Impact of reduced group size on patient adherence and functional outcomes in cardiac rehabilitation: insights from a COVID-19 pandemic natural experiment.

Introduction: Cardiac rehabilitation (CR) adherence and functional outcomes were measured after COVID-19 regulations reduced group sizes to one-on-one, modeling a natural experiment. Methods: A retrospective analysis using a natural experiment model measured participants in 12 weeks of CR during the 17 months before and after a COVID-19-related closure was conducted. The age, sex, race, ethnicity, and referral diagnoses of the pre-COVID-19 closure and post-COVID-19 closure groups were analyzed using a student's unpaired T-test. Adherence (completion rate of CR) and functional outcomes [change in six-minute walk test (6MWT)] were assessed between the two groups using unpaired two-tailed student T tests in GraphPad Prism and confidence intervals were calculated with the Baptista-Pike method. Results: There were 204 patients in the pre-COVID-19 group and 51 patients in the post-COVID-19 group, due to the smaller group sizes in the post-COVID-19 group, with no significant differences in baseline characteristics between the groups. The pre-COVID-19 group had a higher patient-to-provider ratio [2.8 patients/provider (SD 0.74)] relative to the post-COVID-19 group [0.4 patients/provider (SD 0.12); p < 0.0001]. The post-COVID-19 group had a higher completion rate than pre-COVID-19 group [75% vs. 21%; OR 10.9 (95% CI, 5.3-21.3, p < 0.0001)]. Among those that completed CR, there was no significant difference between groups in 6MWT improvement [+377.9 ft. (n = 47; SD 275.67 ft.) vs. +346.9 ft. (n = 38; SD 196.27 ft.); p = 0.59]. Discussion: The reduction in group size to one-on-one was associated with 10 times higher odds of CR completion. Among those that completed CR, functional outcomes were not influenced by group size. Thus, pursuit of one-on-one sessions may improve CR adherence.

Remote Patient Monitoring Is Associated with Improved Outcomes in Hypertension: A Large, Retrospective, Cohort Analysis.

Hypertension (HTN) is a chronic condition that requires careful monitoring and management. Blood pressure readings in the clinic and self-reported blood pressure readings are often too intermittent to allow for careful management. Remote patient monitoring is a solution that may have positive impacts on HTN management. Individuals at cardiac and primary care clinics were prescribed a remote patient-monitoring (RPM) program. Patients were sent blood pressure monitors that were enabled to transmit data over cellular networks. We reviewed trends in HTN management retrospectively in patients who had previously been on conventional therapy for a year and participated in RPM for a minimum of 90 days. There were 6595 patients enrolled, and the mean duration on RPM was 289 days. A total of 4370 participants (66.3%) had uncontrolled HTN, and 2476 (37.5%) had stage 2 HTN. After at least 90 days on the RPM program, the number of patients with uncontrolled HTN reduced to 2648 (40.2%, p < 0.01), and the number of patients with stage 2 HTN reduced to 1261 (19.1%, p < 0.01). Systolic blood pressure improved by 7.3 mmHg for all patients and 16.7 mmHg for stage 2 HTN. There was improvement in mean arterial pressure (MAP) in all patients with uncontrolled HTN by 8.5 mmHg (p < 0.0001). RPM is associated with improved HTN control and provides further evidence supporting telehealth programs which can aid in chronic disease management.

Beyond the M.D.: Transdisciplinary approaches of high-volume dual degree M.D./Masters programs at U.S. allopathic medical schools.

PURPOSE: Transdisciplinarity has been described as a fusion of theories, methods, and expertise across disciplinary boundaries to address complex, global problems. This approach has coincided with an increase in US medical schools offering masters degrees along with an MD degree to equip medical students to practice in complex, interconnected health systems. This study focused on medical schools that graduate the most dual degree students per year and explored the alignment of such programs with a transdisciplinary approach. METHODS: We identified 19 allopathic medical schools that annually graduated an average of 10 or more dual-degree students from 2015-2020. We surveyed these schools and asked participants to describe the reason(s) their institutions offered dual-degree programs. Two authors coded the narrative responses from the survey. RESULTS: Responses were received from 17 of the 19 schools. The analysis of participants' responses regarding their institutions' purpose for offering dual programs revealed several themes associated with a transdisciplinary approach to training. The most common themes were expand skill sets beyond a medical degree (73%), provide opportunity for interdisciplinary collaboration (67%), expand career interest and goals (60%), develop leaders (53%), enhance residency applications (47%) and further the institution's vision and mission (45%). CONCLUSIONS: This study is the first comprehensive evaluation of MD/Masters programs in the United States that includes a summary of the medical schools with the largest dual degree programs and their reasons for offering them. The findings support the hypothesis that allopathic medical schools recognize the need for a transdisciplinary approach to prepare students for the complexities in healthcare. These programs provide students with opportunities for additional areas of expertise, leadership development, enhancement of competitiveness for residency application, and interdisciplinary collaboration. Medical schools without dual-degree programs may consider developing these programs to provide benefits to students and institutions.

The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Brain endothelium-derived extracellular vesicles containing amyloid-beta induce mitochondrial alterations in neural progenitor cells.

