Emerging Subspecialties: Pediatric Movement Disorders Neurology.

Pediatric movement disorders (PMD) neurologists care for infants, children, and adolescents with conditions that disrupt typical movement; serving as important subspecialist child neurologists in both academic and private practice settings. In contrast to adult movement disorders neurologists whose "bread and butter" is hypokinetic Parkinson disease, PMD subspecialty practice is often dominated by hyperkinetic movement disorders including tics, dystonia, chorea, tremor, and myoclonus. PMD neurology practice intersects with a variety of subspecialties, including neonatology, developmental pediatrics, rehabilitation medicine, epilepsy, child & adolescent psychiatry, psychology, orthopedics, genetics & metabolism, and neurosurgery.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

Background: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF).

Objective: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes.

Tumor Immune Cell Targeting Chimeras (TICTACs) For Targeted Depletion of Macrophage-Associated Checkpoint Receptors.

Immune cells in the tumor microenvironment are not only powerful regulators of immunosuppression and tumorigenesis, but also represent a dominant cell type, with tumor-associated macrophages (TAMs) comprising up to 50% of total cell mass in solid tumors. Immunotherapies such as immune checkpoint inhibitors (ICIs) derive their efficacy from this cancer-immune cell interface, however, immune-related adverse events resulting from systemic blockade remain a significant challenge. To address this need for potent, yet highly tumor-specific immunotherapies, we developed Tumor-Immune Cell Targeting Chimeras (TICTACs), antibody conjugates that are capable of selectively depleting immune checkpoint receptors such as SIRPa from the surface of TAMs.

Loss of CD20 expression as a mechanism of resistance to mosunetuzumab in relapsed/refractory B-cell lymphomas.

CD20 is an established therapeutic target in B-cell malignancies. The CD20 × CD3 bispecific antibody mosunetuzumab has significant efficacy in B-cell non-Hodgkin lymphomas (NHLs). Because target antigen loss is a recognized mechanism of resistance, we evaluated CD20 expression relative to clinical response in patients with relapsed and/or refractory NHL in the phase 1/2 GO29781 trial investigating mosunetuzumab monotherapy.

Microglia Mediate Contact-Independent Neuronal Network Remodeling via Secreted Neuraminidase-3 Associated with Extracellular Vesicles.

Neurons communicate with each other through electrochemical transmission at synapses. Microglia, the resident immune cells of the central nervous system, modulate this communication through a variety of contact-dependent and -independent means. Microglial secretion of active sialidase enzymes upon exposure to inflammatory stimuli is one unexplored mechanism of modulation.

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.

Methods: We enrolled 436 patients with HCM (median age, 60 years; 28.

Directed Evolution of Genetically Encoded LYTACs for Cell-Mediated Delivery.

Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites.

Anterior Cruciate Ligament Reconstruction Using Femoral Cortical Button Fixation: A Case Series of Intraoperative Malpositioning.

Background: Malpositioning of the femoral button is a known technical complication after anterior cruciate ligament (ACL) reconstruction with cortical suspensory fixation. The incidence of malpositioning, as well as the efficacy of methods to prevent malpositioning of cortical suspensory fixation devices, has not been reported.

Purpose: To determine the rate of malpositioned cortical suspensory fixation devices after ACL reconstruction, investigate which intraoperative technique yields the lowest rate of malpositioning, and determine the return-to-duty rate for active-duty service members with malpositioned buttons and the revision rate for malpositioned buttons.

Increased posterior tibial slope is an independent risk factor of anterior cruciate ligament reconstruction graft rupture irrespective of graft choice.

Introduction: Anterior cruciate ligament (ACL) reconstruction failure remains a commonly seen complication despite advances in technique and graft options. Recently, several studies have shown that the inclination of the tibial plateau in the sagittal plane affects the stability of the knee joint. The purpose of this study was to determine if an increased posterior slope of the tibia is associated with failure of ACL reconstruction irrespective of the graft used.

Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras.

Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs) harness receptors, such as the cation-independent mannose 6-phosphate receptor (CI-M6PR), to direct extracellular proteins to lysosomes. In this work, we used a genome-wide CRISPR knockout approach to identify modulators of LYTAC-mediated membrane protein degradation in human cells.

Galectin-3 does not interact with RNA directly.

