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Student run free clinics (SRFCs) fill a void in healthcare access for many communities and have been subject to unprecedented shifts in care delivery brought about by the coronavirus disease 2019 (COVID-19) pandemic. Our single-center institution serving uninsured patients in central Missouri switched from in-person visits to strictly telehealth visits with the onset of the pandemic. This study investigated the impact of the pandemic and the switch to telehealth on the clinic return rates by ethnicity, race, gender, rurality, and age. The pandemic led to a 47.4% reduction in the number of monthly patient encounters. Of the established SRFC population (N = 309), only 87 patients (28.2%) returned for a telehealth visit during the COVID-19 pandemic. Older patients (≥ 45 years old) were more likely to return (OR 1.71, 95% CI 1.02–2.85) for care via telehealth after the onset of the pandemic than younger patients (

Student run free health clinics (SRFCs) provide medical care to vulnerable populations in communities throughout the United States. The COVID-19 pandemic had a significant impact on the delivery of healthcare services and demanded a rapid adjustment in care delivery methods in both resource-rich and resource-poor settings. The aim of this study is to evaluate the impact of the pandemic on the management of chronic disease, specifically diabetes. Patients with diabetes who received care continuously throughout the pre-pandemic (face-to-face) and pandemic (telehealth) study periods at MedZou Community Health Center, a SRFC located in central Missouri, were evaluated. This sample of patients (n = 29) was evaluated on six quality measures including annual eye exams, blood pressure, hemoglobin A1c, chronic kidney disease monitoring, flu vaccination, and statin therapy. Overall diabetes care, as measured by the number of quality measures met per patient, decreased by 0.37 after the onset of the pandemic. The median COVID-era ranks were not statistically significantly different than the pre-pandemic ranks (z = 1.65, P = 0.099). Fewer patients received an influenza vaccination the year following the onset of the pandemic (10.3%) compared to the year before the pandemic (37.9%; difference in proportions 0.276, 95% CI 0.079, 0.473; p = 0.005). No other individual measures of diabetes care statistically differed significantly in the year after the pandemic began. Twenty-six (90%) patients received diabetes care using telehealth after the onset of the pandemic. Diabetes care using telehealth in a SRFC may be an acceptable alternative model when face-to-face visits are not feasible. Observed decreases in diabetes-related clinical quality measure performance warrant further study.

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron (SMN1) gene. An important hallmark of disease progression is the pathology of neuromuscular junctions (NMJs). Affected NMJs in the SMA context exhibit delayed maturation, impaired synaptic transmission, and loss of contact between motor neurons and skeletal muscle. Protection and maintenance of NMJs remains a focal point of therapeutic strategies to treat SMA, and the recent implication of the NMJ-organizer Agrin in SMA pathology suggests additional NMJ organizing molecules may contribute. DOK7 is an NMJ organizer that functions downstream of Agrin. The potential of DOK7 as a putative therapeutic target was demonstrated by adeno-associated virus (AAV)-mediated gene therapy delivery of DOK7 in Amyotrophic Lateral Sclerosis (ALS) and Emery Dreyefuss Muscular Dystrophy (EDMD). To assess the potential of DOK7 as a disease modifier of SMA, we administered AAV-DOK7 to an intermediate mouse model of SMA. AAV9-DOK7 treatment conferred improvements in NMJ architecture and reduced muscle fiber atrophy. Additionally, these improvements resulted in a subtle reduction in phenotypic severity, evidenced by improved grip strength and an extension in survival. These findings reveal DOK7 is a novel modifier of SMA.

