Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.

The Impact of a Lifestyle Intervention on Postpartum Cardiometabolic Risk Factors Among Hispanic Women With Abnormal Glucose Tolerance During Pregnancy: Secondary Analysis of a Randomized Trial.

BACKGROUND: Women with abnormal glucose tolerance during pregnancy are at risk for cardiovascular disease (CVD), with higher rates among Hispanics. However, studies on the impact of lifestyle interventions on postpartum CVD profiles are sparse. METHODS: This is a secondary analysis of a controlled trial among a subsample of Hispanic women with abnormal glucose tolerance participating in Estudió PARTO (Project Aiming to Reduce Type twO diabetes; mean age = 28.2 y, SD: 5.8) who were randomized to a culturally modified Lifestyle intervention (n = 45) or a comparison Health and Wellness intervention (n = 55). Primary endpoints were biomarkers of cardiovascular risk (lipids, C-reactive protein, fetuin-A, and albumin-to-creatinine ratio) and insulin resistance (fasting insulin, glucose, HbA1c, homeostasis model assessment, leptin, tumor necrosis factor-alpha, and adiponectin) measured at baseline (6-wk postpartum) and 6 and 12 months. RESULTS: In intent-to-treat analyses, there were no significant differences in changes in biomarkers of CVD risk or insulin resistance over the postpartum year. In prespecified sensitivity analyses, women adherent with the Lifestyle Intervention had more favorable improvements in insulin (intervention effect = -4.87, SE: 1.93, P = .01) and HOMA-IR (intervention effect = -1.15, SE: 0.53, P = .03) compared with the Health and Wellness arm. In pooled analyses, regardless of intervention arm, women with higher postpartum sports/exercise had greater increase in HDL-cholesterol (intervention effect = 6.99, SE: 1.72, P = .0001). CONCLUSIONS: In this randomized controlled trial among Hispanic women with abnormal glucose tolerance, we did not observe a significant effect on postpartum biomarkers of CVD risk or insulin resistance. Women adherent to the intervention had more favorable changes in insulin and HOMA-IR.

Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials.

Duchenne muscular dystrophy (DMD) is a serious, rare genetic disease, affecting primarily boys. It is caused by mutations in the DMD gene and is characterized by progressive muscle degeneration that results in loss of function and early death due to respiratory and/or cardiac failure. Although limited treatment options are available, some for only small subsets of the patient population, DMD remains a disease with large unmet medical needs. The adeno-associated virus (AAV) vector is the leading gene delivery system for addressing genetic neuromuscular diseases. Since the gene encoding the full-length dystrophin protein exceeds the packaging capacity of a single AAV vector, gene replacement therapy based on AAV-delivery of shortened, yet, functional microdystrophin genes has emerged as a promising treatment. This article seeks to explain the rationale for use of the accelerated approval pathway to advance AAV microdystrophin gene therapy for DMD. Specifically, we provide support for the use of microdystrophin expression as a surrogate endpoint that could be used in clinical trials to support accelerated approval.

Quantitative Muscle Analysis in FSHD Using Whole-Body Fat-Referenced MRI: Composite Scores for Longitudinal and Cross-sectional Analysis.

BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease characterized by progressive muscle weakness. MRI is a sensitive assessment of disease severity and progression. We developed a quantitative whole-body (WB) musculoskeletal MRI (WB-MSK-MRI) protocol analyzing muscles in their entirety. This study aimed to assess WB-MSK-MRI as a potential imaging biomarker providing reliable measurements of muscle health that capture disease heterogeneity and clinically meaningful composite assessments correlating with severity and more responsive to change in clinical trials. METHODS: Participants aged 18-65 years, with genetically confirmed FSHD1, clinical severity 2 to 4 (Ricci scale, range 0-5), and ≥1 short tau inversion recovery-positive lower extremity muscle eligible for needle biopsy, enrolled at 6 sites and were imaged twice 4-12 weeks apart. Volumetric analysis of muscle fat infiltration (MFI), muscle fat fraction (MFF), and lean muscle volume (LMV) in 18 (36 total) muscles from bilateral shoulder, proximal arm, trunk, and legs was performed after automated atlas-based segmentation, followed by manual verification. A WB composite score, including muscles at highest risk for progression, and functional cross-sectional composites for correlation with relevant functional outcomes including timed up and go (TUG), FSHD-TUG, and reachable workspace (RWS), were developed. RESULTS: Seventeen participants enrolled in this study; 16 follow-up MRIs were performed at 52 days (range 36-85 days). Functional cross-sectional composites (MFF and MFI) showed moderate to strong correlations: TUG (ρ = 0.71, ρ = 0.83), FSHD-TUG (ρ = 0.73, ρ = 0.73), and RWS (left arm: ρ = -0.71, ρ = -0.53; right arm: ρ = -0.61, ρ = -0.65). WB composite variability: LMVtot, coefficient of variation (CV) 1.9% and 3.4%; MFFtot, within-subject SD (Sw) 0.5% and 1.5%; and MFItot (Sw), 0.3% and 0.4% for normal and intermediate muscles, respectively. CV and Sw were higher in intermediate (MFI ≥0.10; MFF <0.50) than in normal (MFI <0.10, MFF <0.50) muscles. DISCUSSION: We developed a WB-MSK-MRI protocol and composite measures that capture disease heterogeneity and assess muscle involvement as it correlates with FSHD-relevant clinical endpoints. Functional composites robustly correlate with functional assessments. Stability of the WB composite shows that it could be an assessment of change in therapeutic clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that quantitative WB-MSK-MRI findings associate with FSHD1 severity measured using established functional assessments.

Piezo1: opening the way to preventing muscle atrophy.

The loss of skeletal muscle mass and size, or muscle atrophy, is a common human experience, linked to disability, for which there are no widely accepted pharmacological therapies. Piezo1 is a mechanosensitive cation channel that opens upon alteration of the plasma membrane lipid bilayer, such as through increased membrane tension. In this issue of the JCI, Hirata et al. identified Piezo1 and its downstream effectors, Krüppel-like factor 15 (KLF15) and interleukin-6 (IL-6), as an important signaling pathway in a murine model of disuse atrophy. Through genetic and pharmacological modulation of the pathway, the authors demonstrated that immobilization resulted in downregulation of Piezo1 and basal intracellular calcium concentration ([Ca2+]i), increasing expression of Klf15 and its downstream target Il6 and thereby inducing muscle atrophy. Piezo1 has been considered a therapeutic target for diverse disorders, including atherosclerosis and kidney fibrosis, and with this publication should now also be considered a viable target for disuse atrophy.

Human pluripotent stem cell-derived myogenic progenitors undergo maturation to quiescent satellite cells upon engraftment.

Human pluripotent stem cell (hPSC)-derived myogenic progenitor cell (MPC) transplantation is a promising therapeutic approach for a variety of degenerative muscle disorders. Here, using an MPC-specific fluorescent reporter system (PAX7::GFP), we demonstrate that hPSC-derived MPCs can contribute to the regeneration of myofibers in mice following local injury and in mice deficient of dystrophin (mdx). We also demonstrate that a subset of PAX7::GFP MPCs engraft within the basal lamina of regenerated myofibers, adopt a quiescent state, and contribute to regeneration upon reinjury and in mdx mouse models. This subset of PAX7::GFP MPCs undergo a maturation process and remodel their molecular characteristics to resemble those of late-stage fetal MPCs/adult satellite cells following in vivo engraftment. These in-vivo-matured PAX7::GFP MPCs retain a cell-autonomous ability to regenerate and can repopulate in the niche of secondary recipient mice, providing a proof of principle for future hPSC-based cell therapy for muscle disorders.

iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease modeling.

