Cellular and electrophysiological characterization of triadin knockout syndrome using induced pluripotent stem cell-derived cardiomyocytes.

Triadin knockout syndrome (TKOS) is a malignant arrhythmia disorder caused by recessive null variants in TRDN-encoded cardiac triadin. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from two unrelated TKOS patients and an unrelated control. CRISPR-Cas9 gene editing was used to insert homozygous TRDN-p.

Suppression and Replacement Gene Therapy for -Mediated Arrhythmias.

Background: -mediated arrhythmia syndromes are caused by loss-of-function (type 2 long QT syndrome [LQT2]) or gain-of-function (type 1 short QT syndrome [SQT1]) pathogenic variants in the -encoded K11.1 potassium channel, which is essential for the cardiac action potential.

Methods: A dual-component "suppression-and-replacement" (SupRep) gene therapy was created by cloning into a single construct a custom-designed short hairpin RNA with ~80% knockdown (suppression) and a "short hairpin RNA-immune" cDNA (replacement).

Characterization of N-terminal RYR2 variants outside CPVT1 hotspot regions using patient iPSCs reveal pathogenesis and therapeutic potential.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy causing ventricular tachycardia following adrenergic stimulation. Pathogenic variants in RYR2-encoded ryanodine receptor 2 (RYR2) cause CPVT1 and cluster into domains I-IV, with the most N-terminal domain involving residues 77-466. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated for RYR2-F13L, -L14P, -R15P, and -R176Q variants.

A phenotype-enhanced variant classification framework to decrease the burden of missense variants of uncertain significance in type 1 long QT syndrome.

Background: Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%.

Perceptions of Barriers and Facilitators to Becoming a Medical Professional Among Underrepresented Undergraduate and Postbaccalaureate Learners.

Objective: To assess underrepresented undergraduate and postbaccalaureate learners' perceptions of (1) the medical field, (2) barriers that might prevent individuals from pursuing professional medical careers, and (3) resources that assist in overcoming these barriers.

Participants And Methods: A qualitative study with focus groups was designed to achieve the objective. Participants were recruited from a community initiative to provide early exploration of the medical field to disadvantaged and minority individuals.

Suppression-Replacement Gene Therapy for Type 1 Long QT Syndrome.

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the -encoded K7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1.

Corrected QT Interval-Polygenic Risk Score and Its Contribution to Type 1, Type 2, and Type 3 Long-QT Syndrome in Probands and Genotype-Positive Family Members.

Background: Long-QT syndrome (LQTS) is characterized by a prolonged heart rate-corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population.

Methods: Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc-polygenic risk score (QTc-PRS).

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population.

Background: Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in -encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown.

Methods: Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained death in the young cases.

Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for as a Definitive Noonan Syndrome-Susceptibility Gene.

Background: was identified recently as a novel Noonan syndrome (NS)-susceptibility gene. Phenotypically, both patients with NS, harboring pathogenic variants, displayed severe cardiac hypertrophy. This study aimed to demonstrate both the necessity and sufficiency of a patient-specific variant (p.

Characterization of the CACNA1C-R518C Missense Mutation in the Pathobiology of Long-QT Syndrome Using Human Induced Pluripotent Stem Cell Cardiomyocytes Shows Action Potential Prolongation and L-Type Calcium Channel Perturbation.

Background: The CACNA1C-encoded cardiac L-type calcium channel (Cav1.2) is essential for cardiocyte action potential duration (APD). We previously reported the CACNA1C-p.

Extended use of the modified Berlin Definition based on age-related subgroup analysis in pediatric ARDS.

Background: Pediatric acute respiratory distress syndrome (pARDS) is a rare but very severe condition. Management of the condition remains a major challenge for pediatric intensive care specialists.

Objective: To perform a descriptive assessment of pARDS based on the modified Berlin Definition by using the SpO/FiO ratio in order to establish an extended patient registry divided into age-related subgroups.

Defensive Perimeter in the Central Nervous System: Predominance of Astrocytes and Astrogliosis during Recovery from Varicella-Zoster Virus Encephalitis.

Unlabelled: Varicella-zoster virus (VZV) is a highly neurotropic virus that can cause infections in both the peripheral nervous system and the central nervous system. Several studies of VZV reactivation in the peripheral nervous system (herpes zoster) have been published, while exceedingly few investigations have been carried out in a human brain. Notably, there is no animal model for VZV infection of the central nervous system.

Severe hemolytic disease of the newborn from anti-e.

Maternal antibody-mediated fetal red blood cell destruction secondary to non-D Rhesus (Rh) antibodies is a significant cause of hemolytic disease of the newborn (HDN). Here, we report a rare case of severe HDN associated with maternal antibody to Rh e. In addition to severe anemia, the infant developed thrombocytopenia, conjugated hyperbilirubinemia and cholelithiasis.

Long-distance air medical transport of extremely low birth weight infants with pneumoperitoneum.

Objective: Long-distance air transport (LDAT) of infants with pneumoperitoneum for pediatric surgical evaluation has not been previously reported. We examined whether extremely low birth weight (ELBW) infants with and without pneumoperitoneum would tolerate transport differently.

Study Design: A retrospective cohort study was conducted comparing ELBW infants diagnosed with pneumoperitoneum to other ELBW infants transported>2000 miles by a trained team from a US Department of Defense tertiary care neonatal intensive care unit in Okinawa, Japan.

Distribution of corticotropin releasing hormone in the fetus, newborn, juvenile, and adult baboon.

Corticotropin releasing hormone (CRH) has previously been identified in extrahypothalamic tissues and may act in a paracrine fashion within these tissues. To date, CRH production and its role in the fetus and newborn have not been investigated. The aim of this study was to explore the distribution and ontogeny of CRH in extrahypothalamic tissues of the fetus, newborn, juvenile, and adult baboon.