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CONTEXT: Rural Appalachia has significantly higher overall cancer mortality compared with national rates, and lack of cancer screening is believed to be one of the contributing factors. Reducing the cancer disparity in this region must include strategies to address suboptimal cancer screening practices by rural Appalachian primary care providers (PCPs). PURPOSE: To identify and investigate barriers to recommending and/or performing cancer screening among rural Appalachian PCPs. METHODS: A semistructured focus group research design was used to elicit perceived barriers to recommending and/or performing cancer screening from 36 rural Appalachian PCPs (in 5 groups), including physicians, nurse practitioners, and a physician assistant. FINDINGS: Findings indicate that rural Appalachian PCPs may not be performing recommended cancer screenings for a number of reasons. Time constraints, conflicting guidelines, and perceptions that patients do not value prevention were reported barriers to cancer screening. The PCPs in this study expressed frustration in attempting to encourage cancer screening and cited patient factors such as socioeconomic status, Appalachian culture, and cancer fatalism as barriers to cancer screening. CONCLUSIONS: Rural Appalachian PCPs encounter various barriers, such as lack of time and multiple cancer screening guidelines, to incorporating cancer screening into their practice routine. The findings underscore the negative impact of some cultural factors on preventive care delivered by PCPs. Increased provider education is needed on how best to encourage cancer screening within a cultural context and should include clarification and understanding of current cancer screening guidelines. [ABSTRACT FROM AUTHOR]

This article describes research findings on individual difference in stereotyping and shows how these findings have been and can he further applied to prejudice reduction efforts. A notable strength of this "new" generation of individual difference work is its dynamic nature--that individual differences can be both stable and malleable. The first section of this article reviews work showing that both adults and children differ in social-cognitive factors related to stereotyping, namely the way they process social information and their endorsement social ideologies. The second section describes intervention strategies that target these factors. In the final section, limitations and future directions of basic and applied research on individual differences and stereotyping are discussed. [ABSTRACT FROM AUTHOR]

The purposes of this study were (a) to examine the role of social evaluative concerns in the self-report of sympathy and in the relation of sympathy to helping; and (b) to determine the role of "altruistic personality" traits and situationally induced vicarious emotional responses in the intention to help. Dispositional and situational self-reports of sympathy and other vicarious emotional reactions were obtained for persons who also were given the opportunity to assist a needy other. Moreover, dispositional measures of concern with social evaluation and an altruistic orientation were obtained, and a bogus pipeline manipulation was instituted for half the study participants. Both dispositional and situational self-reported sympathy were positively related to helping, as were other personality indices viewed as reflecting altruistic characteristics. The relations for the dispositional indices of sympathy were not due solely to social evaluative concerns or to other egoistic concerns. The effects on intended helping of dispositional sympathy, perspective taking, and the tendency to ascribe responsibility for others to the self appeared to be both direct and mediated by situational sympathetic responding. Finally, situational sadness did not mediate the effects of sympathetic responsiveness. [ABSTRACT FROM AUTHOR]

Demonstrating the impact of increasing therapeutic options and the improvement in standards of care on mortality for Muscular Dystrophy (MD) in the US has been limited by challenges in broad data collection with long-term follow-up. We assessed whole-population overall survival (OS) among males with MD in the US using National Center for Health Statistics (NCHS, which completely captures deaths in the US) and birth data (1979–2021). OS was estimated using the Kaplan-Meier method applied to survival times inferred from estimated MD births and reported deaths associated with MD by year and age at death. Bayesian analysis was used to estimate 95% credible intervals (CrI) accounting for uncertainty in MD incidence. From 1979 to 2021, 30,242 deaths with MD in males were recorded. Median OS was 25 years (95% CrI 23, 27). Compared to the 1979-1989 birth cohort, males born later experienced a lower hazard of death by 17.8% (3.6%, 20.5%) for those born 1990-2000, by 48.7% (41.8%, 50.0%) for those born 2001-2011 and by 60.6% (55.2%, 61.6%) for those born 2012-2021. Across these birth cohorts, increasing proportions survived to age 20 years (0.63, 0.71, 0.79, n/a) and to age 30 years (0.25, 0.30, n/a, n/a). Of all deaths, nearly 1/2 were coded with respiratory failure, and nearly 1/3 with heart failure. Proportions of deaths coded with respiratory, or heart failure were similar across birth cohorts after accounting for age at death. The substantial MD survival gains observed over recent decades in this whole-population study are consistent with findings from smaller cohort studies and recent meta-analyses. Despite these improvements, male MD survival falls short of the general population. As the MD care and research community continues to invest in innovation and broader adoption of care standards and therapeutics, our findings support continued use of NCHS data to benchmark impacts on whole-population MD survival and cause of death. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.Methods: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×1013 vg per kilogram of body weight), and 12 received a high dose (2.0×1014 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts).Results: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.Conclusions: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .). [ABSTRACT FROM AUTHOR]

