Mannitol and hyponatremia regulate cardiac ventricular conduction in the context of sodium channel loss of function.

Scn5a heterozygous null (Scn5a+/-) mice have historically been used to investigate arrhythmogenic mechanisms of diseases such as Brugada syndrome (BrS) and Lev's disease. Previously, we demonstrated that reducing ephaptic coupling (EpC) in ex vivo hearts exacerbates pharmacological voltage-gated sodium channel (Nav)1.5 loss of function (LOF). Whether this effect is consistent in a genetic Nav1.5 LOF model is yet to be determined. We hypothesized that loss of EpC would result in greater reduction in conduction velocity (CV) for the Scn5a+/- mouse relative to wild type (WT). In vivo ECGs and ex vivo optical maps were recorded from Langendorff-perfused Scn5a+/- and WT mouse hearts. EpC was reduced with perfusion of a hyponatremic solution, the clinically relevant osmotic agent mannitol, or a combination of the two. Neither in vivo QRS duration nor ex vivo CV during normonatremia was significantly different between the two genotypes. In agreement with our hypothesis, we found that hyponatremia severely slowed CV and disrupted conduction for 4/5 Scn5a+/- mice, but 0/6 WT mice. In addition, treatment with mannitol slowed CV to a greater extent in Scn5a+/- relative to WT hearts. Unexpectedly, treatment with mannitol during hyponatremia did not further slow CV in either genotype, but resolved the disrupted conduction observed in Scn5a+/- hearts. Similar results in guinea pig hearts suggest the effects of mannitol and hyponatremia are not species specific. In conclusion, loss of EpC through either hyponatremia or mannitol alone results in slowed or disrupted conduction in a genetic model of Nav1.5 LOF. However, the combination of these interventions attenuates conduction slowing.NEW & NOTEWORTHY Cardiac sodium channel loss of function (LOF) diseases such as Brugada syndrome (BrS) are often concealed. We optically mapped mouse hearts with reduced sodium channel expression (Scn5a+/-) to evaluate whether reduced ephaptic coupling (EpC) can unmask conduction deficits. Data suggest that conduction deficits in the Scn5a+/- mouse may be unmasked by treatment with hyponatremia and perinexal widening via mannitol. These data support further investigation of hyponatremia and mannitol as novel diagnostics for sodium channel loss of function diseases.

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Calcium Pyrophosphate Crystal Formation and Deposition: Where Do we Stand and What Does the Future hold?

PURPOSE OF THE REVIEW: Although calcium pyrophosphate deposition (CPPD) has been known since the 1960s, our understanding of its pathogenesis remains rudimentary. This review aims to illustrate the known mechanisms underlying calcium pyrophosphate (CPP) crystal formation and deposition and explore future directions in research. By examining various perspectives, from basic research to clinical and imaging assessments, as well as new emerging methodologies, we can establish a starting point for a deeper understanding of CPPD pathogenesis. RECENT FINDINGS: Recent years have seen significant advances in CPPD research, particularly in the clinical field with the development of the 2023 ACR/EULAR classification criteria for CPPD disease, and in imaging with the introduction of the OMERACT ultrasonographic definitions and scoring system. However, progress in basic research has been slower. New laboratory approaches, such as Raman spectroscopy and omics sciences, offer promising insights that may help piece together the puzzle of CPPD. CPPD is a common yet understudied condition. As the population ages and CPPD becomes more prevalent, there is an urgent need to better understand the disease and the mechanisms involved in crystal formation and deposition, in order to improve diagnosis and therapeutic approaches.

Enhancing the Connection Between Basic and Applied Research in Eating Disorders: Steps Toward More Effective Translation.

Translational research applies laboratory-generated scientific discoveries to real-world practice with the goal of potentiating more rapid solutions to health challenges. In 2023, the authors of this editorial (Hildebrandt and Goldschmidt) aimed to develop a special issue for the International Journal of Eating Disorders (IJED) focusing on translational eating disorder research. The goal for this issue was to begin closing the gap between basic and applied research by soliciting articles that improve our understanding of mechanisms that cause or maintain eating disorders, which could result in more robust research advances and dissemination of information to the public. Further goals for the issue included exposing IJED's readership to a wide range of translational research and inspiring new collaborative efforts. While strong submissions were received, challenges were encountered in soliciting enough articles, potentially reflecting long-standing communication barriers between basic and clinical scientists within the eating disorders field. In this editorial, we highlight work included in the special section, identify potential barriers in translational eating disorder research, and offer a multipronged approach to support more rapid progress across the translational spectrum. By improving how our field approaches translational research, we can promote better outcomes for those with or at risk for eating disorders.

