Scientific Advisory Panel Research Articles

The 2023 American Burn Association Research and Advocacy Summit: Our Roadmap.

Research is one of the American Burn Association's (ABA) strategic priorities. Advocacy is required not only to promote burn research, but also, the ABA's other strategic priorities (Prevention, Quality, and Education). The ABA convened a two-day Research and Advocacy (R&A) Summit in September 2023, to develop a roadmap for the organization's research and advocacy efforts. The in-person summit identified fourteen key R&A initiatives. A multidisciplinary workgroup then developed strategies to achieve each initiative. The initiatives and strategies were then approved by the ABA's Board of Trustees as our organization's roadmap for research and advocacy. The next task will be to implement the initiatives. This will require not only oversight from the ABA's Board of Trustees, but also, effort from and collaboration between several of the ABA's committees and panels, including the Burn Science Advisory panel (BSAP), the Research Committee, the Prevention Committee, The Governmental Affairs Committee, The Organization and Delivery of Burn care Committee, the Quality and Burn Registry Committee, the ad hoc Coding Committee, and the ABA's Central Office.

The Clinical Nurse Practitioner's Essential Role in Early Diagnosis and Management of Multiple Sclerosis in Europe: A Consensus Report.

Timely diagnosis of multiple sclerosis (MS) is a challenge due to factors such as prompt identification of symptoms and consequent delays in hospital visits and treatment initiation. In part to address this challenge, an expert scientific advisory panel of clinical nurse practitioners (CNPs) from different European nations was convened by Viatris on October 25, 2022, in Amsterdam, the Netherlands. This meeting was an interactive discussion to understand the role of clinical nurse practitioners in MS management. The objectives were to (1) understand the current delays in MS diagnosis from the perspective of expert CNPs; (2) determine the role of the CNP in MS management; and (3) identify the opportunities to improve accessibility, foster collaboration among stakeholders, and promote initiatives to educate people with MS. The recommendations of the panel underline the multidimensional role of CNPs in the management of MS at all stages. Health care stakeholders need to work together to achieve better access to treatment regimens and facilitate outcomes in the management of MS through shared decision-making and follow-ups. Further exploration of the role of CNPs in the management of MS, as well as recommendations for early diagnosis, will help both general practitioners and specialists better manage MS care.

Development of a Comprehensive Regulatory Model for Medical Devices

Abstract Background: The development of a comprehensive regulatory model for medical devices is essential to ensure the safety, efficacy, and quality of medical devices throughout their lifecycle, from design and development to post-market surveillance. This paper outlines a robust framework for such a regulatory model, detailing key components and processes necessary for effective regulation. Methods: The data and literature were collected from various databases including Springer, Science Direct, Taylor and Francis, Wiley, Bentham Science, and websites of different regulatory agencies. The collected data were utilized in the research work to formulate the new regulatory model. Results: Different guidelines represent acceptable regulatory practices for all medical items. There are four risk classification levels of the medical devices (class I–IV, based on the risk level). For every country, the regulatory requirements are different. Global regulations for medical device approval are essential to guaranteeing their quality, safety, efficacy, and performance before they can be put on the market to safeguard, prevent, enhance, and maintain public health. Different classes have different regulatory steps for approval of the devices, which varies from region to region. The World Health Organization’s Department of Essential Health Technologies’ Diagnostic Imaging and Medical Devices team has developed and implemented the Baseline Country Survey on Medical Devices. The proposed model includes the establishment of a clear legislative and regulatory framework, featuring a risk-based classification system aligned with international standards. It emphasizes rigorous pre-market requirements, including design controls, clinical evaluation, quality management systems, and technical documentation. Market authorization processes are described, highlighting pathways such as Premarket Notification (510(k)), Premarket Approval (PMA), and De Novo Classification, supported by thorough scientific review and expert advisory panels. The present study is all about the global requirements of the regulation of the medical devices and it was concluded that overall, a global comprehensive regulatory model for medical devices aims to strike a balance between ensuring patient safety, facilitating innovation, and enabling timely access to life-saving medical technologies around the world. Conclusion: The model advocates for international harmonization and collaboration, promoting regulatory convergence and the adoption of global standards. It also supports innovation through accelerated approval pathways and regulatory sandboxes, alongside continuous improvement driven by regulatory science research and stakeholder engagement. By integrating these elements, the comprehensive regulatory model aims to protect public health while fostering medical device innovation and ensuring global regulatory compatibility.

