Characterizing the Blood Pressure Response to Physical Counterpressure Manoeuvres Using Surface Electromyography in Adults With Long Covid

Orthostatic intolerance (OI) is common in Long Covid. Physical counterpressure manoeuvres (PCM) may improve OI in other disorders. We characterised the blood pressure-rising effect of PCM using surface electromyography (sEMG) and investigated its association with fatigue in adults with Long Covid. Participants performed an active stand with beat-to-beat hemodynamic monitoring and sEMG of both thighs, including PCM at 3-minutes post-stand. Multivariable linear regression investigated the association between change in systolic blood pressure (SBP) and change in normalised root mean square (RMS) of sEMG amplitude, controlling for confounders including the Chalder Fatigue Scale (CFQ). In 90 participants (mean age 46), mean SBP rise with PCM was 13.7 (SD 9.0) mmHg. In regression, SBP change was significantly, directly associated with change in RMS sEMG ( 0.25 , 95% CI 0.07-0.43, P = 0.007);however, CFQ was not significant. PCM measured by sEMG augmented SBP without the influence of fatigue. Copyright © 2013 IEEE.

Impact of COVID-19 on longitudinal breast cancer research studies involving TNBC patients

Background Triple-negative breast cancer (TNBC) accounts for ~15% of breast cancer diagnoses but is linked to worse outcomes and comprises a disproportionate number of breast cancer deaths. The TNBC pilot study is a prospective longitudinal study to provide a critical resource for understanding TNBC disease. However, the pandemic impacted the collection of samples. Objective To highlight the impacts of COVID-19 on this longitudinal cancer translational research study including the patient's perspective and to develop recommendations to avoid future disruptions. Methods 389 participants were enrolled in the prospective longitudinal cohort, which collected serial blood samples for up to 5 years. Due to the pandemic, research was curtailed for 6 months due to concerns about patient safety, halting the collection of blood samples. Missed samples and data gaps were documented. To complement this, we initiated a survey capturing the patient perspective on their experience of the study disruption due to COVID. Results 217 enrolled participants missed a blood draw or had a collection outside the study window. 158 patients missed 1 time-point collection, and 59 patients missed >= 2 collections. Of the 217 participants who missed a collection, 6 disease recurrence diagnoses and 3 deaths occurred during research curtailment. The collection of survey responses from participants is ongoing and will be presented at the AACR Annual Meeting. Conclusion Missed samples resulted in irreplaceable data gaps critical to monitoring patient outcomes, and reduced cohort sampling during the pandemic. Our current knowledge of the risks suggests that with proper informed consent, collections could have continued. To mitigate disruption in future clinical studies, clear plans should be part of study design to provide continuity. The participants' experience to be reported will also help researchers understand their issues and help develop policies. (Table Presented).

The Effect of FOXP3+Regulatory T Cells on Infectious and Inflammatory Diseases

CD4+CD25+FOXP3+regulatory T cells (Tregs) contribute to the maintenance of immune homeostasis and tolerance in the body. The expression levels and functional stability of FOXP3 control the function and plasticity of Tregs. Tregs critically impact infectious diseases, especially by regulating the threshold of immune responses to pathogenic microorganisms. The functional regulatory mechanism and cell-specific surface markers of Tregs in different tissues and inflammatory microenvironments have been investigated in depth, which can provide novel ideas and strategies for immunotherapies targeting infectious diseases.Copyright © 2021. All rights reserved.

Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research.

A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.

Development of a clinical and translational research curriculum for undergraduate students.