The Future of Basic Science: Development of the Next Generation of Mechanistic Researchers in Female Pelvic Medicine.

INTRODUCTION AND HYPOTHESIS: The International Urogynecological Association (IUGA) brought together senior and junior members actively engaged in scholarly and educational activities for a consensus conference centered on developing a strategy for sustainable training of the next generation of mechanistic researchers in female pelvic medicine. METHODS: Four a priori identified major foci were explored in a half-day virtual consensus conference. Participants included representatives from various countries and disciplines with diverse backgrounds-clinicians, physician-scientists, and basic scientists in the fields of urogynecology, biomechanical engineering, and molecular biology. Following a keynote address, each focus area was first tackled by a dedicated breakout group, led by the Chair(s) of the most relevant IUGA committees. The break-out sessions were followed by an iterative discussion among all attendees to identify mitigating strategies to address the shortage of mechanistic researchers in the field of female pelvic medicine. RESULTS: The major focus areas included: research priorities for IUGA basic science scholar program; viable strategies for sustainable basic science mentorship; core competencies in basic science training; and the challenges of conducting complex mechanistic experiments in low-resource countries. Key gaps in knowledge and core competencies that should be incorporated into fellowship/graduate training were identified, and existing training modalities were discussed. Recommendations were made for pragmatic approaches to increasing the exposure of trainees to learning tools to enable sustainable training of the next generation of basic science researchers in female pelvic medicine worldwide. CONCLUSIONS: The attendees presented multiple perspectives to gain consensus regarding critical areas of need for training future generations of mechanistic researchers. Recommendations for a sustainable Basic Science Scholar Program were developed using IUGA as a platform. The overarching goal of such a program is to ensure a successful bench-to-bedside-and-back circuit in Urogynecology and Pelvic Reconstructive Surgery, ultimately improving lives of millions of women worldwide through scientifically rational effective preventative and therapeutic interventions.

Poor recall of genetics curriculum by medical students highlights barriers to use in clinical practice.

Many current and upcoming healthcare providers do not feel comfortable ordering or discussing genetic tests and using genetic information in medicine. Nationally, a little over a quarter of medical students indicate that they do not feel prepared to use genetic information in clinical rotations, despite attempts at many schools to remodel the genetics curriculum. This study was conducted at Emory University School of Medicine to identify gaps within the medical curriculum that may contribute to student reports that they feel underprepared to apply genetic knowledge in clinical practice. The analysis included a comprehensive curriculum inventory of genetic content that was then compared to the responses from focus groups of randomly selected second- and fourth-year medical students without a prior genetics degree or background. This joint analysis of precisely what was taught and how it was perceived by students was informative in the development of targeted interventions in our curriculum, and it highlighted the important role of genetic counselors in the education of medical students. Our curriculum has a structure similar to that at many other schools, in which core genetics concepts are concentrated in a brief segment in the first year. We believe our results will be useful for other medical schools to address the perception by medical students that they are underprepared to use genetic information and other basic sciences clinically.

Using a boundary crossing lens to understand basic science educator and clinical educator collaboration in instructional design.

PURPOSE: Collaborations between basic science educators (BE) and clinical educators (CE) in medical education are common and necessary to create integrated learning materials. However, few studies describe experiences of or processes used by educators engaged in interdisciplinary teamwork. We use the lens of boundary crossing to explore processes described by BE and CE that support the co-creation of integrated learning materials, and the impact that this work has on them. MATERIALS AND METHODS: We conducted qualitative content analysis on program evaluation data from 27 BE and CE who worked on 12 teams as part of a multi-institutional instructional design project. RESULTS: BE and CE productively engaged in collaboration using boundary crossing mechanisms. These included respecting diverse perspectives and expertise and finding efficient processes for completing shared work that allow BE and CE to build on each other's contributions. BE and CE developed confidence in connecting clinical concepts with causal explanations, and willingness to engage in and support such collaborations at their own institutions. CONCLUSIONS: BE and CE report the use of boundary crossing mechanisms that support collaboration in instructional design. Such practices could be harnessed in future collaborations between BE and CE.

The Role of Exosomes in Upper-Extremity Tissue Regeneration.