The value of the ‘Science and Economic Development’ Parliamentary Links Day 2023

Potential impact is an important driver in the career choices and journeys of many. There have even been organizations set up to help people make career decisions that can boost their global impact, such as ‘80000hours.org’. Impact has always been an important motivator for me in my decisions; however, I often find myself feeling helpless to make a significant impact through my research. Informing policymaking is an activity where scientists can use their expertise to have a beneficial impact, but how to engage with policymakers can be unclear. This is why I was so excited to have been invited to attend the Royal Society of Biology’s 2023 Parliamentary Links Day on Science and Economic Development. ‘The best way to make an impact is to join scientific advisory councils and panels” was the most important recommendation I took home with me following the event; advice which helped me walk away with more clarity on how I can be impactful.

Do Insomnia Treatments Improve Daytime Function?

A scientific advisory panel of seven U.S. and Canadian sleep experts performed a clinical appraisal by comparing general medical opinion, assessed via a survey of practicing clinicians, regarding insomnia treatment, with the available scientific evidence. This clinical appraisal focuses on the specific statement, "Treatments for insomnia have uniformly been shown to significantly improve the associated daytime impairment seen with insomnia." The advisory panel reviewed and discussed the available body of evidence within the published medical literature to determine what discrepancies may exist between the currently published evidence base and general medical opinion. The advisory panels' evaluation of this statement was also compared with the results of a national survey of primary care physicians, psychiatrists, nurse practitioners, physician assistants, and sleep specialists in the United States. Contrary to general medical opinion, the expert advisory panel concluded that the medical literature did not support the statement. This gap highlights the need to educate the general medical community regarding insomnia treatment efficacy in pursuit of improved treatment outcomes.

Paraquat, Parkinson's Disease, and Agnotology.

Paraquat, Parkinson's Disease, and Agnotology.

Sugary solutions

Sugary solutions

Oral chronic toxicity and carcinogenicity study of alpha-glycosyl isoquercitrin (AGIQ) in Sprague Dawley rats

alpha-Glycosyl isoquercitrin (AGIQ) is a flavonoid that possesses antioxidant and tumor suppressive capabilities and is marketed as a food additive in Japan. The aim of this study was to assess the potential for oral chronic toxicity and carcinogenicity of AGIQ in male and female Sprague Dawley rats following up to 5.0% dietary exposure. In the chronic toxicity study, rats were exposed to AGIQ or vehicle for one year with a 6-month interim termination point; for the carcinogenicity study, rats were treated for 24 months. No signs of AGIQ-related toxicity clinically or histologically were observed for up to one year except for yellow discoloration of bone. In the carcinogenicity study, a statistically significant increase in the incidence of malignant glioma of the brain or spinal cord was observed in female rats exposed to 5.0% AGIQ compared to those exposed to control feed. A Scientific Advisory Panel of experienced neuropathologists reviewed the gliomas (routine stains and glial cell markers) and concluded that the gliomas were a rare, spontaneous, rat-specific neoplasm: malignant microglial tumor. The lesions could not definitively be attributed to AGIQ exposure and have limited implications with respect to predicting human cancer risk.

Best practices for exposure model peer review – A SciPinion advisory panel report

The extent and rigor of peer review that a model undergoes during and after development influences the confidence of users and managers in model predictions. A process for determining the breadth and depth of peer review of exposure models was developed with input from a panel of exposure-modeling experts. This included consideration of the tiers and types of models (e.g., screening, deterministic, probabilistic, etc.). The experts recommended specific criteria be considered when evaluating the degree to which a model has been peer reviewed, including quality of documentation and the model peer review process (e.g., internal review with a regulatory agency by subject matter experts, expert review reports, formal Scientific Advisory Panels, and journal peer review). In addition, because the determination of the confidence level for an exposure model's predictions is related to the degree of evaluation the model has undergone, irrespective of peer review, the experts recommended the approach include judging the degree of model rigor using a set of specific criteria: (1) nature and quality of input data, (2) model verification, (3) model corroboration, and (4) model evaluation. Other key areas considered by the experts included recommendations for addressing model uncertainty and sensitivity, defining the model domain of applicability, and flags for when a model is used outside its domain of applicability. The findings of this expert engagement will help developers as well as users of exposure models have greater confidence in their application and yield greater transparency in the evaluation and peer review of exposure models.

Proceedings of the 2021 American Burn Association State and Future of Burn Science Meeting.

