Faculty Bibliography

NEEDS AND OBJECTIVES: To address rising education costs, physician shortages, and the need for educational reform, several medical schools have developed accelerated 3-year MD programs. In 2013, NYU School of Medicine began its new 3-year MD program with guaranteed acceptance into residency upon graduation. Using the AAMC's 13 Core Entrustable Professional Activities for Entry into Residency (CEPAER) framework, we designed an immersive 4-hour simulated "Night on Call" (NOC) experience to compare performance of our first graduating cohort of fifteen 3-year MD students (3A), with third (3T) and fourth year (4T) students in the traditional 4-year MD program. SETTING AND PARTICIPANTS: 73 medical students (39 women, age 26.5 (+2.6) years; 36 '3T', 12 '3A', 25 '4T') completed an IRB-approvedNOC at our simulation center 4 weeks prior to the end of their third or final year of medical school. DESCRIPTION: We developed NOC to measure competence and entrustment across all 13 CEPAERs from the perspective of patients, nurses, and attendings. During the simulation, a medical student rotated through a series of 8 clinical coverage scenarios including: 4 standardized patient (SP) cases with varying degrees of complexity, each of which require answering a call from a standardized nurse (SN), evaluating an SP with the SN in the room, making immediate management decisions and writing a coverage note; a phone call to an experienced clinician to orally present (OP) the case; formulation of a clinical question and finding the most appropriate evidence-based medicine (EBM) answer using digital library resources; a clinical vignette (CV) to test ability to recognize a pre-entrustable peer; and a handoff (HO) of 4 cases to a peer (a senior medical student). CEPAERs assessments based on validated tools included communication, physical exam, patient education and interprofessional teamwork skills assessed by an SP and SN, and clinical reasoning based on notes, OP, EBM, CV, HO. Each rater also provided an entrustment judgment. EVALUATION: Although overall student performance improved across cases and some interesting individual performance patterns emerged, there were no significant differences across the three groups in the core competency and entrustment measures evaluated across various NOC activities. DISCUSSION/REFLECTION/LESSONS LEARNED: The 13 CEPAERs are meant to define what students should be expected to perform (without direct supervision) prior to entering residency. Our results, based on multiple rater perspectives, suggest that our cohort of 3A students is as prepared for residency as their 4T counterparts

In the last decade, there has been renewed interest in three-year MD pathway programs. In 2015, with support from the Josiah Macy Jr., Foundation, eight North American medical schools with three-year accelerated medical pathway programs formed the Consortium of Accelerated Medical Pathway Programs (CAMPP). The schools are two campuses of the Medical College of Wisconsin; McMaster University Michael G. DeGroote School of Medicine; Mercer University School of Medicine; New York University School of Medicine; Penn State College of Medicine; Texas Tech University Health Sciences Center School of Medicine; University of California, Davis School of Medicine; and University of Louisville School of Medicine. These programs vary in size and medical specialty focus but all include the reduction of student debt from savings in tuition costs. Each school's mission to create a three-year pathway program differs; common themes include the ability to train physicians to practice in underserved areas or to allow students for whom the choice of specialty is known to progress more quickly. Compared with McMaster, these programs are small, but most capitalize on training and assessing competency across the undergraduate medical education-graduate medical education continuum and include conditional acceptance into an affiliated residency program. This article includes an overview of each CAMPP school with attention to admissions, curriculum, financial support, and regulatory challenges associated with the design of an accelerated pathway program. These programs are relatively new, with a small number of graduates; this article outlines opportunities and challenges for schools considering the development of accelerated programs.

Objectives Degeneration of articular cartilage is central to OA pathology; however, the molecular mechanisms leading to these irreversible changes are still poorly understood. Here, we investigated how changes in the chondrocyte translational apparatus may contribute to the pathology of OA. Methods Normal and OA human knee cartilage was used to analyze the activity of different components of the translational machinery. Chondrocytes isolated from lesional and non-lesional areas of OA cartilage were used to estimate relative rate of protein synthesis by metabolic labeling. Experimental OA was induced by transection of the anterior cruciate ligament in rats to investigate changes in the translational apparatus associated with OA. The role of IL-1beta signaling was assessed in vitro using rat articular chondrocytes. Expression of mRNAs was analyzed by qPCR and protein levels by immunohistochemistry and Western blotting. Results We identified several novel traits of OA chondrocytes, including upregulation of the Serine/Threonine kinases AKT2 and AKT3 at the post-transcriptional level and increased rate of total protein synthesis, likely due to inactivation of 4E-BP1, a known repressor of cap-dependent translation. We found that 4E-BP1 inactivation is mTOR-dependent and crucial for upregulation of protein synthesis in general and in particular for MMP13 and ADAMTS5 expression. In addition, IL-1beta treatment led to 4E-BP1 inactivation and upregulation of protein synthesis in articular chondrocytes. Conclusions Precise control of protein synthesis is vital for cartilage homeostasis and its dysregulation contributes to the molecular pathology of OA. Our study therefore identifies a novel set of potential therapeutic targets

