Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Findings from the Longitudinal CINRG Becker Natural History Study.

BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

Monomeric myeloperoxidase is a specific biomarker for early-stage ovarian cancer.

Background: Ovarian cancer cells are known to express myeloperoxidase (MPO), an oxidant-producing enzyme with a 150 kDa homodimer, consisting of two identical monomers connected by a disulfide bond. Here, we aim to validate monomeric MPO (mMPO) as a biomarker for the early detection of ovarian cancer.Methods: Human ovarian cancer cells, sera from patients at various stages, sera from non-cancer inflammatory gynecological diseases, and healthy volunteers were used. Monomeric and dimeric MPO were measured by ELISA. Receiver operating curves were used to compare the predictive powers of serum dimeric and monomeric MPO to discriminate between samples.Results: The expression of MPO was unique to ovarian cancer cells. Specifically, mMPO was found to be the only form of MPO in all ovarian cancer cell lines. Intriguingly, mMPO was detected in the sera from all patients with ovarian cancer at various stages, but not from healthy individuals. Serum mMPO discriminated between early-stage ovarian cancer, healthy controls, and benign inflammatory gynecologic disorders. In addition, mMPO discriminated between the early and late stages of the disease.Conclusion: This work highlights mMPO as a potential biomarker for early detection of ovarian cancer, which is critically needed.

Impact of the COVID-19 Pandemic on a Clinical Trial: A Quantitative Report on Study Engagement and Strategies.

INTRODUCTION: The COVID-19 pandemic impacted clinical research worldwide potentially altering research findings. The study purpose was to measure the effect of the pandemic on recruitment, retention, assessment, and intervention completion rates. METHODS: Enrollment and participation data from a clinical trial evaluating efficacy of a physical therapy intervention for high-risk preterm infants were compared across 3 pandemic periods (February 2019 through November 2021). RESULTS: Recruitment, retention, assessment, and intervention completion rates were lowest during the peak pandemic period. CONCLUSIONS: In compliance with the Human Subjects Review Board, and for the participants' and staff safety, transition from in-person to telehealth or hybrid visits was required to continue this longitudinal study. Despite the negative effect of the pandemic, parental resilience and commitment to the study was clear. Flexibility, quick action, dedication, and efficiency of the research team were key elements enabling study continuation with successful transition to telehealth assessments/interventions during the peak pandemic period.

Factors Influencing Receipt and Type of Therapy Services in the NICU.

Understanding the type and frequency of current neonatal intensive care unit (NICU) therapy services and predictors of referral for therapy services is a crucial first step to supporting positive long-term outcomes in very preterm infants. This study enrolled 83 very preterm infants (<32 weeks, gestational age mean 26.5 ± 2.0 weeks; 38 male) from a longitudinal clinical trial. Race, neonatal medical index, neuroimaging, and frequency of therapy sessions were extracted from medical records. The Test of Infant Motor Performance and the General Movement Assessment were administered. Average weekly sessions of occupational therapy, physical therapy, and speech therapy were significantly different by type, but the magnitude and direction of the difference depended upon the discharge week. Infants at high risk for cerebral palsy based on their baseline General Movements Assessment scores received more therapy sessions than infants at low risk for cerebral palsy. Baseline General Movements Assessment was related to the mean number of occupational therapy sessions but not physical therapy or speech therapy sessions. Neonatal Medical Index scores and Test of Infant Motor Performance scores were not predictive of combined therapy services. Medical and developmental risk factors, as well as outcomes from therapy assessments, should be the basis for referral for therapy services in the neonatal intensive care unit.

Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). OBJECTIVE: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. METHODS: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. RESULTS: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. CONCLUSIONS: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.

Binding of Intracellular Myeloperoxidase to αV/ß1 Integrin Serves as a Mechanism of Survival in Epithelial Ovarian Cancer.

