Community and Academic Physicians Working Together in Integrated Health Care Systems.

OBJECTIVE: To examine best practices and policies for effectively merging community and academic physicians in integrated health care systems. METHODS: Deans of US allopathic medical schools were systematically interviewed between February and June 2017 regarding growth in their faculty practice plan (FPP), including logistics and best practices for integration of community physicians. RESULTS: The survey was completed by 107 of 143 (74.8) of US medical school deans approached. Of these institutions, 73 met criteria for final analysis (research-based medical schools with FPPs of >300 physicians). Most academic medical center-based FPPs have increased in size over the last 5 years, with further growth anticipated via adding community physicians (85%). Because of disparate practice locations, integration of community and academic physicians has been slow. When fully integrated, community physicians predominantly have a clinical role with productivity incentives. Deans report that cultural issues must be addressed to avoid conflict. Consensus exists that transparent clinical work requirements for all FPP members, clearly defined productivity incentives, additional promotion tracks, and early involvement of department chairs and other leaders enhances trust and creates better synergy among all physician providers. CONCLUSION: Findings from this study should help guide FPPs, academic medical center leaders, chief medical officers, and professional and trade organizations in working toward positive physician synergy in consolidated health care organizations. Work and cultural considerations must be addressed to honor distinct talents of each physician group, facilitating smooth transition from disparate groups to healthy synergy.

Putting students at the center: moving beyond time-variable one-size-fits-all medical education to true individualization.

Medical education has undergone a wave of creative innovation over the last decade, with new curricular structures, pedagogy, content, and team-based approaches. Augmenting these changes, integration of clinical and scientific principles increasingly occurs across all years of training. Given success in innovation and integration, as well as recent interest and national pilots in time-variable (competency-based) education, we propose the next important step in medical education evolution is individualization.

Comprehensive history of 3-year and accelerated US medical school programs: a century in review.

Within the context of major medical education curricular reform ongoing in the United States, a subset of schools has re-initiated accelerated (3-year) medical education. It would be helpful for education leaders to pause and consider historical reasons such accelerated medical schools were started, and then abandoned, over the last century to proactively address important issues. As no comprehensive historical review of 3-year medical education exists, we examined all articles published on this topic since 1900. In general, US medical educational curricula began standardizing into 4-year programs in the early 1900s through contributions from William Osler, Abraham Flexner, and establishment of the American Medical Association (AMA) Council of Medical Education (CME). During WWII (1939-1945), accelerated 3-year medical school programs were initiated as a novel approach to address physician shortages; government incentives were used to boost the number of 3-year medical schools along with changed laws aiding licensure for graduates. However, this quick solution generated questions regarding physician competency, resulting in rallying cries for oversight of 3-year programs. Expansion of 3-year MD programs slowed from 1950s to 1960s until federal legislation was passed between the 1960s and the 1970s to support training healthcare workers. With renewed government financial incentives and stated desire to increase physician numbers and reduce student debt, a second rapid expansion of 3-year medical programs occurred in the 1970s. Later that decade, a second decline occurred in these programs, reportedly due to discontinuation of government funding, declining physician shortage, and dissatisfaction expressed by students and faculty. The current wave of 3-year MD programs, beginning in 2010, represents a 'third wave' for these programs. In this article, we identify common societal and pedagogical themes from historical experiences with accelerated medical education. These findings should provide today's medical education leaders a historical context from which to design and optimize accelerated medical education curricula.

Time-variable medical education innovation in context.