Skeletal muscle myoblasts (iMyoblasts) were generated from human induced pluripotent stem cells (iPSCs) using an efficient and reliable transgene-free induction and stem cell selection protocol. Immunofluorescence, flow cytometry, qPCR, digital RNA expression profiling, and scRNA-Seq studies identify iMyoblasts as a PAX3+/MYOD1+ skeletal myogenic lineage with a fetal-like transcriptome signature, distinct from adult muscle biopsy myoblasts (bMyoblasts) and iPSC-induced muscle progenitors. iMyoblasts can be stably propagated for >12 passages or 30 population doublings while retaining their dual commitment for myotube differentiation and regeneration of reserve cells. iMyoblasts also efficiently xenoengrafted into irradiated and injured mouse muscle where they undergo differentiation and fetal-adult MYH isoform switching, demonstrating their regulatory plasticity for adult muscle maturation in response to signals in the host muscle. Xenograft muscle retains PAX3+ muscle progenitors and can regenerate human muscle in response to secondary injury. As models of disease, iMyoblasts from individuals with Facioscapulohumeral Muscular Dystrophy revealed a previously unknown epigenetic regulatory mechanism controlling developmental expression of the pathological DUX4 gene. iMyoblasts from Limb-Girdle Muscular Dystrophy R7 and R9 and Walker Warburg Syndrome patients modeled their molecular disease pathologies and were responsive to small molecule and gene editing therapeutics. These findings establish the utility of iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease pathogenesis and for the development of muscle stem cell therapeutics.

Muscular dystrophies are a group of inherited genetic diseases characterised by progressive muscle weakness. They lead to disability or even death, and no cure exists against these conditions. Advances in genome sequencing have identified many mutations that underly muscular dystrophies, opening the door to new therapies that could repair incorrect genes or rebuild damaged muscles. However, testing these ideas requires better ways to recreate human muscular dystrophy in the laboratory. One strategy for modelling muscular dystrophy involves coaxing skin or other cells from an individual into becoming 'induced pluripotent stem cells'; these can then mature to form almost any adult cell in the body, including muscles. However, this approach does not usually create myoblasts, the 'precursor' cells that specifically mature into muscle during development. This limits investigations into how disease-causing mutations impact muscle formation early on. As a response, Guo et al. developed a two-step protocol of muscle maturation followed by stem cell growth selection to isolate and grow 'induced myoblasts' from induced pluripotent stem cells taken from healthy volunteers and muscular dystrophy patients. These induced myoblasts can both make more of themselves and become muscle, allowing Guo et al. to model three different types of muscular dystrophy. These myoblasts also behave as stem cells when grafted inside adult mouse muscles: some formed human muscle tissue while others remained as precursor cells, which could then respond to muscle injury and start repair. The induced myoblasts developed by Guo et al. will enable scientists to investigate the impacts of different mutations on muscle tissue and to better test treatments. They could also be used as part of regenerative medicine therapies, to restore muscle cells in patients.

Harnessing the epic electronic medical record to track indwelling ureteral stents in a pediatric population.

