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Importance Although the Martin-Hopkins equation is widely validated and used to estimate low-density lipoprotein cholesterol (LDL-C) for clinical care, a simplified equation could streamline implementation and enable broader adoption. Objective To develop a simplified machine learning–based alternative to the Martin-Hopkins equation using multivariate adaptive regression splines (LDL-C–MH-MARS) and compare its performance with the Friedewald (LDL-C–F), Sampson–National Institutes of Health (LDL-C–S), Modified Sampson (LDL-C–MS), and Martin-Hopkins (LDL-C–MH) equations. Design, Setting, and Participants The Very Large Database of Lipids is a cross-sectional database of clinical lipid measurements from a population-representative convenience sample of adult and pediatric patients. Lipid measurements were performed by Vertical Auto Profile ultracentrifugation between October 1, 2015, and June 30, 2019. The study included patients with complete lipid panel data who were randomly assigned to a training set and a test set. External validation against preparative ultracentrifugation-based LDL-C measurements was performed in reference laboratory datasets from the Mayo Clinic (broad LDL-C concentrations) and the Further Cardiovascular Outcomes Research With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition in Subjects with Elevated Risk (FOURIER) trial (observations from patients with low LDL-C concentrations while taking evolocumab). Study data were analyzed from January to October 2025. Exposures LDL-C–F, LDL-C–S, LDL-C–MS, LDL-C–MH, and LDL-C–MH-MARS equations. Main Outcomes and Measures Accuracy of estimated vs ultracentrifugation-measured LDL-C concentration based on bias, root mean square error (RMSE), and concordance by guideline-based categories. Results The study included 4 939 528 patients (mean [SD] age, 56 [16] years; 2 635 486 female [53%]) with complete lipid panel data who were randomly assigned to a training set (n = 3 292 889) and a test set (n = 1 646 639). LDL-C–MH-MARS equation demonstrated a very low median (IQR) bias of −0.1 (−2.1 to 1.8) mg/dL (to convert to millimoles per liter, multiply by 0.0259), comparable with LDL-C–MH. The median (IQR) difference between the MARS and original Martin-Hopkins equations (ie, LDL-C–MH-MARS – LDL-C–MH) was −0.5 (−1.2 to 0) mg/dL, further suggesting comparability between the 2 methods. The RMSE was smallest for LDL-C–MH-MARS (4.7 mg/dL) and LDL-C–MH (4.9 mg/dL), followed by LDL-C–S (5.8 mg/dL), LDL-C-MS (6.0 mg/dL), and LDL-C–F (7.2 mg/dL). The proportion of patients correctly classified according to clinical categories was nearly identical for LDL-C–MH-MARS (89.7%) and LDL-C–MH (89.6%) but lower for LDL-C–S (86.3%), LDL-C–MS (84.7%), and LDL-C–F (83.1%). The LDL-C–MH-MARS, LDL-C–MH, LDL-C–MS, LDL-C–S, and LDL-C–F equations underestimated LDL-C concentration in 16%, 17%, 28%, 39%, and 60%, respectively, when classifying LDL-C less than 70 mg/dL in patients with triglyceride concentrations of 200 to 399 mg/dL (to convert to millimoles per liter, multiply by 0.0113). The patterns of results were similar in external validation datasets, with the LDL-C–MH-MARS and LDL-C–MH equations demonstrating the highest accuracy. Conclusions and Relevance Study results suggest that the new machine learning–based LDL-C equation provided results comparable with those of the original Martin-Hopkins method while simplifying implementation to a single equation.