Periodically, the American Burn Association (ABA) has convened a State of the Science meeting on various topics representing multiple disciplines within burn care and research. In 2021 at the request of the ABA President, meeting development was guided by the ABA's Burn Science Advisory Panel (BSAP) and a subgroup of meeting chairs. The goal of the meeting was to produce both an evaluation of the current literature and ongoing studies, and to produce a research agenda and/or define subject matter-relevant next steps to advance the field(s). Members of the BSAP defined the topics to be addressed and subsequently solicited for nominations of expert speakers and topic leaders from the ABA's Research Committee. Current background literature for each topic was compiled by the meeting chairs and the library then enhanced by the invited topic and breakout discussion leaders. The meeting was held in New Orleans, LA on November 2nd and 3rd and was formatted to allow for 12 different topics, each with two subtopics, to be addressed. Topic leaders provided a brief overview of each topic to approximately 100 attendees, followed by expert-lead breakout sessions for each topic that allowed for focused discussion among subject matter experts and interested participants. The breakout and topic group leaders worked with the participants to determine research needs and associated next steps including white papers, reviews and in some cases collaborative grant proposals. Here, summaries from each topic area will be presented to highlight the main foci of discussion and associated conclusions.

The Role of Cooling Centers in Protecting Vulnerable Individuals from Extreme Heat.

The Role of Cooling Centers in Protecting Vulnerable Individuals from Extreme Heat.

From Theory to Practice: The Student Experience Evaluating Development Projects Focused on Nature-Based Solutions

Graduate students often seek hands-on experiences in the international development field. Given that Multilateral Development Banks (MDBs) provide hundreds of billions of dollars in aid each year, we expected that reviewing the design, implementation, and outcomes of their environmental projects would provide valuable learning outcomes for students. This novel study on Nature-based Solutions (NbS) in the Global Environment Facility (GEF) gave students the opportunity to engage directly with practitioners in the review of 50 environmental projects across 45 countries. A team of professionals from the Scientific and Technical Advisory Panel (STAP) of the GEF and eight students from the University of Michigan School for Environment and Sustainability and the University of Maryland School of Public Policy developed lessons learned from reviewing the GEF portfolio over a twenty-year time span. When screening projects for enabling conditions including theory of change, climate risk screening, multi-stakeholder engagement, and adaptive management, most had stronger explanations of the environmental than the social outcomes sought, and only more recent ones incorporated climate risk screening. The process and findings associated with this educational experience contributed to students’ climate change leadership development; for example, by learning about the tradeoffs and possible co-benefits of improving both environmental conditions and livelihoods in less developed countries. Our research led to practice advice for the design of future GEF projects, as well as ideas for future coursework to further bridge the gap between theory and practice in academia, which we believe to be essential to preparing the next generation of climate leaders.

Bioanalytical and chemical-specific screening of contaminants of concern in three California (USA) watersheds

To broaden the scope of contaminants monitored in human-impacted riverine systems, water, sediment, and treated wastewater effluent were analyzed using receptor-based cell assays that provide an integrated response to chemicals based on their mode of biological activity. Samples were collected from three California (USA) watersheds with varying degrees of urbanization and discharge from municipal wastewater treatment plants (WWTPs). To complement cell assay results, samples were also analyzed for a suite of contaminants of emerging concern (CECs) using gas and liquid chromatography-mass spectrometry (GC- and LC-MS/MS). For most water and sediment samples, bioassay equivalent concentrations for estrogen and glucocorticoid receptor assays (ER- and GR-BEQs, respectively) were near or below reporting limits. Measured CEC concentrations compared to monitoring trigger values established by a science advisory panel indicated minimal to moderate concern in water but suggested that select pesticides (pyrethroids and fipronil) had accumulated to levels of greater concern in river sediments. Integrating robust, standardized bioanalytical tools such as the ER and GR assays utilized in this study into existing chemical-specific monitoring and assessment efforts will enhance future CEC monitoring efforts in impacted riverine systems and coastal watersheds.