5q spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by absence of the SMN1 gene with three FDA approved genetic therapies which significantly improve outcomes. The AAV9 mediated gene replacement therapy, onasemnogene abeparvovec, has the greatest potential for side effects. Here we report the safety and outcomes from 46 children treated with onasemnogene abeparvovec in the state of Ohio between December 2018 and January 2023. In our cohort, onasemnogene abeparvovec treatment remained safe and no child experienced any significant adverse events, including thrombotic microangiopathy, liver failure or death. All children experienced benefit, although the benefit in those with 2 copies of SMN2 was variable. 79 % of the children treated when symptomatic had a SMN2 modifying therapy added on. With careful screening and post treatment monitoring, onasemnogene abeparvovec is safe and effective for children with SMA in the state of Ohio, but more work needs to be done to ensure optimal outcomes for all children with 2 copies of SMN2., Competing Interests: Declaration of Competing Interest Dr. Waldrop has served on advisory boards for Novartis Gene Therapies and received clinical trial support for Novartis Gene Therapies. Dr. Storey has served on an advisory board for and received consulting fees from Novartis Gene Therapies. Lindsay Alfano has served on an advisory board from Genentech-Roche. Dr. Lowes has received grant support from Novartis Gene Therapies. Dr. Bass has served on speaker and advisory boards for Biogen. Dr. Shell has served as a consultant for Novartis Gene Therapies and serves on an adjudication committee for Biogen. Dr. Mendell has received clinical trial support and personal fees from Novartis Gene Therapies. Dr. Connolly has served on advisory boards for Biohaven and Scholar Rock. All other authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction/aims: Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD., Methods: An open-label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 10 14 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests., Results: Four patients (mean age, 5.1 years) were enrolled. There were 18 treatment-related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score, relative to a propensity-score-weighted external control cohort (least-squares mean [standard error] = 9.4 [3.4]; P = .0125)., Discussion: Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression., (© 2023 Sarepta Therapeutics Inc and The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Isolated teeth belonging to the genus Ptychodus Agassiz, 1834 (Chondrichthyes; Elasmobranchii) from the Upper Cretaceous of the Ryazan and Moscow Oblast regions (European Russia) are described and discussed in detail herein. The taxonomic composition of the Ptychodus assemblage from the Ryazan region is very diverse including the first records of the cuspidate species P . altior and P . anonymus , which thus is largely consistent with those from other contemporaneous European localities. Ptychodus ubiquitously inhabited epicontinental seas of Europe during most of the Cretaceous with the most diverse assemblages coming from southern England, northern Italy, Belgium, and European Russia. Additionally, the material documented here from the Cenomanian of Varavinsky ravine area (Moscow Oblast) represents the northernmost occurrence of Ptychodus hitherto reported from Europe. It is evident that the Late Cretaceous shallow seas of the Russian platform represented a crucial pathway for the dispersal of Ptychodus from the European peri-Tethys to the eastern margins of the Neo-Tethyan Ocean. The Albian-Campanian records of Ptychodus from Europe indicate that its dominance in the peri-Tethys persisted for most of its evolutionary history. A local temperature drop across most of the European shallow seas probably contributed to the narrowing of its geographic range in the peri-Tethyan seas towards the end of the Mesozoic Era. The fossil remains of Ptychodus documented herein are accordingly of utmost importance for better understanding the taxonomic composition of Russian fossil ichthyofaunas and also inform about the dispersal of Ptychodus towards western and eastern peri-Tethyan seas during the Late Cretaceous.

Chronic respiratory failure is a common endpoint in the loss of respiratory muscle function in patients with progressive neuromuscular disease (NMD). Identifying the onset of hypoventilation is critical to allow for the timely introduction of ventilator support and effectively manage respiratory failure [1-3]. While there are accepted criteria governing the diagnosis of hypoventilation during polysomnography (PSG) [4], there is concern that criteria are insufficient for identifying hypoventilation in the earlier stages of respiratory insufficiency related to NMD. The purpose of this project was to identify more sensitive criteria for identifying hypoventilation., Methods: Fifteen pediatric pulmonologists with broad experience in managing patients with NMD, 10 of whom were board certified in and practice sleep medicine, were assembled and performed a review of the pertinent literature and a two-round Delphi process with 6 domains (Table 1)., Results: Within the 6 domains there were three pertinent items per domain (Table 2). There was clear agreement on findings on history (morning headaches) and pulmonary function testing (FVC < 50% or awake TcCO2 > 45 mmHg) indicating a high concern for nocturnal hypoventilation. There was close agreement on the definitions for nocturnal hypercapnia and hypoxemia. PSG criteria were identified that indicate a patient is likely in the transitional phase from adequate ventilation to hypoventilation., Discussion: We identified a set of clinical criteria that may allow for more sensitive diagnosis of hypoventilation in NMD and earlier initiation of non-invasive ventilation leading to a reduction in the respiratory morbidity in progressive NMD. These criteria need to be further and more broadly validated prospectively to confirm their utility.