Introduction: Research participation during undergraduate years has a powerful influence on career selection and attitudes toward scientific research. Most undergraduate research programs in academic health centers are oriented toward basic research or address a particular disease focus or research discipline. Undergraduate research programs that expose students to clinical and translational research may alter student perceptions about research and influence career selection. Methods: We developed an undergraduate summer research curriculum, anchored upon a clinical and translational research study developed to address a common unmet needs in neonatal nurseries (e.g., assessment of neonatal opioid withdrawal syndrome). Program topics reflected the cross-disciplinary expertise that contributed to the development of this "bedside to bench" study, including opioid addiction, vulnerable populations, research ethics, statistics, data collection and management, assay development, analytical laboratory analysis, and pharmacokinetics. The curriculum was delivered through three offerings over 12 months, using Zoom video-conferencing due to restrictions imposed by the COVID-19 pandemic. Results: Nine students participated in the program. Two-thirds reported the course enhanced their understanding of clinical and translational research. Over three-quarters reported the curriculum topics were very good or excellent. In open-ended questions, students reported that the cross-disciplinary nature of the curriculum was the strongest aspect of the program. Conclusion: The curriculum could be readily adapted by other Clinical and Translational Science Award programs seeking to provide clinical and translational research-oriented programs to undergraduate students. Application of cross-disciplinary research approaches to a specific clinical and translational research question provides students with relevant examples of translational research and translational science.

New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

Anthropause and Human Behaviour: Contributions from a Situated Educational Neuroscience

Objective: We develop a theoretical discussion from our perspective of the situated educational neuroscience, based on the relational anthropology point of view, to generate ambits of discussion in which the educational neuroscience can contribute into the context of COVID-19 pandemic and pospandemic. Subject: The context of the COVID-19 pandemic has made it possible to put in tension issues that were pending on the global agenda. Among these issues, the importance of the human being as part of the ecosystem with which they maintain co-construction relationships is not minor. Situated educational neuroscience is a tool that can bring valuable contributions to the discussion to collaborate in addressing this tension. Development: We organize de argumentation in four sections: 1. The opportunity the anthropause posts to the humankind and its relations with their environment, 2. The role that studies on behaviour and evolution have on this opportunity, 3. The contribution of a situated educational neuroscience as a framework and transdiscipline which works on translational research in this context of pandemics and anthropause, and 4. The succinct presentation of two examples where we argue that a situated educational neuroscience has tools to contribute. Conclusions: We propose conclusions open to discussion where we return to the idea of a situated educational neuroscience which is committed with its context. As an approach or as a transdiscipline with translational research functions, we consider that a situated educational neuroscience contains tools that can contribute to the conversation with other sciences and disciplines and with the empirical knowledge of communities, in order to join efforts to overcome social injustices and move forward as humankind from this current pandemic situa- tion, having acquired strategies of resilience that can serve to deal with other persistent and future situations.

The evolving regulatory landscape in regenerative medicine.

Regenerative medicine as a field has emerged as a new component of modern medicine and medical research that encompasses a wide range of products including cellular and acellular therapies. As this new field emerged, regulatory agencies like the Food and Drug Administration (FDA) rapidly adapted existing regulatory frameworks to address the transplantation, gene therapy, cell-based therapeutics, and acellular biologics that fall under the broader regenerative medicine umbrella. Where it has not been possible to modify existing regulation and processes, entirely new frameworks have been generated with the intention of providing flexible, forward-facing systems to regulate this rapidly growing field. This review discusses the current state of FDA regulatory affairs in the context of stem cells and extracellular vesicles by highlighting gaps in the current regulatory system and then discussing where regulatory science in regenerative medicine may be headed based on these gaps and the FDA's historical ability to deal with emerging fields. Lastly, we utilize case studies in stem cell and acellular based treatments to demonstrate how regulatory science has evolved in regenerative medicine and highlight the ongoing clinical efforts and challenges of these therapies.

Resilience: Biological Basis and Clinical Significance - A Perspective Report from the International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force.

The Resilience is a construct receiving growing attention from the scientific community in geriatrics and gerontology. Older adults show extremely heterogeneous (and often unpredictable) responses to stressors. Such heterogeneity can (at least partly) be explained by differences in resilience (i.e., the capacity of the organism to cope with stressors). The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met in Boston (MA,USA) on April 20, 2022 to discuss the biological and clinical significance of resilience in older adults. The identification of persons with low resilience and the prompt intervention in this at-risk population may be critical to develop and implement preventive strategies against adverse events. Unfortunately, to date, it is still challenging to capture resilience, especially due to its dynamic nature encompassing biological, clinical, subjective, and socioeconomic factors. Opportunities to dynamically measure resilience were discussed during the ICFSR Task Force meeting, emphasizing potential biomarkers and areas of intervention. This article reports the results of the meeting and may serve to support future actions in the field.