A Comprehensive Review of Vaccines against Covid-19

A Comprehensive Review of Vaccines against Covid-19

SARS-CoV-2-Specific T-Cell Responses are Amplified in Children with Multisystem Inflammatory Syndrome in Children

Background: Despite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. The cause of these differences in presentation may relate to differences in the host response to infection between adults and children. We thus set out to measure the SARS-CoV-2-specific T cell (CST) response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection.Methods: CSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay.Findings: Twenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses were significantly increased in adults versus children with uncomplicated SARS-CoV-2 infection (P=0.008), while children with MIS-C displayed a CST response that was similar to convalescent adults.Interpretation: Age-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults. Children with MIS-C have T cell immunity to SARS-CoV-2 that is similar to convalescent adults and greater than children with uncomplicated SARS-CoV-2, despite near uniform seropositivity.Funding: This study was funded by the Board of Visitors of Children’s National Hospital, the Connor Family Foundation, the Katzen Foundation, the National Institute of Allergy and Infectious Diseases, and the National Institute of Dental and Craniofacial Research.Declaration of Interest: C.M.B. is a co-founder and on the scientific advisory boards for Catamaran Bio and Mana Therapeutics with stock and/or ownership, is on the Board of Directors for Caballeta Bio with stock options and has stock in Neximmune and Repertoire Immune Medicines. M.D.K. is on a scientific advisory panel for Enzyvant. The other authors declare that there are no conflicts of interest.Ethical Approval: Peripheral blood mononuclear cells (PBMCs) were obtained from participants recruited from Children’s National Hospital (Washington, DC) and the National Institutes of Health under informed consent approved by the Institutional Review Board of both institutions in accordance with the Declaration of Helsinki.

Assessment of risks to listed species from the use of atrazine in the USA: a perspective

ABSTRACT Atrazine is a triazine herbicide used predominantly on corn, sorghum, and sugarcane in the US. Its use potentially overlaps with the ranges of listed (threatened and endangered) species. In response to registration review in the context of the Endangered Species Act, we evaluated potential direct and indirect impacts of atrazine on listed species and designated critical habitats. Atrazine has been widely studied, extensive environmental monitoring and toxicity data sets are available, and the spatial and temporal uses on major crops are well characterized. Ranges of listed species are less well-defined, resulting in overly conservative designations of “May Effect”. Preferences for habitat and food sources serve to limit exposure among many listed animal species and animals are relatively insensitive. Atrazine does not bioaccumulate, further diminishing exposures among consumers and predators. Because of incomplete exposure pathways, many species can be eliminated from consideration for direct effects. It is toxic to plants, but even sensitive plants tolerate episodic exposures, such as those occurring in flowing waters. Empirical data from long-term monitoring programs and realistic field data on off-target deposition of drift indicate that many other listed species can be removed from consideration because exposures are below conservative toxicity thresholds for direct and indirect effects. Combined with recent mitigation actions by the registrant, this review serves to refine and focus forthcoming listed species assessment efforts for atrazine. Abbreviations: a.i. = Active ingredient (of a pesticide product). AEMP = Atrazine Ecological Monitoring Program. AIMS = Avian Incident Monitoring SystemArach. = Arachnid (spiders and mites). AUC = Area Under the Curve. BE = Biological Evaluation (of potential effects on listed species). BO = Biological Opinion (conclusion of the consultation between USEPA and the Services with respect to potential effects in listed species). CASM = Comprehensive Aquatic System Model. CDL = Crop Data LayerCN = field Curve Number. CRP = Conservation Reserve Program (lands). CTA = Conditioned Taste Avoidance. DAC = Diaminochlorotriazine (a metabolite of atrazine, also known by the acronym DACT). DER = Data Evaluation Record. EC25 = Concentration causing a specified effect in 25% of the tested organisms. EC50 = Concentration causing a specified effect in 50% of the tested organisms. EC50RGR = Concentration causing a 50% reduction in relative growth rate. ECOS = Environmental Conservation Online System. EDD = Estimated Daily Dose. EEC = Expected Environmental Concentration. EFED = Environmental Fate and Effects Division (of the USEPA). EFSA = European Food Safety Agency. EIIS = Ecological Incident Information System. ERA = Environmental Risk Assessment. ESA = Endangered Species Act. ESU = Evolutionarily Significant UnitsFAR = Field Application RateFIFRA = Federal Insecticide, Fungicide, and Rodenticide Act. FOIA = Freedom of Information Act (request). GSD = Genus Sensitivity Distribution. HC5 = Hazardous Concentration for ≤ 5% of species. HUC = Hydrologic Unit Code. IBM = Individual-Based Model. IDS = Incident Data System. KOC = Partition coefficient between water and organic matter in soil or sediment. KOW = Octanol-Water partition coefficient. LC50 = Concentration lethal to 50% of the tested organisms. LC-MS-MS = Liquid Chromatograph with Tandem Mass Spectrometry. LD50 = Dose lethal to 50% of the tested organisms. LAA = Likely to Adversely Affect. LOAEC = Lowest-Observed-Adverse-Effect Concentration. LOC = Level of Concern. MA = May Affect. MATC = Maximum Acceptable Toxicant Concentration. NAS = National Academy of Sciences. NCWQR = National Center of Water Quality Research. NE = No Effect. NLAA = Not Likely to Adversely Affect. NMFS = National Marine Fisheries Service. NOAA = National Oceanic and Atmospheric Administration. NOAEC = No-Observed-Adverse-Effect Concentration. NOAEL = No-Observed-Adverse-Effect Dose-Level. OECD = Organization of Economic Cooperation and Development. PNSP = Pesticide National Synthesis Project. PQ = Plastoquinone. PRZM = Pesticide Root Zone Model. PWC = Pesticide in Water Calculator. QWoE = Quantitative Weight of Evidence. RGR = Relative growth rate (of plants). RQ = Risk Quotient. RUD = Residue Unit Doses. SAP = Science Advisory Panel (of the USEPA). SGR = Specific Growth Rate. SI = Supplemental Information. SSD = Species Sensitivity Distribution. SURLAG = Surface Runoff Lag Coefficient. SWAT = Soil & Water Assessment Tool. SWCC = Surface Water Concentration Calculator. UDL = Use Data Layer (for pesticides). USDA = United States Department of Agriculture. USEPA = United States Environmental Protection Agency. USFWS = United States Fish and Wildlife Service. USGS = United States Geological Survey. WARP = Watershed Regressions for Pesticides.