We were the first to report that epithelial ovarian cancer (EOC) cells and tissues express myeloperoxidase (MPO) that is known to play a role in immune surveillance and inflammation by myeloid cells. Additionally, we reported that MPO is colocalized with inducible nitric oxide synthase (iNOS), a key pro-oxidant enzyme, and plays a key role in regulating apoptosis in EOC cells. Whereas myeloid cells express MPO in a dimeric form, intriguingly, here we report the unique expression of only the monomeric form of MPO in EOC cells, tissues, and blood of an ovarian cancer patient. Additionally, we have identified a cell membrane receptor, αV/ß1 integrin, that is uniquely expressed by both chemosensitive and chemoresistant EOC cells with significantly higher expression in chemoresistant EOC cells. More importantly, we have demonstrated that monoclonal antibodies against αV/ß1 integrin induced cytotoxicity in EOC cells, but not in normal cells, that is also synergistic with conventional chemotherapies. Cytotoxicity of αV/ß1 antibodies is due to conformational changes in αV/ß1 integrin which prevents monomeric MPO binding to αV/ß1 integrin inhibiting the activation of MPO, leading to increased apoptosis. Since normal epithelial cells and macrophages lack monomeric MPO and αV/ß1 integrin system, targeting this unique MPO-dependent survival mechanism will selectively eliminate EOC cells and will be the target for developing specific ovarian cancer therapies.

Talcum powder induces malignant transformation in normal human primary ovarian epithelial cells.

BACKGROUND: Several studies have linked perineal use of talcum powder to increased risk of ovarian cancer (OC). Here, we determined that exposure to talcum powder induces malignant transformation in human normal ovarian cells. METHODS: Human primary ovarian epithelial cells (HPOE), ovarian epithelial cells (HOSEpiC), and primary fibroblasts (NF) were treated with either 100 or 500 µg/mL of talcum powder or titanium dioxide (TiO2) as a particulate control for 72 hours before assessment with a cell transformation assay and p53 and Ki-67 immunohistochemistry. RESULTS: Treatment with talcum powder resulted in formation of colonies, indicating cell malignant transformation in a dose dependent manner in ovarian cell lines. No colonies formed in the untreated ovarian cells or control ovarian cells (TiO2 treated) at either dose. There were no colonies formed in talc treated NF cells. Transformed ovarian cells were increased by 11% and 20% in HPOE and 24% and 40% in HOSEpic cells for talcum powder 100 and 500 µg/mL doses, respectively (P<0.05). There were no detectible transformed cells when cells were treated with TiO2. Importantly, p53 mutant type as well as increased expression of Ki-67 were detected in HPOE and HOSEpic cells when exposed to talcum powder. CONCLUSIONS: Exposure to talcum powder induces malignant transformation in ovarian epithelial cells but not in NF cells. These findings represent a direct effect of talcum powder exposure that is specific to normal ovarian cells and further supports previous studies demonstrating an association between the genital use of talcum powder and an increased risk of OC.

Hereditary motor and sensory neuropathy type VIA with optic nerve pallor in two sisters with pathologic myopia: a case series and review.

PURPOSE: Hereditary Motor Sensory Neuropathy Type VIA with Optic Atrophy (HMSN6A) is a rare variant subtype of mitofusin 2 (MFN2) associated Charcot-Marie-Tooth disease, with ophthalmic manifestations largely limited to optic atrophy. We report a case series of two sisters with HMSN6A corresponding to known variants in the MFN2 gene. The proband's mother, maternal aunt, and maternal grandfather were also reportedly affected with the condition, although not examined at our institution. The clinical presentations of the proband and her sister are reviewed in detail. In addition, a comprehensive review of ophthalmic findings from prior reported cases of HMSN6A is provided. OBSERVATIONS: HMSN6A is a neurologic disorder characterized by a motor sensory axonal neuropathy and optic atrophy. A range of additional ophthalmic manifestations have been reported in the literature. We highlight the proband and her sister who demonstrate this phenotype but also manifested other ocular abnormalities from an early age. In addition to optic nerve pallor, both sisters had additional ophthalmic features of bilateral pathologic myopia, limited vision, nystagmus, and strabismus. CONCLUSIONS AND IMPORTANCE: This case series and review describe the ophthalmologic findings of HMSN6A and provides incentive to further investigate the correlation between molecular findings and the phenotype.

Effect of a NICU to Home Physical Therapy Intervention on White Matter Trajectories, Motor Skills, and Problem-Solving Skills of Infants Born Very Preterm: A Case Series.