PIMT is a novel and potent suppressor of endothelial activation.

Proinflammatory agonists provoke the expression of cell surface adhesion molecules on endothelium in order to facilitate leukocyte infiltration into tissues. Rigorous control over this process is important to prevent unwanted inflammation and organ damage. Protein L-isoaspartyl O-methyltransferase (PIMT) converts isoaspartyl residues to conventional methylated forms in cells undergoing stress-induced protein damage. The purpose of this study was to determine the role of PIMT in vascular homeostasis. PIMT is abundantly expressed in mouse lung endothelium and PIMT deficiency in mice exacerbated pulmonary inflammation and vascular leakage to LPS(lipopolysaccharide). Furthermore, we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6) and its ability to methylate asparagine residues in the coiled-coil domain. This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation and subsequent expression of endothelial adhesion molecules. Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation, causing effects on protein stability that ultimately translated into reduced EC(endothelial cell)-leukocyte interactions. Our study has identified PIMT as a novel and potent suppressor of endothelial activation. Taken together, these findings suggest that therapeutic targeting of PIMT may be effective in limiting organ injury in inflammatory vascular diseases.

The Challenge of Mass Casualty Incident Response Simulation Exercise Design and Creation: A Modified Delphi Study.

BACKGROUND: A Mass Casualty Incident response (MCI) full scale exercise (FSEx) assures MCI first responder (FR) competencies. Simulation and serious gaming platforms (Simulation) have been considered to achieve and maintain FR competencies. The translational science (TS) T0 question was asked: how can FRs achieve similar MCI competencies as a FSEx through the use of MCI simulation exercises? METHODS: T1 stage (Scoping Review): PRISMA-ScR was conducted to develop statements for the T2 stage modified Delphi (mD) study. 1320 reference titles and abstracts were reviewed with 215 full articles progressing for full review leading to 97 undergoing data extraction.T2 stage (mD study): Selected experts were presented with 27 statements derived from T1 data with instruction to rank each statement on a 7-point linear numeric scale, where 1 = disagree and 7 = agree. Consensus amongst experts was defined as a standard deviation ≤ 1.0. RESULTS: After 3 mD rounds, 19 statements attained consensus and 8 did not attain consensus. CONCLUSIONS: MCI simulation exercises can be developed to achieve similar competencies as FSEx by incorporating the 19 statements that attained consensus through the TS stages of a scoping review (T1) and mD study (T2), and continuing to T3 implementation, and then T4 evaluation stages.

Increase in weight-for-age and vegetable intake in young children with cystic fibrosis treated with lumacaftor/ivacaftor for 24 weeks