Tissue-engineering techniques have been successful in developing cartilage-like tissues in vitro using cells from animal sources. The successful translation of these strategies to the clinic will likely require cell expansion to achieve sufficient cell numbers. Using a two-dimensional (2D) cell migration assay to first identify the passage at which chondrocytes exhibited their greatest chondrogenic potential, the objective of this study was to determine a more optimal culture medium for developing three-dimensional (3D) cartilage-like tissues using human cells. We evaluated combinations of commonly used growth factors that have been shown to promote chondrogenic growth and development. Human articular chondrocytes (AC) from osteoarthritic (OA) joints were cultured in 3D environments, either in pellets or encapsulated in agarose. The effect of growth factor supplementation was dependent on the environment, such that matrix deposition differed between the two culture systems. ACs in pellet culture were more responsive to bone morphogenetic protein (BMP2) alone or combinations containing BMP2 (i.e. BMP2 with PDGF or FGF). However, engineered cartilage development within agarose was better for constructs cultured with TGFbeta3. These results with agarose and pellet culture studies set the stage for the development of conditions appropriate for culturing 3D functional engineered cartilage for eventual use in human therapies

BACKGROUND: Oral vancomycin remains the mainstay of therapy for severe infections produced by Clostridium difficile, the most prevalent cause of healthcare-associated infectious diarrhoea in developed countries. However, its short- and long-term effects on the human intestinal microbiota remain largely unknown. METHODS: We utilized high-throughput sequencing to analyse the effects of vancomycin on the faecal human microbiota up to 22 weeks post-antibiotic cessation. The clinical relevance of the observed microbiota perturbations was studied in mice. RESULTS: During vancomycin therapy, most intestinal microbiota genera and operational taxonomic units (OTUs) were depleted in all analysed subjects, including all baseline OTUs from the phylum Bacteroidetes. This was accompanied by a vast expansion of genera associated with infections, including Klebsiella and Escherichia/Shigella. Following antibiotic cessation, marked differences in microbiota resilience were observed among subjects. While some individuals recovered a microbiota close to baseline composition, in others, up to 89% of abundant OTUs could no longer be detected. The clinical relevance of the observed microbiota changes was further demonstrated in mice, which developed analogous microbiota alterations. During vancomycin treatment, mice were highly susceptible to intestinal colonization by an antibiotic-resistant pathogen and, upon antibiotic cessation, a less-resilient microbiota allowed higher levels of pathogen colonization. CONCLUSIONS: Oral vancomycin induces drastic and consistent changes in the human intestinal microbiota. Upon vancomycin cessation, the microbiota recovery rate varied considerably among subjects, which could influence, as validated in mice, the level of susceptibility to pathogen intestinal colonization. Our results demonstrate the negative long-term effects of vancomycin, which should be considered as a fundamental aspect of the cost-benefit equation for antibiotic prescription.

Background/Purpose: We aimed to understand the mechanism by which membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) controls bone and cartilage homeostasis. MT1-MMP, a cell-membrane-bound proteinase with an extracellular catalytic site and a 20-amino acid cytoplasmic tail, plays a key role in postnatal bone formation. The genetic deficiency of MT1-MMP in the mouse causes dwarfism, osteopenia and severe arthritis. Deletion of MT1-MMP in bone marrow-derived mesenchymal progenitor cells (BM-MSC) recapitulates this phenotype, showing that MT1-MMP controls osteogenic differentiation in MSC. The phenotype of MT1-MMP-/- mice has been proposed to result from lack of MT1-MMP proteolytic activity. However, mounting evidence shows a variety of proteolysis-independent signaling functions of MT1-MMP. The unique tyrosine (Y573) in the MT1-MMP cytoplasmic tail is fundamental for the control of intracellular signaling. Methods: We generated a mouse with the Y573D mutation in MT1-MMP (MT1-MMP Y573D) and characterized its skeletal phenotype by histological and microCT analyses. Isolated BM-MSC were induced to differentiate into osteoblasts, chondrocytes and adipocytes, using qRT-PCR to analyze gene expression. Mouse C3H10T1/2 MSC were transfected with MT1-MMP cDNA and analyzed for Wnt signaling by luciferase reporter assays. Results: MT1-MMP Y573D mice had increased trabecular bone relative to wt littermates, marked thinning of articular cartilage with disorganized tissue architecture, clustering and cloning of chondrocytes, and pronounced decrease in bone marrow-associated and total body fat. We induced BM-MSC from wt and MT1-MMP Y573D littermates to differentiate into osteoblast and chondrocytes, and myeloid precursors into osteoclasts. The Y573D mutation dramatically increased MSC expression of osteoblast markers and strongly downregulated chondrocyte and osteoclast markers. These findings indicated that Wnt signaling is upregulated in MT1-MMP Y573D-expressing MSC. Therefore, we analyzed Wnt signaling. We transiently transfected C3H10T1/2 MSC cells in osteoblast medium with the cDNAs for wt MT1-MMP and MT1-MMP Y573D. As controls the cells were transfected with the empty vector (pcDNA) or with MT1-MMP E240A, a mutant devoid of proteolytic activity. MT1-MMP Y573D dramatically upregulated Wnt signaling relative to wt MT1-MMP and MT1-MMP E240A. Conclusion: MT1-MMP controls Wnt signaling by a mechanism independent of extracellular proteolysis and mediated by its cytoplasmic tail. MT1-MMP is a bifunctional protein, with an extracellular proteolytic activity that promotes bone formation through ECM remodeling and a cytoplasmic tail that controls osteogenesis by interacting with a key pro-osteogenic signaling pathway