The Mean Delta Method: Quantifying Assessor Stringency and Leniency and Identifying Outliers in Workplace-Based Assessments.

ABSTRACT: Assessor stringency and leniency (ASL)-an assessor's tendency to award low or high scores-has a significant effect on workplace-based assessments. Outliers on this spectrum have a disproportionate effect. However, no method has been published for quantifying ASL or identifying outlier stringent or lenient assessors using workplace-based assessment data. The authors propose the mean delta method, which compares the scores that an assessor awards to trainees with those trainees' mean scores. This novel, simple method can be used to quantify ASL and identify outlier assessors without requiring specialized statistical knowledge or software. As a worked example, the mean delta method was applied to a set of end-of-shift assessments completed in a large Canadian academic emergency department from July 1, 2017, to May 31, 2018, and used to examine the net effect of ASL on learners' assessment scores. A total of 3,908 assessments were completed by 99 assessors for 151 trainees, with a median (interquartile range) of 37 (12-39) completed assessments per trainee. Using cutoff values of 1.5 and 2 standard deviations, a total of 11 and 3 outlier assessors were identified, respectively. Moreover, ASL changed overall scores by more than the mean difference between years of training for nearly 1 in 4 learners. The mean delta method was able to quantify ASL and identify outlier lenient and stringent assessors. It was also used to quantify the net effect of ASL on individual trainees. This method could be used to further study outlier assessors, to identify assessors who may benefit most from targeted coaching and feedback, and to measure changes in assessors' tendencies over time or with specific intervention.

Early and Late Aortic-Related Mortality and Rupture After Fenestrated-Branched Endovascular Aortic Repair of Thoracoabdominal Aortic Aneurysms: A Prospective Multicenter Cohort Study.

BACKGROUND: Fenestrated-branched endovascular aortic repair (FB-EVAR) has been used as a minimally invasive alternative to open surgical repair to treat patients with thoracoabdominal aortic aneurysms (TAAAs). The aim of this study was to evaluate aortic-related mortality (ARM) and aortic aneurysm rupture after FB-EVAR of TAAAs. METHODS: Patients enrolled in 8 prospective, nonrandomized, physician-sponsored investigational device exemption studies between 2005 and 2020 who underwent elective FB-EVAR of asymptomatic intact TAAAs were analyzed. Primary end points were ARM, defined as any early mortality (30 days or in hospital) or late mortality from aortic rupture, dissection, organ or limb malperfusion attributable to aortic disease, complications of reinterventions, or aortic rupture. Secondary end points were early major adverse events, TAAA life-altering events (defined as death, permanent spinal cord injury, permanent dialysis, or stroke), all-cause mortality, and secondary interventions. RESULTS: A total of 1109 patients were analyzed; 589 (53.1%) had extent I-III and 520 (46.9%) had extent IV TAAAs. Median age was 73.4 years (interquartile range, 68.1-78.3 years); 368 (33.2%) were women. Early mortality was 2.7% (n=30); congestive heart failure was associated with early mortality (odds ratio, 3.30 [95% CI, 1.22-8.02]; P=0.01). Incidence of early aortic rupture was 0.4% (n=4). Incidence of early major adverse events and TAAA life-altering events was 20.4% (n=226) and 7.7% (n=85), respectively. There were 30 late ARMs; 5-year cumulative incidence was 3.8% (95% CI, 2.6%-5.4%); older age and extent I-III TAAAs were independently associated with late ARM (each P<0.05). Fourteen late aortic ruptures occurred; 5-year cumulative incidence was 2.7% (95% CI, 1.2%-4.3%); extent I-III TAAAs were associated with late aortic rupture (hazard ratio, 5.85 [95% CI, 1.31-26.2]; P=0.02). Five-year all-cause mortality was 45.7% (95% CI, 41.7%-49.4%). Five-year cumulative incidence of secondary intervention was 40.3% (95% CI, 35.8%-44.5%). CONCLUSIONS: ARM and aortic rupture are uncommon after elective FB-EVAR of asymptomatic intact TAAAs. Half of the ARMs occurred early, and most of the late deaths were not aortic related. Late all-cause mortality rate and the need for secondary interventions were 46% and 40%, respectively, 5 years after FB-EVAR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02089607, NCT02050113, NCT02266719, NCT02323581, NCT00583817, NCT01654133, NCT00483249, NCT02043691, and NCT01874197.

Decreased patient discharges on weekends: part 2-what do the ward nurses tell us?

BACKGROUND: Hospital and emergency department (ED) crowding is exacerbated on Mondays because fewer in-patients are discharged during the weekend. We evaluated the experiences and attitudes of in-patient ward nurses to better understand the challenges they face when considering the weekend discharge of their patients. METHODS: We conducted a qualitative study of in-patient ward nurses, using the theoretical domains framework (TDF), at two campuses of a major academic health sciences centre. The interview guides consisted of, first, a series of questions to explore the typical processes involved for safe patient discharges and, second, exploration of the influence of the 14 TDF domains. All interviews were audio-recorded, transcribed verbatim, and anonymized and then imported into NVivo qualitative software for data management and analysis. Analysis was conducted in three stages (coding, generation of specific beliefs, identification of relevant and nonrelevant domains). RESULTS: The 28 interviewed nurses represented a variety of medical, surgical and other wards, and reported being acutely aware of the pressures to discharge patients on weekends (knowledge). They believed that increasing weekend discharges would improve hospital flow and aid in decanting the ED (beliefs about consequences). However, they also acknowledged that the weekend discharge pressures might result in patients being discharged prematurely and bouncing back to the hospital (beliefs about consequences). Overall, the nurses reported that as a hospital culture, discharging patients was not much of a priority (goals; environmental context and resources). CONCLUSION: We know there are much fewer discharges on weekends, and this is associated with significant hospital and ED crowding on Mondays. This study has illuminated the many challenges faced by in-patient ward nurses when considering the discharge of admitted patients on weekends. In order to decrease ED and hospital crowding related to decreased weekend discharges, hospitals will need to effect a culture change amongst all staff.