Background: Modulator therapy has improved nutritional status in individuals with cystic fibrosis (CF), which is associated with favorable outcomes. Because of the high metabolic demands of CF, nutritional recommendations include energy intake of 110% to 200% of daily estimated needs for healthy individuals. With changes in energy balance after initiation of modulator therapy, these recommendations may no longer be appropriate for some people with CFand may lead to excessiveweight gain. Overweight and obesity are being reported, and nutrition concerns now include dietary quality. Dietary quality in relation to growth in young children starting lumacaftor/ivacaftor therapy has not been examined over a 24-week period and may provide new data for future nutrition guidance for individuals with CF. Method(s): The purpose of this observational study was to determine the effect of lumacaftor/ivacaftor treatment on growth and diet in medicationnaive children. Subjects aged 2 to 5 with D508/D508 mutations were recruited from the United States and Canada. Length/height, weight, and body mass index (BMI) were measured in triplicate and averaged. Z-scores were calculated using Centers for Disease Control and Prevention reference data. Dietary data were captured using 3-day weighted food records after study visits. The Healthy Eating Index (HEI) was generated using the U.S. Department of Agriculture scoring system for each recorded day and averaged. Outcomes were assessed before treatment (baseline) and 12 and 24 weeks after beginning medication. Mixed longitudinal models were used for analysis over time. Result(s): Participants (mean age 2.9 +/- 1.4, 50% female) who completed food records for at least their baseline visit plus one other visit (n = 14) had significant increases inweight-for-age z-score (WAZ) 12 (0.6 +/- 1.7, p = 0.02) and 24 (0.21 +/- 1.8, p = 0.001) weeks after therapy. There was no significant change in height-for-age (HAZ), BMI-for-age (BMIZ), or head circumference- for-age (HCZ) z-score at 12 or 24 weeks. Although not statistically significant, percentage estimated energy requirement (%EER) decreased at 12 (-7 +/- 90%, p = 0.54) and 24 (-27 +/- 90%, p = 0.08) weeks. HEI total score did not change over the 24 weeks, although vegetables and greens and beans HEI subgroup scores decreased significantly from baseline to 24 weeks (-0.73 +/- 2.2, p = 0.02;-0.68 +/- 2.1, p = 0.02, respectively). Pooled visit correlation between total vegetables and WAZ indicated a positive association (r = 0.35, p = 0.04). Conclusion(s): WAZ increased significantly over 24 weeks of lumacaftor/ ivacaftor therapy and was positively correlated with total vegetable intake, suggesting that participants with greater WAZ scores consumed more vegetables, although over the course of the study, total vegetable intake and intake of greens and beans decreased, and WAZ increased. %EER decreased over the course of the study, but not statistically significantly so, probably because of variability in energy intake within this small study sample with some COVID-19 interruptions. In summary, WAZ of children aged 2 to 5 with D508/D508 mutations increased, with no significant changes in HAZ, BMIZ, or HCZ, and they consumed fewer total vegetables and greens and beans after 24 weeks of lumacaftor/ivacaftor therapy. Acknowledgements: Supported by Vertex Pharmaceutics Inc. and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001878.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

The Impact of N-butyldeoxynojirimycin and 1-deoxymannojirimycin on SARS-CoV-2 S1 Subunit and Angiotensin-Converting Enzyme 2 Interaction in Intestinal Epithelial Cells

The severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) targets mainly the respiratory tract. In addition to respiratory symptoms, many extrapulmonary manifestations were observed in the gastrointestinal tract and reported by SARS-CoV-2 patients, including abdominal pain, nausea, and diarrhea. SARS-CoV-2 binds initially to angiotensin-converting enzyme 2 (ACE2) on the host cell surface via its spike (S) protein before it undergoes endocytosis and fusion with the lysosomal membrane. The spike protein of SARS-CoV-2 is a heavily N- and O-glycosylated trimer. Glycosylation is an essential posttranslational modification in the life cycle of membrane and secretory proteins that affects their structural and functional characteristics as well as their trafficking and sorting patterns. This study aimed at elucidating the impact of glycosylation modulation on the trafficking of both S1 subunit and ACE2 as well as their interaction at the cell surface of intestinal epithelial cells. For this purpose, the S1 protein was expressed in COS-1 cells and its glycosylation modified using N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of ER-located alpha-glucosidases I and II, and or 1-deoxymannojirimycin (dMM), an inhibitor of the Golgi-located alpha-mannosidase I. The intracellular and secreted S1 proteins were analyzed by endoglycosidase H treatment. Similarly, ACE2 trafficking to the brush border membrane of intestinal Caco-2 cells was also assessed in the presence or absence of the inhibitors. Finally, the interaction between the S1 protein and ACE2 was investigated at the surface of Caco-2 cells by co-immunoprecipitation. Our data show that NB-DNJ significantly reduced the secretion of S1 proteins in COS-1 cells, while dMM affected S1 secretion to a lesser extent. Moreover, NB-DNJ and dMM differentially affected ACE2 trafficking and sorting to the brush border membrane of intestinal Caco-2 cells. Strikingly, the interaction between S1 and ACE2 was significantly reduced when both proteins were processed by the glycosylation inhibitors, rendering glycosylation and its inhibitors potential candidates for SARS-CoV-2 treatment. This work has been supported by a grant from the German Research Foundation (DFG) grant NA331/15-1 to HYN. M.K. was supported by a scholarship from the Hannover Graduate School for Veterinary Pathobiology, Neuroinfectiology, and Translational Medicine (HGNI) and by the DFG grant NA331/15-1.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Proceedings of the 6th National Patient Reported Outcome Measures (PROMs) Annual Conference

