ONO-8590580, a Novel GABAAα5 Negative Allosteric Modulator Enhances Long-Term Potentiation and Improves Cognitive Deficits in Preclinical Models.

GABAA receptors containing α5 subunits (GABAAα5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABAAα5-deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABAAα5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABAAα5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl-N-[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human α5-containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAAα5 NAM activity for GABA-induced Cl- channel activity with a maximum 44.4% inhibition and an EC50 of 1.1 nM. In rat hippocampal slices, tetanus-induced long-term potentiation of CA1 synapse response was significantly augmented in the presence of 300 nM ONO-8590580. Orally administered ONO-8590580 (1-20 mg/kg) dose-dependently occupied hippocampal GABAAα5 in a range of 40%-90% at 1 hour after intake. In the rat passive avoidance test, ONO-8590580 (3-20 mg/kg, by mouth) significantly prevented (+)-MK-801 hydrogen maleate (MK-801)-induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving the cognitive deficit induced by scopolamine and MK-801 in the rat eight-arm radial maze test with equal or greater activity than 0.5 mg/kg donepezil. No anxiogenic-like or proconvulsant effect was associated with ONO-8590580 at 20 mg/kg p.o. in the elevated plus maze test or pentylenetetrazole-induced seizure test, respectively. In sum, ONO-8590580 is a novel GABAAα5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.

Should There Be A Part II ABPMR Examination?: A Psychometric Inquiry.

BACKGROUND: Certification by the American Board of Physical Medicine and Rehabilitation (ABPMR) requires passing both a written multiple choice examination (Part I) and an oral examination (Part II), but it has been unclear whether the two examinations measure the same or different dimensions of knowledge. OBJECTIVE: To evaluate the concordance between the Part I and Part II examinations for ABPMR initial certification with regard to candidate performance on the examinations and their subsets. Our question is whether the Part II examination provides additional assessment of a candidate beyond what Part I provides. DESIGN: Retrospective psychometric evaluation of deidentified board examination scores. SETTING: ABPMR database of Part I and Part II examination scores. PARTICIPANTS: Candidates for the ABPMR Part I and Part II examinations after 2005, with a more detailed analysis of candidates for the Part I examination from 2014 to 2016. Examination scores of candidates who took the Part II examination both before and after the examination was standardized in 2005 were also used for an additional analysis. METHODS: Correlations, simple linear regressions, and principal components analysis. MAIN OUTCOME MEASUREMENTS: Correlation coefficients, variance analysis, and unexplained variance in the principal components analysis. RESULTS: There is a weak to moderate correlation between performance on the Part I and Part II examinations: r = 0.33, P < .001. There is an additional dimension of assessment that is demonstrated on the Part II examination, with this being primarily in the domains of systems-based practice and interpersonal communication skills. CONCLUSION: The Part I and Part II examinations, although with some overlap, contribute different and meaningful components to the overall evaluation of candidates for board certification in PM&R. LEVEL OF EVIDENCE: III.

Does Performance on the American Board of Physical Medicine and Rehabilitation Initial Certification Examinations Predict Future Physician Disciplinary Actions?

OBJECTIVE: The aim of the study was to determine the relationship between performance on the American Board of Physical Medicine and Rehabilitation primary certification examinations and the risk of subsequent disciplinary actions by state medical boards over a physician's career. The hypothesis is that physicians who do not pass either or both of the two initial specialty certification examinations are at higher risk of disciplinary action from a state medical licensing board. DESIGN: This is a retrospective cohort study that analyzed board certification examination data from all physicians who completed physical medicine and rehabilitation residency between 1968 and 2017. RESULTS: Matching examination and license data were available for 9889 physical medicine and rehabilitation physicians, who received a total of 547 disciplinary action reports through the Federation of State Medical Boards. The results showed a significant correlation between failing an American Board of Physical Medicine and Rehabilitation certification examination and the risk of subsequent disciplinary action by a state medical board. Failure to pass either the written (Part I) or oral (Part II) examination increased the risk of subsequent disciplinary action by 5.77-fold (P < 0.0001, 95% confidence interval = 4.07-8.18). CONCLUSIONS: Physicians in physical medicine and rehabilitation who do not pass initial certification examinations and become board certified are at higher risk of disciplinary action from a state medical licensing board throughout their careers.

Burnout in Diplomates of the American Board of Physical Medicine and Rehabilitation-Prevalence and Potential Drivers: A Prospective Cross-Sectional Survey.

BACKGROUND: Physician burnout is of growing concern. Burnout among physical medicine and rehabilitation (PM&R) physicians has shown a significant increase, positioning PM&R as one of the most "burned out" of specialties. Little has been written about potential factors contributing to physiatrist burnout or potential interventions. OBJECTIVE: To determine the prevalence of burnout among physiatrists and identify risk factors for burnout and potential strategies to decrease burnout among physiatrists. DESIGN: Prospective cross-sectional survey. SETTING: National survey of board certified physiatrists. PARTICIPANTS: One thousand five hundred thirty-six physiatrists certified by the American Board of PM&R. OUTCOME: The Mini-Z Burnout Survey, 1 question from the Maslach Burnout Scale on callousness toward patients, and several potential drivers of burnout. The probability of burnout, identified by question 3 on the Mini-Z, was the dependent variable. Other questions on the Mini-Z were explored as independent variables using logistic regression. RESULTS: Seven hundred seventy physiatrists (50.7%) fulfilled the definition of burnout. Only 38% of physiatrists reported not becoming more callous toward patients. The top 3 causes of burnout identified by physiatrists were increasing regulatory demands, workload and job demands, and practice inefficiency and lack of resources. Higher burnout rate was associated with high levels of job stress and working more hours per week. Lower burnout rates were associated with higher job satisfaction, control over workload, professional values aligned with those of department leaders, and sufficient time for documentation. There was no significant association between burnout and sex, years in practice, practice focus, or practice area. CONCLUSION: Burnout is a significant problem among PM&R physicians and is pervasive throughout the specialty. Opportunities exist to address major contributing drivers of burnout relating to practice patterns and efficiency of care within PM&R. These opportunities are, to varying degrees, under the control of hospital leaders, practice administrators, and practitioners.