tertiary academic center. Methods Charts of DCR cases with at least 3 months follow-up done at a single institution over a 5-year period (2018-2022) were reviewed. Patient and surgical characteristics were recorded and compared between secondary and primary NLDO groups. The primary outcome was early functional success of DCR, assessed by improvement or resolution of epiphora at 3 months. Results A total of 236 cases were included. Of those, 79 (33.5%) were classified as secondary NLDO associated with sinonasal pathology. Reasons for sNLDO were sinonasal cancer (46.8%), chronic inflammatory disease (24.1%), trauma (16.5%), or prior head and neck radiation (31.6%). When comparing primary acquired NLDO to sNLDO cases, DCR for sNLDO was more likely to be performed endoscopically (68.4% vs 31.8%, P < .01), by a multidisciplinary team of rhinologist and oculoplastic surgeon (70.9% vs 8.3%, P < .01), and required bilateral surgery (36.7% vs 5.7%, P < .01). The overall functional success rate was 79.7% for sNLDO compared to 87.9% for primary acquired NLDO ( P < .01). Revision surgery for sNLDO, history of sinonasal malignancy, and radiation were associated with lower functional success rates (66.7%, 70.3%, and 68.0%, respectively). Canalicular pathology was more common in sNLDO cases (29.0% vs 8.3%, P < .01). Conclusions Secondary NLDO was more commonly managed with an endoscopic approach by a multidisciplinary team. Revisions for sNLDO, as well as cases with a history of sinonasal malignancy and radiation, had a markedly lower success rate, and sNLDO was frequently associated with canalicular obstruction. These findings may facilitate surgical planning and patient counseling.

Abstract INTRODUCTION Few African American (AA) donors have been included in post mortem Alzheimer's disease (AD) studies compared to European‐ancestry (EA) individuals. METHODS We generated transcriptome‐wide bulk pre‐frontal cortex (PFC) gene expression data from 125 AA donors with neuropathologically determined AD and 82 AA controls. RESULTS Transcriptome‐wide significant differential expression was observed with 482 genes. The most significant, ADAMTS2 , showed 1.52 times higher expression in AD cases ( p = 2.96x10 −8 ). Comparison of findings with those from a recent gene expression study of EA brain donors revealed substantial concordance, including ADAMTS2 . Other associations not observed in EA results may be especially relevant to AD risk in the AA population. Examination of AA AD GWAS‐implicated variants identified several expression quantitative trait loci. CONCLUSION This first large‐scale AA brain AD gene expression study identified many differentially expressed genes, including ADAMTS2 , and supports gene expression as a molecular pathway underlying the impact of several AA AD risk variants. Highlights We performed the largest African American brain tissue Alzheimer's disease (AD) gene expression study. Expression differences for 482 genes, notably ADAMTS2 , were study‐wide significant. Many significant differentially expressed genes are involved in energy metabolism. Several previously known AD‐associated variants in African Americans are eQTLs. These results advance knowledge of the genetic basis of AD in the AA population.

ABSTRACT Objective Data on bone health in patients with mild autonomous cortisol secretion (MACS) are limited and heterogenous. We sought to assess the prevalence of osteoporosis and symptomatic fragility fractures in patients with adrenal adenomas and hypercortisolism, and explore associations with the degree of cortisol excess and frailty. Design This multicenter cross ‐sectional study involved prospective enrollment of adults with nonfunctioning adrenal adenomas (NFA), MACS, Cushing syndrome (CS) and referent subjects without adrenal disorders during the study period (January 2019–September 2022). All participants completed a bone health questionnaire at enrollment and had dual‐energy X ‐ray absorptiometry bone mineral density assessment within 12‐months. Final analyses were adjusted for age, sex, body mass index, smoking status, alcohol use. Results Participants included 117 with NFA (median age 62 years, 80% women), 191 with MACS (median age 63 years, 74% women), 62 with CS (median age 50 years, 92% women), and 101 referent subjects (median age 59 years, 47% women). Both patients with CS (OR: 3.0, 95% CI: 1.1–8.3) and MACS (OR: 2.2, 95% CI: 1.9–4.9) had a higher prevalence of osteoporosis when compared to referents. Among patients with MACS, only those with post 1‐mg dexamethasone suppression test (post‐1mg‐DST) cortisol > 83 nmol/L had a higher prevalence of osteoporosis when compared to referents (OR: 3.2, 95% CI: 1.4–7.5) and NFA (OR: 2.2, 95% CI: 1.1–4.4). For clinical fragility fractures, only patients with CS showed an increased prevalence when compared to referents (OR: 6.1, 95% CI: 1.7–26.4) and NFA (OR: 3.8, 95% CI: 1.3–11.2). Prevalence of clinical fragility fractures was similar to referents in patients with MACS (OR: 1.8, 95% CI: 0.6–6.9) and NFA (OR: 1.5, 95% CI: 0.4–6.1), and was not associated with post‐1mg‐DST cortisol or frailty in the MACS and NFA groups. Conclusion Patients with CS, and those with MACS and post‐1mg‐DST cortisol > 83 nmol/L, exhibited a higher burden of osteoporosis. However, only CS was associated with an elevated risk of symptomatic fragility fractures.