The proceedings contain 47 papers. The topics discussed include: long COVID rehabilitation services, Cardiff and Vale and Cwm Taf Morgannwg University health boards: social return on investment;the clinical meaning of family reported outcome measure (FROM-16) scores: translational research to support holistic clinical practice;patient-centered outcome measure design: the perspectives and preferences of children and young people with life-limiting or life-threatening conditions;co-creation of a patient reported outcome measure for older people with frailty and acute care needs (PROM-OPAC);PROMs: coming of age in lymphoedema services in Wales;ForMi-person-centered planning and outcomes recording app;true colors online mood monitoring in the bipolar disorder research network (BDRN) research program: challenges, benefits and importance of personalization;patient reported outcome measures for rheumatoid arthritis disease activity: using Rasch measurement theory to achieve more meaningful measurement;developing a roadmap towards national collection of electronic patient-reported outcomes for people with chronic kidney disease in the UK;and measuring bereavement support needs in people bereaved during Covid-19;the adaptation and development of a bereavement support needs scale.

Are researchers in academic medicine flourishing? A survey of midcareer Ph.D. and physician investigators.

Introduction: Midcareer research faculty are a vital part of the advancement of science in U.S. medical schools, but there are troubling trends in recruitment, retention, and burnout rates. Methods: The primary sampling frame for this online survey was recipients of a single R01 or equivalent and/or K-award from 2013 to 2019. Inclusion criteria were 3-14 years at a U.S. medical school and rank of associate professor or two or more years as assistant professor. Forty physician investigators and Ph.D. scientists volunteered for a faculty development program, and 106 were propensity-matched controls. Survey items covered self-efficacy in career, research, work-life; vitality/burnout; relationships, inclusion, trust; diversity; and intention to leave academic medicine. Results: The majority (52%) reported receiving poor mentoring; 40% experienced high burnout and 41% low vitality, which, in turn, predicted leaving intention (P < 0.0005). Women were more likely to report high burnout (P = 0.01) and low self-efficacy managing work and personal life (P = 0.01) and to be seriously considering leaving academic medicine than men (P = 0.003). Mentoring quality (P < 0.0005) and poor relationships, inclusion, and trust (P < 0.0005) predicted leaving intention. Non-underrepresented men were very likely to report low identity self-awareness (65%) and valuing differences (24%) versus underrepresented men (25% and 0%; P < 0.0005). Ph.D.s had lower career advancement self-efficacy than M.D.s (P < .0005). Conclusions: Midcareer Ph.D. and physician investigators faced significant career challenges. Experiences diverged by underrepresentation, gender, and degree. Poor quality mentoring was an issue for most. Effective mentoring could address the concerns of this vital component of the biomedical workforce.

Building an infrastructure to support the development, conduct, and reporting of informative clinical studies: The Rockefeller University experience.

Introduction: Clinical trials are a vital component of translational science, providing crucial information on the efficacy and safety of new interventions and forming the basis for regulatory approval and/or clinical adoption. At the same time, they are complex to design, conduct, monitor, and report successfully. Concerns over the last two decades about the quality of the design and the lack of completion and reporting of clinical trials, characterized as a lack of "informativeness," highlighted by the experience during the COVID-19 pandemic, have led to several initiatives to address the serious shortcomings of the United States clinical research enterprise. Methods and Results: Against this background, we detail the policies, procedures, and programs that we have developed in The Rockefeller University Center for Clinical and Translational Science (CCTS), supported by a Clinical and Translational Science Award (CTSA) program grant since 2006, to support the development, conduct, and reporting of informative clinical studies. Conclusions: We have focused on building a data-driven infrastructure to both assist individual investigators and bring translational science to each element of the clinical investigation process, with the goal of both generating new knowledge and accelerating the uptake of that knowledge into practice.