ABSTRAIT: CONTEXTE: Le surpeuplement des hôpitaux et des services d'urgence (SU) est exacerbé le lundi parce que moins de patients hospitalisés sont libérés pendant la fin de semaine. Nous avons évalué les expériences et les attitudes des infirmières en salle afin de mieux comprendre les défis auxquels elles font face lorsqu'elles envisagent le congé de fin de semaine de leurs patients. MéTHODES: Nous avons mené une étude qualitative sur les infirmières en salle, en utilisant le cadre des domaines théoriques (TDF), sur deux campus d'un grand centre universitaire des sciences de la santé. Les guides d'entrevue ont consisté, d'une part, en une série de questions visant à explorer les processus typiques de sortie sécuritaire des patients et, d'autre part, en une exploration de l'influence des 14 domaines du TDF. Toutes les entrevues ont été enregistrées, transcrites mot à mot et rendues anonymes, puis importées dans le logiciel qualitatif NVivo pour la gestion et l'analyse des données. L'analyse a été menée en trois étapes (codage, génération de croyances spécifiques, identification de domaines pertinents et non pertinents). RéSULTATS: Les 28 infirmières interrogées représentaient une variété de services médicaux, chirurgicaux et autres, et ont déclaré être très conscientes des pressions exercées sur les patients pour qu'ils quittent la clinique les fins de semaine (connaissance). Ils croyaient que l'augmentation des congés de fin de semaine améliorerait le flux hospitalier et aiderait à décanter le DE (croyances sur les conséquences). Cependant, ils ont également reconnu que les pressions de sortie du week-end pourraient entraîner le renvoi prématuré des patients à l'hôpital (croyances sur les conséquences). Dans l'ensemble, les infirmières ont indiqué qu'en tant que culture hospitalière, le congé des patients n'était pas une grande priorité (objectifs ; contexte environnemental et ressources). CONCLUSION: Nous savons qu'il y a beaucoup moins de congés la fin de semaine, et cela est associé à un grand nombre d'hôpitaux et de services d'urgence le lundi. Cette étude a mis en lumière les nombreux défis auxquels font face les infirmières en salle lorsqu'elles envisagent de quitter les patients admis les fins de semaine. Afin de réduire le surpeuplement des urgences et des hôpitaux liés à la diminution des congés de fin de semaine, les hôpitaux devront effectuer un changement de culture parmi tout le personnel.

Antithrombotic Therapy in Patients With Atrial Fibrillation and Coronary Artery Disease With Recent or Remote Events: Systematic Review and Meta-analysis.

Background: Ongoing debate remains regarding optimal antithrombotic therapy in patients with atrial fibrillation (AF) and coronary artery disease. Methods: We performed a systematic review and meta-analysis to synthesize randomized controlled trials (RCTs) comparing the following: (i) dual-pathway therapy (DPT; oral anticoagulant [OAC] plus antiplatelet) vs triple therapy (OAC and dual-antiplatelet therapy) after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS), and (iii) OAC monotherapy vs DPT at least 1 year after PCI or ACS. Following a 2-stage process, we identified systematic reviews published between 2019 and 2022 on these 2 clinical questions, and we updated the most comprehensive search for additional RCTs published up to October 2022. Outcomes of interest were major adverse cardiovascular events (MACE), death, stent thrombosis, and major bleeding. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model. Results: Based on 6 RCTs (n = 10,435), DPT reduced major bleeding (RR 0.62, 95% CI 0.52-0.73) and increased stent thrombosis (RR 1.55, 95% CI 1.02-2.36), vs triple therapy after PCI or medically-managed ACS, with no significant differences in MACE and death. In 2 RCTs (n = 2905), OAC monotherapy reduced major bleeding (RR 0.66, 95% CI 0.49-0.91) vs DPT in AF patients with remote PCI or ACS, with no significant differences in MACE or death. Conclusions: In patients with AF and coronary artery disease, using less-aggressive antithrombotic treatment (DPT after PCI or ACS, and OAC alone after remote PCI or ACS) reduced major bleeding, with an increase in stent thrombosis with recent PCI. These results support a minimalist yet personalized antithrombotic strategy for these patients.

Contexte: La question du traitement antithrombotique optimal chez les personnes présentant une fibrillation auriculaire (FA) et une coronaropathie demeure controversée. Méthodologie: Nous avons réalisé une revue systématique et une méta-analyse pour synthétiser les essais contrôlés randomisés ayant comparé i) la bithérapie (anticoagulant oral et antiplaquettaire) et la trithérapie (anticoagulant oral et bithérapie antiplaquettaire) après une intervention coronarienne percutanée (ICP) ou un syndrome coronarien aigu (SCA), et ii) un anticoagulant oral en monothérapie et la bithérapie au moins 1 an après une ICP ou un SCA. Nous avons procédé en 2 temps, d'abord en répertoriant les revues systématiques publiées entre 2019 et 2022 sur ces 2 questions cliniques, puis en effectuant la recherche la plus exhaustive possible pour trouver d'autres essais contrôlés randomisés publiés jusqu'en octobre 2022. Les paramètres qui nous intéressaient étaient les événements cardiovasculaires indésirables majeurs (ECIM), le décès, la thrombose de l'endoprothèse et l'hémorragie majeure. Nous avons estimé les rapports de risques (RR) et les intervalles de confiance (IC) à 95 % à l'aide d'un modèle à effets aléatoires. Résultats: D'après 6 essais contrôlés randomisés (n = 10 435), la bithérapie a réduit les hémorragies majeures (RR : 0,62; IC à 95 % : 0,52 à 0,73) et augmenté les thromboses de l'endoprothèse (RR : 1,55; IC à 95 % : 1,02 à 2,36), comparativement à la trithérapie après une ICP ou un SCA ayant fait l'objet d'une prise en charge médicale, tandis qu'aucune différence significative n'a été observée quant aux ECIM et aux décès. Dans 2 essais contrôlés randomisés (n = 2 905), un anticoagulant oral en monothérapie a réduit les hémorragies majeures (RR : 0,66; IC à 95 % : 0,49 à 0,91) comparativement à la bithérapie chez des patients présentant une FA après une ICP ou un SCA plus lointain, sans différence significative quant aux ECIM et aux décès. Conclusions: Chez les patients présentant une FA et une coronaropathie, l'utilisation d'un traitement antithrombotique moins agressif (bithérapie après un ICP ou un SCA, et anticoagulant oral en monothérapie après une ICP ou un SCA plus lointain) réduit les hémorragies majeures, mais s'accompagne d'une augmentation des thromboses de l'endoprothèse en cas d'ICP récente. Ces résultats plaident en faveur d'une stratégie antithrombotique minimaliste, mais personnalisée chez ces patients.