INTRODUCTION: Retention of indwelling ureteral stents due to loss to follow-up can result in significant harm to patients, often requiring multiple trips to the operating room. Despite widespread use of electronic medical records, there are few standardized options for urologists to track ureteral stents and no data on the rate of retained stents in a pediatric population. OBJECTIVE: This pilot quality improvement project aims to: 1) develop a simple process to track indwelling ureteral stents using the Epic electronic medical record and 2) determine the incidence of forgotten stents in a pediatric population. METHODS: We identified that operating room staff scan a barcode for ureteral stents at the time of surgery to log the stent as "Implanted" in the patient's medical record. The stent can later be marked as "Explanted" at the time of removal. A report was designed within Epic to identify all patients with a ureteral stent implanted from April 2014 to June 2019 at our hospital. We reviewed the records of patients whose stents had never been marked as "Explanted" to determine if any had a retained stent. A workflow was then designed to ensure staff would mark stents as "Explanted" at the time of removal and to periodically run the report within Epic to ensure that all patients with ureteral stents in place have appropriate follow-up. RESULTS: Our report identified 152 ureteral stents with a status of "Implanted". 3 patients did not have evidence of stent removal documented in their medical record. Follow up with these patients revealed stent removal at an outside location. DISCUSSION: Current approaches to stent tracking are laborious with limitations to adherence. The Epic software directly incorporates stent tracking into the individual patient chart allowing for easy implementation and follow up. Our study revealed no retained stents in our pediatric population. CONCLUSIONS: All patients with ureteral stents placed at a single institution over a 5-year period were easily identified using an automated Epic report. Through this report, we will prevent morbidity associated with stent retention. This technique could easily be implemented at other hospital systems that use Epic, and similar reporting tools could be designed within other electronic medical record systems. The incidence of ureteral stent retention in the pediatric population is likely significantly lower than for their adult counterparts.

Analysis of the Impact of the COVID-19 Pandemic on the Multidisciplinary Management of Breast Cancer: Review from the American Society of Breast Surgeons COVID-19 and Mastery Registries.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in rapid and regionally different approaches to breast cancer care. METHODS: In order to evaluate these changes, a COVID-19-specific registry was developed within the American Society of Breast Surgeons (ASBrS) Mastery that tracked whether decisions were usual or modified for COVID-19. Data on patient care entered into the COVID-19-specific registry and the ASBrS Mastery registry from 1 March 2020 to 15 March 2021 were reviewed. RESULTS: Overall, 177 surgeons entered demographic and treatment data on 2791 patients. Mean patient age was 62.7 years and 9.0% (252) were of African American race. Initial consultation occurred via telehealth in 6.2% (173) of patients and 1.4% (40) developed COVID-19. Mean invasive tumor size was 2.1 cm and 17.8% (411) were node-positive. In estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) disease, neoadjuvant endocrine therapy (NET) was used as the usual approach in 6.9% (119) of patients and due to COVID-19 in an additional 31% (542) of patients. Patients were more likely to receive NET due to COVID-19 with increasing age and if they lived in the Northeast or Southeast (odds ratio [OR] 1.1, 2.3, and 1.7, respectively; p < 0.05). Genomic testing was performed on 51.5% (781) of estrogen-positive patients, of whom 20.7% (162) had testing on the core due to COVID-19. Patients were less likely to have core biopsy genomic testing due to COVID-19 if they were older (OR 0.89; p = 0.01) and more likely if they were node-positive (OR 4.0; p < 0.05). A change in surgical approach due to COVID-19 was reported for 5.4% (151) of patients. CONCLUSION: The ASBrS COVID-19 registry provided a platform for monitoring treatment changes due to the pandemic, highlighting the increased use of NET.

Cross-Sectional Analysis of Medical Conditions in the U.S. Deaf Transgender Community.

Purpose: This first U.S.-based, descriptive study of transgender Deaf adults looks to contribute to the gap in research regarding those who lie at the intersection of Deaf and transgender identities. The study objective is to identify characteristics that associate with medical conditions, including depression and anxiety disorders, among Deaf transgender adults. Methods: We gathered self-reported data from 74 Deaf transgender adults who used American Sign Language. Modified Poisson regression with robust standard errors was used to calculate relative risk estimates of having a medical condition among nonbinary individuals compared with gender binary individuals. Results: The sample lifetime prevalence for medical conditions in the Deaf transgender sample were as follows: 48.6% for depression/anxiety disorders, 28.8% for hypertension, 20.3% for lung conditions, 16.2% for arthritis/rheumatism, 12.3% for diabetes, 7.0% for cirrhosis/liver/kidney problems, 5.5% for heart conditions, and 2.7% for cancer. In cross-tabulation analysis across binary and nonbinary subsamples, the lifetime prevalence was significantly different only for depression and anxiety disorder with higher percentage in the nonbinary subsample. After adjusting for covariates in a regression model, identification as nonbinary increased a Deaf person's risk for being diagnosed with depression or anxiety disorder by 80% (95% confidence interval, 1.11-2.90) relative to Deaf people who self-identified as a binary gender. Conclusion: Study findings suggest that the Deaf transgender community is at risk for developing mental and physical health conditions.

