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.

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.

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.

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.

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.

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.

The United States National Center for Interprofessional Practice and Education: Integrating an informatics approach to interprofessional work.

The National Center for Interprofessional Practice and Education, a United States public-private partnership, was formed to provide national leadership, scholarship, evidence, and coordination to advance interprofessional education (IPE) and practice. Many external drivers led to the creation of the partnership that culminated in the National Center: patient safety initiatives, the need for care coordination and transitions efforts, quality improvement imperatives, calls for teamwork and workforce optimization, newly defined national core competencies for interprofessional collaborative practice, practice redesign, escalating health care costs, and state and federal policies. The National Center principals who have served in a variety of senior leadership roles--a clinician, educationalist, and informaticist--recognized the opportunity to leverage the potential that informatics could bring not only to the center but also to the field of IPECP. An informatics approach focuses on collaborative processes and works to address information processing, communications, and data collection. To do so, the National Center created multiple platforms: informatics education, a resource exchange, communication strategy, incubator network, national data repository, and learning system.

The National United States Center Data Repository: Core essential interprofessional practice & education data enabling triple aim analytics.

Understanding the impact that interprofessional education and collaborative practice (IPECP) might have on triple aim patient outcomes is of high interest to health care providers, educators, administrators, and policy makers. Before the work undertaken by the National Center for Interprofessional Practice and Education at the University of Minnesota, no standard mechanism to acquire and report outcome data related to interprofessional education and collaborative practice and its effect on triple aim outcomes existed. This article describes the development and adoption of the National Center Data Repository (NCDR) designed to capture data related to IPECP processes and outcomes to support analyses of the relationship of IPECP on the Triple Aim. The data collection methods, web-based survey design and implementation process are discussed. The implications of this informatics work to the field of IPECP and health care quality and safety include creating standardized capacity to describe interprofessional practice and measure outcomes connecting interprofessional education and collaborative practice to the triple aim within and across sites/settings, leveraging an accessible data collection process using user friendly web-based survey design to support large data scholarship and instrument testing, and establishing standardized data elements and variables that can potentially lead to enhancements to national/international information system and academic accreditation standards to further team-based, interprofessional, collaborative research in the field.

Application of Bother in patient reported outcomes instruments across cultures.

BACKGROUND: The objective of this study was to determine the applicability of the term bother, as used in Patient Reported Outcomes (PRO) instruments that will be translated into foreign languages from English for the United States. Bother is versatile in English for the U.S., in that it can describe negative mental states and physical sensations, as well as social disturbances. Bother has many different meanings across cultures, due to this versatility. Alternatives for bother were explored for future PRO instrument development. METHODS: A PRO instrument used to evaluate the degree of bother resulting from psoriasis was analyzed. This disease can negatively impact patients physically, emotionally and socially. Translations of bother were analyzed to determine its meaning when translated into other languages. Cognitive debriefing was conducted on psoriasis patients with the instrument containing bother. Following cognitive debriefing, a questionnaire was distributed to linguists and cognitive debriefing subjects to collect definitions of bother in each target language, and detail any difficulty with translation.To establish alternatives to bother and demonstrate the breakdown of concepts within bother, translations of the Dermatology Quality of Life Index (DLQI) were analyzed. This instrument was selected for its focus on psoriasis and use of terminology that lacks the ambiguity of bother. RESULTS: An analysis of back-translations revealed that bother yielded a back-translation that was conceptually different from the source 20% of the time (5/26). Analysis of alternative terminology found in the DLQI revealed much greater conceptual equivalence when translated into other languages. CONCLUSION: When developing the wording of PRO instruments, the terminology chosen should be applicable across languages to allow for international pooling and comparison of data. While all linguists and subjects of cognitive debriefing understood bother to have a negative connotation, a large variety of definitions and synonyms provided across languages showed a lack of conceptual equivalence. Ambiguity of the term across cultures may result in variation in translation, impacting subsequent international data pooling. Analysis of alternatives revealed that measurement of unambiguous terminology produces the greatest conceptual equivalency across languages and cultures.

A scoping review of interprofessional collaborative practice and education using the lens of the Triple Aim.

