The Experiences of Patients With Rare Diseases in Pennsylvania: A Community-Based Study.

Objective: Rare diseases collectively affect approximately 30 million people in the United States. Despite advances in genomic medicine, early diagnosis is challenging because of limited awareness of, accessibility to, and disparities in health care resources. We assessed the real-world experiences of patients with rare diseases in Pennsylvania and evaluated the effect of delayed diagnosis on psychosocial and financial burdens.

Integrative exome sequencing and machine learning identify MICB and interferon pathway genes as contributors to SSc risk.

Objectives: Systemic sclerosis (SSc) is a complex autoimmune disease with both known and unidentified genetic contributors. While genome-wide association studies (GWAS) have implicated multiple loci, many reside in noncoding regions. We aimed to identify novel protein-coding variants and pathogenic pathways using exome sequencing (ES) integrated with an Evolutionary Action-Machine Learning (EAML) framework, single-cell RNA sequencing (scRNA-seq), and expression quantitative trait locus (eQTL) analysis.

De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies.

Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.

ATRX silences Cartpt expression in osteoblastic cells during skeletal development.

ATP-dependent chromatin remodeling protein ATRX is an essential regulator involved in maintenance of DNA structure and chromatin state and regulation of gene expression during development. ATRX was originally identified as the monogenic cause of X-linked α-thalassemia mental retardation (ATR-X) syndrome. Affected individuals display a variety of developmental abnormalities and skeletal deformities.

The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5).

Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance.

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure.

Implementation of CYP2D6-guided opioid therapy at Cincinnati Children's Hospital Medical Center.

Purpose: We describe the implementation of CYP2D6-focused pharmacogenetic testing to guide opioid prescribing in a quaternary care, nonprofit pediatric academic medical center.

Summary: Children are often prescribed oral opioids after surgeries, for cancer pain, and occasionally for chronic pain. In 2004, Cincinnati Children's Hospital Medical Center implemented pharmacogenetic testing for CYP2D6 metabolism phenotype to inform codeine prescribing.

Yap and Taz promote osteogenesis and prevent chondrogenesis in neural crest cells in vitro and in vivo.

Neural crest cells (NCCs) are multipotent stem cells that can differentiate into multiple cell types, including the osteoblasts and chondrocytes, and constitute most of the craniofacial skeleton. Here, we show through in vitro and in vivo studies that the transcriptional regulators Yap and Taz have redundant functions as key determinants of the specification and differentiation of NCCs into osteoblasts or chondrocytes. Primary and cultured NCCs deficient in and switched from osteogenesis to chondrogenesis, and NCC-specific deficiency for and resulted in bone loss and ectopic cartilage in mice.

Taking the plunge: When is best for hot water immersion to complement exercise in heat and hypoxia.

This investigation assessed the psycho-physiological and performance effects of hot water immersion (HWI) implemented either before or after a repeated-sprint training in hypoxia (RSH) session conducted in the heat. Ten participants completed three RSH trials (3 × 10 × 5-s sprints), conducted at 40°C and simulated altitude of 3000 m. A 30-min monitoring period preceded and followed all exercise sessions.

Repeated-sprint training in heat and hypoxia: Acute responses to manipulating exercise-to-rest ratio.

The aim of this study was to investigate acute performance and physiological responses to the manipulation of exercise-to-rest ratio (E:R) during repeated-sprint hypoxic training (RSH) in hot conditions. Twelve male team-sport players completed two experimental sessions at a simulated altitude of ∼3000 m (FO 0.144), air temperature of 40°C and relative humidity of 50%.

DDRGK1 is required for the proper development and maintenance of the growth plate cartilage.

Loss-of-function mutations in DDRGK1 have been shown to cause Shohat type spondyloepimetaphyseal dysplasia (SEMD). In zebrafish, loss of function of ddrgk1 leads to defects in early cartilage development. Ddrgk1-/- mice show delayed mesenchymal condensation in the limb buds and early embryonic lethality.

4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis.

Genetic Testing in Patients with Neurodevelopmental Disorders: Experience of 511 Patients at Cincinnati Children's Hospital Medical Center.

Our institution developed and continuously improved a Neurodevelopmental Reflex (NDR) algorithm to help physicians with genetic test ordering for neurodevelopmental disorders (NDDs). To assess its performance, we performed a retrospective study of 511 patients tested through NDR from 2018 to 2019. SNP Microarray identified pathogenic/likely pathogenic copy number variations in 27/511 cases (5.

