Energizing scholarly activity in a regional medical campus.

Medical education is increasingly delivered at distributed sites away from Academic Health Sciences Centres. The Council of Ontario Faculties of Medicine recommends schools develop resources and metrics to foster regional campus scholarly activity. Opportunities for distributed program trainees must support learning core skills in research and critical appraisal to comply with medical school accreditation standards and to develop their interests and skills in scholarly work for their future medical careers. We describe a scholarly activity program that is a template for distributed campuses or regional teaching sites seeking to increase learner and faculty engagement and research productivity.

La formation médicale décentralisée se déroule de plus en plus souvent loin des centres universitaires de sciences de la santé. Le Conseil des facultés de médecine de l'Ontario recommande aux facultés de se doter de ressources et de indicateurs pour encourager les activités d'érudition sur les campus régionaux. Les possibilités offertes aux stagiaires des programmes décentralisés doivent favoriser l'apprentissage des habiletés de base en recherche et en lecture critique pour se conformer aux normes d'agrément des facultés de médecine et développer des intérêts et des habiletés en érudition qui leur seront utiles dans leur carrière médicale. Nous décrivons un programme d'activités d'érudition qui peut servir de modèle pour les milieux de formation décentralisés ou les sites d'enseignement régionaux souhaitant stimuler la productivité scientifique et l'implication des apprenants et du corps professoral dans la recherche.

Applying the Knowledge-to-Action Framework to Implement Gait and Balance Assessments in Inpatient Stroke Rehabilitation.

OBJECTIVES: The overall objectives of this project were to implement and sustain use of a gait assessment battery (GAB) that included the Berg Balance Scale, 10-meter walk test, and 6-minute walk test during inpatient stroke rehabilitation. The study objective was to assess the effect of the study intervention on clinician adherence to the recommendations and its effect on clinician perceptions and the organization. DESIGN: Pre- and post-training intervention study. SETTING: Subacute inpatient rehabilitation facility. PARTICIPANTS: Physical therapists (N=6) and physical therapist assistants (N=2). INTERVENTION: The intervention comprised a bundle of activities, including codeveloping and executing the plan with clinicians and leaders. The multicomponent implementation plan was based on the Knowledge-to-Action Framework and included implementation facilitation, implementation leadership, and a bundle of knowledge translation interventions that targeted barriers. Implementation was an iterative process in which results from one implementation phase informed planning of the next phase. MAIN OUTCOME MEASURES: Clinician administration adherence, surveys of perceptions, and organizational outcomes. RESULTS: Initial adherence to the GAB was 46% and increased to more than 85% after 6 months. These adherence levels remained consistent 48 months after implementation. Clinician perceptions of measure use were initially high (>63%), with significant improvements in knowledge and use of one measure after implementation. CONCLUSIONS: We successfully implemented the assessment battery with high levels of adherence to recommendations, likely because of using the bundle of knowledge translation activities, facilitation, and use of a framework to codevelop the plan. These changes in practice were sustainable, as determined by a 4-year follow-up.

Highly efficient neuronal gene knockout in vivo by CRISPR-Cas9 via neonatal intracerebroventricular injection of AAV in mice.

CRISPR-Cas systems have emerged as a powerful tool to generate genetic models for studying normal and diseased central nervous system (CNS). Targeted gene disruption at specific loci has been demonstrated successfully in non-dividing neurons. Despite its simplicity, high specificity and low cost, the efficiency of CRISPR-mediated knockout in vivo can be substantially impacted by many parameters. Here, we used CRISPR-Cas9 to disrupt the neuronal-specific gene, NeuN, and optimized key parameters to achieve effective gene knockout broadly in the CNS in postnatal mice. Three cell lines and two primary neuron cultures were used to validate the disruption of NeuN by single-guide RNAs (sgRNA) harboring distinct spacers and scaffold sequences. This triage identified an optimal sgRNA design with the highest NeuN disruption in in vitro and in vivo systems. To enhance CRISPR efficiency, AAV-PHP.B, a vector with superior neuronal transduction, was used to deliver this sgRNA in Cas9 mice via neonatal intracerebroventricular (ICV) injection. This approach resulted in 99.4% biallelic indels rate in the transduced cells, leading to greater than 70% reduction of total NeuN proteins in the cortex, hippocampus and spinal cord. This work contributes to the optimization of CRISPR-mediated knockout and will be beneficial for fundamental and preclinical research.

