Unveiling the Role of Exosomes in the Pathophysiology of Sepsis: Insights into Organ Dysfunction and Potential Biomarkers.

Extracellular vesicles (EVs) are tools for intercellular communication, mediating molecular transport processes. Emerging studies have revealed that EVs are significantly involved in immune processes, including sepsis. Sepsis, a dysregulated immune response to infection, triggers systemic inflammation and multi-organ dysfunction, posing a life-threatening condition. Although extensive research has been conducted on animals, the complex inflammatory mechanisms that cause sepsis-induced organ failure in humans are still not fully understood. Recent studies have focused on secreted exosomes, which are small extracellular vesicles from various body cells, and have shed light on their involvement in the pathophysiology of sepsis. During sepsis, exosomes undergo changes in content, concentration, and function, which significantly affect the metabolism of endothelia, cardiovascular functions, and coagulation. Investigating the role of exosome content in the pathogenesis of sepsis shows promise for understanding the molecular basis of human sepsis. This review explores the contributions of activated immune cells and diverse body cells' secreted exosomes to vital organ dysfunction in sepsis, providing insights into potential molecular biomarkers for predicting organ failure in septic shock.

Integrative Epigenetic and Molecular Analysis Reveals a Novel Promoter for a New Isoform of the Transcription Factor TEAD4.

TEAD4 is a transcription factor that plays a crucial role in the Hippo pathway by regulating the expression of genes related to proliferation and apoptosis. It is also involved in the maintenance and differentiation of the trophectoderm during pre- and post-implantation embryonic development. An alternative promoter for the TEAD4 gene was identified through epigenetic profile analysis, and a new transcript from the intronic region of TEAD4 was discovered using the 5'RACE method. The transcript of the novel promoter encodes a TEAD4 isoform (TEAD4-ΔN) that lacks the DNA-binding domain but retains the C-terminal protein-protein interaction domain. Gene expression studies, including end-point PCR and Western blotting, showed that full-length TEAD4 was present in all investigated tissues. However, TEAD4-ΔN was only detectable in certain cell types. The TEAD4-ΔN promoter is conserved throughout evolution and demonstrates transcriptional activity in transient-expression experiments. Our study reveals that TEAD4 interacts with the alternative promoter and increases the expression of the truncated isoform. DNA methylation plays a crucial function in the restricted expression of the TEAD4-ΔN isoform in specific tissues, including the umbilical cord and the placenta. The data presented indicate that the DNA-methylation status of the TEAD4-ΔN promoter plays a critical role in regulating organ size, cancer development, and placenta differentiation.

From the Nexus vision to the NexusIPE™ learning model.

The Nexus vision of simultaneously transforming health professions education and healthcare delivery to achieve Triple (now Quadruple) Aim outcomes was first articulated in the 2012 proposal and funding of the National Center for Interprofessional Practice and Education (National Center). Over the past decade, the National Center has worked with over 70 sites implementing large scale and practice-based interprofessional practice and education (IPE) programs. Because what is needed to implement the Nexus to achieve Quadruple Aim outcomes was not well understood in 2012, the National Center took a social innovations and developmental evaluation approach. This iterative method led to the development of the National Center NexusIPE™ Learning Model that adapts the 3-P high-level stages (Presage, Process, and Product), proposed as a framework for IPE by Barr and colleagues. National Center collaborators' lessons learned about the Nexus vision are highlighted in this issue and provide real-world examples of elements of the NexusIPETM Learning Model. Reflecting on ten years of experience, the National Center leaders recognize the need for Nexus transformation and the relevance of the NexusIPETM Learning Model today as education and health systems grapple with mounting workforce challenges. The model provides opportunities to address growing workforce shortages, provide equitable care that leads to health, and support the well-being of practice teams in the face of challenges such as the COVID-19 pandemic.

A Promising Way to Overcome Temozolomide Resistance through Inhibition of Protein Neddylation in Glioblastoma Cell Lines.