Exosomes are cell-free membrane vesicles secreted by a wide variety of cells as secretomes into the extracellular matrix. Alongside facilitating intercellular communication, exosomes carry various bioactive molecules consisting of nucleic acids, proteins, and lipids. Exosome applications have increased in popularity by overcoming the disadvantages of mesenchymal stem cell therapies. Despite this, a better understanding of the underlying mechanisms of action of exosomes is necessary prior to clinical application in upper-extremity tissue regeneration. The purpose of this review is to introduce the concept of exosomes and their possible applications in upper-extremity tissue regeneration, detail the shortcomings of current exosome research, and explore their potential clinical application in the upper extremity.

Factors affecting pharmacology learning in integrated PBL in diverse medical students: a mixed methods study.

INTRODUCTION: Problem-based learning (PBL) was introduced to address passive teaching limitations. However, it is not fully characterised as a teaching modality in pharmacology. The present study investigated the factors affecting pharmacology learning in an integrated PBL-based curriculum in diverse learners. METHODS: Year 1 undergraduate medical students from two cohorts at St. George's University of London and University of Nicosia, participated. Statistical analysis of pharmacology knowledge scores, at the beginning (pre-test) and end of the academic year (post-test), investigated readiness to benefit from PBL based on diverse student characteristics (educational background, age, gender, country of origin, ethnicity, native language, PBL experience). Focus groups/interviews and a survey investigated aspects of integrated PBL impacting learning in depth. RESULTS: Pre- and post-test scores were positively correlated. Students with biomedical sciences degrees performed better at the pharmacology pre- and post-tests, while post-graduate degree holders performed better only at the pre-test. Effect size was of moderate magnitude. However, progress in learning (post-test performance after controlling for pre-test scores) was unaffected. Qualitative analysis revealed three major themes: 1) PBL as a learning environment; 2) PBL as a learning environment in pharmacology; and 3) PBL as a learning environment and confidence in prescribing. Under theme one, skill development, knowledge acquisition through collaboration and self-directed learning, group dynamics and preferred teaching methods were discussed. Under theme two, contextual learning, depth of knowledge and material correctness were raised. Under theme 3, students expressed variability in prescribing confidence. They perceived that learning could be improved by better integration, further references earlier on, more lectures and PBL facilitators with greater content expertise. The survey findings were consistent with those from focus groups/interviews. CONCLUSION: Pharmacology learning in a PBL-based curriculum is facilitated by constructive, collaborative and contextual learning. While baseline pharmacology knowledge may be advantageous, the other aforementioned characteristics studied may not affect readiness to benefit from PBL. However, further instructional scaffolding is needed, for example through further resources, lectures and self-assessment. The results from our study can inform evidence-based curriculum reform to support student learning further. Addressing learning needs could ultimately contribute to reducing medication errors through effective training of future prescribers.

Three-dimensional changes in the cranial base associated with soft-diet feeding.

BACKGROUND: Masticatory activity affects the morphology of the maxillo-mandibular complex, however, its influence on the cranial base remains to be elucidated. The recent integration of quantitative morphometric analysis with 3D imaging enabled a comprehensive and high-resolution morphological characterization of the craniofacial complex. We aimed to investigate the influence of masticatory activity on the morphology of the growing cranial base by three-dimensional (3D) geometric morphometric approach using micro-CT. METHODS: The micro-CT data was reanalyzed to illustrate the 3D shape of the cranial base, and wireframe models were generated by connecting landmarks on the images. In the original study, mice were fed a soft diet (SD) of powdered pellets or a conventional hard diet (HD) for 6 weeks from 3 to 9 weeks of age, immediately after weaning. A principal component (PC) analysis analyzed shape variations and assessed their significance, while canonical variate (CV) analysis facilitated the comparison and differentiation of groups based on shape, unveiling meaningful shape distinctions. RESULTS: Three PCs were extracted that significantly separated the SD and HD groups among those explaining variations in shape. These PCs were related to the length of the sphenoid bone, the width of the anterior part of the sphenoid bone, and the length of the cranial base. Furthermore, one CV effectively distinguished SD from HD, and CV analysis showed that the sphenoid was shortened in the length and narrowed at the border of the temporal bone in SD mice. CONCLUSIONS: Masticatory loading affects the skeletal development of the cranial base. The morphology of the sphenoid bone was affected in both the sagittal and transverse axes.

The development and training effect of innovative undergraduate dental talents training project: A 6-year retrospective study.