Intravascular Imaging in the Diagnosis and Management of Patients With Suspected Intracoronary Pathologies: A CJC White Paper.

Intravascular imaging has become an integral part of the diagnostic and management strategies for intracoronary pathologies. In this White Paper we summarize current evidence and its implications on the use of intravascular imaging in interventional cardiology practice. The areas addressed are planning and optimization of percutaneous coronary intervention, management of stent failure, and evaluation of ambiguous coronary lesions and myocardial infarction with nonobstructive coronary disease. The findings presented followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system in an expert consensus process that involved a diverse writing group vetted by a review group. Expert consensus was achieved around 9 statements. Use of intravascular imaging in guiding percutaneous revascularization is supported by high-quality evidence, particularly for lesions with increased risk of recurrent events or stent failure. Specific considerations for intravascular imaging guidance of intervention in left main lesions, chronic occlusion lesions, and in patients at high risk of contrast nephropathy are explored. Use of intravascular imaging to identify pathologies associated with stent failure and guide repeat intervention, resolve ambiguities in lesion assessment, and establish diagnoses in patients who present with myocardial infarction with nonobstructive coronary disease is supported by moderate- to low-quality evidence. Each topic is accompanied by clinical pointers to aid the practicing interventional cardiologist in implementation of the White Paper findings. The findings presented in this White Paper will help to guide the use of intravascular imaging toward situations in which the balance of efficacy, safety, and cost are most optimal.

Decreased patient discharges on weekends part 3: what do the leaders tell us?

BACKGROUND: Emergency department (ED) crowding is a significant challenge to providing safe and quality care to patients. We know that hospital and ED crowding is exacerbated on Mondays because fewer in-patients are discharged on the weekend. We evaluated barriers and potential solutions to improve in-patient flow and diminished weekend discharges, in hopes of decreasing the severe ED crowding observed on Mondays. METHODS: In this observational study, we conducted interviews of (a) leaders at The Ottawa Hospital, a major academic health sciences centre (nursing, allied health, physicians), and (b) leaders of community facilities (long-term care and chronic hospital) that receive patients from the hospital, and (c) home care. Each interview was conducted individually and addressed perceived barriers to the discharge of hospital in-patients on weekends as well as potential solutions. An inductive thematic analysis was conducted whereby themes were organized into a summary table of barriers and solutions. RESULTS: We interviewed 40 leaders including 30 nursing, physician, and allied health leaders from the hospital as well as 10 senior personnel from community facilities and home care. Many barriers to weekend discharges were identified, highlighting that this problem is complex with many interdependent internal and external factors. Fortunately, many specific potential solutions were suggested, in immediate, short-term and long-term time horizons. While many solutions require additional resources, others require a culture change whereby hospital and community stakeholders recognize that services must be provided consistently, seven days a week. INTERPRETATION: We have identified the complex and interdependent barriers to weekend discharges of in-patients. There are numerous specific opportunities for hospital staff and services, physicians, and community facilities to provide the same patient care on weekends as on weekdays. This will lead to improved patient flow and safety, and to decreased ED crowding on Mondays.

ABSTRAIT: CONTEXTE: Le surpeuplement des services d'urgence (SU) est un défi important pour fournir des soins sécuritaires et de qualité aux patients. Nous savons que le surpeuplement des hôpitaux et des urgences est exacerbé le lundi parce que moins de patients hospitalisés reçoivent leur congé le week-end. Nous avons évalué les obstacles et les solutions potentielles pour améliorer le flux de patients hospitalisés et diminuer les congés de fin de semaine, dans l'espoir de réduire le surpeuplement sévère observé le lundi. MéTHODES: Dans cette étude observationnelle, nous avons interviewé (a) des dirigeants de l'Hôpital d'Ottawa, un important centre universitaire des sciences de la santé (soins infirmiers, soins paramédicaux, médecins), et (b) des dirigeants d'établissements communautaires (soins de longue durée et hôpitaux de soins chroniques) qui reçoivent des patients de l'hôpital et (c) des soins à domicile. Chaque entrevue a été menée individuellement et a abordé les obstacles perçus au congé des patients hospitalisés le week-end ainsi que les solutions potentielles. Une analyse thématique inductive a été menée, dans le cadre de laquelle les thèmes ont été organisés en un tableau récapitulatif des obstacles et des solutions RéSULTATS: Nous avons interviewé 40 dirigeants, dont 30 chefs de file des soins infirmiers, des médecins et des professions paramédicales de l'hôpital, ainsi que 10 cadres supérieurs d'établissements communautaires et de soins à domicile. De nombreux obstacles aux congés de fin de semaine ont été cernés, ce qui souligne que ce problème est complexe et qu'il comporte de nombreux facteurs internes et externes interdépendants. Heureusement, de nombreuses solutions potentielles spécifiques ont été proposées, à court terme et à long terme. Bien que de nombreuses solutions exigent des ressources supplémentaires, d'autres exigent un changement de culture par lequel les intervenants hospitaliers et communautaires reconnaissent que les services doivent être fournis de façon uniforme, sept jours par semaine. INTERPRéTATION: Nous avons identifié les obstacles complexes et interdépendants aux sorties de fin de semaine des patients hospitalisés. Il existe de nombreuses possibilités précises pour le personnel et les services hospitaliers, les médecins et les établissements communautaires d'offrir les mêmes soins aux patients les fins de semaine que les jours de semaine. Cela permettra d'améliorer la circulation et la sécurité des patients, et de réduire le surpeuplement des urgences le lundi.