BACKGROUND: Medical education is undergoing robust curricular reform with several innovative models emerging. In this study, we examined current trends in 3-year Doctor of Medicine (MD) education and place these programs in context. METHODS: A survey was conducted among Deans of U.S. allopathic medical schools using structured phone interview regarding current availability of a 3-year MD pathway, and/or other variations in curricular innovation, within their institution. Those with 3-year programs answered additional questions. RESULTS: Data from 107 institutions were obtained (75% survey response rate). The most common variation in length of medical education today is the accelerated 3-year pathway. Since 2010, 9 medical schools have introduced parallel 3-year MD programs and another 4 are actively developing such programs. However, the total number of students in 3-year MD tracks remains small (n=199 students, or 0.2% total medical students). Family medicine and general internal medicine are the most common residency programs selected. Benefits of 3-year MD programs generally include reduction in student debt, stability of guaranteed residency positions, and potential for increasing physician numbers in rural/underserved areas. Drawbacks include concern about fatigue/burnout, difficulty in providing guaranteed residency positions, and additional expense in teaching 2 parallel curricula. Four vignettes of alternative innovative and relevant curricular initiatives are also presented in order to place 3-year MD programs in a broader context of medical education reform in the U.S. CONCLUSION: Three-year MD pathways are the most common accelerated alternative available at a small number of medical schools for highly selected students. Long-term evaluation of these programs will be essential to determine if these programs are meeting their goals (e.g., increasing the number of physicians in rural/underserved areas). Benefits and shortcomings of such programs should be carefully examined when considering this approach, or others described, as part of MD curricular options designed to individualize medical education.

EDUCATE TO TRANSFORM: THE ART OF DEVELOPING CURIOUS MINDS.

With rapid changes in health care and academic medicine, deans and medical educators need to carefully optimize medical education in order to best prepare our students for the future. Fundamentally, it is critical that future medical practitioners develop curious minds that look beyond the obvious to ask questions not yet asked and glean reality. This paper summarizes optimal adult learning, including (for example) concepts such as deliberate practice, active and interactive learning, and the flipped classroom.

Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway.

α1a Adrenergic receptors (α1aARs) are the predominant AR subtype in human vascular smooth muscle cells (SMCs). α1aARs in resistance vessels are crucial in the control of blood pressure, yet the impact of naturally occurring human α1aAR genetic variants in cardiovascular disorders remains poorly understood. To this end, we present novel findings demonstrating that 3D cultures of vascular SMCs expressing human α1aAR-247R (247R) genetic variant demonstrate significantly increased SMC contractility compared with cells expressing the α1aAR-WT (WT) receptor. Stable expression of 247R genetic variant also triggers MMP/EGFR-transactivation dependent serum- and agonist-independent (constitutive) hyperproliferation and agonist-dependent hypertrophy of SMCs. Agonist stimulation reduces contractility Using pathway-specific inhibitors we determined that the observed hyperproliferation of 247R-expressing cells is triggered via ß-arrestin1/Src/MMP-2/EGFR/ERK-dependent mechanism. MMP-2-specific siRNA inhibited 247R-triggered hyperproliferation indicating MMP-2 involvement in 247R-triggered hyperproliferation in SMCs. ß-arrestin1-specific shRNA also inhibited 247R-triggered hyperproliferation but did not affect hypertrophy in 247R-expressing SMCs, indicating that agonist-dependent hypertrophy is independent of ß-arrestin1. Our data reveal that in different cardiovascular cells the same human receptor genetic variant can activate alternative modulators of the same signaling pathway. Thus, our findings in SMCs demonstrate that depending on the type of cells expressing the same receptor (or receptor variant), different target-specific inhibitors could be used to modulate aberrant hyperproliferative or hypertrophic pathways in order to restore normal phenotype.

Temporal Dissection of Rate Limiting Transcriptional Events Using Pol II ChIP and RNA Analysis of Adrenergic Stress Gene Activation.