There is no effective therapy for the lately increased incidence of glioblastoma multiforme (GBM)-the most common primary brain tumor characterized by a high degree of invasiveness and genetic heterogeneity. Currently, DNA alkylating agent temozolomide (TMZ) is the standard chemotherapy. Nevertheless, TMZ resistance is a major problem in the treatment of GBM due to numerous molecular mechanisms related to DNA damage repair, epigenetic alterations, cellular drug efflux, apoptosis-autophagy, and overactive protein neddylation. Low molecular weight inhibitors of NEDD8-activating enzyme (NAE), such as MLN4924, attenuate protein neddylation and present a promising low-toxicity anticancer agent. The aim of our study was to find an effective combination treatment with TMZ and MLN4924 in our TMZ-resistant GBM cell lines and study the effect of these combination treatments on different protein expressions such as O6-methylguanine methyltransferase (MGMT) and p53. The combination treatment successfully decreased cell viability and sensitized TMZ-resistant cells to TMZ, foreshadowing a new treatment strategy for GBM.

National Center for Interprofessional Practice and Education 2023: reflecting back, looking forward.

The United States (US) National Center for Interprofessional Practice and Education was funded at the University of Minnesota to serve as the National Coordinating Center for Interprofessional Education and Collaborative Practice (IPECP) in the US In 2012, the funders had specific expectations for operationalizing their vision that included scholarship, programs and leadership as an unbiased, neutral convener to align education with health system redesign. While US specific, the National Center benefited from and contributed to the international maturity of the field over the past decade. Through its various services and technology platforms, the National Center has a wide reach nationally and internationally. This perspective provides a unique view of the field in the US with observations and implications for the future.

Development and validation of a tool to assess the readiness of a clinical teaching site for interprofessional education (InSITE).

Interprofessional education within clinical teaching sites is a key part of training for pre-professional students. However, the necessary characteristics of these interprofessional clinical teaching sites is unclear. We developed a tool, the Interprofessional Education Site Readiness, or InSITE, tool, for individuals at a site to use as a self-assessment of the site's current readiness for providing interprofessional education. The tool progressed through six stages of development, collecting evidence for validity and reliability, resulting in a final tool with 23 questions distributed across five domains. Data from 94 respondents from a variety of national sites were used for the item analysis showing acceptable item-to-total correlations. Internal reliability testing gave a Cronbach's coefficient alpha of more than 0.70 for each group level comparison. Known groups validity testing provides strong evidence for its responsiveness in detecting differences in sites where IPE is implemented. The results of the testing lead us to conclude that the InSITE tool has acceptable psychometric properties. Additionally, we discovered that the process in which the InSITE tool was used demonstrated that it can facilitate learning in practice for the health professionals and can help make implicit, informal workplace learning and the hidden curriculum explicit.

National Center for Interprofessional Practice and Education IPE core data set and information exchange for knowledge generation.

Since 2012, the National Center for Interprofessional Practice and Education has worked with over 70 sites implementing over 100 interprofessional education and collaborative practice (IPECP) programs in the United States (U.S.). Program leaders have contributed data and information to the National Center to inform an approach to advancing the science of interprofessional practice and education (IPE), called IPE Knowledge Generation. This paper describes how the evolution of IPE Knowledge Generation blends traditional research and evaluation approaches with the burgeoning field of health informatics and big data science. The goal of IPE Knowledge Generation is to promote collaboration and knowledge discovery among IPE program leaders who collect comparable, sharable data in an information exchange. This data collection then supports analysis and knowledge generation. To enable the approach, the National Center uses a structured process for guiding IPE program design and implementation in practice settings focused on learning and the Quadruple Aim outcomes while collecting the IPE core data set and the contribution of contemporary big data science.

Improving the Health of Rural Communities Through Academic-Community Partnerships and Interprofessional Health Care and Training Models.

Health disparities between rural and urban areas are widening at a time when urban health care systems are increasingly buying rural hospitals to gain market share. New payment models, shifting from fee-for-service to value-based care, are gaining traction, creating incentives for health care systems to manage the social risk factors that increase health care utilization and costs. Health system consolidation and value-based care are increasingly linking the success of urban health care systems to rural communities. Yet, despite the natural ecosystem rural communities provide for interprofessional learning and collaborative practice, many academic health centers (AHCs) have not invested in building team-based models of practice in rural areas. With responsibility for training the future health workforce and major investments in research infrastructure and educational capacity, AHCs are uniquely positioned to develop interprofessional practice and training opportunities in rural areas and evaluate the cost savings and quality outcomes associated with team-based care models. To accomplish this work, AHCs will need to develop academic-community partnerships that include networks of providers and practices, non-AHC educational organizations, and community-based agencies. In this commentary, the authors highlight 3 examples of academic-community partnerships that developed and implemented interprofessional practice and education models and were designed around specific patient populations with measurable outcomes: North Carolina's Asheville Project, the Boise Interprofessional Academic Patient Aligned Care model, and the Interprofessional Care Access Network framework. These innovative models demonstrate the importance of academic-community partnerships to build teams that address social needs, improve health outcomes, and lower costs. They also highlight the need for more rigorous reporting on the components of the academic-community partnerships involved, the different types of health workers deployed, and the design of the interprofessional training and practice models implemented.