Cardiovascular Magnetic Resonance Radiomics to Identify Components of the Extracellular Matrix in Dilated Cardiomyopathy.

BACKGROUND: Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and inflammation. We sought to investigate whether cardiovascular magnetic resonance radiomics analysis can distinguish between noncollagen and inflammation from collagen in dilated cardiomyopathy. METHODS: We identified data from 132 patients with dilated cardiomyopathy scheduled for an invasive septal biopsy who underwent cardiovascular magnetic resonance at 3 T. Cardiovascular magnetic resonance imaging protocol included native and postcontrast T1 mapping and late gadolinium enhancement (LGE). Radiomic features were computed from the midseptal myocardium, near the biopsy region, on native T1, extracellular volume (ECV) map, and LGE images. Principal component analysis was used to reduce the number of radiomic features to 5 principal radiomics. Moreover, a correlation analysis was conducted to identify radiomic features exhibiting a strong correlation (r>0.9) with the 5 principal radiomics. Biopsy samples were used to quantify ECS, myocardial fibrosis, and inflammation. RESULTS: Four histopathological phenotypes were identified: low collagen (n=20), noncollagenous ECS expansion (n=49), mild to moderate collagenous ECS expansion (n=42), and severe collagenous ECS expansion (n=21). Noncollagenous expansion was associated with the highest risk of myocardial inflammation (65%). Although native T1 and ECV provided high diagnostic performance in differentiating severe fibrosis (C statistic, 0.90 and 0.90, respectively), their performance in differentiating between noncollagen and mild to moderate collagenous expansion decreased (C statistic: 0.59 and 0.55, respectively). Integration of ECV principal radiomics provided better discrimination and reclassification between noncollagen and mild to moderate collagen (C statistic, 0.79; net reclassification index, 0.83 [95% CI, 0.45-1.22]; P<0.001). There was a similar trend in the addition of native T1 principal radiomics (C statistic, 0.75; net reclassification index, 0.93 [95% CI, 0.56-1.29]; P<0.001) and LGE principal radiomics (C statistic, 0.74; net reclassification index, 0.59 [95% CI, 0.19-0.98]; P=0.004). Five radiomic features per sequence were identified with correlation analysis. They showed a similar improvement in performance for differentiating between noncollagen and mild to moderate collagen (native T1, ECV, LGE C statistic, 0.75, 0.77, and 0.71, respectively). These improvements remained significant when confined to a single radiomic feature (native T1, ECV, LGE C statistic, 0.71, 0.70, and 0.64, respectively). CONCLUSIONS: Radiomic features extracted from native T1, ECV, and LGE provide incremental information that improves our capability to discriminate noncollagenous expansion from mild to moderate collagen and could be useful for detecting subtle chronic inflammation in patients with dilated cardiomyopathy.

Practice patterns of antiplatelet and anticoagulant therapy after fenestrated/branched endovascular aortic repair.

OBJECTIVE: Antiplatelet and/or anticoagulant therapy are commonly prescribed after fenestrated/branched endovascular aortic repair (F/BEVAR). However, the optimal regimen remains unknown. We sought to characterize practice patterns and outcomes of antiplatelet and anticoagulant use in patients who underwent F/BEVAR. METHODS: Consecutive patients enrolled (2012-2023) as part of the United States Aortic Research Consortium (US-ARC) from 10 independent physician-sponsored investigational device exemption studies were evaluated. The cohort was characterized by medication regimen on discharge from index F/BEVAR: (1) Aspirin alone OR P2Y12 alone (single-antiplatelet therapy [SAPT]); (2) Anticoagulant alone; (3) Aspirin + P2Y12 (dual-antiplatelet therapy [DAPT]); (4) Aspirin + anticoagulant OR P2Y12 + anticoagulant (SAPT + anticoagulant); (5) Aspirin + P2Y12 + anticoagulant (triple therapy [TT]); and (6) No therapy. Kaplan-Meier analysis and Cox proportional hazards modeling were used to compare 1-year outcomes including survival, target artery patency, freedom from bleeding complication, freedom from all reinterventions, and freedom from stent-specific reintervention. RESULTS: Of the 1525 patients with complete exposure and outcome data, 49.6% were discharged on DAPT, 28.8% on SAPT, 13.6% on SAPT + anticoagulant, 3.2% on TT, 2.6% on anticoagulant alone, and 2.2% on no therapy. Discharge medication regimen was not associated with differences in 1-year survival, bleeding complications, composite reintervention rate, or stent-specific reintervention rate. However, there was a significant difference in 1-year target artery patency. On multivariable analysis comparing with SAPT, DAPT conferred a lower hazard of loss of target artery patency (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27-0.84; P = .01). On sub-analyses of renal stents alone or visceral stents alone, DAPT no longer had a significantly lower hazard of loss of target artery patency (renal: HR, 0.66; 95% CI, 0.35-1.27; P = .22; visceral: HR, 0.31; 95% CI, 0.05-1.9; P = .21). Lastly, duration of DAPT therapy (1 month, 6 months, or 1 year) did not significantly affect target artery patency. CONCLUSIONS: Practice patterns for antiplatelet and anticoagulant regimens after F/BEVAR vary widely across the US-ARC. There were no differences in bleeding complications, survival or reintervention rates among different regimens, but higher branch vessel patency was noted in the DAPT cohort. These data suggest there is a benefit in DAPT therapy. However, the generalizability of this finding is limited by the retrospective nature of this data, and the clinical significance of this finding is unclear, as there is no difference in survival, bleeding, or reintervention rates amongst the different regimens. Hence, an "optimal" regimen, including the duration of such regimen, could not be clearly discerned. This suggests equipoise for a randomized trial, nested within this cohort, to identify the most effective antiplatelet/anticoagulant regimen for the growing number of patients being treated globally with F/BEVAR.