Purpose: To review the results of a postoperative respiratory pathway for patients with muscular dystrophy (MD) and spinal muscular atrophy (SMA) undergoing spinal surgery., Methods: With IRB approval, a retrospective review was done on all patients with SMA and MD undergoing spinal surgery on a neuromuscular protocol. Baseline demographics, perioperative results, and long-term outcomes were collected. Per the protocol, patients remained intubated after surgery and were transported to the intensive care unit (ICU) for extubation. We present the results of protocol implementation and compare patients with MD to those with SMA., Results: Twenty-four patients were treated using the protocol. Average age was 13.1 years. Severe restrictive lung disease was present in 75% of patients. Nocturnal BiPAP was required in 68% of patients. Average number of instrumented levels was 17. All patients were immediately extubated upon entering the ICU. There were three respiratory complications and only was patient was re-intubated. Average ICU stay was 1.8 days and average hospital length of stay was 6.7 days. No differences in postoperative inspiratory or expiratory positive airway pressures were observed between the MD and SMA groups., Conclusion: Through a multidisciplinary neuromuscular protocol, excellent clinical outcomes were achieved in patients with neuromuscular scoliosis and restrictive lung disease, with complication rates and length of stay significantly lower than previously published data., Level of Evidence: IV., (© 2021. The Author(s), under exclusive licence to Scoliosis Research Society.)

Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial filamentous actin (F-actin) status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated versus non-treated mice via Western blotting at four weeks after transplant. Capillary pericyte, basement membrane laminin, and endothelial F-actin magnitudes were determined in cervical/lumbar spinal cord tissues in ALS mice, including controls, by immunohistochemistry and fluorescent staining. Results showed that cell-treated versus media-treated ALS mice substantially increased tight junction protein levels, capillary pericyte coverage, basement membrane laminin immunoexpressions, and endothelial cytoskeletal F-actin fluorescent expressions. The greatest benefits were detected in mice receiving hBM-EPCs versus hBM34+ cells. These study results support treatment with a specific cell type derived from human bone marrow toward BSCB repair in ALS. Thus, hBM-EPCs may be advanced for clinical applications as a cell-specific approach for ALS therapy through restored barrier integrity., (Copyright © 2021 Garbuzova-Davis et al.)

Background: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities., Methods: Patients with genetically confirmed SMA completed functional testing at each visit including the Neuromuscular GRO and other appropriate gross motor outcomes., Results: We enrolled 91 patients with SMA types 1 to 3 between 8 days and 32.1 years. The GRO utilizes a 0- to 2-point scale with scores in our cohort ranging from 1 to 95 points with no floor or ceiling effect. GRO scores were significantly different across functional categories (P < 0.001) and treatment status (P = 0.01) and correlated to other functional assessments (P ≤ 0.001). All patients were measured using the GRO, whereas traditional outcomes were only appropriate on 36% to 59% of our cohort., Conclusion: The Neuromuscular GRO quantifies function across the span of age and abilities included in our cohort, allowing for continuous longitudinal monitoring on one scale to reduce the burden of testing in our heterogeneous clinic population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We describe six teenagers presenting with fever and severe abdominal symptoms admitted with concerns for multisystem inflammatory syndrome in children (MIS-C). Laboratory evaluation revealed elevated markers of inflammation, lymphopenia, and increased D-dimers. Imaging studies revealed multifocal airspace disease and ground-glass opacities. SARS-CoV-2 polymerase chain reaction and serologies were negative. All patients reported a history of vaping, prompting E-cigarette, or vaping, product use-associated lung injury (EVALI) diagnosis. MIS-C has overlapping clinical and laboratory features highlighting the added challenge of diagnosing EVALI during the COVID-19 pandemic. Keywords COVID-19 pandemic, EVALI, MIS-C., (© 2021 Wiley Periodicals LLC.)