Fusing subnational with national climate action is central to decarbonization: the case of the United States.

Approaches that root national climate strategies in local actions will be essential for all countries as they develop new nationally determined contributions under the Paris Agreement. The potential impact of climate action from non-national actors in delivering higher global ambition is significant. Sub-national action in the United States provides a test for how such actions can accelerate emissions reductions. We aggregated U.S. state, city, and business commitments within an integrated assessment model to assess how a national climate strategy can be built upon non-state actions. We find that existing commitments alone could reduce emissions 25% below 2005 levels by 2030, and that enhancing actions by these actors could reduce emissions up to 37%. We show how these actions can provide a stepped-up basis for additional federal action to reduce emissions by 49%-consistent with 1.5 °C. Our analysis demonstrates sub-national actions can lead to substantial reductions and support increased national action.

MRE11 and ATM Expression Levels Predict Rectal Cancer Survival and Their Association with Radiotherapy Response.

BACKGROUND: Aberrant expression of DNA repair proteins is associated with poor survival in cancer patients. We investigated the combined expression of MRE11 and ATM as a predictive marker of response to radiotherapy in rectal cancer. METHODS: MRE11 and ATM expression were examined in tumor samples from 262 rectal cancer patients who underwent surgery for rectal cancer, including a sub-cohort of 54 patients who were treated with neoadjuvant radiotherapy. The relationship between expression of the two-protein panel and tumor regression grade (TRG) was assessed by Mann-Whitney U test and receiver operating characteristics area under curve (ROC-AUC) analysis. The association between expression of the two-protein panel and clinicopathologic variables and survival was examined by Kaplan-Meier methods and Cox regression analysis. RESULTS: A high score for two-protein combined expression in the tumor center (TC) was significantly associated with worse disease-free survival (DFS) (P = 0.035) and overall survival (OS) (P = 0.003) in the whole cohort, and with DFS (P = 0.028) and OS (P = 0.024) in the neoadjuvant subgroup (n = 54). In multivariate analysis, the two-protein combination panel (HR = 2.178, 95% CI 1.115-4.256, P = 0.023) and perineural invasion (HR = 2.183, 95% CI 1.222-3.899, P = 0.008) were significantly associated with DFS. Using ROC-AUC analysis of good versus poor histological tumor response among patients treated preoperatively with radiotherapy, the average ROC-AUC was 0.745 for the combined panel, 0.618 for ATM alone, and 0.711 for MRE11 alone. CONCLUSIONS: The MRE11/ATM two-protein panel developed in this study may have clinical value as a predictive marker of tumor response to neoadjuvant radiotherapy, and a prognostic marker for disease-free and overall survival.

Locked plating of distal femur fractures leads to inconsistent and asymmetric callus formation.

OBJECTIVES: Locked plating constructs may be too stiff to reliably promote secondary bone healing. This study used a novel imaging technique to quantify periosteal callus formation of distal femur fractures stabilized with locking plates. It investigated the effects of cortex-to-plate distance, bridging span, and implant material on periosteal callus formation. DESIGN: Retrospective cohort study. SETTING: One Level I and one Level II trauma center. PATIENTS: Sixty-four consecutive patients with distal femur fractures (AO types 32A, 33A-C) stabilized with periarticular locking plates. INTERVENTION: Osteosynthesis using indirect reduction and bridge plating with periarticular locking plates. MAIN OUTCOME MEASUREMENT: Periosteal callus size on lateral and anteroposterior radiographs. RESULTS: Callus size varied from 0 to 650 mm2. Deficient callus (20 mm2 or less) formed in 52%, 47%, and 37% of fractures at 6, 12, and 24 weeks postsurgery, respectively. Callus formation was asymmetric, whereby the medial cortex had on average 64% more callus (P=0.001) than the anterior or posterior cortices. A longer bridge span correlated minimally with an increased callus size at Week 6 (P=0.02), but no correlation was found at Weeks 12 and 24 postsurgery. Compared with stainless steel plates, titanium plates had 76%, 71%, and 56% more callus at Week 6 (P=0.04), Week 12 (P=0.03), and Week 24 (P=0.09), respectively. CONCLUSIONS: Stabilization of distal femur fractures with periarticular locking plates can cause inconsistent and asymmetric formation of periosteal callus. A larger bridge span only minimally improves callus formation. The more flexible titanium plates enhanced callus formation compared with stainless steel plates.