Human muscle stem cells are refractory to aging.

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.

Vascularized Rib Bone Grafting: Indications, Techniques, and Clinical Outcomes.

Pseudarthrosis is a difficult complication often seen in patients with complex spinal pathology. To supplement existing neurosurgical approaches to cervicothoracic spinal instrumentation and fusion, novel vascularized rib bone grafts can be utilized in patients at high risk for failed spinal fusion. In this article, we discuss the indications, benefits, surgical technique, feasibility, and limitations of using rib vascularized rib bone grafts to augment spinal fusion.

Endoscope-assisted posterior quadrant disconnection plus corpus callosotomy: case report.

Intractable epilepsy impacts many children. Surgically resective and palliative treatments have developed to increase seizure freedom or palliate the seizure burden in those with medically refractory epilepsy. However, surgical epilepsy treatment can confer significant morbidity and death. Endoscope-assisted surgical approaches may be helpful in reducing the morbidity related to traditional open surgical approaches while allowing for good visualization of surgical targets. Here, the authors report a case utilizing an endoscope-assisted keyhole approach to perform a posterior quadrantectomy and corpus callosotomy, achieving the surgical goals of disconnection and reducing the need for large craniotomy exposure. They present the case of a 17-year-old male with medically refractory epilepsy treated with endoscope-assisted posterior quadrantectomy and corpus callosotomy through two mini-craniotomies to achieve a functional disconnection. To the authors' knowledge, this is the first reported case of an endoscope-assisted approach for a posterior quadrantectomy for surgical epilepsy treatment in an adult or a pediatric patient. The case is reported to highlight the technical nuances and benefits of this approach in select patients as well as the expansion of applications of endoscope-assisted epilepsy surgery.

Standard work tools for dynamic stereoelectroencephalography using ROSA: naming convention and perioperative planning.

OBJECTIVE: The grid-based orthogonal placement of depth electrodes (DEs), initially defined by Jean Talairach and Jean Bancaud, is known as stereo-electroencephalography (sEEG). Although acceptance in the United States was initially slow, advances in imaging and technology have spawned a proliferation of North American epilepsy centers offering sEEG. Despite publications highlighting minimal access techniques and varied indications, standard work for phase I targeted DE has not been defined. In this article, the authors propose the term "dynamic sEEG" and define standard work tools and related common data elements to promote uniformity in the field. METHODS: A multidisciplinary approach from July to August 2016 resulted in the production of 4 standard work tools for dynamic sEEG using ROSA: 1) a 34-page illustrated manual depicting a detailed workflow; 2) a planning form to collocate all the phase I data; 3) a naming convention for DEs that encodes the data defining it; and 4) a reusable portable perioperative planning and documentation board. A retrospective review of sEEG case efficiency was performed comparing those using standard work tools (between July 2016 and April 2017) with historical controls (between March 2015 and June 2016). The standard work tools were then instituted at another epilepsy surgery center, and the results were recorded. RESULTS: The process for dynamic sEEG was formally reviewed, including anesthesia, positioning, perioperative nursing guidelines, surgical steps, and postoperative care for the workflow using cranial fixation and ROSA-guided placement. There was a 40% improvement in time per electrode, from 44.7 ± 9.0 minutes to 26.9 ± 6.5 minutes (p = 0.0007) following the development and use of the manual, the naming convention, and the reusable portable perioperative planning and documentation board. This standardized protocol was implemented at another institution and yielded a time per electrode of 22.3 ± 4.4 minutes. CONCLUSIONS: The authors propose the term dynamic sEEG for stereotactic depth electrodes placed according to phase I workup data with the intention of converting to ablation. This workflow efficiency can be optimized using the standard work tools presented. The authors also propose a novel naming convention that encodes critical data and allows portability among providers. Use of a planning form for common data elements optimizes research, and global adoption could facilitate multicenter studies correlating phase I modality and seizure onset zone identification.

