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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]

STUDY QUESTION Does 8 weeks of daily low-dose hCG administration affect androgen or inhibin B levels in serum and/or follicular fluid (FF) during the subsequent IVF/ICSI cycle in women with low ovarian reserve? SUMMARY ANSWER Androgen levels in serum and FF, and inhibin B levels in serum, decreased following 8 weeks of hCG administration. WHAT IS KNOWN ALREADY Recently, we showed that 8 weeks of low-dose hCG priming, in between two IVF/ICSI treatments in women with poor ovarian responder (anti-Müllerian hormone (AMH) <6.29 pmol/l), resulted in more follicles of 2–5 mm and less of 6–10-mm diameter at the start of stimulation and more retrieved oocytes at oocyte retrieval. The duration of stimulation and total FSH consumption was increased in the IVF/ICSI cycle after priming. Hypothetically, hCG priming stimulates intraovarian androgen synthesis causing upregulation of FSH receptors (FSHR) on granulosa cells. It was therefore unexpected that antral follicles were smaller and the stimulation time longer after hCG priming. This might indicate a different mechanism of action than previously suggested. STUDY DESIGN, SIZE, DURATION Blood samples were drawn on stimulation day 1, stimulation days 5–6, trigger day, day of oocyte retrieval, and oocyte retrieval + 5 days in the IVF/ICSI cycles before and after hCG priming (the control and study cycles, respectively). FF was collected from the first aspirated follicle on both sides during oocyte retrieval in both cycles. The study was conducted as a prospective, paired, non-blinded, single-center study conducted between January 2021 and July 2021 at a tertiary care center. The 20 participants underwent two identical IVF/ICSI treatments: a control cycle including elective freezing of all blastocysts and a study cycle with fresh blastocyst transfer. The control and study cycles were separated by 8 weeks (two menstrual cycles) of hCG priming by daily injections of 260 IU recombinant hCG. PARTICIPANTS/MATERIALS, SETTING, METHODS Women aged 18–40 years with cycle lengths of 23–35 days and AMH <6.29 pmol/l were included. Control and study IVF/ICSI cycles were performed in a fixed GnRH-antagonist protocol. MAIN RESULTS AND THE ROLE OF CHANCE Inhibin B was lower on stimulation day 1 after hCG priming (P  = 0.05). Dehydroepiandrosterone sulfate (DHEAS) was significantly lower on stimulation day 1 (P  = 0.03), and DHEAS and androstenedione were significantly lower on stimulation days 5–6 after priming (P  = 0.02 and P  = 0.02) The testosterone level in FF was significantly lower in the study cycle (P  = 0.008), while the concentrations of inhibin B and androstenedione in the FF did not differ between the study and control cycles. A lower serum inhibin B in the study cycle corresponds with the antral follicles being significantly smaller after priming, and this probably led to a longer stimulation time in the study cycle. This contradicts the theory that hCG priming increases the intraovarian androgen level, which in turn causes more FSHR on developing (antral up to preovulatory) follicles. However, based on this study, we cannot rule out that an increased intra-follicular androgen level was present at initiation of the ovarian stimulation, without elevating the androgen level in serum and that an increased androgen level may have rescued some small antral follicles that would have otherwise undergone atresia by the end of the previous menstrual cycle. We retrieved significantly more oocytes in the Study cycle, and the production of estradiol per follicle ≥10-mm diameter on trigger day was comparable in the study and control cycles, suggesting that the rescued follicles were competent in terms of producing oocytes and steroid hormones. LIMITATIONS, REASONS FOR CAUTION The sample size was small, and the study was not randomized. Our study design did not allow for the measurement and comparison of androgen levels or FSHR expression in small antral follicles before and immediately after the hCG-priming period. WIDER IMPLICATIONS OF THE FINDINGS The results make us question the mechanism of action behind hCG priming prior to IVF. It is important to design a study with the puncture of small antral follicles before and immediately after priming to investigate the proposed hypothesis. Improved cycle outcomes, i.e. more retrieved oocytes, must be confirmed in a larger, preferably randomized study. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by an unrestricted grant from Gedeon Richter awarded to the institution. A.P. reports personal consulting fees from PregLem SA, Novo Nordisk A/S, Ferring Pharmaceuticals A/S, Gedeon Richter Nordics AB, Cryos International, and Merck A/S outside the submitted work and payment or honoraria for lectures from Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, Merck A/S, and Theramex and Organon & Co and payment for participation in an advisory board for Preglem. Grants to the institution have been provided by Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, and Merck A/S, and equipment and travel support has been given to the institution by Gedeon Richter Nordics AB. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT04643925. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Which substances and signal transduction pathways are potentially active downstream to the effect of FSH and LH in the regulation of human oocyte maturation in vivo ? SUMMARY ANSWER The regulation of human oocyte maturation appears to be a multifactorial process in which several different signal transduction pathways are active. WHAT IS KNOWN ALREADY Many studies in animal species have provided insight into the mechanisms that govern the final maturation of oocytes. Currently, these studies have identified several different mechanisms downstream to the effects of FSH and LH. Some of the identified mechanisms include the regulation of cAMP/cGMP levels in oocytes involving C-type natriuretic peptide (CNP), effects of epidermal growth factor (EGF)-related peptides such as amphiregulin (AREG) and/or epiregulin (EREG), effect of TGF-β family members including growth differentiation factor 9 (GDF9) and morphogenetic protein 15 (BMP15), activins/inhibins, follicular fluid meiosis activating sterol (FF-MAS), the growth factor midkine (MDK), and several others. However, to what extent these pathways and mechanisms are active in humans in vivo is unknown. STUDY DESIGN, SIZE, DURATION This prospective cohort study included 