Infants born very preterm (VPT; ≤29 weeks of gestation) are at high risk of developmental disabilities and abnormalities in neural white matter characteristics. Early physical therapy interventions such as Supporting Play Exploration and Early Development Intervention (SPEEDI2) are associated with improvements in developmental outcomes. Six VPT infants were enrolled in a randomised clinical trial of SPEEDI2 during the transition from the neonatal intensive care unit to home over four time points. Magnetic resonance imaging scans and fixel-based analysis were performed, and fibre density (FD), fibre cross-section (FC), and fibre density and cross-section values (FDC) were computed. Changes in white matter microstructure and macrostructure were positively correlated with cognitive, motor, and motor-based problem solving over time on developmental assessments. In all infants, the greatest increase in FD, FC, and FDC occurred between Visit 1 and 2 (mean chronological age: 2.68-6.22 months), suggesting that this is a potential window of time to optimally support adaptive development. Results warrant further studies with larger groups to formally compare the impact of intervention and disparity on neurodevelopmental outcomes in infants born VPT.

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. Objective: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). Design, Setting, and Participants: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. Interventions: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. Main Outcomes and Measures: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. Results: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. Conclusions and Relevance: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03439670.

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group. OBJECTIVE: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy. METHODS: This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. RESULTS: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations. CONCLUSIONS: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of function.

OBJECTIVE: Distinct dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically cause nonoverlapping diseases of either the neuromuscular or skeletal systems. However, accumulating evidence suggests that some patients develop mixed phenotypes that include elements of both neuromuscular and skeletal disease. We sought to define the genetic and clinical features of these patients. METHODS: We report a 2-year-old with a novel R616G mutation in TRPV4 with a severe neuropathy phenotype and bilateral vocal cord paralysis. Interestingly, a different substitution at the same residue, R616Q, has been reported in families with isolated skeletal dysplasia. To gain insight into clinical features and potential genetic determinants of mixed phenotypes, we perform in-depth analysis of previously reported patients along with functional and structural assessment of selected mutations. RESULTS: We describe a wide range of neuromuscular and skeletal manifestations and highlight specific mutations that are more frequently associated with overlap syndromes. We find that mutations causing severe, mixed phenotypes have an earlier age of onset and result in more marked elevations of intracellular calcium, increased cytotoxicity, and reduced sensitivity to TRPV4 antagonism. Structural analysis of the two mutations with the most dramatic gain of ion channel function suggests that these mutants likely cause constitutive channel opening through disruption of the TRPV4 S5 transmembrane domain. INTERPRETATION: These findings demonstrate that the degree of baseline calcium elevation correlates with development of mixed phenotypes and sensitivity to pharmacologic channel inhibition, observations that will be critical for the design of future clinical trials for TRPV4 channelopathies.

Child Neurology: Hypotonia and Delayed Teeth Eruption in a 2-Year-Old Girl.

POLR3-related disorders are rare hypomyelinating leukodystrophies associated with hypodontia. We present a female patient, who was referred to pediatric neurology at 2 years of age for tremor, low tone, and motor delays. In addition, she was noted to have a delay in her teeth eruption and myopia. Neurologic examination was significant for ataxic features and global developmental delay. Laboratory workup was unrevealing. MRI was significant for hypomyelination. Genetic testing confirmed a pathogenic variant of POLR3B POLR3-related leukodystrophies should be considered in patients who present with hypotonia, ataxia, and hypodontia. There are many different subtypes of POLR-related leukodystrophies each with distinguishing phenotypic and radiographic features. Although MRI can be helpful in initial evaluation, genetic testing is needed for confirmatory diagnosis and to guide prognosis.

Longitudinal Changes in the Sensorimotor Pathways of Very Preterm Infants During the First Year of Life With and Without Intervention: A Pilot Study.

Objective: Evaluate longitudinal changes in brain microstructure and volumes in very preterm infants during the first year of life with and without intervention.Design: Descriptive pilot study.Methods: Five preterm infants in a three-arm clinical trial, one SPEEDI Early, two SPEEDI Late, and two usual care. Brain structural and diffusion MRI's were acquired within 72 hours after neonatal intensive care unit discharge (n = 5), three months post-baseline (n = 5), and six months post-baseline (n = 3). Fractional anisotropy (FA), Mean diffusivity (MD), and volume metrics were computed for five brain regions.Results: More than 60% of eligible participants completed 100% of the scheduled MRIs. FA and volume increased from baseline to six months across all brain regions. Rate of white matter volume change from baseline to six months was highest in SPEEDI Early.Conclusions: Non-sedated longitudinal MRI is feasible in very preterm infants and appears to demonstrate longitudinal changes in brain structure and connectivity.