Cognitive outcomes after unruptured intracranial aneurysm treatment with endovascular coiling.

BACKGROUND: We aimed to determine the effects of endovascular coiling of unruptured intracranial aneurysms (UIAs) on cognition to inform treatment decisions. We present the first study using the Montreal Cognitive Assessment (MoCA) to determine neurocognitive changes after endovascular coiling. METHODS: We prospectively collected data on all patients with UIAs undergoing endovascular coiling, primary or assisted. Patients completed the MoCA prior to intervention and 1 month and 6 months' post-procedure. A repeated measures linear mixed effects model was used to compare pre-procedure and post-procedure cognition. RESULTS: Thirty-three patients with 33 aneurysms who underwent coiling from April 2017 to May 2020 were included (mean age 55.5, 81.8% female). All procedures used general anesthesia. There was no difference between baseline and post-procedure MoCA scores at any time interval (P>0.05). Mean MoCA scores at baseline, 1 month post-procedure, and 6 months' post-procedure were 25.4, 26.8, and 26.3 respectively. There was also no difference between pre- and post-procedure scores on any individual MoCA domain (visuospatial, naming, memory, attention, language, abstraction, delayed recall, and orientation) at any time interval (P>0.05). Seventeen patients had follow-up MRI or CT imaging, of which 11.8% showed radiographic changes or ischemia. 77.8% of patients with 6-month angiographic follow-up achieved class I, and 22.2% achieved class II Raymond-Roy Occlusion. Thirty-two out of 33 patients had follow-up mRS ≤2. CONCLUSION: Our study suggests that endovascular coiling does not diminish neurocognitive function. Patients with UIAs in our cohort also had baseline MoCA scores below the cut-off for mild cognitive impairment despite pre-procedure mRS and NIHSS of 0.

Sociodemographic Factors in Pediatric Epilepsy Surgery.

BACKGROUND: Despite documented efficacy of surgical treatment in carefully selected patients, surgery is delayed and/or underutilized in both adult and children with focal onset epilepsy. The reasons for surgical delay are often assumed or theorized, and studies have predominantly targeted the adult population. To focus on a more targeted pediatric population and to determine identifiable reasons for intervention, this study aimed to investigate time to epilepsy surgery among pediatric patients with medically intractable epilepsy associated with focal cortical dysplasia and to identify sociodemographic and clinical associations in time to epilepsy surgery. METHODS: We reviewed 96 consecutive pediatric patients who underwent surgery for medically intractable epilepsy with a diagnosis of focal cortical dysplasia. Descriptive statistics, univariate and multivariate analyses were conducted to study the association of sociodemographic variables of patients with focal cortical dysplasia and time to epilepsy surgery and postoperative seizure control. RESULTS: We identified that non-white patients on average had a longer duration of epilepsy before surgery and traveled shorter distances for care. Non-white patients were more likely to have government-funded insurance. Patients who traveled the shortest distance to the surgical center underwent epilepsy surgery at an older age. CONCLUSIONS: Sociodemographic factors of travel distance, insurance, and race influenced time to epilepsy surgery for children with focal cortical dysplasia. Further research is warranted to target barriers in access to subspecialty care and develop ways to identify earlier the patients who may benefit from evaluation and deployment of surgical intervention.

Staged Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Hypothalamic Hamartoma: Analysis of Ablation Volumes and Morphological Considerations.