The Extended Amphibian Metamorphosis Assay: A Thyroid-Specific and Less Animal-Intensive Alternative to the Larval Amphibian Growth and Development Assay.

The amphibian metamorphosis assay (AMA; US Environmental Protection Agency [USEPA] test guideline 890.1100 and Organisation for Economic Co‐Operation and Development test guideline 231) has been used for more than a decade to assess the potential thyroid‐mediated endocrine activity of chemicals. In 2013, in the context of the Endocrine Disruptor Screening Program of the USEPA, a Scientific Advisory Panel reviewed the results from 18 studies and recommended changes to the AMA test guideline, including a modification to a fixed‐stage design rather than a fixed‐time (i.e., 21‐d) design. We describe an extended test design for the AMA (or EAMA) that includes thyroid histopathology and time to metamorphosis (Nieuwkoop–Faber [NF] stage 62), to address both the issues with the fixed‐time design and the specific question of thyroid‐mediated adversity in a shorter assay than the larval amphibian growth and development assay (LAGDA; Organisation for Economic Co‐Operation and Development test guideline 241), using fewer animals and resources. A demonstration study was conducted with the EAMA (up to NF stage 58) using sodium perchlorate. Data analyses and interpretation of the fixed‐stage design of the EAMA are more straightforward than the fixed‐time design because the fixed‐stage design avoids confounded morphometric measurements and thyroid histopathology caused by varying developmental stages at test termination. It also results in greater statistical power to detect metamorphic delays than the fixed‐time design. By preferentially extending the AMA to NF stage 62, suitable data can be produced to evaluate thyroid‐mediated adversity and preclude the need to perform a LAGDA for thyroid mode of action analysis. The LAGDA remains of further interest should investigations of longer term effects related to sexual development modulated though the hypothalamus–pituitary–gonadal axis be necessary. However, reproduction assessment or life cycle testing is currently not addressed in the LAGDA study design. This is better addressed by higher tier studies in fish, which should then include specific thyroid‐related endpoints. Environ Toxicol Chem 2021;40:2135–2144. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Risk factors, symptom reporting, healthcare-seeking behaviour and adherence to public health guidance: protocol for Virus Watch, a prospective community cohort study

IntroductionThe coronavirus (COVID-19) pandemic has caused significant global mortality and impacted lives around the world. Virus Watch aims to provide evidence on which public health approaches are most likely to...

Science Advisory Panels: Results of a Survey of Panel Participants

Science panel deliberations serve as an important step in policy and regulatory decision making, ideally providing independent validation that the decisions under consideration are based on sound scientific evidence and interpretation. To be useful, the findings from a science panel should be trusted by all parties involved (e.g., regulatory decision makers, participating scientists, general public, regulated industries). A survey was conducted of scientists who had participated in science advisory panels for regulatory agencies to gain a better understanding of their experiences.