In mammals, increasing evidence supports mechanisms of co-transcriptional gene regulation and the generality of genetic control subsequent to RNA polymerase II (Pol II) recruitment. In this report, we use Pol II Chromatin Immunoprecipitation to investigate relationships between the mechanistic events controlling immediate early gene (IEG) activation following stimulation of the α1a-Adrenergic Receptor expressed in rat-1 fibroblasts. We validate our Pol II ChIP assay by comparison to major transcriptional events assessable by microarray and PCR analysis of precursor and mature mRNA. Temporal analysis of Pol II density suggests that reduced proximal pausing often enhances gene expression and was essential for Nr4a3 expression. Nevertheless, for Nr4a3 and several other genes, proximal pausing delayed the time required for initiation of productive elongation, consistent with a role in ensuring transcriptional fidelity. Arrival of Pol II at the 3' cleavage site usually correlated with increased polyadenylated mRNA; however, for Nfil3 and probably Gprc5a expression was delayed and accompanied by apparent pre-mRNA degradation. Intragenic pausing not associated with polyadenylation was also found to regulate and delay Gprc5a expression. Temporal analysis of Nr4a3, Dusp5 and Nfil3 shows that transcription of native IEG genes can proceed at velocities of 3.5 to 4 kilobases/min immediately after activation. Of note, all of the genes studied here also used increased Pol II recruitment as an important regulator of expression. Nevertheless, the generality of co-transcriptional regulation during IEG activation suggests temporal and integrated analysis will often be necessary to distinguish causative from potential rate limiting mechanisms.

Research in academic medical centers: two threats to sustainable support.

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.

Fostering interprofessional teamwork in an academic medical center: Near-peer education for students during gross medical anatomy.

The purpose of this report is to describe student satisfaction with a near-peer interprofessional education (IPE) session for physical therapy and medical students. Ten senior physical therapy students worked in peer-groups to develop a musculoskeletal anatomy demonstration for first-semester medical students. Together with their classmates, they demonstrated observation, palpation, and musculoskeletal assessment of the shoulder and scapular-thoracic articulation to medical student dissection groups in the Gross Anatomy laboratory. The medical students were encouraged to consider the synergistic function of shoulder structures and the potential impact of a selected pathology: rotator cuff injury. The session provided the medical students with an opportunity to integrate their new anatomical knowledge into a framework for clinical musculoskeletal evaluation. The experience offered senior physical therapy students an opportunity to work in teams with their peers, internalize and adapt to constructive feedback, and seek common ground with members of another profession. Both student groups reported a high degree of satisfaction with the sessions and expressed a desire for further interaction. These positive perceptions by student stakeholders have prompted us to consider additional IPE exchanges for the anatomy course in the upcoming school year. Given the positive outcome of this descriptive study, we now plan to systematically test whether near-peer IPE interactions can enhance the degree that students learn key anatomical concepts.

Alpha1a-adrenoceptor genetic variant induces cardiomyoblast-to-fibroblast-like cell transition via distinct signaling pathways.

The role of naturally occurring human α1a-Adrenergic Receptor (α1aAR) genetic variants associated with cardiovascular disorders is poorly understood. Here, we present the novel findings that expression of human α1aAR-247R (247R) genetic variant in cardiomyoblasts leads to transition of cardiomyoblasts into a fibroblast-like phenotype, evidenced by morphology and distinct de novo expression of characteristic genes. These fibroblast-like cells exhibit constitutive, high proliferative capacity and agonist-induced hypertrophy compared with cells prior to transition. We demonstrate that constitutive, synergistic activation of EGFR, Src and ERK kinases is the potential molecular mechanism of this transition. We also demonstrate that 247R triggers two distinct EGFR transactivation-dependent signaling pathways: 1) constitutive Gq-independent ß-arrestin-1/Src/MMP/EGFR/ERK-dependent hyperproliferation and 2) agonist-induced Gq- and EGFR/STAT-dependent hypertrophy. Interestingly, in cardiomyoblasts agonist-independent hyperproliferation is MMP-dependent, but in fibroblast-like cells it is MMP-independent, suggesting that expression of α1aAR genetic variant in cardiomyocytes may trigger extracellular matrix remodeling. Thus, these novel findings demonstrate that EGFR transactivation by α1aAR-247R leads to hyperproliferation, hypertrophy and alterations in cardiomyoblasts, suggesting that these unique genetically-mediated alterations in signaling pathways and cellular function may lead to myocardial fibrosis. Such extracellular matrix remodeling may contribute to the genesis of arrhythmias in certain types of heart failure.

Stimulation of α1a adrenergic receptors induces cellular proliferation or antiproliferative hypertrophy dependent solely on agonist concentration.