50 women undergoing fertility treatment in a standard antagonist protocol at a university hospital affiliated fertility clinic in 2016–2018. PARTICIPANTS/MATERIALS, SETTING, METHODS We evaluated the substances and signalling pathways potentially affecting human oocyte maturation in follicular fluid (FF) and granulosa cells (GCs) collected at five time points during the final maturation of follicles. Using ELISA measurement and proteomic profiling of FF and whole genome gene expression in GC, the following substances and their signal transduction pathways were collectively evaluated: CNP, the EGF family, inhibin-A, inhibin-B, activins, FF-MAS, MDK, GDF9, and BMP15. MAIN RESULTS AND THE ROLE OF CHANCE All the evaluated substances and signal transduction pathways are potentially active in the regulation of human oocyte maturation in vivo except for GDF9/BMP15 signalling. In particular, AREG, inhibins, and MDK were significantly upregulated during the first 12–17 h after initiating the final maturation of follicles and were measured at significantly higher concentrations than previously reported. Additionally, the genes regulating FF-MAS synthesis and metabolism were significantly controlled in favour of accumulation during the first 12–17 h. In contrast, concentrations of CNP were low and did not change during the process of final maturation of follicles, and concentrations of GDF9 and BMP15 were much lower than reported in small antral follicles, suggesting a less pronounced influence from these substances. LARGE SCALE DATA None. LIMITATIONS, REASONS FOR CAUTION Although GC and cumulus cells have many similar features, it is a limitation of the current study that information for the corresponding cumulus cells is not available. However, we seldom recovered a cumulus–oocyte complex during the follicle aspiration from 0 to 32 h. WIDER IMPLICATIONS OF THE FINDINGS Delineating the mechanisms governing the regulation of human oocyte maturation in vivo advances the possibility of developing a platform for IVM that, as for most other mammalian species, results in healthy offspring with good efficacy. Mimicking the intrafollicular conditions during oocyte maturation in vivo in small culture droplets during IVM may enhance oocyte nuclear and cytoplasmic maturation. The primary outlook for such a method is, in the context of fertility preservation, to augment the chances of achieving biological children after a cancer treatment by subjecting oocytes from small antral follicles to IVM. Provided that aspiration of oocytes from small antral follicles in vivo can be developed with good efficacy, IVM may be applied to infertile patients on a larger scale and can provide a cheap alternative to conventional IVF treatment with ovarian stimulation. Successful IVM has the potential to change current established techniques for infertility treatment. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the University Hospital of Copenhagen, Rigshospitalet, the Independent Research Fund Denmark (grant number 0134-00448), and the Interregional EU-sponsored ReproUnion network. There are no conflicts of interest to be declared. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does 8 weeks of continuous low-dose hCG administration increase the proportion of antral follicles that reach the preovulatory state during ovarian stimulation (OS) in women with low ovarian reserve? SUMMARY ANSWER The proportion of antral follicles (2–10 mm) that reached the preovulatory state did not increase. WHAT IS KNOWN ALREADY The administration of androgens prior to OS might upregulate FSH receptor (FSHR) expression on granulosa cells, making follicles more responsive to exogenous FSH stimulation during OS. LH and hCG stimulate the local follicular androgen synthesis in theca cells and may be used as an endogenous androgen priming method. Exogenous priming by testosterone and dehydroepiandrosterone (DHEA) have been shown to increase the number of retrieved oocytes and live birth rate but the studies are small, and their use is associated with side effects. STUDY DESIGN, SIZE, DURATION A prospective, paired, non-blinded single-center study including 20 women serving as their own controls conducted between January 2021 and July 2021 at The University Hospital Copenhagen Rigshospitalet, Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants underwent two identical consecutive IVF/ICSI treatments, a Control cycle and a Study cycle, separated by ∼8 weeks (two menstrual cycles) of daily injections of 260 IU recombinant hCG (rhCG). A freeze-all strategy was applied in the Control cycle. Both IVF/ICSI cycles were performed in a fixed GnRH antagonist protocol using a daily dose of 300 IU recombinant FSH (rFSH) and GnRH antagonist 0.25 mg from stimulation days 5–6. MAIN RESULTS AND THE ROLE OF CHANCE Follicular output rate, defined as the number of follicles >16 mm on hCG trigger day divided by the antral follicle count (2–10 mm) at baseline, did not increase after 8 weeks of hCG priming (P  = 0.8). The mean number of oocytes retrieved was significantly higher after the hCG priming being 4.7 (2.8) vs 3.2 (1.7) in the Study and Control cycle, respectively (P  = 0.01). The duration of stimulation was longer in the Study versus the Control cycle (P  = 0.05), despite the use of identical hCG trigger criterion and similar diameters of the three biggest follicles on hCG trigger day in the two cycles (P  = 0.9). LIMITATIONS, REASONS FOR CAUTION The sample size was small, and the number of oocytes retrieved was not the primary endpoint. Larger studies are needed to confirm this finding. WIDER IMPLICATIONS OF THE FINDINGS Long-term, low-dose rhCG administration may increase the number of oocytes retrieved during IVF/ICSI in women with low ovarian reserve, but more research is needed before firm conclusions can be drawn. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by an unrestricted grant from Gedeon Richter. A.P. reports personal consulting fees from PregLem SA, Novo Nordisk A/S, Ferring Pharmaceuticals A/S, Gedeon Richter Nordics AB, Cryos International, and Merck A/S outside the submitted work and payment or honoraria for lectures from Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, Merck A/S, and Theramex and Organon & Co. Grants to the institution have been provided by Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, and Merck A/S and receipt of equipment by the institution from Gedeon Richter Nordics AB is reported. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT04643925. [ABSTRACT FROM AUTHOR]