BACKGROUND: Hypothalamic hamartomas (HH) are a challenging pathology that cause gelastic seizures. Magnetic Resonance Imaging-guided Laser Interstitial Thermal Therapy (MRgLITT) offers a safe and effective treatment for HHs via a minimally invasive technique. OBJECTIVE: To determine how clinical outcome correlates to residual tumor volume and surgical strategy by analyzing radiographic data and reconstructing volumetric imaging. METHODS: Clinical and radiographic information of 58 pediatric patients who underwent MRgLITT for HH with at least 6 mo of follow-up were retrospectively reviewed. MR imaging was volumetrically reconstructed to analyze the impact of hamartoma and ablation volumes on outcome. Primary outcome measure was freedom from gelastic seizures. RESULTS: Eighty-one percent of patients were completely free of gelastic seizures at last follow-up; of 22 patients with secondary nongelastic epilepsy, 15 were free of additional seizures. Postoperative complication rate was low. There was no significant difference in gelastic seizure outcome related to pre- or postoperative hamartoma size. Residual hamartoma percentage in those free of gelastic seizures was 43% compared to 71% in those with continued seizures (P = .021). Larger hamartomas required multiple ablations to achieve seizure freedom. CONCLUSION: This large series of patients confirms the safety and efficacy of MRgLITT for pediatric HH and describes morphological considerations that predict success. Our data suggest that complete ablation of the lesion is not necessary, and that the focus should be on appropriate disconnection of the epileptogenic network. We have found that a staged approach to hamartoma ablation allows adequate disconnection of the hamartoma while mitigating risk to surrounding structures.

Diabetes, metformin and cancer risk in myotonic dystrophy type I.

Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well-established agent for the management of T2D, is thought to have cancer-preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age-, sex- and clinic-matched cohort of 12,318 DM1-free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18-10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06-3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91-1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72-1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1.

Stem cell-based therapies for Duchenne muscular dystrophy.

Muscular dystrophies are a group of genetic muscle disorders that cause progressive muscle weakness and degeneration. Within this group, Duchenne muscular dystrophy (DMD) is the most common and one of the most severe. DMD is an X chromosome linked disease that occurs to 1 in 3500 to 1 in 5000 boys. The cause of DMD is a mutation in the dystrophin gene, whose encoded protein provides both structural support and cell signaling capabilities. So far, there are very limited therapeutic options available and there is no cure for this disease. In this review, we discuss the existing cell therapy research, especially stem cell-based, which utilize myoblasts, satellite cells, bone marrow cells, mesoangioblasts and CD133+ cells. Finally, we focus on human pluripotent stem cells (hPSCs) which hold great potential in treating DMD. hPSCs can be used for autologous transplantation after being specified to a myogenic lineage. Over the last few years, there has been a rapid development of isolation, as well as differentiation, techniques in order to achieve effective transplantation results of myogenic cells specified from hPSCs. In this review, we summarize the current methods of hPSCs myogenic commitment/differentiation, and describe the current status of hPSC-derived myogenic cell transplantation.

Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic derepression of the germline/embryonic transcription factor DUX4 in skeletal muscle. However, the etiology of muscle pathology is not fully understood, as DUX4 misexpression is not tightly correlated with disease severity. Using a DUX4-inducible cell model, we show that multiple DUX4-induced molecular pathologies that have been observed in patient-derived disease models are mediated by the signaling molecule hyaluronic acid (HA), which accumulates following DUX4 induction. These pathologies include formation of RNA granules, FUS aggregation, DNA damage, caspase activation, and cell death. We also observe previously unidentified pathologies including mislocalization of mitochondria and the DUX4- and HA-binding protein C1QBP. These pathologies are prevented by 4-methylumbelliferone, an inhibitor of HA biosynthesis. Critically, 4-methylumbelliferone does not disrupt DUX4-C1QBP binding and has only a limited effect on DUX4 transcriptional activity, establishing that HA signaling has a central function in pathology and is a target for FSHD therapeutics.