Importance As the use of robotic cholecystectomy increases, its value remains poorly defined for complex elective cholecystectomy (CEC), where complex gallbladder pathology results in increased technical difficulty. Objective To determine whether a robotic approach is associated with improved clinical outcomes and altered total hospital cost as compared with a laparoscopic approach for patients undergoing CEC. Design, Setting, and Participants This cohort study analyzed data from an academic hepatobiliary referral center for patients who underwent cholecystectomy from August 2018 to August 2024. CEC was defined by preoperative criteria: prior aborted or partial cholecystectomy, presence of a cholecystostomy tube, and/or history of gallbladder perforation or fistula. Exposure Robotic-assisted vs laparoscopic cholecystectomy. Main Outcomes and Measures The primary outcome was a composite of an unplanned postoperative endoscopic retrograde cholangiopancreatography or interventional radiology procedure. Secondary outcomes included operative time, postoperative complications, and operative and total hospital costs. Results A total of 863 patients underwent cholecystectomy and met inclusion criteria; 525 (60.8%) were female and 338 (39.2%) were male, and their median (IQR) age was 61 (45-71) years. Among patients undergoing CEC, the laparoscopic approach was independently associated with an increased need for unplanned endoscopic or percutaneous intervention compared with the robotic group (odds ratio, 4.24; 95% CI, 1.24-14.52; P = .02). There were no significant differences in postoperative outcomes between the laparoscopic and robotic groups in patients undergoing non-CEC. Patients undergoing the laparoscopic approach had significantly reduced operating room costs when compared with patients undergoing a robotic approach in both the CEC ($7720 vs $8936, respectively) and non-CEC groups ($6368 vs $ 8351, respectively). However, there was no difference in the overall total cost of care between laparoscopic CEC and robotic CEC groups ($14 309 vs $14 476, respectively). The overall total cost of care was significantly higher for patients undergoing robotic non-CEC as compared with laparoscopic non-CEC ($11 416 vs $9925, respectively). Conclusions and Relevance This study found that for complex gallbladder disease, robotic cholecystectomy offers a clinical advantage, reducing complications and downstream interventions without increasing the overall costs of care. These findings suggest strategic application of the robotic platform may offer clinical advantages in high-complexity gallbladder surgery, maximizing patient benefit and resource efficiency.

Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in type 1 and type 2 diabetes. Although α-cell dysfunction also contributes to disease pathology, α-cells remain remarkably resistant to senescence and increased cell death under diabetogenic stress. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, whereas α-cells compensate for their greater DNA-damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental and postnatal epigenetic programs shape the differential DNA damage vulnerability of postnatal β- and α-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of β-cells from neonatal growth through adulthood. Complementing this developmental process, enhancer analyses reveal lineage-specific DNA damage response regulatory landscapes that are remodeled in β-cells under metabolic stress. Collectively, our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal β- and α-cells during growth and diabetes. Article Highlights Mechanisms underlying the differential susceptibility of pancreatic β- and α-cells to diabetogenic stress remain unclear. We investigated whether replication, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal β- and α-cells to DNA damage, a key driver of β-cell failure in diabetes. Replication introduces DNA damage vulnerability in both neonatal β- and α-cells, yet β-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens β-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic stress preferentially compromises β-cell repair fidelity. These findings reveal how developmental programs shape β-cell resilience and may influence lifelong diabetes risk.

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by lifelong immune dysregulation leading to high rates of autoimmune disorders, elevated risk of complications from infections, immune hypersensitivity, and a unique form of immunodeficiency. It is now appreciated that DS shares key hallmarks with interferonopathies, with vast remodeling of all branches of the immune system, hypercytokinemia, and widespread autoantibody production. Here within, we review the existing literature with an emphasis on clinical considerations toward monitoring, management, and therapeutic opportunities. We highlight recent research advances that illuminate diagnostic approaches to evaluate immune dysregulation in DS. We also discuss the evidence supporting specific immunomodulatory strategies that could have multidimensional benefits in this population, including JAK inhibitors, intravenous immunoglobulin, and B cell–depleting agents.

Background: Alzheimer’s disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50–70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. Aims and Methods: In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. Results: We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules ( COL4A1/4A2, HTRA1, TRIM47, FOXF2 ) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. Conclusion: The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities. Data Access Statement: no original data are presented in this document.