The Importance of Interprofessional Practice in Family Medicine Residency Education.

The practice of family medicine is undergoing rapid transformation, with increasing recognition that family physicians can most effectively meet the needs of individual patients and populations within the context of highly effective interprofessional teams. A substantive evidence base exists to support effective workplace learning by practicing health care teams and learners, much of which has been developed in primary care teaching practices. A strong national consensus now emphasizes the importance of the interprofessional clinical learning environment, including in graduate medical education. Evidence for the impact of improved team function on quadruple aim outcomes is increasingly robust. The World Health Organization, Interprofessional Education Consortium, National Collaborative for Improving the Clinical Learning Environment, and National Center for Interprofessional Practice and Education have developed evidence-based approaches and tools for improving interprofessional collaboration to improve important health outcomes in the clinical learning environment. Embracing the practice as the curriculum and preparing our residency graduates to work within high-functioning interprofessional collaborative practice teams, family medicine has the opportunity to lead the way in demonstrating the value of effective interprofessional practice across health care settings, including virtual teaming, to improve the health of the communities we serve, and across the nation.

DNA Methylation-Governed Gene Expression in Autoimmune Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease hallmarked by progressive and irreversible joint destruction. RA pathogenesis is a T cell-regulated and B cell-mediated process in which activated lymphocyte-produced chemokines and cytokines promote leukocyte infiltration that ultimately leads to destruction of the joints. There is an obvious need to discover new drugs for RA treatment that have different biological targets or modes of action than the currently employed therapeutics. Environmental factors such as cigarette smoke, certain diet components, and oral pathogens can significantly affect gene regulation via epigenetic factors. Epigenetics opened a new field for pharmacology, and DNA methylation and histone modification-implicated factors are feasible targets for RA therapy. Exploring RA pathogenesis involved epigenetic factors and mechanisms is crucial for developing more efficient RA therapies. Here we review epigenetic alterations associated with RA pathogenesis including DNA methylation and interacting factors. Additionally, we will summarize the literature revealing the involved molecular structures and interactions. Finally, potential epigenetic factor-based therapies will be discussed that may help in better management of RA in the future.

Toward a system where workforce planning and interprofessional practice and education are designed around patients and populations not professions.

Traditional workforce planning methodologies and interprofessional education (IPE) approaches will not address the significant challenges facing health care systems seeking to integrate services, eliminate waste and meet rising demand within fixed or shrinking budgets. This article describes how New Zealand's workforce planning approach could be used as a model by other countries to move toward needs-based, interprofessional workforce planning. Such an approach requires a paradigm shift to reframe health workforce planning away from a focus on shortages toward assessing how to more effectively deploy and retrain the existing workforce; away from silo-based workforce projection models toward methodologies that recognize professions' overlapping scopes of practice; and away from a focus on traditional health professions toward including both health and social care workers. We propose that IPE must develop new models of learning that are delivered in the context of practice. This will require a shift from today's predominant focus on preparing students in the pipeline to be collaboration-ready to designing clinical practice environments that support continuous learning that benefits not just learners, but patients, populations, and providers as well. We highlight the need for improved data and methods to evaluate IPE and call for better collaboration between health workforce planners and IPE stakeholders.

Untying the Interprofessional Gordian Knot: The National Collaborative for Improving the Clinical Learning Environment.

