Innovation in Dermatomyositis.

Dermatomyositis (DM) is a rare autoimmune disease defined by the presence of characteristic cutaneous findings, an increased cancer risk, and variable extracutaneous pathology involving the muscles, lungs, gastrointestinal tract, heart, and/or joints. Although the pathogenesis of DM remains incompletely understood, the discovery of myositis-specific autoantibodies has been an important step forward in understanding disease heterogeneity in DM and stratifying risk for extracutaneous disease and malignancy. Moreover, the recent elucidation of key immunologic drivers of DM has laid the groundwork for the development of novel, targeted treatments in the DM therapeutic pipeline.

A Survey of Current Approaches to Inguinal Hernia Repair by Pediatric General Surgeons in the United States.

Introduction: Inguinal hernia repair (IHR) is a common pediatric operation performed via open or laparoscopic approaches. The objective of this survey study was to assess current approaches to IHR in a national sample of pediatric general surgeons.

Methods: A REDCap survey was distributed to all pediatric general surgeons at 21 US institutions in 2023.

Pathophysiology of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, progressive immune-mediated disease associated with antigen-driven type 2 inflammation and symptoms of esophageal dysfunction. Research over the last 2 decades has dramatically furthered our understanding of the complex interplay between genetics, environmental exposures, and cellular and molecular interactions involved in EoE. This review provides an overview of our current understanding of EoE pathogenesis.

Causal effect of serum 25 hydroxyvitamin D concentration on cardioembolic stroke: Evidence from two-sample Mendelian randomization.

Background And Aims: The putative association between serum 25-hydroxyvitamin D concentration [25(OH)D] and the risk of cardioembolic stroke (CES) has been examined in observational studies, which indicate controversial findings. We performed Mendelian randomization (MR) analysis to determine the causal relationship of serum 25(OH)D with the risk of CES.

Methods And Results: The summary statistics dataset on the genetic variants related to 25(OH)D was used from the published GWAS of European descent participants in the UK Biobank, including 417,580 subjects, yielding 143 independent loci in 112 1-Mb regions.

Variant to gene mapping for carpal tunnel syndrome risk loci implicates skeletal muscle regulatory elements.

Background: Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, a growing body of evidence supports a strong genetic contribution. Recent genome-wide association study (GWAS) efforts have reported 53 independent signals associated with CTS.

Amelioration of Subglottic Stenosis by Antimicrobial Peptide Eluting Endotracheal Tubes.

Introduction: Pediatric subglottic stenosis (SGS) results from prolonged intubation where scar tissue leads to airway narrowing that requires invasive surgery. We have recently discovered that modulating the laryngotracheal microbiome can prevent SGS. Herein, we show how our patent-pending antimicrobial peptide-eluting endotracheal tube (AMP-ET) effectively modulates the local airway microbiota resulting in reduced inflammation and stenosis resolution.

-An Emerging Master Regulator of Autoimmunity and Neurodegeneration.

CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic development. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypofunction predisposes to both autoinflammatory phenotype and neurodegeneration.

Long-term outcomes of bilateral thoracoscopic T3 sympathectomy for primary focal hyperhidrosis in children.

Background: Thoracoscopic bilateral T3 sympathectomy for primary focal palmar hyperhidrosis in children has excellent short-term outcomes. However, data in the literature, on the long-term outcomes of the operation are scarce.

Methods: We conducted a retrospective institutional review of all children and adolescents undergoing T3 bilateral thoracoscopic sympathectomy for primary focal palmar hyperhidrosis between June 2013 and October 2020.

Best Practice for Clinical Somatic Variant Interpretation and Reporting.

Because the clinical impact of cancer genomics is being increasingly recognized, tumor sequencing will likely continue to expand in breadth and scope. Therefore, it is vital for laboratory professionals to adopt the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists guidelines and create a standardized system of classification and nomenclature for somatic variants. Combining robust bioinformatics pipelines with thorough data analysis is necessary to efficiently and reproducibly identify and assess the impact of clinically relevant variants.

Transduction characteristics of alternative adeno-associated virus serotypes in the cat brain by intracisternal delivery.

Multiple studies have examined the transduction characteristics of different AAV serotypes in the mouse brain, where they can exhibit significantly different patterns of transduction. The pattern of transduction also varies with the route of administration. Much less information exists for the transduction characteristics in large-brained animals.

Interstitial deletion 4p15.32p16.1 and complex chromoplexy in a female proband with severe neurodevelopmental delay, growth failure and dysmorphism.

Complex chromosomal rearrangements involve the restructuring of genetic material within a single chromosome or across multiple chromosomes. These events can cause serious human disease by disrupting coding DNA and gene regulatory elements via deletions, duplications, and structural rearrangements. Here we describe a 5-year-old female with severe developmental delay, dysmorphic features, multi-suture craniosynostosis, and growth failure found to have a complex series of balanced intra- and inter-chromosomal rearrangements involving chromosomes 4, 11, 13, and X.

