Poly ADP-ribose signaling is dysregulated in Huntington disease.

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.

Myosin Heavy Chain 7 (MYH7) Variant Associated Cardiovascular Disease: An Unusual Case of Heart Failure in a Young Male.

A 37-year-old male with type two diabetes presented to the hospital with new-onset heart failure and renal dysfunction. His left ventricular (LV) ejection fraction was less than 10%. Transthoracic echocardiography and cardiovascular magnetic resonance (CMR) imaging also revealed severe bicuspid aortic valve stenosis, dilated cardiomyopathy with LV hypertrophy, prominent LV trabeculations, and features suggestive of mild myocarditis with active inflammation. While myocarditis was suspected on CMR imaging, his mild degree of myocardial involvement did not explain the entirety of his clinical presentation, degree of LV dysfunction, or other structural abnormalities. An extensive work-up for his LV dysfunction was unremarkable for ischemic, metabolic, infiltrative, infectious, toxic, oncologic, connective tissue, and autoimmune etiologies. Genetic testing was positive for a myosin heavy chain 7 (MYH7) variant, which was deemed likely to be a unifying etiology underlying his presentation. The MYH7 sarcomere gene allows beta-myosin expression in heart ventricles, with variants associated with hypertrophic and dilated cardiomyopathies, congenital heart diseases, myocarditis, and excessive trabeculation (formerly known as left ventricular noncompaction). This case highlights the diverse array of cardiac pathologies that can present with MYH7 gene variants and reviews an extensive work-up for this unusual presentation of heart failure in a young patient.

Mock Wards: Incorporating a Theoretical Framework to Create a Blended Virtual and In-Person Clinical Reasoning Education Platform.

Introduction The coronavirus 2019 pandemic highlighted virtual learning (VL) as a promising tool for medical education, yet its effectiveness in teaching clinical reasoning (CR) remains underexplored. Past studies have suggested VL can effectively prepare students for clinical settings. Informed by the Milestones of Observable Behaviours for CR (MOBCR) and whole-case theoretical frameworks, the Mock Wards (MW) program was created using a novel blended in-person learning (IPL) and VL platform. MW consisted of case-based small-group formats for medical students interested in learning approaches and differentials to commonly encountered presenting symptoms and diagnoses in internal medicine. This study sought to use MW's blended design to qualitatively analyze CR development and compare its utility between VL and IPL. Methods Qualitative analysis was conducted using in-depth semi-structured interviews with first-year pre-clerkship medical students (n = 8) who completed the MW program and participated in the study. The interview guide was informed by the MOBCR framework. Interview transcripts were analyzed using a directed qualitative content analysis approach. Translational coding and HyperRESEARCHTM (Researchware, Inc., Randolph, MA) software-generated mind maps guided the theme development. Results Three overarching themes were constructed: (1) tailoring pedagogical frameworks to learning modalities, (2) learning through interactivity, and (3) balancing accessibility with learner engagement. Participants emphasized that teaching CR skills is modality-specific and not fully interchangeable, with IPL being superior in facilitating social cohesion, non-verbal communication, and feedback. In contrast, VL required structured approaches and relied more on verbal communication and pre-made digital materials. IPL also enhanced interactivity, peer relationships, and spontaneous communication, whereas VL faced challenges such as social awkwardness and technological constraints hindering effective collaboration. VL provided superior accessibility to facilitate distributed learning and management of concurrent academic obligations. Conclusion The MW-blended platform highlights the importance of focusing on modality-tailored pedagogies, emphasizing group interactability, and balancing VL accessibility against decreased engagement within the IPL environment when teaching CR skills. Blended education models may benefit from a scaffolding approach, using IPL as a prerequisite to VL to improve CR development and alignment within a learner's zone of proximal development.

Are Simulation Learning Objectives Educationally Sound? A Single-Center Cross-Sectional Study.

INTRODUCTION: Accreditation standards of simulation stress the importance of educationally sound learning objectives. We aimed to assess whether learning objectives adhered to theoretical frameworks outlined by accreditation standards, lending themselves to maximal learning outcomes. METHODS: A retrospective study was conducted at the Centre for Simulation-Based Learning at McMaster University. Raters coded 848 faculty-designed learning objectives from 722 sessions based on Bloom's Taxonomy, SMART (Specific, Measurable, Attainable, Realistic, and Timely) criteria, and the presence of inappropriate verbs. Learning objective categorization was compared with student evaluations. RESULTS: Using Bloom's Taxonomy, learning objectives were mostly focused on application 53%, followed by smaller percentages focused on knowledge 21.4% and comprehension 12.2%. Few learning objectives focused on higher levels of analysis 7.2%, synthesis 2.3%, and evaluation 3.7%. By SMART criteria, learning objectives were 49.6% specific, 60.8% measurable, 88.8% attainable, 85.0% realistic, and 9.1% timely. Approximately 1 in 5 objectives used inappropriate verbs. No correlations were observed between categorization by Bloom's Taxonomy or inappropriate verbs to student ratings. However, those containing attainable and timely goals were associated with lower levels of perceived achievement by students. CONCLUSIONS: There was a disconnect between simulation accreditation standards and current practices at McMaster University's simulation center. Most objectives were classified at lower stages of Bloom's Taxonomy. The majority followed SMART guidelines, with the exception of specificity and mention of time frames. A minority of learning objectives contained inappropriate verbs. Given the costs associated with simulation-based education, educators should focus simulation learning objectives on higher levels of Bloom's Taxonomy and include references to time frames.