INTRODUCTION: To summarize the development of Innovative Undergraduate Dental Talents Training Project (IUDTTP) and investigate the training effect of this extracurricular dental basic research education activity from 2015 to 2020 to obtain educational implications. MATERIALS AND METHODS: The Guanghua School of Stomatology established the IUDTTP in 2015. The authors recorded the development process and analysed the participation situation, training effect, academic performance and overall satisfaction during 2015-2020 through documental analysis, questionnaire and quiz. The t-test, chi-square test and ANOVA were used to test the difference. RESULTS: The educational goal, education module and assessment system of IUDTTP evolved and developed every year. A total of 336 students and 79 mentors attended the IUDTTP from 2015 to 2020, with the participation rate increasing from 45.1% to 73.5%. The participants exhibited favourable basic research abilities, manifesting as the increase of funded projects and published papers and satisfying quiz scores. Almost all students (94.94%) admitted their satisfaction with the IUDTTP. Moreover, the attended students surpassed the non-participants in terms of GPA, the number of acquired scholarships and outstanding graduates (p < .05). Likewise, the enrolment rate of postgraduate participants was significantly higher than non-participants. CONCLUSIONS: To date, the training effect indicated that the IUDTTP has fulfilled the education aim. It brought positive effects on promoting research interest, cultivating research capacities and enhancing academic performance. The potential deficiencies of extracurricular educational activities, including inflexibility in schedule and insufficiency in systematisms, may be remedied by more systematic educational settings in the future.

Endocrine Entropy.

This communication defines and describes the novel concept of endocrine entropy. The authors share insights regarding the various facets of entropy in endocrine epidemiology, physiology, clinical presentation and management. The discussion opens up a new way of approaching endocrinology. Recent advances in artificial intelligence, assessment and addressal of entropy may become integral part of endocrine diagnostics and therapeutics.

Endocrine Entropy.

This communication defines and describes the novel concept of endocrine entropy. The authors share insights regarding the various facets of entropy in endocrine epidemiology, physiology, clinical presentation and management. The discussion opens up a new way of approaching endocrinology. Recent advances in artificial intelligence, assessment and addressal of entropy may become integral part of endocrine diagnostics and therapeutics.

Building capacity for collaborative research between basic scientists and underrepresented communities in cancer research.

PURPOSE: Basic science research is critical for understanding biological mechanisms essential to advances in cancer prevention, diagnoses and treatment. However, most of this research is conducted outside of the purview of community observation or input, leaving these research processes mysterious and subsequent findings disconnected from the communities they intend to benefit. This paper discusses strategies to build capacity for collaborations between basic scientists and Hispanic community members at the University of Arizona Cancer Center (UACC). METHODS: Through partnership of the Cancer Biology Program and Office of Community Outreach and Engagement both at UACC, the Research Outreach for Southern Arizona (ROSA) program was developed as a way to forward the following strategies to build capacity for collaboration: forming a community working group, launching a community and student ambassador program, hosting scientific cafés and developing a community-based survey. RESULTS: The strategies underpinning the ROSA program have been integral in bridging dialogue between basic scientists and the community and fostering bidirectional learning opportunities. Each of the strategies presented have documented successes and based on the lessons learned, they have evolved into productive and integral parts of UACC's overall strategy of bridging scientific research and communities. CONCLUSION: While the strategies discussed are evolving, they help foster dialogue and exchange between basic scientists and community members that demystifies basic science research and facilitates culturally tailored approaches to address health disparities of vulnerable communities. These strategies also have the potential to shift cancer research into a paradigm that is more collaborative and transformative.

Building relationships to connect cancer researchers with community members: 'bench to community pipeline'.

PURPOSE: Partnerships between researchers and community members and organizations can offer multiple benefits for research relevance and dissemination. The goal of this project was to build infrastructure to create bidirectional relationships between University of Wisconsin Carbone Cancer Center (UWCCC) researchers and community educators in the Division of Extension, which connects the knowledge and resources of the university to communities across the state. METHODS: This project had three aims: (1) create linkages with Extension; (2) establish an in-reach program to educate and train researchers on the science of Community Outreach and Engagement (COE); and (3) identify and facilitate collaborative projects between scientists and communities. Survey and focus group-based needs assessments were completed with both researchers and Extension educators and program activity evaluations were conducted. RESULTS: Most Extension educators (71%) indicated a strong interest in partnering on COE projects. UWCCC faculty indicated interest in further disseminating their research, but also indicated barriers in connecting with communities. Outreach webinars were created and disseminated to community, a "COE in-reach toolkit" for faculty was created and a series of "speed networking" events were hosted to pair researchers and community. Evaluations indicated the acceptability and usefulness of these activities and supported continuation of collaborative efforts. CONCLUSION: Continued relationship and skill building, along with a sustainability plan, is critical to support the translation of basic, clinical, and population research to action in the community outreach and engagement context. Further incentives for faculty should be explored for the recruitment of basic scientists into community engagement work.

