Beyond burnout: a four-year survey of osteopathic medical student mental health and the implications for the development of wellness and mental health programs.

CONTEXT: The mental health crisis in medicine cannot be explained by burnout alone. Physicians are not immune to this crisis and are known to have higher rates of suicide and depression than the general population. A high prevalence of mental health symptoms has been observed in early medical training. OBJECTIVES: This study was completed to characterize medical students' mental well-being and provide guidance for timely intervention. METHODS: An annual prospective, voluntary, anonymous, cross-sectional survey of medical students was completed over a 4-year period in medical school from 2016 to 2019. The survey was created based on standardized psychiatric screening tools assessing symptoms of depression, anxiety, burnout, and sleep problems. In each of those years, 1,257 (2016), 1,254 (2017), 1,221 (2018), and 1,220 (2019) enrolled students, respectively, were invited to participate. Data on students' mental health were analyzed in relation to their year of school separately for each survey year utilizing SAS 9.4. RESULTS: A total of 973 students in 2016, 889 students in 2017, 547 students in 2018, and 606 students in 2019 participated in the study. For depression and burnout subscales, an increase in symptom scores were observed every survey year (2016, 2017, 2018, and 2019) by the second or third year of medical school with a clinically significant effect size. Persistently high levels of anxiety were observed throughout medical school, with significant increases after the first year noted in the 2016 and 2017 surveys, but not in the 2018 or 2019 surveys. Similarly, significant changes in sleep disturbance were found in the 2016 and 2017 surveys, but not in 2018 or 2019. CONCLUSIONS: Symptoms of burnout, depression, and anxiety were observed throughout all four years of medical school, with increases starting after the first year. Early intervention is needed to support students' mental health and increase access to care and resources.

Open-Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off-label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence-based knowledge to guide future treatment decisions. OBJECTIVES: To describe an open-label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP-Richardson's syndrome (PSP-RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. METHODS: For 6 months, 10 PSP-RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP-RS patients from the davunetide clinical trial and the 4-Repeat Tauopathy Neuroimaging Initiative. RESULTS: Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (-0.07 ± 0.03), young plasma (-0.06 ± 0.03), and historical controls (-0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. CONCLUSIONS: Neither salsalate nor young plasma had a detectable effect on disease progression in PSP-RS. Focused open-label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP-directed therapies.

Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome: A Randomized Clinical Trial.

Importance: Basket-design clinical trials that allow investigation of treatment effects on different clinical syndromes that share the same molecular pathophysiology have not previously been attempted in neurodegenerative disease. Objective: To assess the safety, tolerability, and pharmacodynamics of the microtubule stabilizer TPI-287 (abeotaxane) in Alzheimer disease (AD) or the 4-repeat tauopathies (4RT) progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Design, Setting, and Participants: Two parallel-design, double-blind, placebo-controlled phase 1 randomized clinical trials in AD and 4RT were conducted from December 20, 2013, through May 4, 2017, at the University of California, San Francisco, and University of Alabama at Birmingham. A total of 94 patients with clinically diagnosed AD (n = 39) and 4RT (n = 55) were screened; of these, 3 refused to participate, and 10 with AD and 11 with 4RT did not meet inclusion criteria. A total of 29 patients with AD, 14 with PSP, and 30 with ß-amyloid-negative CBS (determined on positron emission tomography findings) were enrolled. Data were analyzed from December 20, 2013, through May 4, 2017, based on modified intention to treat. Interventions: Randomization was 8:3 drug to placebo in 3 sequential dose cohorts receiving 2.0, 6.3, or 20.0 mg/m2 of intravenous TPI-287 once every 3 weeks for 9 weeks, with an optional 6-week open-label extension. Main Outcomes and Measures: Primary end points were safety and tolerability (maximal tolerated dose) of TPI-287. Secondary and exploratory end points included TPI-287 levels in cerebrospinal fluid (CSF) and changes on biomarker, clinical, and neuropsychology measures. Results: A total of 68 participants (38 men [56%]; median age, 65 [range, 50-85] years) were included in the modified intention-to-treat analysis, of whom 26 had AD (14 women [54%]; median age, 63 [range, 50-76] years), and 42 had 4RT (16 women [38%]; median age, 69 [range, 54-83] years). Three severe anaphylactoid reactions occurred in TPI-287-treated patients with AD, whereas none were seen in patients with 4RT, leading to a maximal tolerated dose of 6.3 mg/m2 for AD and 20.0 mg/m2 for 4RT. More falls (3 in the placebo group vs 11 in the TPI-287 group) and a dose-related worsening of dementia symptoms (mean [SD] in the CDR plus NACC FTLD-SB [Clinical Dementia Rating scale sum of boxes with frontotemporal dementia measures], 0.5 [1.8] in the placebo group vs 0.7 [1.6] in the TPI-287 group; median difference, 1.5 [95% CI, 0-2.5]; P = .03) were seen in patients with 4RT. Despite undetectable TPI-287 levels in CSF, CSF biomarkers demonstrated decreased chitinase-3-like protein-1 (YKL-40) levels in the 4RT treatment arm (mean [SD], -8.4 [26.0] ng/mL) compared with placebo (mean [SD], 10.4 [42.3] ng/mL; median difference, -14.6 [95% CI, -30.0 to 0.2] ng/mL; P = .048, Mann-Whitney test). Conclusions and Relevance: In this randomized clinical trial, TPI-287 was less tolerated in patients with AD than in those with 4RT owing to the presence of anaphylactoid reactions. The ability to reveal different tau therapeutic effects in various tauopathy syndromes suggests that basket trials are a valuable approach to tau therapeutic early clinical development. Trial Registration: ClinicalTrials.gov identifiers: NCT019666666 and NCT02133846.

An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations.

INTRODUCTION: Frontotemporal lobar degeneration-causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. METHODS: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. RESULTS: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2 ± 10.9% in plasma and -10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. DISCUSSION: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

Modulation of the GABAergic pathway for the treatment of fragile X syndrome.

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS.

Childhood spinal muscular atrophy and stem cell research: Is cellular replacement therapy the answer? (Review).

Childhood spinal muscular atrophy (SMA) is an autosomal disorder caused by mutations in the survival motor neuron (SMN) gene. Although SMN is a ubiquitously expressed protein, mutations in SMN specifically cause the targeted deterioration of α-motor neurones of the spinal cord. This results in the progressive wasting of the voluntary muscles of the limbs and trunk. Although there is currently no treatment or cure for SMA, several lines of investigation are underway. These include a) screens for small compounds that modulate disease phenotype, b) gene therapy and c) stem cell therapy. In this review, we discuss the current state of stem cell research, concentrating on recent advances and highlighting areas where more research is needed. We also discuss the implications of this research for SMA.