Importance: This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy., Objective: The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained., Design, Setting, and Participants: This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020., Exposures: Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort., Main Outcomes and Measures: The primary outcome measure was the incidence of serious adverse events (SAEs)., Results: At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen., Conclusions and Relevance: The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose., Trial Registration: ClinicalTrials.gov Identifier: NCT03421977.

The phenotype of spinal muscular atrophy (SMA) has been changing with the recent availability of three FDA-approved treatments: intrathecal nusinersen, intravenous onasemnogene abeparvovec-xioi, and enteral risdiplam. The degree of improvement in muscle strength and respiratory health varies with SMA genotype, severity of baseline neuromuscular and pulmonary impairment, medication used, and timing of the first dose. A spectrum of pulmonary outcomes has been reported with these novel medications when used early and in conjunction with proactive multidisciplinary management of comorbidities. In this review, we summarize the reported impact of these novel therapies on pulmonary well-being and the improving trajectory of pulmonary morbidity, compared to the natural history of SMA. The importance of ongoing clinical monitoring albeit the improved phenotype is reiterated. We also discuss the limitations of the current SMA-therapy trials and offer suggestions for future clinical-outcome studies and long-term monitoring., (© 2020 Wiley Periodicals LLC.)

Case Presentation: A 17-year-old male patient who was diagnosed with Becker muscular dystrophy (nonsense mutation [c.3822C>A] within exon 28 of the DMD gene) at 6 years of age was evaluated in the multidisciplinary neuromuscular clinic for loss of ambulation for 1 year. From a pulmonary perspective, there were no acute or chronic respiratory symptoms, and no history of pneumonia or aspiration. Clinical examination revealed a nonambulant teenager, with normal oxygen saturation and end-tidal CO 2 when awake, no respiratory distress, and symmetrically diminished aeration due to obesity (BMI 40 kg/m 2 ). Results of pulmonary function testing revealed FVC of 83% predicted with actual volume of 3.5 L and peak cough flow of 445 L/min (all within normal limits)., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Bronchiectasis (BE) is defined as a permanent, irreversible dilation of the bronchial tree. In the pediatric population, this disease process is most commonly associated with patients with cystic fibrosis (CF). However, BE unrelated to CF is increasingly noted as a cause of chronic respiratory related morbidity worldwide. Chronic inflammation and recurrent infection result in cellular cascades that lead to irreversible structural changes of the airways. When these architectural changes occur, they confer extensive risks to morbidity usually due to continued infections. In the adult population, BE has been associated with chronic obstructive pulmonary disease, which is mainly caused by cigarette smoking. In this report, the authors reviewed various cases of BE in the pediatric population at our institution. After a comprehensive case by case review, we compiled details of three cases of newly diagnosed BE where the most likely inciting factor was the electronic cigarette use. Common features of the three cases included at least a year of e-cigarette use with conjunction of tetrahydrocannabinol and radiologic findings of BE, ground glass opacities, and nodule formation., (© 2020 Wiley Periodicals LLC.)

Importance: Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7)., Objective: To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD., Design, Setting, and Participants: This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks)., Interventions: A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion)., Main Outcomes and Measures: Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes., Results: Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year., Conclusions and Relevance: This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care., Trial Registration: ClinicalTrials.gov Identifier: NCT03375164.

Idiopathic acute eosinophilic pneumonia is a rare and potentially life-threatening condition that is defined by bilateral pulmonary infiltrates and fever in the presence of pulmonary eosinophilia. It often presents acutely in previously healthy individuals and can be difficult to distinguish from infectious pneumonia. Although the exact etiology of idiopathic acute eosinophilic pneumonia remains unknown, an acute hypersensitivity reaction to an inhaled antigen is suggested, which is further supported by recent public health risks of vaping (electronic cigarette) use and the development of lung disease. In this case, a patient with a year-long history of vaping in conjunction with tetrahydrocannabinol cartridge use who was diagnosed with idiopathic acute eosinophilic pneumonia with associated bilateral hilar lymphadenopathy is described., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.

Background: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1)., Methods: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ≥20 (n = 3)., Results: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months)., Conclusions: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 gene replacement therapy., Methods: Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function., Results: All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently., Conclusions: AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy., Trial Registration: ClinicalTrials.gov number, NCT02122952., (© 2018 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.)

Background: Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma®) gene replacement therapy, are emerging., Objective: This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants., Methods: Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n = 16) and healthy infants (n = 27) enrolled in the NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events., Results: Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101-treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101-treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101-treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively)., Conclusions: In this study, AVXS-101 increased the probability of survival, rapidly improved motor function, and enabled motor milestone achievement in SMA1 infants.