Effects of Empagliflozin on Extracellular Volume, Plasma Volume, and Measured Glomerular Filtration Rate in Patients with Heart Failure: A Double-Blind, Randomised, and Placebo-Controlled Trial (Empire HF Renal)

Background: Sodium-glucose co-transporter-2 inhibitors are a promising new treatment option for patients with heart failure and reduced ejection fraction (HFrEF) with and without type 2 diabetes. We investigated the effects of empagliflozin on estimated extracellular volume (ECV), estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with HFrEF. Methods: Empire HF Renal was an investigator-initiated, double-blind, placebo-controlled, randomised trial with recruitment from four hospitals in Denmark. Patients in New York Heart Association class I-III, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or placebo once daily for 12 weeks. The co-primary renal outcomes were the between-group difference in the change of estimated ECV, estimated plasma volume, and measured GFR from baseline to 12 weeks. The trial is registered at ClinicalTrials.gov (NCT03198585). Findings: Between June 29, 2017, and July 15, 2019, 391 patients were screened and 120 (31%) were assigned to empagliflozin or placebo; 59 (98%) in the empagliflozin group and 58 (97%) in the placebo group were included in the analyses. Significant reductions in estimated ECV, estimated plasma volume, and measured GFR with empagliflozin versus placebo were observed [estimated ECV; adjusted mean difference of change empagliflozin versus placebo -0·12 L; 95% confidence interval (CI) -0·18 to -0·05, P=0·0006. Estimated plasma volume; -7·3%; 95% CI -10·3 to -4·3, P<0·0001. Measured GFR; -7·5 mL/min; 95% CI -11·2 to -3·8, P=0·0001]. These findings were consistent across important clinical heart failure subgroups. In the empagliflozin group, five patients (8·3%) had one or more serious adverse events, versus three patients (5·0%) in the placebo group. Interpretation: In patients with HFrEF, empagliflozin reduced estimated ECV, estimated plasma volume, and measured GFR after 12 weeks. Trial Registration Number: The trial is registered with ClinicalTrials.gov (number NCT03198585) and EudraCT (number 2017-001341-27). Funding: This work was supported by the Research Council at Herlev and Gentofte University Hospital, Herlev, Denmark [institutional research grant]; the Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Herlev, Denmark [institutional research grant]; the Capital Region of Denmark, Copenhagen, Denmark [grant number A6058]; the Danish Heart Foundation, Copenhagen, Denmark [grant numbers 17-R116-A7714-22076, 18 R124-A8573-22107]; the A.P. Moller Foundation for the Advancement of Medical Science, Copenhagen, Denmark [grant number 17-L-0002]. Conflict of Interest: JJ reports grants from the Research Council at Herlev and Gentofte University Hospital, Denmark, grants from the Research and Innovation Foundation of the Department of Cardiology ((FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Denmark, and grants from the A.P. Moller Foundation for the Advancement of Medical Science, Denmark, during the conduct of the study. MO reports grants from The Steno Diabetes Center Odense, Denmark, during the conduct of the study. CK reports personal fees from scientific advisory panel and speaker fees from Boehringer Ingelheim, Merck, Sharp & Dohme, AstraZeneca, Amgen, Novartis,Novo Nordisk, and Shire, outside the submitted work. CT has nothing to disclose. IG has nothing to disclose. LK reports personal fees from speaker honorarium from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim, outside the submitted work. FG reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Novartis, grants and personal fees from Pfizer, personal fees from Orion Pharma Abbott, Bayer, AstraZeneca, and Carmat, outside the submitted work. JF has nothing to disclose. MEM has nothing to disclose. ELF has nothing to disclose. NEB has nothing to disclose. JLF has nothing to disclose. LTJ has nothing to disclose. JEM reports grants and personal fees from Abiomed, personal fees from Novartis, and Orion Pharma, outside the submitted work. MS reports grant from The Capital Region of Denmark, and grants from The Danish Heart Foundation, during the conduct of the study; personal fees and non-financial support from AstraZeneca, personal fees from Novo Nordisk and Boehringer Ingelheim, outside the submitted work. Ethical Approval: The trial was approved by the local ethics committee, and all patients provided written informed consent (Danish National Committee on Health Research Ethics, number H-17010756).