Sex and APOE genotype influence respiratory function under hypoxic and hypoxic-hypercapnic conditions.

The apolipoprotein E (APOE) gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often copresent with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenges. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. In addition, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.NEW & NOTEWORTHY This study is the first to use whole body plethysmography (WBP) to measure the impact of APOE alleles on breathing under normoxia and during adverse respiratory challenges in a targeted replacement Alzheimer's model. Both sex and genotype were shown to affect breathing under normoxia, hypoxic challenge, and hypoxic-hypercapnic challenge. This work has important implications regarding the impact of genetics on respiratory control as well as applications pertaining to conditions of disordered breathing including sleep apnea and neurotrauma.

Adjusting Atrial Size Parameters for Body Surface Area: Does it Affect the Association With Pulmonary Embolism-related Adverse Events?

PURPOSE: Small left atrial (LA) volume was recently reported to be one of the best predictors of acute pulmonary embolism (PE)-related adverse events (AE). There is currently no data available regarding the impact that body surface area (BSA)-indexing of atrial measurements has on the association with PE-related adverse events. Our aim is to assess the impact of indexing atrial measurements to BSA on the association between computed tomography (CT) atrial measurements and AE. MATERIALS AND METHODS: Retrospective study (IRB: 2015P000425). A database of hospitalized patients with acute PE diagnosed on CT pulmonary angiography (CTPA) between May 2007 and December 2014 was reviewed. Right and left atrial volume, largest axial area, and axial diameters were measured. Patients undergo both echocardiographies (from which the BSA was extracted) and CTPAs within 48 hours of the procedure. The patient's body weight was measured during each admission. LA measurements were correlated to AE (defined as the need for advanced therapy or PE-related mortality at 30 days) before and after indexing for BSA. The area under the ROC curve was calculated to determine the predictive value of the atrial measurements in predicting AE. RESULTS: The study included 490 acute PE patients; 62 (12.7%) had AE. There was a significant association of reduced BSA-indexed and non-indexed LA volume (both <0.001), area (<0.001 and 0.001, respectively), and short-axis diameters (both <0.001), and their respective RA/LA ratios (all <0.001) with AE. The AUC values were similar for BSA-indexed and non-indexed LA volume, diameters, and area with LA volume measurements being the best predictor of adverse outcomes (BSA-indexed AUC=0.68 and non-indexed AUC=0.66), followed by non-indexed LA short-axis diameter (indexed AUC=0.65, non-indexed AUC=0.64), and LA area (indexed AUC=0.64, non-indexed AUC=0.63). CONCLUSION: Adjusting for BSA does not substantially affect the predictive ability of atrial measurements on 30-day PE-related adverse events, and therefore, this adjustment is not necessary in clinical practice. While LA volume is the better predictor of AE, LA short-axis diameter has a similar predictive value and is more practical to perform clinically.

Competence By Design: a transformational national model of time-variable competency-based postgraduate medical education.

Postgraduate medical education is an essential societal enterprise that prepares highly skilled physicians for the health workforce. In recent years, PGME systems have been criticized worldwide for problems with variable graduate abilities, concerns about patient safety, and issues with teaching and assessment methods. In response, competency based medical education approaches, with an emphasis on graduate outcomes, have been proposed as the direction for 21st century health profession education. However, there are few published models of large-scale implementation of these approaches. We describe the rationale and design for a national, time-variable competency-based multi-specialty system for postgraduate medical education called Competence by Design. Fourteen innovations were bundled to create this new system, using the Van Melle Core Components of competency based medical education as the basis for the transformation. The successful execution of this transformational training system shows competency based medical education can be implemented at scale. The lessons learned in the early implementation of Competence by Design can inform competency based medical education innovation efforts across professions worldwide.

Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs): A Modular Platform for Generating Reversible, Self-Assembling Bifunctional Targeted Degraders.

Proteolysis-Targeting Chimeras (PROTACs) are bifunctional molecules that bring a target protein and an E3 ubiquitin ligase into proximity to append ubiquitin, thus directing target degradation. Although numerous PROTACs have entered clinical trials, their development remains challenging, and their large size can produce poor drug-like properties. To overcome these limitations, we have modified our Coferon platform to generate Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs). CURE-PROs are small molecule degraders designed to self-assemble through reversible bio-orthogonal linkers to form covalent heterodimers. By modifying known ligands for Cereblon, MDM2, VHL, and BRD with complementary phenylboronic acid and diol/catechol linkers, we have successfully created CURE-PROs that direct degradation of BRD4 both in vitro and in vivo. The combinatorial nature of our platform significantly reduces synthesis time and effort to identify the optimal linker length and E3 ligase partner to each target and is readily amenable to screening for new targets.

The fundamental theorem of natural selection: the end of a story.

