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We provide an overview of the status of Monte-Carlo event generators for high-energy particle physics. Guided by the experimental needs and requirements, we highlight areas of active development, and opportunities for future improvements. Particular emphasis is given to physics models and algorithms that are employed across a variety of experiments. These common themes in event generator development lead to a more comprehensive understanding of physics at the highest energies and intensities, and allow models to be tested against a wealth of data that have been accumulated over the past decades. A cohesive approach to event generator development will allow these models to be further improved and systematic uncertainties to be reduced, directly contributing to future experimental success. Event generators are part of a much larger ecosystem of computational tools. They typically involve a number of unknown model parameters that must be tuned to experimental data, while maintaining the integrity of the underlying physics models. Making both these data, and the analyses with which they have been obtained accessible to future users is an essential aspect of open science and data preservation. It ensures the consistency of physics models across a variety of experiments.

Christina Andersen,1 Inge Schjødt,1 Anne Nakano,2 Søren Paaske Johnsen,3 Kenneth Egstrup,4 Brian B Løgstrup1,5 1Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2The Danish Clinical Registries (RKKP), Aarhus, Denmark; 3Danish Center for Clinical Health Services Research (DACS), Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 4Department of Cardiology, Odense University Hospital, Svendborg, Denmark; 5Institute of Clinical Medicine, Aarhus University, Aarhus, DenmarkCorrespondence: Brian B Løgstrup, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark, Email bbl@skejby.rm.dkBackground: The Danish Heart Failure Registry (DHFR) is a clinical quality database established to monitor and improve the quality of heart failure (HF) care in Denmark.Objective: We examined the validity of the content of the DHFR.Methods: In a random sample of patients registered in DHFR between the 1st of January 2016 to the 31st of December 2018, we determined the agreement between the information entered in the database and information in the medical records regarding 1) content; 2) sensitivity; 3) specificity; 4) positive predictive values (PPV) as well as negative predictive values (NPV) of all patient characteristics and performance measures obtained in the DHFR.Results: The study population included 453 patients. In general, the content of the DHFR was accurate. Patient characteristics showed high PPV between 93.0% and 99.5% for all variables. Sensitivity ranged from 81.0% to 95.2%, specificity from 79.8% to 99.5% and NPV ranged from 81.4% to 99.0%. The pharmacological performance measures showed high agreement regarding sensitivity (77.4% to 98.6%) and PPV (84.0% to 94.0%). Further, the specificity ranged from 66.7% to 98.0% and NPP ranged from 90.1% to 96.5%. For the non-pharmacological performance measures, patient education showed high sensitivity (98.0%, 95% CI 96.1– 99.1) and PPV (94.9% CI: 93.0– 96.3), whereas referral to exercise training had a lower sensitivity of 77.8% (CI: 71.6– 83.1) and a PPV of 74.5% (CI: 69.6– 78.6).Conclusion: Overall, the Danish Heart Failure Registry have a high degree of completeness and validity, making it a valuable tool for clinical epidemiological research in HF.Keywords: heart failure, database, epidemiology, registries, Danish Heart Failure Registry