Aim: Elevated brain deposits of amyloid beta (Aß40) contribute to neuropathology and cognitive dysfunction in Alzheimer's disease (AD). However, the role of the blood-brain barrier (BBB) as an interface for the transfer of Aß40 from the periphery into the brain is not well characterized. In addition, a substantial population of neural progenitor cells (NPCs) resides in close proximity to brain capillaries that form the BBB. The aim of this study is to understand the impact of brain endothelium-derived extracellular vesicles (EV) containing Aß40 on metabolic functions and differentiation of NPCs. Methods: Endothelial EVs were derived from an in vitro model of the brain endothelium treated with 100 nM Aß40 or PBS. We then analyzed the impact of these EVs on mitochondrial morphology and bioenergetic disruption of NPCs. In addition, NPCs were differentiated and neurite development upon exposure to EVs was assessed using the IncuCyte Zoom live cell imaging system. Results: We demonstrate that physiological concentrations of Aß40 can be transferred to accumulate in NPCs via endothelial EVs. This transfer results in mitochondrial dysfunction, disrupting crista morphology, metabolic rates, fusion and fission dynamics of NPCs, as well as their neurite development. Conclusion: Intercellular transfer of Aß40 is carried out by brain endothelium-derived EVs, which can affect NPC differentiation and induce mitochondrial dysfunction, leading to aberrant neurogenesis. This has pathological implications because NPCs growing into neurons are incorporated into cerebral structures involved in learning and memory, two common phenotypes affected in AD and related dementias.

Generation of hiPSC line UMi030-A from an individual with the hearing loss-related GJB2 mutation c.109G > A.

Genetic variants in the GJB2 gene which encodes for the Connexin 26 protein account for âˆ¼ 60% of cases of genetic hearing loss. A novel hiPSC line was generated from an individual with the hearing loss-related variant c.109G > A in GJB2 leading to the p.V37I alteration in the Connexin26 protein. These cells will help to delineate the role of GJB2 in hearing loss pathogenesis and serve as a platform for drug discovery and development.

Peripheral vestibular system: Age-related vestibular loss and associated deficits.

Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision, cognition), it is important to examine the individual contributions of these factors with ARVL. While the relationship between the vestibular and visual systems has been well studied (Bronstein et al., 2015), little is known about the association of the peripheral vestibular system with neurodegenerative disorders (Cronin et al., 2017). Further, emerging research developments implicate the vestibular system as an opportunity for examining brain function beyond balance, and into other areas, such as cognition and psychological functioning. Additionally, the bidirectional impact of psychological functioning is understudied in ARVL. Recognition of ARVL as part of a multifaceted aging process will help guide the development of integrated interventions for patients who remain at risk for decline. In this review, we will discuss a wide variety of characteristics of the peripheral vestibular system and ARVL, how it relates to neurodegenerative diseases, and correlations between ARVL and balance, vision, cognitive, and psychological dysfunction. We also discuss clinical implications as well as future directions for research, with an emphasis on improving care for patients with ARVL.

Usher Syndrome in the Inner Ear: Etiologies and Advances in Gene Therapy.

Hearing loss is the most common sensory disorder with ~466 million people worldwide affected, representing about 5% of the population. A substantial portion of hearing loss is genetic. Hearing loss can either be non-syndromic, if hearing loss is the only clinical manifestation, or syndromic, if the hearing loss is accompanied by a collage of other clinical manifestations. Usher syndrome is a syndromic form of genetic hearing loss that is accompanied by impaired vision associated with retinitis pigmentosa and, in many cases, vestibular dysfunction. It is the most common cause of deaf-blindness. Currently cochlear implantation or hearing aids are the only treatments for Usher-related hearing loss. However, gene therapy has shown promise in treating Usher-related retinitis pigmentosa. Here we review how the etiologies of Usher-related hearing loss make it a good candidate for gene therapy and discuss how various forms of gene therapy could be applied to Usher-related hearing loss.

Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art.

Progressive non-syndromic sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment, affecting more than a third of individuals over the age of 65. PNSHL includes noise-induced hearing loss (NIHL) and inherited forms of deafness, among which is delayed-onset autosomal dominant hearing loss (AD PNSHL). PNSHL is a prime candidate for genetic therapies due to the fact that PNSHL has been studied extensively, and there is a potentially wide window between identification of the disorder and the onset of hearing loss. Several gene therapy strategies exist that show potential for targeting PNSHL, including viral and non-viral approaches, and gene editing versus gene-modulating approaches. To fully explore the potential of these therapy strategies, a faithful in vitro model of the human inner ear is needed. Such models may come from induced pluripotent stem cells (iPSCs). The development of new treatment modalities by combining iPSC modeling with novel and innovative gene therapy approaches will pave the way for future applications leading to improved quality of life for many affected individuals and their families.

Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development.

Molecular mechanisms governing the development of the mammalian cochlea, the hearing organ, remain largely unknown. Through genome sequencing in 3 subjects from 2 families with nonsyndromic cochlear aplasia, we identified homozygous 221-kb and 338-kb deletions in a noncoding region on chromosome 8 with an approximately 200-kb overlapping section. Genomic location of the overlapping deleted region started from approximately 350 kb downstream of GDF6, which codes for growth and differentiation factor 6. Otic lineage cells differentiated from induced pluripotent stem cells derived from an affected individual showed reduced expression of GDF6 compared with control cells. Knockout of Gdf6 in a mouse model resulted in cochlear aplasia, closely resembling the human phenotype. We conclude that GDF6 plays a necessary role in early cochlear development controlled by cis-regulatory elements located within an approximately 500-kb region of the genome in humans and that its disruption leads to deafness due to cochlear aplasia.