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OBJECTIVE: This study examined whether phone reminders increased attendance at intake and therapy appointments in an Appalachian community mental health center and whether it mattered who (therapist or staff) made the call. METHODS: One of three conditions (no reminder calls, therapist made calls, or staff made calls) was assigned to each week of the nine-week study. During the study period, 451 appointments were scheduled (310 for therapy and 141 for intake). Mixed-effects logistic regression was used to analyze the data. RESULTS: Phone reminders were effective for intake appointments when therapists made direct contact with patients (43% for no contact and 94% for direct therapist contact). The other conditions did not significantly increase appointment keeping. As a result of these findings, therapists were asked to place reminder calls to patients scheduled for intake appointments for a ten-week period. Findings from the second pilot study replicated findings from the first, with direct contact resulting in significantly more kept appointments. CONCLUSIONS: Direct contact with therapists before initial appointments may increase appointment keeping by patients. [ABSTRACT FROM AUTHOR]

Objective: --Oxidative phosphorylation (OXPHOS) deficiency due to hypoxemia or other causes was hypothesized to increase oxygen radical generation, damage mitochondrial DNA (mtDNA), and reduce adenosine triphosphate synthesis, resulting in compensatory OXPHOS gene induction. Therefore, we investigated the levels of mtDNA damage and OXPHOS transcripts in normal and ischemic hearts, and then in other forms of heart disease.Design: --DNA was extracted from the heart and the levels of the common 4977 base pair mtDNA deletion were quantitated as an index for mtDNA damage. Total RNA was extracted from hearts and analyzed for OXPHOS transcript levels.Results: --In control hearts, the 4977 base pair mtDNA deletion appeared at age 40 years and reached a maximum deletion of 0.0035%. Much higher levels were found in ischemic hearts (0.02% to 0.85%), as well as in three of 10 cases with other types of heart disease (0.017% to 0.16%). The OXPHOS transcripts were increased in all diseased hearts.Conclusion: --Ischemic hearts have increased mtDNA damage and OXPHOS gene expression, suggesting that mtDNA damage is associated with OXPHOS deficiency. Oxidative phosphorylation defects may also play a role in some other forms of cardiac disease. [ABSTRACT FROM AUTHOR]

Low Earth Orbit (LEO) has emerged as a unique environment for evaluating altered stem cell properties in microgravity. LEO has become increasingly accessible for research and development due to progress in private spaceflight. Axiom Mission 2 (Ax-2) was launched as the second all-private astronaut mission to the International Space Station (ISS). Frozen human induced pluripotent stem cells (hiPSCs) expressing green fluorescent protein (GFP) under the SOX2 promoter, as well as fibroblasts differentiated from SOX2-GFP hiPSCs, were sent to the ISS. Astronauts then thawed and seeded both cell types into commercially available 96-well plates, which provided surface tension that reduced fluid movement out of individual wells and showed that hiPSCs or hiPSC-derived fibroblasts could survive either in suspension or attached to a Matrigel substrate. Furthermore, both cell types could be transfected with red fluorescent protein (RFP)-expressing plasmid. We demonstrate that hiPSCs and hiPSC-fibroblasts can be thawed in microgravity in off-the-shelf, commercially-available cell culture hardware, can associate into 3D spheroids or grow adherently in Matrigel, and can be transfected with DNA. This lays the groundwork for future biomanufacturing experiments in space., (© 2024. The Author(s).)

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing., Objective: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients., Methods: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls., Results: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01)., Conclusions: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Objective: We developed a novel, hybrid method combining both blue-native (BN-PAGE) and clear-native (CN-PAGE) polyacrylamide gel electrophoresis, termed BCN-PAGE, to perform in-gel activity stains on the mitochondrial electron transport chain (ETC) complexes in skin fibroblasts., Methods: Four patients aged 46-65 years were seen in the Metabolic Clinic at Alberta Children's Hospital and investigated for mitochondrial disease and had BN-PAGE or CN-PAGE on skeletal muscle that showed incomplete assembly of complex V (CV) in each patient. Long-range PCR performed on muscle-extracted DNA identified 4 unique mitochondrial DNA (mtDNA) deletions spanning the ATP6 gene of CV. We developed a BCN-PAGE method in skin fibroblasts taken from the patients at the same time and compared the findings with those in skeletal muscle., Results: In all 4 cases, BCN-PAGE in skin fibroblasts confirmed the abnormal CV activity found from muscle biopsy, suggesting that the mtDNA deletions involving ATP6 were most likely germline mutations that are associated with a clinical phenotype of mitochondrial disease., Conclusions: The BCN-PAGE method in skin fibroblasts has a potential to be a less-invasive tool compared with muscle biopsy to screen patients for abnormalities in CV and other mitochondrial ETC complexes.

Background: Neuromuscular disorders are a phenotypically and genotypically diverse group of diseases that can be difficult to diagnose accurately because of overlapping clinical features and nonspecific muscle pathology. Next-generation sequencing (NGS) is a high-throughput technology that can be used as a more time- and cost-effective tool for identifying molecular diagnoses for complex genetic conditions, such as neuromuscular disorders., Methods: One hundred and sixty-nine patients referred to a Canadian neuromuscular clinic for evaluation of possible muscle disease were screened with an NGS panel of muscular dystrophy-associated genes. Patients were categorized by the reason of referral (1) muscle weakness (n=135), (2) recurrent episodes of rhabdomyolysis (n=18), or (3) idiopathic hyperCKemia (n=16)., Results: Pathogenic and likely pathogenic variants were identified in 36.09% of patients (61/169). The detection rate was 37.04% (50/135) in patients with muscle weakness, 33.33% (6/18) with rhabdomyolysis, and 31.25% (5/16) in those with idiopathic hyperCKemia., Conclusions: This study shows that NGS can be a useful tool in the molecular workup of patients seen in a neuromuscular clinic. Evaluating the utility of large panels of a muscle disease-specific NGS panel to investigate the genetic susceptibilities of rhabdomyolysis and/or idiopathic hyperCKemia is a relatively new field. Twenty-eight of the pathogenic and likely pathogenic variants reported here are novel and have not previously been associated with disease.