Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies.

Objective: TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and limbic-predominant age-related TDP-43 encephalopathy, encompass a spectrum of clinical and neuropathological traits. Despite mounting evidence for shared genetic risk across TDP-43 proteinopathies, the modifiers of individual-level traits are unknown. We aimed to identify polygenic contributions to trait heterogeneity across TDP-43 proteinopathies.

Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy.

Background And Objectives: Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression.

A Novel Rexinoid Agonist, UAB116, Decreases Metastatic Phenotype in Hepatoblastoma by Inhibiting the Wnt/β-Catenin Pathway via Upregulation of .

Hepatoblastoma (HB) is the most common pediatric primary liver tumor. About 20% of affected children have pulmonary metastasis at presentation. Survival rates for these children are dismal, not exceeding 25%.

Investigation of an oncolytic herpes simplex virus as a potential therapeutic agent for gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) present unique challenges due to their heterogeneity and limited treatment options. Oncolytic virotherapy has emerged as a promising therapeutic for other NETs and thus, we sought to investigate the potential of an engineered oncolytic herpes simplex virus (oHSV), M002, for GEP-NETS. We employed an established long-term passage GEP-NET cell line and a unique, human pediatric patient-derived xenograft GEP-NET line.

An Iterative Shifting Disaggregation Algorithm for Multi-Source, Irregularly Sampled, and Overlapped Time Series.

Accurate time series forecasting often requires higher temporal resolution than that provided by available data, such as when daily forecasts are needed from monthly data. Existing temporal disaggregation techniques, which typically handle only single, uniformly sampled time series, have limited applicability in real-world, multi-source scenarios. This paper introduces the Iterative Shifting Disaggregation (ISD) algorithm, designed to process and disaggregate time series derived from sensor-sourced low-frequency measurements, transforming multiple, nonuniformly sampled sensor data streams into a single, coherent high-frequency signal.

ALS Motor Observational Telemedicine Objective Rasch-Built Assessment: A Quantitative Scale for the Era of Teleneurology.

Background And Objectives: Telemedicine has become a mainstay of ALS clinical care, but there is currently no standardized approach for assessing and tracking changes to the neurologic examination in this format. The goal of this study was to create a standardized telemedicine-based motor examination scale to objectively and reliably track ALS progression and use Rasch methodology to validate the scale and improve its psychometric properties.

Methods: A draft telemedicine examination scale with 25 items assessing movement in the bulbar muscles, neck, trunk, and extremities was created by an ALS expert panel, incorporating input from patient advisors.

Atrial Fibrillation and Flutter in a Contemporary Cohort of Patients With Myotonic Muscular Dystrophy.

Background: Literature on the prevalence and management of atrial arrhythmias in patients with myotonic muscular dystrophy type 1 (MMD1) or myotonic muscular dystrophy type 2 (MMD2) is limited.

Objectives: This study sought to describe incidence, prevalence, and predictors of atrial fibrillation (AF) and atrial flutter (AFL) in a contemporary cohort of patients with myotonic muscular dystrophy (MMD).

Methods: Associations between patient factors and incident AF/AFL were analyzed in patients with MMD referred for routine electrophysiology evaluation between January 2013 and September 2023.

Caring for young adult men with inflammatory bowel disease: Clinician and patient perspectives.

Inflammatory bowel disease (IBD) presents unique challenges for young adult men that extend beyond physical symptoms, encompassing psychosocial dimensions affecting all aspects of life. This article draws insights from a roundtable discussion facilitated by the Crohn's and Colitis Young Adults Network (CCYAN), focusing on the experiences of young men living with IBD. It sheds light on the intersections of IBD and men's sexual and reproductive health, fertility, and mental well-being while identifying gaps in care.

The Impact of Peer-Led Learning Groups on First-Year Medical Students.

Active learning and peer instruction contribute to positive learning outcomes. We developed a 25-week, question-based program for first-year medical students (MS1). Senior students developed weekly question and answer sets.

PP2A activation overcomes leptomeningeal dissemination in group 3 medulloblastoma.

Leptomeningeal dissemination (LMD) is the primary cause of treatment failure in children with group 3 medulloblastoma (MB). Building on our previous work on protein phosphatase 2A (PP2A) activation in MB, here we present preclinical and molecular data on the effects of two novel classes of PP2A activators on disease processes of LMD in group 3 MB. The PP2A activators used in this study are ATUX-6156 and ATUX-6954 (diarylmethylcycloamine sulfonylureas), and ATUX-1215 and ATUX-5800 (diarylmethyl-4-aminotetrahydropyran-sulfonamides).

Oncolytic virotherapy augments self-maintaining natural killer cell line cytotoxicity against neuroblastoma.

Background: Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer related deaths. Targeting neuroblastoma with immunotherapies has proven challenging due to a paucity of immune cells in the tumor microenvironment and the release of immunosuppressive cytokines by neuroblastoma tumor cells. We hypothesized that combining an oncolytic Herpes Simplex Virus (oHSV) with natural killer (NK) cells might overcome these barriers and incite tumor cell death.

Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma.

Glioblastoma (GBM) is an immunologically cold tumor, but several immunotherapy-based strategies show promise, including the administration of ex vivo expanded and activated cytotoxic gamma delta T cells. Cytotoxicity is partially mediated through interactions with natural killer group 2D ligands (NKG2DL) on tumor cells. We sought to determine whether the addition of the blood-brain barrier penetrant PARP inhibitor niraparib to the standard of care DNA alkylator temozolomide (TMZ) could upregulate NKG2DL, thereby improving immune cell recognition.

Cumulative Incidence of Motor and Cognitive Features in the ALS-FTD Spectrum.

Unlabelled: In frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS), subsequent motor or cognitive-behavioral features, respectively, are associated with shorter survival. However, factors influencing subsequent feature development remain largely unexplored. In this study, we examined whether the presence of a expansion or the initial clinical syndrome was associated with increased risk of subsequent feature development in individuals with ALS and FTD.

A single ALS center experience with clinical use of sodium phenylbutyrate-taurursodiol.

Introduction/aims: The aim of this study was to examine clinical utilization and discontinuation rates of sodium phenylbutyrate-taurursodiol (PB-TURSO) in a single Amyotrophic Lateral Sclerosis (ALS) center. PB-TURSO was approved by the United States Food and Drug Administration (FDA) in September 2022. Prior experience has been limited to clinical trials or expanded access protocols.

Cognitive reserve in ALS: the role of occupational skills and requirements.

Objective: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor and cognitive impairment. We assessed the impact of specific, empirically derived occupational skills and requirements on cognitive and motor functioning in ALS.

Methods: Individuals with ALS (n = 150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic.

PIM Kinase Inhibition Sensitizes Neuroblastoma to Doxorubicin.

Background: Chemoresistance contributes to relapse in high-risk neuroblastoma. Cancer cells acquire resistance through multiple mechanisms, including drug efflux pumps. In neuroblastoma, multidrug resistance-associated protein-1 (MRP1/ABCC1) efflux pump expression correlates with worse outcomes.

Disparities in Genetic Testing for Neurologic Disorders.

Background And Objectives: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions.

The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.

Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of neuropathy, -related disease, -ALS, related progressive gait decline and spasticity, and -related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E.