The Triple Aim unequivocally connects interprofessional healthcare teams to the provision of better healthcare services that would eventually lead to improved health outcomes. This review of the interprofessional education (IPE) and collaborative practice empirical literature from 2008 to 2013 focused on the impact of this area of inquiry on the outcomes identified in the Triple Aim. The preferred reporting items for systematic reviews and meta-analyses methodology were employed including: a clearly formulated question, clear inclusion criteria to identify relevant studies based on the question, an appraisal of the studies or a subset of the studies, a summary of the evidence using an explicit methodology and an interpretation of the findings of the review. The initial search yielded 1176 published manuscripts that were reduced to 496 when the inclusion criteria were applied to refine the selection of published manuscripts. Despite a four-decade history of inquiry into IPE and/or collaborative practice, scholars have not yet demonstrated the impact of IPE and/or collaborative practice on simultaneously improving population health, reducing healthcare costs or improving the quality of delivered care and patients' experiences of care received. We propose moving this area of inquiry beyond theoretical assumptions to systematic research that will strengthen the evidence base for the effectiveness of IPE and collaborative practice within the context of the evolving imperative of the Triple Aim.

LUTS patient reported outcomes tool: linguistic validation in 10 European languages.

AIM: To linguistically validate the translation of the Lower Urinary Tract Symptoms (LUTS) Tool from English to 10 European languages and assess whether the translations adequately reflected the concepts in the original version and if urological terms and the individual items were readily understood. METHODS: Residents of the target countries who spoke the native language and had LUTS were asked to evaluate a harmonized translation of the LUTS Tool, which was developed in 10 languages: Danish (Denmark), Dutch (Belgium, Netherlands), Finnish (Finland), French (Belgium, France, Luxembourg, and Switzerland), German (Germany, Switzerland), Greek (Greece), Icelandic (Iceland), Italian (Italy), Norwegian (Norway), and Spanish (Spain). After reviewing the language-appropriate version, participants were asked to explain why any words were difficult to understand and to paraphrase each sentence during a standardized cognitive debriefing interview. Linguistic validation teams (original translators, back translator, project manager, interviewer, and survey research expert) conducted a qualitative analysis of the cognitive debriefing findings. RESULTS: The terminology and concepts in the English-language version of the LUTS Tool were adequately captured in all language translations. The overall item comprehension rate, across languages, was 98.5%. Terms related to storage, voiding, and post-micturition LUTS were comprehensible. Minor difficulties with comprehension were identified in 9 of 10 translations, and those changes were made to improve clarity. CONCLUSIONS: Individuals with LUTS from 10 countries understood the individual items captured in translated versions of the LUTS Tool. The overall comprehension rate was high. Most changes were made to improve conceptual clarity based on country-specific linguistic and cultural nuances.

Linguistic validation of translation of the Self-Assessment Goal Achievement (SAGA) questionnaire from English.

BACKGROUND: A linguistic validation of the Self-Assessment Goal Achievement (SAGA) questionnaire was conducted for 12 European languages, documenting that each translation adequately captures the concepts of the original English-language version of the questionnaire and is readily understood by subjects in the target population. METHODS: Native-speaking residents of the target countries who reported urinary problems/lower urinary tract problems were asked to review a translation of the SAGA questionnaire, which was harmonized among 12 languages: Danish, Dutch, English (UK), Finnish, French, German, Greek, Icelandic, Italian, Norwegian, Spanish, and Swedish. During a cognitive debriefing interview, participants were asked to identify any words that were difficult to understand and explain in their own words the meaning of each sentence in the questionnaire. The qualitative analysis was conducted by local linguistic validation teams (original translators, back translator, project manager, interviewer, and survey research expert). RESULTS: Translations of the SAGA questionnaire from English to 12 European languages were well understood by the participants with an overall comprehension rate across language of 98.9%. In addition, the translations retained the original meaning of the SAGA items and instructions. Comprehension difficulties were identified, and after review by the translation team, minor changes were made to 7 of the 12 translations to improve clarity and comprehension. CONCLUSIONS: Conceptual, semantic, and cultural equivalence of each translation of the SAGA questionnaire was achieved thus confirming linguistic validation.

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.