Stimulation of α1aAdrenergic Receptors (ARs) is known to have anti-proliferative and hypertrophic effects; however, some studies also suggests this receptor can increase cell proliferation. Surprisingly, we find the α1aAR expressed in rat-1 fibroblasts can produce either phenotype, depending exclusively on agonist concentration. Stimulation of the α1aAR by high dose phenylephrine (>10(-7) M) induces an antiproliferative, hypertrophic response accompanied by robust and extended p38 activation. Inhibition of p38 with SB203580 prevented the antiproliferative response, while inhibition of Erk or Jnk had no effect. In stark contrast, stimulation of the α1aAR with low dose phenylephrine (∼10(-8) M) induced an Erk-dependent increase in cellular proliferation. Agonist-induced Erk phosphorylation was preceded by rapid FGFR and EGFR transactivation; however, only EGFR inhibition blocked Erk activation and proliferation. The general matrix metalloprotease inhibitor, GM6001, blocked agonist induced Erk activation within seconds, strongly suggesting EGFR activation involved extracellular triple membrane pass signaling. Erk activation required little Ca(2+) release and was blocked by PLCß or PKC inhibition but not by intracellular Ca(2+) chelation, suggesting Ca(2+) independent activation of novel PKC isoforms. In contrast, Ca(2+) release was essential for PI3K/Akt activation, which was acutely maximal at non-proliferative doses of agonist. Remarkably, our data suggests EGFR transactivation leading to Erk induced proliferation has the lowest activation threshold of any α1aAR response. The ability of α1aARs to induce proliferation are discussed in light of evidence suggesting antagonistic growth responses reflect native α1aAR function.

Understanding the TXA seizure connection.

Transexamic acid (TXA) is an antifibrinolytic that has been used successfully to prevent blood loss during major surgery. However, as its usage has increased, there have been growing reports of postsurgical seizure events in cardiac surgery patients. In this issue of the JCI, Lecker et al. explore this connection and suggest that TXA-mediated inhibition of glycine receptors may underlie the effect. This finding prompted the authors to explore the preclinical efficacy of common anesthetics that function by reducing the TXA-mediated inhibition to prevent or modify postsurgical seizures.

Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway.

We previously identified a naturally occurring human SNP, G247R, in the third intracellular loop of the α(1a)-adrenergic receptor (α(1a)-247R) and demonstrated that constitutive expression of α(1a)-247R results in twofold increased cell proliferation compared with WT. In the present study we elucidate molecular mechanisms and signal transduction pathways responsible for increased cell proliferation unique to α(1a)-247R, but not α(1a)-WT, α(1b), or α(1d)AR subtypes. We show that elevated levels of matrix metalloproteinase-7 (MMP7) and a disintegrin and metalloproteinase-12 (ADAM12) in α(1a)-247R-expressing cells are responsible for EGF receptor (EGFR) transactivation, downstream ERK activation, and increased cell proliferation; this pathway is confirmed using MMP, EGFR, and ERK inhibitors. We demonstrate that EGFR transactivation and downstream ERK activation depends on increased shedding of heparin-binding EGF. Finally, we demonstrate that knockdown of MMP7 or ß-arrestin1 by shRNAs results in attenuation of proliferation of cells expressing α(1a)-247R. Importantly, accelerated cell proliferation triggered by the α(1a)-247R is serum- and agonist-independent, providing unique evidence for constitutive active coupling to the ß-arrestin1/MMP/EGFR transactivation pathway by any G protein-coupled receptor. These findings raise the possibility of a previously unexplored mechanism for sympathetically mediated human hypertension triggered by a naturally occurring human genetic variant.

Pharmacogenomics of ß-adrenergic receptor physiology and response to ß-blockade.

Myocardial ß-adrenergic receptors (ßARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The ß1AR and ß2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas ß3AR stimulation results in decreased inotropy. Downregulation of ß1ARs in heart failure, as well as an increased ß3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The ßAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of ßAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the ß1AR (Ser49Gly, Arg389Gly), 3 for the ß2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the ß3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between ßAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although ßAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly ß1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.