Jes S Lindholt, 1–3 Axel C Diederichsen, 2, 4 Lars M Rasmussen, 2, 5 Lars Frost, 6, 7 Flemming H Steffensen, 8 Jess Lambrechtsen, 8 Grazina Urbonaviciene, 6, 7 Martin Busk, 9 Kenneth Egstrup, 8 Katrine L Kristensen, 1–3 Carsten Behr Andersen, 3 Rikke Søgaard 10 1Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark; 2Elitary Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense, Denmark; 3Department of Vascular Surgery, Viborg Hospital, Viborg, Denmark; 4Department of Cardiology, Odense University Hospital, Odense, Denmark; 5Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; 6Department of Cardiology, Diagnostic Centre, Regional Hospital Silkeborg, Silkeborg, Denmark; 7Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 8Department of Cardiology, Vejle Hospital, Vejle, Denmark; 9Department of Cardiology, University Hospital Odense Svendborg, Svendborg, Denmark; 10Department of Public Health and Department of Clinical Medicine, Aarhus University, Aarhus, DenmarkCorrespondence: Jes S LindholtDepartment of Cardiothoracic and Vascular Surgery, Odense University Hospital, J.B. Winsløv Vej 4, Odense 5000, DenmarkTel +45 2464 1214Email Jes.sanddal.lindholt@rsyd.dkAim: The prevalence and mortality of abdominal aortic aneurysms (AAA) has been reported to decline. The aim of this study is to compare survival, prevalence, and repair rate of AAA in Denmark in the 1990s, the 2000s and the 2010s – and to examine any change in factors known to influence the prevalence.Methods: Baseline status and up to 5-year outcomes of 34,079 general population men aged 65– 74 were obtained from three RCTs; the Viborg study (1994– 1998, n=4,860), the Viborg Vascular (VIVA) trial (2008– 2011, n=18,748), and the Danish Cardiovascular (DANCAVAS) trial (2015– 2018, n=10,471). After the millennium (VIVA and DANCAVAS) men with AAA were further offered low dose aspirin and statins. Follow-up data were not available for the DANCAVAS trial yet.Results: Across the three decades, the AAA prevalence was 3.8% (Reference), 3.3% (p< 0.001) and 4.2% (p=0.882), the proportion of smokers were 62%, 42% and 34% (p< 0.001) amongst men with AAA, but AAA risk associations with smoking increased during the decades suggesting increased tobacco consumption of smokers. In addition, the proportions of attenders with ischemic heart disease or stroke increased significantly. The aneurysmal progression rate in the 1990s was 2.90 vs 2.98 mm/year in the 2000s (p=0.91). The need for preventive AAA repair increased insignificantly in the 2000s (Age adj. HR= 1.29, 95% C.I.: 0.95; 1.71, p=0.10), and mortality of men with screen-detected AAA was lower in the 2000s compared to the 1990s (Age-adj. HR= 0.28, 95% C.I.: 0.22; 0.36, p< 0.001).Conclusion: The Danish prevalence of AAA today compares to the nineties. Unchanged aneurysmal progression rates combined with improved survival of men at risk of AAA leave them in longer time to develop an AAA, be diagnosed and to need later aneurysmal repair or experience rupture.Clinical Trial Registrations: Viborg study: No possibility of registration in the nineties. VIVA: NCT00662480, URL: https://clinicaltrials.gov/show/NCT00662480, DANCAVAS: ISRCTN12157806, URL: http://www.isrctn.com/ISRCTN12157806.Keywords: abdominal aortic aneurysms, screening, prevalence, survival, progression, smoking

Morten Rune Blichfeldt-Eckhardt,1,2 Claus Andersen,2 Helle Ørding,1 Peter B Licht,3 Palle Toft2 1Department of Anesthesiology, Vejle Hospital, Vejle, Denmark; 2Department of Anesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark; 3Department of Thoracic Surgery, Odense University Hospital, Odense, Denmark Purpose: Acute postoperative pain is a strong predictor for postthoracotomy pain syndrome (PTPS), but the mechanism is unknown. Even though thoracic pain is usually considered the dominating acute pain after thoracic surgery, up to 45% of patients consider shoulder pain to be dominating pain and often this shoulder pain is referred visceral pain. This study aims to examine which components of the acute pain response after thoracic surgery were associated with PTPS and if any signs of a generalized central hypersensitivity could be identified in patients with PTPS.Patients and methods: In a prospective cohort study, 60 consecutive patients for lobectomy were included and examined preoperatively and 12 months postoperatively for pain and signs of hypersensitivity using a comprehensive protocol for quantitative sensory testing. Thoracic pain, shoulder pain, referred pain, and overall pain were assessed five times daily during the first four postoperative days.Results: Sixteen patients (31% of the 52 patients who completed the study) developed PTPS. Thoracic pain was the only pain component that was associated with PTPS and was a stronger predictor for PTPS than overall pain. There were no signs of hypersensitivity before or after the operation in patients with PTPS, but patients with PTPS more often suffered from preoperative pain.Conclusion: Thoracic pain was the only component of the acute pain response that predicted PTPS and was a stronger predictor than overall pain. Keywords: postthoracotomy pain syndrome, acute postoperative pain, chronic postoperative pain, referred pain, thoracic surgery