The critical role of direct observation in entrustment decisions.

BACKGROUND: Entrustment decisions may be retrospective (based on past experiences with a trainee) or real-time (based on direct observation). We investigated judgments of entrustment based on assessor prior knowledge of candidates and based on systematic direct observation, conducted in an objective structured clinical exam (OSCE). METHODS: Sixteen faculty examiners provided 287 retrospective and real-time entrustment ratings of 16 cardiology trainees during OSCE stations in 2019 and 2020. Reliability and validity of these ratings were assessed by comparing correlations across stations as a measure of reliability, differences across postgraduate years as an index of construct validity, correlation to standardized in-training exam (ITE) as a measure of criterion validity, and reclassification of entrustment as a measure of consequential validity. RESULTS: Both retrospective and real-time assessments were highly reliable (all intra-class correlations >0.86). Both increased with a year of postgraduate training. Real-time entrustment ratings were significantly correlated with standardized ITE scores; retrospective ratings were not. Real-time ratings explained 37% (2019) and 46% (2020) of variance in examination scores vs. 21% (2019) and 7% (2020) for retrospective ratings. Direct observation resulted in a different level of entrustment compared with retrospective ratings in 44% of cases (p = <0.001). CONCLUSIONS: Ratings based on direct observation made unique contributions to entrustment decisions.

CONTEXTE: La décision de confier une activité peut être rétrospective (basée sur les expériences antérieures avec un apprenant) ou en temps réel (basée sur l'observation directe). Nous avons étudié les évaluations de niveaux de confiance fondées sur des interactions antérieures des candidats par les évaluateurs et celles fondées sur l'observation directe systématique, dans le cadre d'un examen clinique objectif structuré (ECOS). MÉTHODES: Seize évaluateurs du corps professoral ont fourni 287 évaluations rétrospectives et en temps réel du niveau de confiance faites lors des stations d'ECOS en 2019 et 2020 concernant 16 stagiaires en cardiologie. La fiabilité et la validité de ces évaluations ont été analysées en comparant les corrélations entre les stations comme mesure de la fiabilité, les différences entre les années d'études postdoctorales comme indice de la validité de construit, la corrélation avec l'examen normalisé en cours de formation (ITE) comme mesure de la validité de critère, et le reclassement des évaluations de la confiance comme mesure de la validité corrélative. RÉSULTATS: Les évaluations rétrospectives et en temps réel étaient toutes les deux très fiables (toutes les corrélations intra-classes >0,86). Les deux augmentaient avec le niveau de formation postdoctorale. Les évaluations de la confiance en temps réel étaient significativement corrélées aux scores de l'examen normalisé en cours de formation; les évaluations rétrospectives ne l'étaient pas. Les évaluations en temps réel expliquaient 37 % (2019) et 46 % (2020) de la variance des notes d'examen, contre 21 % (2019) et 7 % (2020) pour les évaluations rétrospectives. L'observation directe a permis de reclasser 44 % des évaluations rétrospectives de la confiance (p=<0,001 dans les deux cas). CONCLUSION: Les évaluations basées sur l'observation directe contribuent de façon importante à la décision de confier une activité.

Trainee Uncertainty around Intervening When Patients Decompensate.

BACKGROUND: Trainees in acute care specialties often grapple with the decision to perform an invasive procedure in a rapidly decompensating patient, for whom the benefits and risks are inherently uncertain. The difference between trainees who know when to act and when to seek supervision and those who do not is often linked to individual trainee psychological and cultural perceptions of uncertainty. But how much comfort with uncertainty relates to the situational context rather than the trainee traits is underexplored. OBJECTIVE: The objective of this study was to explore trainee actions around decompensating patients and assess the degree to which invasive intervention and supervision seeking depend on situational certainty or individual trait-based perceptions of uncertainty. METHODS: A total of 41 internal medicine residents completed a survey to measure anxiety related to uncertainty using the Physicians' Reactions to Uncertainty (PRU) tool and to measure uncertainty avoidance using the Values Survey Module (VSM) before responding to 14 written emergency situations. Half of the scenarios contain sufficient diagnostic certainty to warrant aggressive intervention, and half lack sufficient diagnostic clarity to offset the risk of intervention. Mixed multivariable modeling was used to identify the relationship between planned invasive intervention, situational uncertainty, and trait-based perceptions of uncertainty measured in the PRU and VSM. RESULTS: Trainees' first actions were appropriate in 60% of cases. Multivariable modeling suggested that situational certainty was more predictive of upfront intervention (odds ratio [OR], 30.5; P < 0.0001) than trait-based PRU (OR, 1.22; P = 0.05) and VSM (OR, 1.73; P < 0.0001). Similarly, situational certainty was more predictive of reduced supervision seeking (OR, 0.20; P < 0.0001) than trait-based PRU (OR, 2.03; P < 0.001) and VSM (P = not significant). CONCLUSIONS: Situation-specific certainty was more strongly correlated with invasive intervention in cases of decompensated patients than individual trainee traits. Focusing on trainee contextual understanding of procedural risk-benefit ratios in decompensating patients holds more promise for improving trainee actions and supervision seeking than tackling their perceptions around uncertainty.