Galectin-3, well characterized as a glycan binding protein, has been identified as a putative RNA binding protein, possibly through participation in pre-mRNA maturation through interactions with splicosomes. Given recent developments with cell surface RNA biology, the putative dual-function nature of galectin-3 evokes a possible non-classical connection between glycobiology and RNA biology. However, with limited functional evidence of a direct RNA interaction, many molecular-level observations rely on affinity reagents and lack appropriate genetic controls.

Closed-loop stimulation in periods with less epileptiform activity drives improved epilepsy outcomes.

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes.

Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE.

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains.

Interval post-colonoscopy colorectal cancer following a negative colonoscopy in a fecal immunochemical test-based screening program.

Background:  In the Dutch colorectal (CRC) screening program, fecal immunochemical test (FIT)-positive individuals are referred for colonoscopy. If no relevant findings are detected at colonoscopy, individuals are reinvited for FIT screening after 10 years. We aimed to assess CRC risk after a negative colonoscopy in FIT-positive individuals.

Microglia mediate contact-independent neuronal pruning via secreted Neuraminidase-3 associated with extracellular vesicles.

Neurons communicate with each other through electrochemical transmission at synapses. Microglia, the resident immune cells of the central nervous system, can prune these synapses through a variety of contact-dependent and -independent means. Microglial secretion of active sialidase enzymes upon exposure to inflammatory stimuli is one unexplored mechanism of pruning.

Design of a mucin-selective protease for targeted degradation of cancer-associated mucins.

Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms.

Chemical generation of checkpoint inhibitory T cell engagers for the treatment of cancer.

Bispecific T cell engagers (BiTEs), a subset of bispecific antibodies (bsAbs), can promote a targeted cancer cell's death by bringing it close to a cytotoxic T cell. Checkpoint inhibitory T cell engagers (CiTEs) comprise a BiTE core with an added immunomodulatory protein, which serves to reverse cancer-cell immune-dampening strategies, improving efficacy. So far, protein engineering has been the main approach to generate bsAbs and CiTEs, but improved chemical methods for their generation have recently been developed.

Video versus Direct Laryngoscopy for Tracheal Intubation of Critically Ill Adults.

Background: Whether video laryngoscopy as compared with direct laryngoscopy increases the likelihood of successful tracheal intubation on the first attempt among critically ill adults is uncertain.

Methods: In a multicenter, randomized trial conducted at 17 emergency departments and intensive care units (ICUs), we randomly assigned critically ill adults undergoing tracheal intubation to the video-laryngoscope group or the direct-laryngoscope group. The primary outcome was successful intubation on the first attempt.

Targeted TLR9 Agonist Elicits Effective Antitumor Immunity against Spontaneously Arising Breast Tumors.

Spontaneous tumors that arise in genetically engineered mice recapitulate the natural tumor microenvironment and tumor-immune coevolution observed in human cancers, providing a more physiologically relevant preclinical model relative to implanted tumors. Similar to many cancer patients, oncogene-driven spontaneous tumors are often resistant to immunotherapy, and thus novel agents that can effectively promote antitumor immunity against these aggressive cancers show considerable promise for clinical translation, and their mechanistic assessment can broaden our understanding of tumor immunology. In this study, we performed extensive immune profiling experiments to investigate how tumor-targeted TLR9 stimulation remodels the microenvironment of spontaneously arising tumors during an effective antitumor immune response.

Bioluminogenic Probe for Rapid, Ultrasensitive Detection of β-Lactam-Resistant Bacteria.

Increasingly difficult-to-treat infections by antibiotic-resistant bacteria have become a major public health challenge. Rapid detection of common resistance mechanisms before empiric antibiotic usage is essential for optimizing therapeutic outcomes and containing further spread of resistance to antibiotics among other bacteria. Herein, we present a bioluminogenic probe, D-Bluco, for rapid detection of β-lactamase activity in viable pathogenic bacteria.

Language Analytics for Assessment of Mental Health Status and Functional Competency.

Background And Hypothesis: Automated language analysis is becoming an increasingly popular tool in clinical research involving individuals with mental health disorders. Previous work has largely focused on using high-dimensional language features to develop diagnostic and prognostic models, but less work has been done to use linguistic output to assess downstream functional outcomes, which is critically important for clinical care. In this work, we study the relationship between automated language composites and clinical variables that characterize mental health status and functional competency using predictive modeling.

MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint.

The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the oncogene causally regulates Siglec ligand production to enable tumor immune evasion.