National Institutes of Health funding among vascular surgeons is rare.

BACKGROUND: The National Institutes of Health (NIH) is an essential source of funding for vascular surgeons conducting research. NIH funding is frequently used to benchmark institutional and individual research productivity, help determine eligibility for academic promotion, and as a measure of scientific quality. We sought to appraise the current scope of NIH funding to vascular surgeons by appraising the characteristics of NIH-funded investigators and projects. In addition, we also sought to determine whether funded grants addressed recent Society for Vascular Surgery (SVS) research priorities. METHODS: In April 2022, we queried the NIH Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER) database for active projects. We only included projects that had a vascular surgeon as a principal investigator. Grant characteristics were extracted from the NIH Research Portfolio Online Reporting Tools Expenditures and Results database. Principal investigator demographics and academic background information were identified by searching institution profiles. RESULTS: There were 55 active NIH awards given to 41 vascular surgeons. Only 1% (41/4037) of all vascular surgeons in the United States receive NIH funding. Funded vascular surgeons are an average of 16.3 years out of training; 37% (n = 15) are women. The majority of awards (58%; n = 32) were R01 grants. Among the active NIH-funded projects, 75% (n = 41) are basic or translational research projects, and 25% (n = 14) are clinical or health services research projects. Abdominal aortic aneurysm and peripheral arterial disease are the most commonly funded disease areas and together accounted for 54% (n = 30) of projects. Three SVS research priorities are not addressed by any of the current NIH-funded projects. CONCLUSIONS: NIH funding of vascular surgeons is rare and predominantly consists of basic or translational science projects focused on abdominal aortic aneurysm and peripheral arterial disease research. Women are well-represented among funded vascular surgeons. Although the majority of SVS research priorities receive NIH funding, three SVS research priorities are yet to be addressed by NIH-funded projects. Future efforts should focus on increasing the number of vascular surgeons receiving NIH grants and ensuring all SVS research priorities receive NIH funding.

Transient gene therapy using cell cycle factors reverses renin-angiotensin-aldosterone system activation in heart failure rat model.

The loss of cardiomyocytes after myocardial infarction (MI) leads to heart failure. Recently, we demonstrated that transient overexpression of 4 cell cycle factors (4F), using a polycistronic non-integrating lentivirus (TNNT2-4F-NIL) resulted in significant improvement in cardiac function in a rat model of MI. Yet, it is crucial to demonstrate the reversal of the heart failure-related pathophysiological manifestations, such as renin-angiotensin-aldosterone system activation (RAAS). To assess that, Fisher 344 rats were randomized to receive TNNT2-4F-NIL or control virus seven days after coronary occlusion for 2 h followed by reperfusion. 4 months after treatment, N-terminal pro-brain natriuretic peptide, plasma renin activity, and aldosterone levels returned to the normal levels in rats treated with TNNT2-4F-NIL but not in vehicle-treated rats. Furthermore, the TNNT2-4F-NIL-treated group showed significantly less liver and kidney congestion than vehicle-treated rats. Thus, we conclude that in rat models of MI, TNNT2-4F-NIL reverses RAAS activation and subsequent systemic congestion.

Hot spot imaging in cardiovascular diseases: an information statement from SNMMI, ASNC, and EANM.

This information statement from the Society of Nuclear Medicine and Molecular Imaging, American Society of Nuclear Cardiology, and European Association of Nuclear Medicine describes the performance, interpretation, and reporting of hot spot imaging in nuclear cardiology. The field of nuclear cardiology has historically focused on cold spot imaging for the interpretation of myocardial ischemia and infarction. Hot spot imaging has been an important part of nuclear medicine, particularly for oncology or infection indications, and the use of hot spot imaging in nuclear cardiology continues to expand. This document focuses on image acquisition and processing, methods of quantification, indications, protocols, and reporting of hot spot imaging. Indications discussed include myocardial viability, myocardial inflammation, device or valve infection, large vessel vasculitis, valve calcification and vulnerable plaques, and cardiac amyloidosis. This document contextualizes the foundations of image quantification and highlights reporting in each indication for the cardiac nuclear imager.

Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study.

OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia. DESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls. SETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven. POPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts. METHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type. MAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations. RESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V. CONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.