The direction of research in population genetics theory is currently, and correctly, retrospective, that is directed toward the past. What events in the past have led to the presently observed genetic constitution of a population? This direction is inspired, first, by the large volumes of genomic data now available and, second, by the success of the classical prospective theory in validating the Darwinian theory in terms of Mendelian genetics. However, the prospective theory should not be forgotten, and in that theory, perhaps the most interesting and certainly the most controversial, is Fisher's so-called "Fundamental Theorem of Natural Selection." This article describes the history and the current status of that theorem.

V2a neurons restore diaphragm function in mice following spinal cord injury.

The specific roles that different types of neurons play in recovery from injury is poorly understood. Here, we show that increasing the excitability of ipsilaterally projecting, excitatory V2a neurons using designer receptors exclusively activated by designer drugs (DREADDs) restores rhythmic bursting activity to a previously paralyzed diaphragm within hours, days, or weeks following a C2 hemisection injury. Further, decreasing the excitability of V2a neurons impairs tonic diaphragm activity after injury as well as activation of inspiratory activity by chemosensory stimulation, but does not impact breathing at rest in healthy animals. By examining the patterns of muscle activity produced by modulating the excitability of V2a neurons, we provide evidence that V2a neurons supply tonic drive to phrenic circuits rather than increase rhythmic inspiratory drive at the level of the brainstem. Our results demonstrate that the V2a class of neurons contribute to recovery of respiratory function following injury. We propose that altering V2a excitability is a potential strategy to prevent respiratory motor failure and promote recovery of breathing following spinal cord injury.

Cardiovascular magnetic resonance characterization of myocardial tissue injury in a miniature swine model of cancer therapy-related cardiovascular toxicity.

BACKGROUND: Left ventricular ejection fraction (LVEF) is the most commonly clinically used imaging parameter for assessing cancer therapy-related cardiac dysfunction (CTRCD). However, LVEF declines may occur late, after substantial injury. This study sought to investigate cardiovascular magnetic resonance (CMR) imaging markers of subclinical cardiac injury in a miniature swine model. METHODS: Female Yucatan miniature swine (n = 14) received doxorubicin (2 mg/kg) every 3 weeks for 4 cycles. CMR, including cine, tissue characterization via T1 and T2 mapping, and late gadolinium enhancement (LGE) were performed on the same day as doxorubicin administration and 3 weeks after the final chemotherapy cycle. In addition, magnetic resonance spectroscopy (MRS) was performed during the 3 weeks after the final chemotherapy in 7 pigs. A single CMR and MRS exam were also performed in 3 Yucatan miniature swine that were age- and weight-matched to the final imaging exam of the doxorubicin-treated swine to serve as controls. CTRCD was defined as histological early morphologic changes, including cytoplasmic vacuolization and myofibrillar loss of myocytes, based on post-mortem analysis of humanely euthanized pigs after the final CMR exam. RESULTS: Of 13 swine completing 5 serial CMR scans, 10 (77%) had histological evidence of CTRCD. Three animals had neither histological evidence nor changes in LVEF from baseline. No absolute LVEF <40% or LGE was observed. Native T1, extracellular volume (ECV), and T2 at 12 weeks were significantly higher in swine with CTRCD than those without CTRCD (1178 ms vs. 1134 ms, p = 0.002, 27.4% vs. 24.5%, p = 0.03, and 38.1 ms vs. 36.4 ms, p = 0.02, respectively). There were no significant changes in strain parameters. The temporal trajectories in native T1, ECV, and T2 in swine with CTRCD showed similar and statistically significant increases. At the same time, there were no differences in their temporal changes between those with and without CTRCD. MRS myocardial triglyceride content substantially differed among controls, swine with and without CTRCD (0.89%, 0.30%, 0.54%, respectively, analysis of variance, p = 0.01), and associated with the severity of histological findings and incidence of vacuolated cardiomyocytes. CONCLUSION: Serial CMR imaging alone has a limited ability to detect histologic CTRCD beyond LVEF. Integrating MRS myocardial triglyceride content may be useful for detection of early potential CTRCD.

Meta-Analysis of Normal Reference Values for Right and Left Ventricular Quantification by Cardiovascular Magnetic Resonance.

BACKGROUND: Cardiovascular magnetic resonance (CMR) reference values are relied upon to accurately diagnose left ventricular (LV) and right ventricular (RV) pathologies. To date, reference values have been derived from modest sample sizes with limited patient diversity and attention to 1 but not both commonly used tracing techniques for papillary muscles and trabeculations. We sought to overcome these limitations by meta-analyzing normal reference values for CMR parameters stemming from multiple countries, vendors, analysts, and patient populations. METHODS: We comprehensively extracted published and unpublished data from studies reporting CMR parameters in healthy adults. A steady-state free-precession short-axis stack at 1.5T or 3T was used to trace either counting the papillary muscles and trabeculations in the LV volume or mass. We used a novel Bayesian hierarchical meta-analysis model to derive the pooled lower and upper reference values for each CMR parameter. Our model accounted for the expected differences between tracing techniques by including informative prior distributions from a large external data set. RESULTS: A total of 254 studies from 25 different countries were systematically reviewed, representing 12 812 healthy adults, of which 52 were meta-analyzed. For LV parameters counting papillary muscles and trabeculations in the LV volume, pooled normative reference ranges in men and women, respectively, were as follows: LV ejection fraction of 52% to 73% and 54% to 75%, LV end-diastolic volume index of 60 to 109 and 56 to 96 mL/m2, LV end-systolic volume index of 18 to 45 and 16 to 38 mL/m2, and LV mass index of 41 to 76 and 33 to 57 g/m2. For LV parameters counting papillary muscles and trabeculations in the LV mass, pooled normative reference ranges in men and women, respectively, were as follows: LV ejection fraction of 57% to 74% and 57% to 75%, LV end-diastolic volume index of 60 to 97 and 55 to 88 mL/m2, LV end-systolic volume index of 18 to 37 and 15 to 34 mL/m2, and LV mass index of 50 to 83 and 38 to 65 g/m2. For RV parameters, pooled normative reference ranges in men and women, respectively, were as follows: RV ejection fraction of 47% to 68% and 49% to 71%, RV end-diastolic volume index of 64 to 115 and 57 to 99 mL/m2, RV end-systolic volume index of 23 to 52 and 18 to 42 mL/m2, and RV mass index of 14 to 29 and 13 to 25 g/m2. CONCLUSIONS: Our Bayesian hierarchical meta-analysis provides normative reference values for CMR parameters of LV and RV size, systolic function, and mass, encompassing both tracing techniques across a diverse multinational sample of healthy men and women.