Increased air temperature during repeated-sprint training in hypoxia amplifies changes in muscle oxygenation without decreasing cycling performance.

The present study aims to investigate the acute performance and physiological responses, with specific reference to muscle oxygenation, to ambient air temperature manipulation during repeated-sprint training in hypoxia (RSH). Thirteen male team-sport players completed one familiarisation and three experimental sessions at a simulated altitude of ∼3000 m (FO 0.144).

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e.

Localized chondro-ossification underlies joint dysfunction and motor deficits in the mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder that features wide-ranging defects in both skeletal and nonskeletal tissues. Previously, we and others reported that loss-of-function mutations in FK506 Binding Protein 10 () lead to skeletal deformities in conjunction with joint contractures. However, the pathogenic mechanisms underlying joint dysfunction in OI are poorly understood.

Characterization of Reference Materials with an Association for Molecular Pathology Pharmacogenetics Working Group Tier 2 Status: CYP2C9, CYP2C19, VKORC1, CYP2C Cluster Variant, and GGCX: A GeT-RM Collaborative Project.

Pharmacogenetic testing is increasingly available from clinical and research laboratories. However, only a limited number of quality control and other reference materials are currently available for many of the variants that are tested. The Association for Molecular Pathology Pharmacogenetic Work Group has published a series of papers recommending alleles for inclusion in clinical testing.

Understanding and interpretation of a variant of uncertain significance (VUS) genetic test result by pediatric providers who do not specialize in genetics.

The advancement of genetic testing technologies has allowed for better diagnosis and management of patients, but also results in more variants of uncertain significance (VUSs) due to the increased number of genes being analyzed. There are more genetic tests available and more providers who do not specialize in genetics ordering genetic testing, but few studies examining how providers who do not specialize in genetics interpret VUSs. This study surveyed pediatric providers at a midwestern pediatric care center who do not specialize in genetics about their understanding of a mock genetic test report with a VUS result and whether their understanding of the result was associated with experience ordering genetic tests.

Heat Added to Repeated-Sprint Training in Hypoxia Does Not Affect Cycling Performance.

Purpose: This study aimed to assess the influence of graded air temperatures during repeated-sprint training in hypoxia (RSH) on performance and physiological responses.

Methods: Ten well-trained athletes completed one familiarization and 4 experimental sessions at a simulated altitude of 3000 m (0.144 FIO2) above sea level.

Nitric oxide modulates bone anabolism through regulation of osteoblast glycolysis and differentiation.

Previous studies have shown that nitric oxide (NO) supplements may prevent bone loss and fractures in preclinical models of estrogen deficiency. However, the mechanisms by which NO modulates bone anabolism remain largely unclear. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable of synthesizing arginine, the sole precursor for nitric oxide synthase-dependent (NOS-dependent) NO synthesis.

Repeat Application of Ischemic Preconditioning Improves Maximal 1,000-m Kayak Ergometer Performance in a Simulated Competition Format.

Halley, SL, Peeling, P, Brown, H, Sim, M, Mallabone, J, Dawson, B, and Binnie, MJ. Repeat application of ischemic preconditioning improves maximal 1,000-m kayak ergometer performance in a simulated competition format. J Strength Cond Res XX(X): 000-000, 2020-This study examined the effects of ischemic preconditioning (IPC) on repeat 1,000-m kayak ergometer time-trial (TT) performance, completed in a simulated competition format.

Refining Treatment Strategies for Iron Deficient Athletes.

Iron deficiency (ID) is a prevailing nutritional concern amongst the athletic population due to the increased iron demands of this group. Athletes' ability to replenish taxed iron stores is challenging due to the low bioavailability of dietary sources, and the interaction between exercise and hepcidin, the primary iron-regulatory hormone. To date, copious research has explored the link between exercise and iron regulation, with a more recent focus on optimising iron treatment applications.

Validity and Reliability of a Field Hockey-Specific Dribbling Speed Test.

Tapsell, LC, Binnie, MJ, Lay, BS, Dawson, BT, and Goods, PSR. Validity and reliability of a field hockey-specific dribbling speed test. J Strength Cond Res 36(6): 1720-1725, 2022-The present study aimed to design a valid and reliable test for field hockey players that concurrently assesses the skill of dribbling and sport-specific agility.