Safety and Efficacy of Moderate-Dose Denosumab in Fibrous Dysplasia: Observational Results from a Phase 2 Clinical Trial.

Context: Fibrous dysplasia (FD) is a rare skeletal mosaic disease associated with fractures and disability. A phase 2 trial of the RANKL inhibitor denosumab (NCT03571191) reported profound reductions in lesion activity and increased lesional mineralization after 6-months of high-dose treatment. Denosumab was well-tolerated, however discontinuation was associated with severe hypercalcemia.

Rycal S48168 (ARM210) for -related myopathies: a phase one, open-label, dose-escalation trial.

Background: -related myopathies (-RM) are caused by pathogenic variants in the gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to -RM pathogenesis.

Neurofilament light chain in cerebrospinal fluid as a novel biomarker in evaluating both clinical severity and therapeutic response in Niemann-Pick disease type C1.

Purpose: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder caused by pathogenic variants in NPC1. Disease progression is monitored using the NPC Neurological Severity Scale, but there are currently no established validated or qualified biomarkers. Neurofilament light chain (NfL) is being investigated as a biomarker in multiple neurodegenerative diseases.

Survivorship Issues in Adult Patients With Histiocytic Neoplasms.

Adult-onset histiocytoses (AOH), primarily Rosai-Dorfman disease (RDD), Erdheim-Chester Disease (ECD), and adult Langerhans cell histiocytosis (ALCH), are a group of related histiocytic neoplastic disorders featuring multisystemic manifestations. The disorders are largely incurable, and are essentially chronic neoplastic diseases with a variable prognosis. Prompt diagnosis and treatment is important to prevent debilitating and even life-threatening complications.

Ryanodine Receptor 1-Related Myopathies: Quantification of Intramuscular Fatty Infiltration from T1-Weighted MRI.

Background: Ryanodine receptor 1-related myopathy (RYR1-RM) can present with a selective pattern and gradient of intramuscular fatty infiltration (IMFI) on magnetic resonance imaging (MRI).

Objective: To demonstrate an automated protocol for quantification of IMFI in the lower extremity muscles of individuals with RYR1-RM using T1-weighted MRI and to examine the relationships of IMFI with motor function and clinical severity.

Methods: Axial images of the lower extremity muscles were acquired by T1-weighted fast spin-echo and short tau inversion recovery (STIR) sequences.

Demographic and functional differences among social security disability claimants.

Purpose: Sociodemographic characteristics may influence responses on self-reported measures. Differential item functioning (DIF) is when individuals expected to have the same ability level on a construct of interest have a different probability of endorsing an item on an item response theory (IRT) scale due to population characteristics. The goal of this study was to identify DIF for items in an outcome instrument by sociodemographic factors and, one controlling for DIF, assess true differences in function by those same factors.

Responsiveness and Minimal Clinically Important Difference of the Motor Function Measure in Collagen VI-Related Dystrophies and Laminin Alpha2-Related Muscular Dystrophy.

Objectives: To investigate the responsiveness of the motor function measure (MFM) and determine the minimal clinically important difference (MCID) in individuals with 2 common types of congenital muscular dystrophy (CMD).

Design: Observational, prospective, single center, cohort study.

Setting: National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH).

Randomized controlled trial of -acetylcysteine therapy for -related myopathies.

Objective: To investigate the efficacy of -acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (-RM).

Methods: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance.

Use of Fatigue Index as a Measure of Local Muscle Fatigability in Ryanodine Receptor Isoform-1-Related Myopathies.

Individuals affected with ryanodine receptor isoform-1-related myopathies (RM) commonly experience fatigability in the quadriceps, which may limit physical function and potentially diminish quality of life. Fatigability, in -RM, results from skeletal muscle injury secondary to dysfunction of the major skeletal muscle Ca channel. However, during fatigability testing, affected individuals did not always reach the point of local muscle fatigue as defined by a fatigue index (FATI) at 50% of peak torque.

White vitreous opacities in five patients with Gaucher disease type 3.

Fundal abnormalities, including preretinal and retinal changes, are a rare finding in patients with the autosomal recessive lysosomal storage disorder Gaucher disease, most often described in patients with the chronic neuronopathic form (type 3). We evaluated whether these ophthalmological findings correlated with other manifestations of type 3 Gaucher disease. Reviewing the records of 40 patients with type 3 Gaucher disease, we identified five with white vitreous opacities and reviewed their clinical course in depth.

Broadening horizons: the case for capturing function and the role of health informatics in its use.

Background: Human activity and the interaction between health conditions and activity is a critical part of understanding the overall function of individuals. The World Health Organization's International Classification of Functioning, Disability and Health (ICF) models function as all aspects of an individual's interaction with the world, including organismal concepts such as individual body structures, functions, and pathologies, as well as the outcomes of the individual's interaction with their environment, referred to as activity and participation. Function, particularly activity and participation outcomes, is an important indicator of health at both the level of an individual and the population level, as it is highly correlated with quality of life and a critical component of identifying resource needs.