Comparison of peer-assisted learning with expert-led learning in medical school ultrasound education: a systematic review and meta-analysis.

INTRODUCTION: Teaching point-of-care ultrasonography (PoCUS) to medical students is resource intensive. Peer-assisted learning, where the teacher can be a medical student, may be a feasible alternative to expert-led learning. The objective of this systematic review and meta-analysis was to compare the PoCUS performance assessments of medical students receiving peer-assisted vs expert-led learning. METHODS: This study was submitted to PROSPERO (CRD42023383915) and reported with PRISMA guidelines. MEDLINE, Embase, ERIC, Education Source, Scopus, and Web of Science were searched from inception to November 2022. Inclusion criteria were studies comparing peer-assisted vs expert-led PoCUS teaching for undergraduate medical students. The primary outcome was performance assessment of PoCUS skills. Two reviewers independently screened citations and extracted data. The Cochrane risk-of-bias tool for randomized trials was used to assess study quality. Studies were included in the meta-analysis if mean performance assessment scores with standard deviations and sample sizes were available. A random-effects meta-analysis was conducted to estimate the accuracy score of practical knowledge test for each group. A meta-regression evaluated difference in mean scores. RESULTS: The search yielded 2890 citations; 1417 unique citations remained after removing duplicates. Nine randomized-controlled studies conducted in Germany, USA, and Israel, with 593 participants, were included in the meta-analysis. The included studies assessed teaching of abdominal, cardiac, thoracic, musculoskeletal, and ocular PoCUS skills. Most studies had some risk-of-bias concerns. The estimate accuracy score after weighting is 0.56 (95% CI [0.47, 0.65]) for peer-assisted learning and 0.59 (95% CI [0.49, 0.69]) for expert-led learning. The regression coefficient estimate is 0.0281 (95% CI [- 0.1121, 0.1683]); P value is 0.69. CONCLUSION: This meta-analysis found that peer-assisted learning was a reasonable alternative to expert-led learning for teaching PoCUS skills to medical students.

RéSUMé: INTRODUCTION: L'enseignement de l'échographie au point d'intervention (PoCUS) aux étudiants en médecine nécessite des ressources importantes. L'apprentissage assisté par les pairs, où l'enseignant peut être un étudiant en médecine, peut être une alternative possible à l'apprentissage dirigé par des experts. L'objectif de cette revue systématique et de cette méta-analyse était de comparer les évaluations de performance PoCUS d'étudiants en médecine bénéficiant d'un apprentissage assisté par des pairs par rapport à un apprentissage dirigé par des experts. MéTHODES: Cette étude a été soumise à PROSPERO (CRD42023383915) et rapportée selon les directives PRISMA. MEDLINE, Embase, ERIC, Education Source, Scopus et Web of Science ont été recherchés depuis leur création jusqu'en novembre 2022. Les critères d'inclusion étaient les études comparant l'enseignement du PoCUS assisté par des pairs à celui dirigé par des experts pour les étudiants en médecine de premier cycle. Le principal résultat était l'évaluation du rendement des compétences PoCUS. Deux évaluateurs ont indépendamment examiné les citations et extrait les données. L'outil Cochrane d'évaluation du risque de biais pour les essais randomisés a été utilisé pour évaluer la qualité des études. Les études ont été incluses dans la méta-analyse si les scores moyens d'évaluation des performances avec les écarts types et la taille des échantillons étaient disponibles. Une méta-analyse à effets aléatoires a été réalisée pour estimer le score de précision du test de connaissances pratiques pour chaque groupe. Une méta-régression a évalué la différence dans les scores moyens. RéSULTATS: La recherche a donné lieu à 2890 citations ; 1417 citations uniques ont été conservées après suppression des doublons. Neuf études contrôlées randomisées menées en Allemagne, aux États-Unis et en Israël, avec 593 participants, ont été incluses dans la méta-analyse. Les études incluses ont évalué l'enseignement des compétences PoCUS abdominales, cardiaques, thoraciques, musculo-squelettiques et oculaires. La plupart des études présentaient des risques de biais. Le score de précision estimé après pondération est de 0,56 (IC à 95 % : [0,47, 0,65]) pour l'apprentissage assisté par les pairs et de 0,59 (IC à 95 % : [0,49, 0,69]) pour l'apprentissage dirigé par des experts. L'estimation du coefficient de régression est de 0,0281 (IC à 95 % : [-0,1121, 0,1683]) ; la valeur P est de 0,69. CONCLUSION: Cette méta-analyse a montré que l'apprentissage assisté par les pairs était une alternative raisonnable à l'apprentissage dirigé par des experts pour enseigner les compétences PoCUS aux étudiants en médecine.

Glia trigger endocytic clearance of axonal proteins to promote rodent myelination.