STUDY QUESTION What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans? SUMMARY ANSWER Intrafollicular concentrations of cortisol become massively upregulated close to ovulation concomitant with an exceptionally high biological activity securing a timely and efficient termination of inflammatory processes. WHAT IS KNOWN ALREADY Ovulation has been described as a local, controlled inflammatory process resulting in the degeneration of the follicle wall which facilitate oocyte extrusion. Ovulation also affects the glucocorticoid metabolism of granulosa cells (GCs) and although de novo synthesis of cortisol only occurs in the adrenal cortex, the mid-cycle surge has been shown to induce a change from high expression of HSD11B2, inactivating cortisol to cortisone, to high expression of HSD11B1 which reversibly catalyses cortisol production from cortisone. Furthermore, high concentrations of progesterone and 17OH-progesterone within follicles may cause dislodging of cortisol from cortisol binding protein (CBP) thereby activating the biological activity of cortisol. STUDY DESIGN, SIZE, DURATION This prospective cohort study included 50 women undergoing fertility treatment according to a standard antagonist protocol at a university hospital-affiliated fertility clinic in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS Women donated FF and GCs from one follicle for research purpose aspirated at one of four time points during the process of final maturation of follicles: T  = 0 h, T  = 12 h, T  = 17 h, T  = 32 h. A second sample was collected at oocyte pick up at T  = 36 h. The concentration of cortisol and cortisone together with a range of sex steroids was measured by LC-MS/MS in FF collected at the five time points mentioned above. Whole genome microarray data, validated by q-PCR analysis, was used to evaluate gene expression of CYP11B1 , CYP21A2 , HSD11B1 , HSD11B2 , and NR3C1 in GCs at the same time points. MAIN RESULTS AND THE ROLE OF CHANCE The concentration of cortisol was significantly increased from a few nM at 0 h to around 100–140 nM (P  ≤ 0.0001) at 32–36 h, whilst cortisone was almost constant from 0 to 17 h at a concentration of between 90 and 100 nM being significantly reduced to 25–40 nM (P  ≤ 0.0001) at 32–36 h. This was paralleled by a 690-fold upregulation of HSD11B1 from 0 to 12 h increasing to a more than 20.000-fold change at 36 h. HSD11B2 was quickly downregulated 15- to 20-fold after ovulation induction. Concentrations of progesterone and 17OH-progesterone increased during the ovulatory process to high levels which in essence displaces cortisol from its binding protein CBP due to similar binding affinities. Furthermore, a significant decrease in 11-deoxycortisol expression was seen, but CYP11B1 expression was below detection limit in GCs. LIMITATIONS, REASONS FOR CAUTION The study included women undergoing ovarian stimulation and results may differ from the natural cycle. More observations at each specific time point may have strengthened the conclusions. Furthermore, we have not been able to measure the actual active biological concentration of cortisol. WIDER IMPLICATIONS OF THE FINDINGS For the first time, this study collectively evaluated the temporal pattern of cortisol and cortisone concentrations during human ovulation, rendering a physiological framework for understanding potential dysregulations in the inflammatory reaction of ovulation. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the University Hospital of Copenhagen, Rigshospitalet, and Novo Nordisk Foundation grant number NNF21OC00700556. Interreg V ÔKS through ReproUnion (www.reprounion.eu); Region Zealand Research Foundation. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]