Background Spinal muscular atrophy (SMA) is a neurodegenerative autosomal recessive disorder characterized by the loss of α-motor neurons. A variety of molecular pathways are being investigated to elevate SMN protein expression in SMA models and in the clinic. One of these approaches involves stabilizing the SMNΔ7 protein by inducing translational read-through. Previous studies have demonstrated that functionality and stability are partially restored to the otherwise unstable SMNΔ7 by the addition of non-specific C-terminal peptide sequences, or by inducing a similar molecular event through the use of read-through inducing compounds such as aminoglycosides. Objective The objective was to determine the efficacy of the macrolide Azithromycin (AZM), an FDA approved read-through-inducing compound, in the well-established severe mouse model of SMA. Methods Initially, dosing regimen following ICV administrations of AZM at different post-natal days and concentrations was determined by their impact on SMN levels in disease-relevant tissues. Selected dose was then tested for phenotypic parameters changes as compared to the appropriate controls and in conjugation to another therapy. Results AZM increases SMN protein in disease relevant tissues, however, this did not translate into similar improvements in the SMA phenotype in a severe mouse model of SMA. Co-administration of AZM and a previously developed antisense oligonucleotide that increases SMN2 splicing, resulted in an improvement in the SMA phenotype beyond either AZM or ASO alone, including a highly significant extension in survival with improvement in body weight and movement. Conclusions It is important to explore various approaches for SMA therapeutics, hence compounds that specifically induce SMNΔ7 read-through, without having prohibitive toxicity, may provide an alternative platform for a combinatorial treatment. Here we established that AZM activity at a low dose can increase SMN protein in disease-relevant animal model and can impact disease severity.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in survival motor neuron 1 (SMN1). The molecular mechanisms underlying motor neuron degeneration in SMA remain elusive, as global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets. Recent reports have implicated microRNA (miRNA) dysregulation as a potential contributor to the pathological mechanism in SMA. To characterize miRNAs that are differentially regulated in SMA, we profiled miRNA levels in SMA induced pluripotent stem cell (iPSC)-derived motor neurons. From this array, miR-23a downregulation was identified selectively in SMA motor neurons, consistent with previous reports where miR-23a functioned in neuroprotective and muscle atrophy-antagonizing roles. Reintroduction of miR-23a expression in SMA patient iPSC-derived motor neurons protected against degeneration, suggesting a potential miR-23a-specific disease-modifying effect. To assess this activity in vivo, miR-23a was expressed using a self-complementary adeno-associated virus serotype 9 (scAAV9) viral vector in the Smn2B/− SMA mouse model. scAAV9-miR-23a significantly reduced the pathology in SMA mice, including increased motor neuron size, reduced neuromuscular junction pathology, increased muscle fiber area, and extended survival. These experiments demonstrate that miR-23a is a novel protective modifier of SMA, warranting further characterization of miRNA dysfunction in SMA.

Loss of Survival Motor Neuron-1 ( SMN1 ) causes Spinal Muscular Atrophy, a devastating neurodegenerative disease . SMN2 is a nearly identical copy gene; however SMN2 cannot prevent disease development in the absence of SMN1 since the majority of SMN2 -derived transcripts are alternatively spliced, encoding a truncated, unstable protein lacking exon 7. Nevertheless, SMN2 retains the ability to produce low levels of functional protein. Previously we have described a splice-switching Morpholino antisense oligonucleotide (ASO) sequence that targets a potent intronic repressor, Element1 (E1), located upstream of SMN2 exon 7. In this study, we have assessed a novel panel of Morpholino ASOs with the goal of optimizing E1 ASO activity. Screening for efficacy in the SMNΔ7 mouse model, a single ASO variant was more active in vivo compared with the original E1 MO -ASO. Sequence variant eleven (E1 MOv11 ) consistently showed greater efficacy by increasing the lifespan of severe Spinal Muscular Atrophy mice after a single intracerebroventricular injection in the central nervous system, exhibited a strong dose-response across an order of magnitude, and demonstrated excellent target engagement by partially reversing the pathogenic SMN2 splicing event. We conclude that Morpholino modified ASOs are effective in modifying SMN2 splicing and have the potential for future Spinal Muscular Atrophy clinical applications.