Axons undergo striking changes in their content and distribution of cell adhesion molecules (CAMs) and ion channels during myelination that underlies the switch from continuous to saltatory conduction. These changes include the removal of a large cohort of uniformly distributed CAMs that mediate initial axon-Schwann cell interactions and their replacement by a subset of CAMs that mediate domain-specific interactions of myelinated fibers. Here, using rodent models, we examine the mechanisms and significance of this removal of axonal CAMs. We show that Schwann cells just prior to myelination locally activate clathrin-mediated endocytosis (CME) in axons, thereby driving clearance of a broad array of axonal CAMs. CAMs engineered to resist endocytosis are persistently expressed along the axon and delay both PNS and CNS myelination. Thus, glia non-autonomously activate CME in axons to downregulate axonal CAMs and presumptively axo-glial adhesion. This promotes the transition from ensheathment to myelination while simultaneously sculpting the formation of axonal domains.

Relevance of BEST-CLI trial endpoints in a tertiary care limb preservation program.

OBJECTIVE: Major adverse limb event-free survival (MALE-FS) differed significantly by initial revascularization approach in the BEST-CLI randomized trial. The BEST-CLI trial represented a highly selected subgroup of patients seen in clinical practice; thus, we examined the endpoint of MALE-FS in an all-comers tertiary care practice setting. METHODS: This is a single-center retrospective study of consecutive, unique patients who underwent technically successful infrainguinal revascularization for chronic limb-threatening ischemia (2011-2021). MALE was major amputation (transtibial or above) or major reintervention (new bypass, open bypass revision, thrombectomy, or thrombolysis). RESULTS: Among 469 subjects, the mean age was 70 years, and 34% were female. Characteristics included diabetes (68%), end-stage renal disease (ESRD) (16%), Wound, Ischemia, and foot Infection (WIfI) stage 4 (44%), Global Limb Anatomic Staging System (GLASS) stage 3 (62%), and high pedal artery calcium score (pMAC) (22%). Index revascularization was autogenous vein bypass (AVB) (30%), non-autogenous bypass (NAB) (13%), or endovascular (ENDO) (57%). The composite endpoint of MALE or death occurred in 237 patients (51%) at a median time of 189 days from index revascularization. In an adjusted Cox model, factors independently associated with MALE or death included younger age, ESRD, WIfI stage 4, higher GLASS stage, and moderate-severe pMAC, whereas AVB was associated with improved MALE-FS. Freedom from MALE-FS, MALE, and major amputation at 30 days were 90%, 92%, and 95%; and at 1 year were 63%, 70%, and 83%, respectively. MALE occurred in 144 patients (31%) and was associated with ESRD, WIfI stage, GLASS stage, pMAC score, and index revascularization approach. AVB had superior durability, with adjusted 2-year freedom from MALE of 72%, compared with 66% for ENDO and 51% for NAB. Within the AVB group, spliced vein conduit had higher MALE compared with single-segment vein (hazard ratio, 1.8; 95% confidence interval, 0.9-3.7; P = .008 after inverse propensity weighting), but there was no statistically significant difference in major amputation. Of the 144 patients with any MALE, the first MALE was major reintervention in 47% and major amputation in 53%. Major amputation as first MALE was associated with non-AVB index approach. Indications for major reintervention were symptomatic stenosis/occlusion (54%), lack of clinical improvement (28%), asymptomatic graft stenosis (16%), and iatrogenic events (3%). Conversion to bypass occurred after 6% of ENDO cases, two-thirds of which involved distal bypass targets at the ankle or foot. CONCLUSIONS: In this consecutive, all-comers cohort, disease complexity was associated with procedural selection and MALE-FS. AVB independently provided the greatest MALE-FS and freedom from MALE and major amputation. Compared with the BEST-CLI randomized trial, MALE after ENDO in this series was more frequently major amputation, with relatively few conversions to open bypass.

Predictors of amputation-free survival and wound healing after infrainguinal bypass with alternative conduits.

OBJECTIVE: Inadequate vein quality or prior harvest precludes use of autologous single segment greater saphenous vein (ssGSV) in many patients with chronic limb-threatening ischemia (CLTI). Predictors of patient outcome after infrainguinal bypass with alternative (non-ssGSV) conduits are not well-understood. We explored whether limb presentation, bypass target, and conduit type were associated with amputation-free survival (AFS) after infrainguinal bypass using alternative conduits. METHODS: A single-center retrospective study (2013-2020) was conducted of 139 infrainguinal bypasses performed for CLTI with cryopreserved ssGSV (cryovein) (n = 71), polytetrafluoroethylene (PTFE) (n = 23), or arm/spliced vein grafts (n = 45). Characteristics, Wound, Ischemia, and foot Infection (WIfI) stage, and outcomes were recorded. Multivariable Cox proportional hazards and classification and regression tree analysis modeled predictors of AFS. RESULTS: Within 139 cases, the mean age was 71 years, 59% of patients were male, and 51% of cases were nonelective. More patients undergoing bypass with cryovein were WIfI stage 4 (41%) compared with PTFE (13%) or arm/spliced vein (27%) (P = .04). Across groups, AFS at 2 years was 78% for spliced/arm, 79% for PTFE, and 53% for cryovein (adjusted hazard ratio for cryovein, 2.5; P = .02). Among cases using cryovein, classification and regression tree analysis showed that WIfI stage 3 or 4, age >70 years, and prior failed bypass were predictive of the lowest AFS at 2 years of 36% vs AFS of 58% to 76% among subgroups with less than two of these factors. Although secondary patency at 2 years was worse in the cryovein group (26% vs 68% and 89% in arm/spliced and PTFE groups; P < .01), in patients with tissue loss there was no statistically significant difference in wound healing in the cryovein group (72%) compared with other bypass types (72% vs 87%, respectively; P = .12). CONCLUSIONS: In patients with CLTI lacking suitable ssGSV, bypass with autogenous arm/spliced vein or PTFE has superior AFS compared with cryovein, although data were limited for PTFE conduits for distal targets. Despite poor patency with cryovein, wound healing is achieved in a majority of cases, although it should be used with caution in older patients with high WIfI stage and prior failed bypass, given the low rates of AFS.