Osteoarthritis and chronic pain: Interleukin-6 as a common denominator and therapeutic target.

Osteoarthritis (OA) is a common and problematic disorder that is often associated with chronic pain, a combination that renders OA a leading cause of physical disability and an unmet clinical challenge. In this issue of , Liao show that interleukin-6 is a driver of both joint tissue degradation and pain, revealing a common culprit and a possible comprehensive target of therapeutic intervention.

Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types.

Background: SARS-CoV-2 infection results in a broad spectrum of COVID-19 disease, from mild or no symptoms to hospitalization and death. COVID-19 disease severity has been associated with some pre-existing conditions and the magnitude of the adaptive immune response to SARS-CoV-2, and a recent genome-wide association study (GWAS) of the risk of critical illness revealed a significant genetic component. To gain insight into how human genetic variation attenuates or exacerbates disease following SARS-CoV-2 infection, we implicated putatively functional COVID risk variants in the cis-regulatory landscapes of human immune cell types with established roles in disease severity and used high-resolution chromatin conformation capture to map these disease-associated elements to their effector genes.

Medical Management of Eosinophilic Esophagitis in Pediatric Patients.

Eosinophilic esophagitis is an immune-mediated allergic disease of the esophagus that affects pediatric patients of all ages. The diagnosis is made by esophagogastroduodenoscopy demonstrating eosinophilic infiltrate of the esophagus. Approaches to treatment involve proton pump inhibitors (PPIs), swallowed topical steroid preparations, as well as dietary elimination.

Local injury and systemic infection in infants alter later nociception and pain affect during early life and adulthood.

Newborns in intensive care are regularly exposed to minor painful procedures at developmental time points when noxious stimulation would be normally absent. Pain from these interventions is inconsistently treated and often exists concurrently with systemic infection, a common comorbidity of prematurity. Our understanding of the independent and combined effects of early painful experiences and infection on pain response is incomplete.

Restriction enzyme selection dictates detection range sensitivity in chromatin conformation capture-based variant-to-gene mapping approaches.

Promoter-focused chromatin conformation techniques directly detect interactions between gene promoters and distal genomic sequences, providing structural information relevant to gene regulation without the excessive non-genic architectural data generated by full-scale Hi-C. 3D promoter 'interactome' maps are crucial for understanding how epigenomic features such as histone modifications and open chromatin, or genetic variants identified in genome-wide association studies (GWAS), contribute to biological function. However, variation in sensitivity between such promoter-focused methods, principally due to restriction enzyme selection, has not been systematically assessed.

Rapid Regulation of Glutamate Transport: Where Do We Go from Here?

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). A family of five Na-dependent transporters maintain low levels of extracellular glutamate and shape excitatory signaling. Shortly after the research group of the person being honored in this special issue (Dr.

Environment-Sensitive Polymeric Micelles Encapsulating SN-38 Potently Suppress Growth of Neuroblastoma Cells Exhibiting Intrinsic and Acquired Drug Resistance.

Conventional treatment approaches fail to provide durable control over aggressive malignancies due to intrinsic or acquired drug resistance characteristic of high-risk disease. SN-38, a potent camptothecin analog specifically targeting DNA topoisomerase I cleavage complexes, has shown promise in preclinical studies against aggressive solid tumors. However, its clinical utility is limited by inadequate solubility in pharmaceutically acceptable vehicles and by poor chemical and metabolic stability.

3D promoter architecture re-organization during iPSC-derived neuronal cell differentiation implicates target genes for neurodevelopmental disorders.

Neurodevelopmental disorders are thought to arise from interrupted development of the brain at an early age. Genome-wide association studies (GWAS) have identified hundreds of loci associated with susceptibility to neurodevelopmental disorders; however, which noncoding variants regulate which genes at these loci is often unclear. To implicate neuronal GWAS effector genes, we performed an integrated analysis of transcriptomics, epigenomics and chromatin conformation changes during the development from Induced pluripotent stem cell-derived neuronal progenitor cells (NPCs) into neurons using a combination of high-resolution promoter-focused Capture-C, ATAC-seq and RNA-seq.

Transfusion and Cellular Therapy in Pediatric Sickle Cell Disease.

Red blood cell (RBC) transfusion is critical in managing acute and chronic complications of sickle cell disease. Alloimmunization and iron overload remain significant complications of transfusion therapy and are minimized with prophylactic Rh and K antigen RBC matching and iron chelation. Matched sibling donor hematopoietic stem cell transplant (HSCT) is a curative therapeutic option.

Postnatal transcriptional activity regulates functional properties of PV interneurons.

The transcription factor Aristaless-related X-linked gene () is a monogenic factor in early onset epileptic encephalopathies (EOEEs) and a fundamental regulator of early stages of brain development. However, expression persists in mature GABAergic neurons with an unknown role. To address this issue, we generated a conditional knockout (CKO) mouse in which postnatal was ablated in parvalbumin interneurons (PVIs).