Five-parameter evaluation of dysphagia: A novel prognostic scale for assessing neurological decline in Gaucher disease type 2.

Background: Gaucher disease type 2 (GD2) is defined by acute neurological decline, failure to thrive, and early demise. Currently, there is no clear standard for evaluating, staging, and counseling regarding neurological decline in GD2. Due to the high prevalence of progressive dysphagia secondary to acute neurological involvement, we aimed to identify key components of swallow function which could serve as markers of disease progression in GD2.

The Work Disability Functional Assessment Battery (WD-FAB).

Accuracy in measuring function related to one's ability to work is central to public confidence in a work disability benefits system. In the United States, national disability programs are challenged to adjudicate millions of work disability claims each year in a timely and accurate manner. The Work Disability Functional Assessment Battery (WD-FAB) was developed to provide work disability agencies and other interested parties a comprehensive and efficient approach to profiling a person's function related to their ability to work.

Insulin Sensitivity, Depression/Anxiety, and Physical Fitness in At-Risk Adolescents.

Poor physical fitness contributes to the early progression of cardiometabolic disease, yet the physiological and psychological factors underpinning poor fitness in at-risk adolescents are not well understood. In this study, we sought to determine the relationship of physical fitness with two developmental phenomena of adolescence, insulin resistance and depression/anxiety symptoms among at-risk youth. We conducted secondary data analyses of 241 overweight or obese adolescents (12-17 years), drawn from two study cohorts.

Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome.

Background: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common.

Methods: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.

Age-Related Changes and Effects of Bisphosphonates on Bone Turnover and Disease Progression in Fibrous Dysplasia of Bone.

Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro-osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept.

Correlation of phenotype with genotype and protein structure in RYR1-related disorders.

Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population.

Scoliosis in Fibrous Dysplasia/McCune-Albright Syndrome: Factors Associated With Curve Progression and Effects of Bisphosphonates.

Scoliosis is a complication of fibrous dysplasia/McCune-Albright syndrome (FD/MAS); however, risk factors and long-term outcomes are unknown. Bisphosphonates are commonly used; however, it is unknown whether their use decrease the risk of progressive scoliosis. Clinical data from the National Institutes of Health (NIH) cohort study was reviewed.

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.

Background: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD.

Automatic data source identification for clinical trial eligibility criteria resolution.

Clinical trial coordinators refer to both structured and unstructured sources of data when evaluating a subject for eligibility. While some eligibility criteria can be resolved using structured data, some require manual review of clinical notes. An important step in automating the trial screening process is to be able to identify the right data source for resolving each criterion.

Electrical impedance myography in individuals with collagen 6 and laminin α-2 congenital muscular dystrophy: a cross-sectional and 2-year analysis.

Introduction: Electrical impedance myography (EIM) is a noninvasive electrophysiological technique that characterizes muscle properties through bioimpedance. We compared EIM measurements to function, strength, and disease severity in a population with congenital muscular dystrophy (CMD).

Methods: Forty-one patients with CMD, either collagen 6 related disorders (COL6-RD; n = 21) or laminin α-2-related disorders (LAMA2-RD; n = 20), and 21 healthy pediatric controls underwent 2 yearly EIM exams.

Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy.

Congenital muscular dystrophy (CMD) comprises a rare group of genetic muscle diseases that present at birth or early during infancy. Two common subtypes of CMD are collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). Traditional outcome measures in CMD include gross motor and mobility assessments, yet significant motor declines underscore the need for valid upper extremity motor assessments as a clinical endpoint.

Comparison of sitting and supine forced vital capacity in collagen VI-related dystrophy and laminin α2-related dystrophy.

Background: Progressive, restrictive, respiratory insufficiency is the major cause of morbidity and mortality in Congenital Muscular Dystrophy (CMD). Nocturnal hypoventilation precedes daytime alveolar hypoventilation, and if untreated, may lead to respiratory failure and cor pulmonale. CMD consensus care guidelines recommend screening for respiratory insufficiency by conventional and dynamic (sitting to supine) pulmonary function testing (PFT) and evaluating for sleep disordered breathing if there is more than 20% relative reduction from sitting to supine FVC(L) (ΔFVC).

A Quantitative and Qualitative Evaluation of Sentence Boundary Detection for the Clinical Domain.

Sentence boundary detection (SBD) is a critical preprocessing task for many natural language processing (NLP) applications. However, there has been little work on evaluating how well existing methods for SBD perform in the clinical domain. We evaluate five popular off-the-shelf NLP toolkits on the task of SBD in various kinds of text using a diverse set of corpora, including the GENIA corpus of biomedical abstracts, a corpus of clinical notes used in the 2010 i2b2 shared task, and two general-domain corpora (the British National Corpus and Switchboard).

Heterogeneous incidence and propagation of spreading depolarizations.

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time.