Aggressive vertebral hemangioma masquerading as neurological disease in a pediatric patient.

Aggressive hemangioma is a rare vertebral lesion in pediatric patients which can present with deteriorating neurological function. It can mimic malignancy on imaging, particularly as it regularly has an extrasosseous soft tissue component. We present a case of a 13-year-old male who presented with a three month history of lower extremity weakness that was found to have an infiltrative mass at T10 with associated cord compression from epidural extension of the lesion. In this report we review the characteristic imaging findings associated with aggressive hemangioma, including its appearance on read-out segmented diffusion-weighted images. It is imperative that radiologists who interpret studies of children be aware that this lesion exists and what it looks like, as it can be associated with massive hemorrhage if encountered unexpectedly during surgery.

Preference for and reinforcing efficacy of different types of attention in preschool children.

It is unknown whether and to what extent common types of attention delivered in early childhood environments are preferred by and function as reinforcers for young children. We assessed children's preference for commonly delivered types of attention across 31 preschool-aged participants (Experiment 1). Next, we conducted a reinforcer assessment (Experiment 2) and a progressive-ratio assessment (Experiment 3) to (a) validate the results of the preference assessment and (b) determine the relative reinforcing efficacy of each type of attention. Results of Experiment 1 showed that most participants preferred conversation or physical interaction. Results of Experiment 2 validated the results of Experiment 1 showing preferred types of attention were more likely to function as reinforcers. Finally, although some types of attention functioned as reinforcers, results of Experiment 3 indicated these reinforcers only maintained responding under relatively dense schedules of reinforcement. Clinical implications and directions for future research are discussed.

Eye manifestations in the NSUN2 intellectual disability syndrome.

The NSUN2-intellectual disability syndrome is a rare disorder of the cellular transcriptome that prevents proper t-RNA splicing. This disorder interrupts cellular function and leads to an accumulation of RNA fragments, producing a constellation of symptoms including dysmorphic facies, hypotonia, microcephaly, and short stature. Eye manifestations have been reported but not well characterized. Our study presents a new case involving a 4-year-old boy with novel NSUN2 variants and clinical features consistent with the syndrome. In addition, through a systemic review, we discuss the 24 previously reported cases of the syndrome with an emphasis on the eye and ocular adnexa clinical features.

Multi-Omics Identifies Circulating miRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy.

The development of therapeutics for muscle diseases such as facioscapulohumeral dystrophy (FSHD) is impeded by a lack of objective, minimally invasive biomarkers. Here we identify circulating miRNAs and proteins that are dysregulated in early-onset FSHD patients to develop blood-based molecular biomarkers. Plasma samples from clinically characterized individuals with early-onset FSHD provide a discovery group and are compared to healthy control volunteers. Low-density quantitative polymerase chain reaction (PCR)-based arrays identify 19 candidate miRNAs, while mass spectrometry proteomic analysis identifies 13 candidate proteins. Bioinformatic analysis of chromatin immunoprecipitation (ChIP)-seq data shows that the FSHD-dysregulated DUX4 transcription factor binds to regulatory regions of several candidate miRNAs. This panel of miRNAs also shows ChIP signatures consistent with regulation by additional transcription factors which are up-regulated in FSHD (FOS, EGR1, MYC, and YY1). Validation studies in a separate group of patients with FSHD show consistent up-regulation of miR-100, miR-103, miR-146b, miR-29b, miR-34a, miR-454, miR-505, and miR-576. An increase in the expression of S100A8 protein, an inflammatory regulatory factor and subunit of calprotectin, is validated by Enzyme-Linked Immunosorbent Assay (ELISA). Bioinformatic analyses of proteomics and miRNA data further support a model of calprotectin and toll-like receptor 4 (TLR4) pathway dysregulation in FSHD. Moving forward, this panel of miRNAs, along with S100A8 and calprotectin, merit further investigation as monitoring and pharmacodynamic biomarkers for FSHD.