Background Genes that enhance T-cell function represent promising targets for improving engineered T-cell therapies for cancer. While extensive CRISPR knockout screens have identified key genes enhancing T-cell persistence, employing Sleeping Beauty ( SB ) insertional mutagenesis, which induces both gain-of-function (GOF) and loss-of-function (LOF) mutations via the generation of fusion transcripts with endogenous genes, may uncover additional critical factors that previous approaches have overlooked. Methods We developed transgenic mice carrying D oxycycline (Dox)- i nducible SB mutag e nesis s y stem (DiSBey) in primary T cells. Using DiSBey, we conducted screens for genetic alterations enhancing T-cell persistence under chronic antigen exposure. Specifically, CD8 + T cells from Dox-fed DiSBey mice were subjected to repeated anti-CD3 stimulation over 18 days to mimic chronic antigenic stimulation. We then identified SB transposon genomic insertion sites and corresponding fusion transcripts from the persistent DiSBey CD8 + T cells using enhanced-specificity tagmentation sequencing and RNA sequencing, respectively. Results Under chronic stimulation, SB -mutagenized CD8 + T cells exhibited improved persistence and reduced terminal exhaustion phenotype. Across six independent screens, we identified 38 genes that were recurrently targeted by the SB transposon T2/Onc2 and differentially expressed under chronic anti-CD3 stimulation. T2/Onc2 insertions into Bach2 and Elmo1 were recurrently identified at the genomic level and were associated with altered nascent transcript expression. Bach2 , known as a key regulator of T-cell memory formation and resistance to chronic viral infection-induced exhaustion but less characterized in engineered T cells for cancer therapy, was found to counteract exhaustion in vitro and enhance in vivo tumor persistence in the B16-Ova tumor model. Further, we showed that ectopic Bach2 expression levels influence engineered T-cell differentiation lineage, as low Bach2 overexpression retained more functional progenitor exhausted T cells and exhibited improved therapeutic efficacy. Finally, in human CART19-28ζ cells, BACH2 overexpression enhanced cytotoxicity and tumor control following chronic cancer stimulation. Conclusions Controllable SB mutagenesis using DiSBey mice provides a novel platform for functional screening of genes that improve T-cell phenotypes important for their use as therapies. Our findings highlight a dose-dependent role of BACH2 in enhancing the function of engineered T cells under conditions of chronic antigenic stimulation.

Abstract Context Biochemical test results are central to clinical decision-making for the diagnosis and management of Cushing syndrome (CS). With emerging research and increasing availability of different tests, updated consensus on the utility of these biomarkers is warranted. Objective To establish an updated consensus on the role of biomarkers in the diagnosis and monitoring of adrenocorticotropic hormone-dependent CS, address novel therapeutic approaches, and identify areas for future research. Design A modified 2-round Delphi panel was conducted. Consensus was defined as ≥70% agreement/disagreement for Likert-scale statements or ≥70% selection of the same option for single-choice questions. Setting Participants represented a range of international expertise. Participants Forty-one participants took part in the Delphi panel, with no attrition between rounds (one nonclinician was not required to complete the second round). An 8-member Steering Committee guided statement development. Results Of statements designed to reach consensus, 45% (14/31) and 44% (11/25) statements reached consensus in Rounds 1 and 2, respectively. Notably, most panelists reported the use of late-night salivary cortisol for diagnosis of mild CS and for monitoring following pituitary surgery or medical or radiation therapy. Most panelists responded that block-and-replace therapies can be considered in patients with cyclical or severe CS, and consensus was reached that restoration of circadian rhythm is a treatment goal for patients with CS. Conclusion Areas of alignment among experts on the diagnosis and monitoring of CS are presented. The findings from this study are intended to support clinicians in their clinical decision-making and highlight priority areas for future research.

Abstract Provided herein are novel compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mental illness or CNS disorders and processes for preparing such compounds.

ABSTRACT Undergraduate anatomy teaching in the UK has been progressively compressed, with reduced contact time and variable integration across medical programs. We examined final‐year medical students' perceptions of anatomy teaching, focusing on total contact hours, longitudinal continuity, and exposure to traditional and emerging teaching modalities. A national cross‐sectional survey was distributed to final‐year students across 40 UK medical schools between December 2024 and February 2025. Satisfaction with anatomy teaching, perceived importance of anatomy for future practice, contact hours, continuity across program years, and exposure to specific teaching modalities and technologies were assessed. Comparative analyses used non‐parametric tests and ANOVA with post hoc testing where appropriate. 628 students responded. Dissatisfaction was greatest for teaching quantity and continuity, whereas breadth, depth, and quality were rated more favourably. Students receiving more than 200 h of anatomy teaching reported significantly higher satisfaction than those receiving fewer than 200 h ( p < 0.001). Satisfaction also varied by continuity pattern, with teaching delivered continuously over three or more years associated with higher satisfaction than shorter or non‐continuous models ( p < 0.01). Cadaveric dissection was the most preferred modality, but higher satisfaction was associated with exposure to selected adjuncts, particularly 3D imaging software and 3D printed models (both p < 0.001); VR/AR showed no significant association. Perceived importance of anatomy differed by intended specialty, with students interested in surgery rating anatomy as most important ( p < 0.0001). Student dissatisfaction with UK undergraduate anatomy teaching appears to stem less from content coverage than from insufficient teaching time and poor longitudinal integration. Anatomy should be protected as a multi‐year component of the curriculum, complemented by selectively integrated adjunctive tools rather than indiscriminate technology adoption.