Citations

Abstract Purpose Assessing expertise using psychometric models usually yields a measure of ability that is difficult to generalize to the complexity of diagnoses in clinical practice. However, using an item response modeling framework, it is possible to create a decision-aligned response model that captures a clinician’s decision-making behavior on a continuous scale that fully represents competing diagnostic possibilities. In this proof-of-concept study, the authors demonstrate the necessary statistical conceptualization of this model using a specific electrocardiogram (ECG) example. Method The authors collected a range of ECGs with elevated ST segments due to either ST-elevation myocardial infarction (STEMI) or pericarditis. Based on pilot data, 20 ECGs were chosen to represent a continuum from “definitely STEMI” to “definitely pericarditis,” including intermediate cases in which the diagnosis was intentionally unclear. Emergency medicine and cardiology physicians rated these ECGs on a 5-point scale (“definitely STEMI” to “definitely pericarditis”). The authors analyzed these ratings using a graded response model showing the degree to which each participant could separate the ECGs along the diagnostic continuum. The authors compared these metrics with the discharge diagnoses noted on chart review. Results Thirty-seven participants rated the ECGs. As desired, the ECGs represented a range of phenotypes, including cases where participants were uncertain in their diagnosis. The response model showed that participants varied both in their propensity to diagnose one condition over another and in where they placed the thresholds between the 5 diagnostic categories. The most capable participants were able to meaningfully use all categories, with precise thresholds between categories. Conclusions The authors present a decision-aligned response model that demonstrates the confusability of a particular ECG and the skill with which a clinician can distinguish 2 diagnoses along a continuum of confusability. These results have broad implications for testing and for learning to manage uncertainty in diagnosis.

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

AbstractBackgroundAlzheimer's disease (AD) and related neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates. A defining hallmark of AD is the formation of neurofibrillary tangles (NFTs) by aggregation of the microtubule‐associated protein tau into pathological oligomers and fibrils. Although NFTs are believed to play a pivotal role in the disease process, we have a poor understanding of how their formation, toxicity, and spread across brain regions is regulated. Recent data suggest that the seeding behavior of tau is governed by patterns of posttranslational modifications and varying filament structures. Understanding how tau‐associated proteins regulate the oligomerization, pathological accumulation, and seeding of tau in affected neurons and glia is of critical importance for therapy development.MethodTo profile the interactome of tau aggregates, we have established proximity‐dependent biotin‐identification (BioID) as a novel method to identify the composition and proximal molecular environment of insoluble protein aggregates in the context of living brain cells and tissue. Using an in vitro and ex vivo model approach coupled with mass spectrometry, we are generating datasets containing top identified proteins, stratified based on significance and molecular pathway. Once we validate their co‐localization with NFTs in the context of human AD pathology, functional characterization of putative modifiers will be performed to assess their impact on tau‐aggregate and toxicity.ResultTo determine the physiological and aggregate specific interacting partners of tau, we are comparing wild type tau (TauWT) with mutant tau (Tau3xMUT) carrying three tauopathy‐associated mutations (A152T/P301L/S320F) that form hyper‐phosphorylated and thioflavin S‐positive aggregates even in the absence of seeding. The proteomic analysis from our pilot study revealed that significantly changed proteins included candidates involved in RNA processing, as well as protein ubiquitination and proteasome degradation.ConclusionThis study provides novel insights into cellular pathways and molecular mechanisms of neurodegeneration, by identifying in the context of living neurons and brain tissue different functional classes of tau‐associated proteins with relevance for AD pathophysiology. These are expected to include proteins that may mediate the toxic effect of NFTs, facilitate the formation or degradation of pathological tau aggregates, and catalyze posttranslational modifications of tau oligomers and associated proteins.

Abstract Purpose Instructional designs promoting personalization (conversational style and visible author), embodiment (human-like mannerisms and presence), and social and cognitive congruence have been shown to enhance learning. However, measurements of these instructional design features are lacking. The authors sought to develop and validate an instrument to measure personalization, embodiment, and congruence in an online course, collecting evidence of content, internal structure, and relationships with other variables. Method Through literature review, expert review, and pilot testing, the authors developed a 15-item, 5-domain instrument. Participants completed this instrument along with assessments of motivation (Instructional Materials Motivation Survey and Motivated Strategies for Learning Questionnaire), knowledge, and course satisfaction immediately after a 30-minute online multimedia learning module comprising slides with voiceover and (for some participants) short video clips, from January to April 2021. Participants included pharmacists, physicians, and advanced practice providers at academic and community hospitals. Confirmatory factor analysis (CFA) was used to examine model fit, followed by structural revisions guided by exploratory factor analysis (EFA) and tested in a new CFA using a split-sample approach. The authors evaluated associations between the revised instrument scores and motivation, knowledge, and satisfaction. Results There were 406 participants. CFA of the original 15-item instrument revealed poor model fit. EFA using 214 randomly selected participants suggested a 2-domain structure. CFA of the revised structure using the other 192 participants revealed good fit for a 9-item, 2-domain instrument: the Congruence–Personalization Questionnaire (CPQ). Linear regression confirmed positive, statistically significant associations for most hypothesized relationships (R2 ≥ 0.12 and P < .001 for 14 of 18 associations with motivation and satisfaction). Associations with knowledge were weak and nonsignificant (R2 ≤ 0.004, P > .23). Conclusions Evidence of content, internal structure, and relationships with other variables support the validity of CPQ scores for measuring personalization and congruence in an online module.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

Abstract Introduction Engaging learners in continuing medical education (CME) is challenging. Recently, CME courses have transitioned to livestreamed CME, with learners viewing live, in‐person courses online. The authors aimed to (1) compare learner engagement and teaching effectiveness in livestreamed with in‐person CME and (2) determine how livestream engagement and teaching effectiveness is associated with (A) interactivity metrics, (B) presentation characteristics and (C) medical knowledge. Methods A 3‐year, non‐randomised study of in‐person and livestream CME was performed. The course was in‐person for 2018 but transitioned to livestream for 2020 and 2021. Learners completed the Learner Engagement Inventory and Teaching Effectiveness Instrument after each presentation. Both instruments were supported by content, internal structure and relations to other variables' validity evidence. Interactivity metrics included learner use of audience response, questions asked by learners and presentation views. Presentation characteristics included presentations using audience response, using pre/post‐test format, time of day and words per slide. Medical knowledge was assessed by audience response. A repeated measures analysis of variance ( anova ) was used for comparisons and a mixed model approach for correlations. Results A total of 159 learners (response rate 27%) completed questionnaires. Engagement did not significantly differ between in‐person or livestream CME. (4.56 versus 4.53, p = 0.64, maximum 5 = highly engaged). However, teacher effectiveness scores were higher for in‐person compared with livestream (4.77 versus 4.71 p = 0.01, maximum 5 = highly effective). For livestreamed courses, learner engagement was associated with presentation characteristics, including presentation using of audience response (yes = 4.57, no = 4.45, p < .0001), use of a pre/post‐test (yes = 4.62, no = 4.54, p < .0001) and time of presentation (morning = 4.58, afternoon = 4.53, p = .0002). Significant associations were not seen for interactivity metrics or medical knowledge. Discussion Livestreaming may be as engaging as in‐person CME. Although teaching effectiveness in livestreaming was lower, this difference was small. CME course planners should consider offering livestream CME while exploring strategies to enhance teaching effectiveness in livestreamed settings.