In 2010, Care Considerations for Duchenne Muscular Dystrophy, sponsored by the Centers for Disease Control and Prevention, was published in Lancet Neurology , and in 2018, these guidelines were updated. Since the publication of the first set of guidelines, survival of individuals with Duchenne muscular dystrophy has increased. With contemporary medical management, survival often extends into the fourth decade of life and beyond. Effective transition of respiratory care from pediatric to adult medicine is vital to optimize patient safety, prognosis, and quality of life. With genetic and other emerging drug therapies in development, standardization of care is necessary to accurately assess treatment effects in clinical trials. This revision of respiratory recommendations preserves a fundamental strength of the original guidelines: namely, reliance on a limited number of respiratory tests to guide patient assessment and management. A progressive therapeutic strategy is presented that includes lung volume recruitment, assisted coughing, and assisted ventilation (initially nocturnally, with the subsequent addition of daytime ventilation for progressive respiratory failure). This revision also stresses the need for serial monitoring of respiratory muscle strength to characterize an individual's respiratory phenotype of severity as well as provide baseline assessments for clinical trials. Clinical controversies and emerging areas are included., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Birnkrant has United States and international patents and patent applications for respiratory devices; he is also a former consultant to the Hill-Rom corporation. Dr Benditt is a consultant for (and has stock options in) Ventec Life Systems; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background/aims: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible., Methods: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study., Results: All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll., Conclusions: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

Vici syndrome is a multisystem disorder characterized by agenesis of the corpus callosum, oculocutaneous hypopigmentation, cataracts, cardiomyopathy, combined immunodeficiency, failure to thrive, profound developmental delay, and acquired microcephaly. Most individuals are severely affected and have a markedly reduced life span. Here we describe an 8-year-old boy with a history of developmental delay, agenesis of the corpus callosum, failure to thrive, myopathy, and well-controlled epilepsy. He was initially diagnosed with a mitochondrial disorder, based in part upon nonspecific muscle biopsy findings, but mitochondrial DNA mutation analysis revealed no mutations. Whole exome sequencing revealed compound heterozygosity for two EPG5 variants, inherited in trans. One was a known pathogenic mutation in exon 13 (c.2461C > T, p.Arg821X). The second was reported as a variant of unknown significance found within intron 16, six nucleotides before the exon 17 splice acceptor site (c.3099-6C > G). Reverse transcription-polymerase chain reaction of the EPG5 mRNA showed skipping of exon 17-which maintains an open reading frame-in 77% of the transcript, along with 23% expression of wild-type mRNA suggesting that intronic mutations may affect splicing of the EPG5 gene and result in symptoms. However, the expression of 23% wild-type mRNA may result in a significantly attenuated Vici syndrome phenotype., (© 2018 Wiley Periodicals, Inc.)

Objective: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes., Methods: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed., Results: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17)., Interpretation: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891., (© 2017 American Neurological Association.)

Background: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease., Methods: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×10 13 vg per kilogram of body weight), and 12 received a high dose (2.0×10 14 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts)., Results: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone., Conclusions: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).

Members of the Burkholderia cepacia complex are virulent, multi-drug resistant pathogens that survive and replicate intracellularly in patients with cystic fibrosis (CF). We have discovered that B. cenocepacia cannot be cleared from CF macrophages due to defective autophagy, causing continued systemic inflammation and infection. Defective autophagy in CF is mediated through constitutive reactive oxygen species (ROS) activation of transglutaminase-2 (TG2), which causes the sequestration (accumulation) of essential autophagy initiating proteins. Cysteamine is a TG2 inhibitor and proteostasis regulator with the potential to restore autophagy. Therefore, we sought to examine the impact of cysteamine on CF macrophage autophagy and bacterial killing. Human peripheral blood monocyte-derived macrophages (MDMs) and alveolar macrophages were isolated from CF and non-CF donors. Macrophages were infected with clinical isolates of relevant CF pathogens. Cysteamine caused direct bacterial growth killing of live B. cenocepacia, B. multivorans, P. aeruginosa and MRSA in the absence of cells. Additionally, B. cenocepacia, B. multivorans, and P. aeruginosa invasion were significantly decreased in CF MDMs treated with cysteamine. Finally, cysteamine decreased TG2, p62, and beclin-1 accumulation in CF, leading to increased Burkholderia uptake into autophagosomes, increased macrophage CFTR expression, and decreased ROS and IL-1β production. Cysteamine has direct anti-bacterial growth killing and improves human CF macrophage autophagy resulting in increased macrophage-mediated bacterial clearance, decreased inflammation, and reduced constitutive ROS production. Thus, cysteamine may be an effective adjunct to antibiotic regimens in CF.