The National Collaborative for Improving the Clinical Learning Environment (NCICLE) is a growing group of over 40 organizations representing a variety of health professions. NCICLE is beginning a discussion of issues related to culture in health care, specifically how the current culture inhibits optimal outcomes, and the discordance between current early interprofessional education (IPE) curricula in health professions schools and traditional practice models in health care. In October 2017, the Accreditation Council for Graduate Medical Education and the Josiah Macy Jr. Foundation sponsored an NCICLE symposium on optimizing interprofessional clinical learning environments. In this Invited Commentary, the authors observe that interprofessional practice and education is a decades-long field that has presented a "Gordian knot" of intractable, complex problems to solve because medicine has often not been at the table for conversations about IPE. The NCICLE symposium represented an important opportunity for medicine to signal that finding new solutions for unraveling the interprofessional Gordian knot and creating optimal clinical learning environments requires meaningful participation from all health professions. Those solutions need to build on the long history of experience and research in IPE and collaborative practice. After the NCICLE symposium provided a promising beginning, the authors propose three essential issues and one key practical step forward to move the interprofessional agenda forward.

Advancing Health Professions Education Research by Creating a Network of Networks.

Producing the best evidence to show educational outcomes, such as competency achievement and credentialing effectiveness, across the health professions education continuum will require large multisite research projects and longitudinal studies. Current limitations that must be overcome to reach this goal include the prevalence of single-institution study designs, assessments of a single curricular component, and cross-sectional study designs that provide only a snapshot in time of a program or initiative rather than a longitudinal perspective.One solution to overcoming these limitations is to develop a network of networks that collaborates, using longitudinal approaches, across health professions and regions of the United States. Currently, individual networks are advancing educational innovation toward understanding the effectiveness of educational and credentialing programs. Examples of such networks include (1) the American Medical Association's Accelerating Change in Medical Education initiative, (2) the National Center for Interprofessional Practice and Education, and (3) the Accreditation Council for Graduate Medical Education's Accreditation System. In this Invited Commentary, the authors briefly profile these existing networks, identify their progress and the challenges they have encountered, and propose a vigorous way forward toward creating a national network of networks designed to determine the effectiveness of health professions education and credentialing.

Reflections From the Intersection of Health Professions Education and Clinical Practice: The State of the Science of Interprofessional Education and Collaborative Practice.

This informed reflection, from the intersection of health professions education and clinical practice, takes stock of the state of the field of interprofessional education (IPE) and collaborative practice (CP) (together IPECP) by answering the following three questions: (1) As a field of study, where is IPECP? (2) As a research enterprise, what are the current analytical gaps? (3) Scientifically, what needs to be done going forward? While IPE and CP, as well as IPECP, have been areas of scholarly inquiry for nearly 50 years, they have collectively and individually had a limited sphere of influence. Analytical gaps identified include little research dealing with big picture health-related outcomes; mixed results on the effectiveness of health care teams; increasing recognition that additional IPECP competencies might be needed; a gap between the identification and application of educational best practices; and the need for sound, reliable, and validated tools for measuring IPECP. The authors outline the work of the National Center for Interprofessional Practice and Education at the University of Minnesota, which is focused on filling the identified analytical gaps by way of strategic actions organized around three domains-(1) developing an IPECP research agenda, (2) nurturing IPECP intervention research grounded in comparative effectiveness research study designs and the assumptions of critical realism, and (3) the creation of a sound informatics platform. The authors argue that filling these gaps is important because if the effectiveness of IPE on CP and of CP on health outcomes is ever to be ascertained, generalizable findings are paramount.

Setting a research agenda for interprofessional education and collaborative practice in the context of United States health system reform.

Interprofessional education (IPE) and collaborative practice (CP) have been prolific areas of inquiry exploring research questions mostly concerned with local program and project assessment. The actual sphere of influence of this research has been limited. Often discussed separately, this article places IPE and CP in the same conceptual space. The interface of these form a nexus where new knowledge creation may be facilitated. Rigorous research on IPE in relation to CP that is relevant to and framed by health system reform in the U.S. is the ultimate research goal of the National Center for Interprofessional Practice and Education at the University of Minnesota. This paper describes the direction and scope for a focused and purposive IPECP research agenda linked to improvement in health outcomes, contextualized by health care reform in the U.S. that has provided a revitalizing energy for this area of inquiry. A research agenda articulates a focus, meaningful and robust questions, and a theory of change within which intervention outcomes are examined. Further, a research agenda identifies the practices the area of inquiry is interested in informing, and the types of study designs and analytic approaches amenable to carrying out the proposed work.