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Reacting astrophysical flows can be challenging to model, because of the difficulty in accurately coupling hydrodynamics and reactions. This can be particularly acute during explosive burning or at high temperatures where nuclear statistical equilibrium is established. We develop a new approach, based on the ideas of spectral deferred corrections (SDC) coupling of explicit hydrodynamics and stiff reaction sources as an alternative to operator splitting, that is simpler than the more comprehensive SDC approach we demonstrated previously. We apply the new method to a double-detonation problem with a moderately sized astrophysical nuclear reaction network and explore the time step size and reaction network tolerances, to show that the simplified-SDC approach provides improved coupling with decreased computational expense compared to traditional Strang operator splitting. This is all done in the framework of the Castro hydrodynamics code, and all algorithm implementations are freely available.

David Nygren,1 Ulrica Mölstad,2 Hans Thulesius,2– 4 Magnus Hillman,5,6 Lars Mikael Broman,7,8 Hanan Tanash,9,10 Mona Landin-Olsson,5,6 Magnus Rasmussen,1 Maria Thunander2,6,11 1Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; 2Department of Research and Development, Health Care Region Kronoberg, Växjö, Sweden; 3Department of Medicine and Optometry, Linnaeus University, Växjö, Sweden; 4Department of Clinical Sciences, Family Medicine, Lund University, Malmö, Sweden; 5Diabetes Research Laboratory, Biomedical Center, Lund University, Lund, Sweden; 6Department of Clinical Sciences, Endocrinology and Diabetes, Lund University, Lund, Sweden; 7ECMO Centre Karolinska, Pediatric Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden; 8Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 9Department of Clinical Sciences, Respiratory Medicine, Lund University, Malmö, Sweden; 10Department of Respiratory Medicine, Skåne University Hospital, Malmö, Sweden; 11Department of Internal Medicine, Endocrinology, Växjö Central Hospital, Växjö, SwedenCorrespondence: David Nygren, Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden, Tel +4646171192, Fax +4646176002, Email david.nygren@med.lu.seIntroduction: Alpha-1-antitrypsin (AAT) has been shown to inhibit SARS-CoV-2 cell entry and suggested as a therapeutic agent for COVID-19. Furthermore, epidemiological association of high prevalence of Alpha-1-antitrypsin deficiency (AATD) and regional severity of COVID-19-impact has been hypothesized. In our study setting, the estimated prevalence rates of mild (PI*MZ, PI*SS or PI*MS) and moderate-to-severe AATD (PI*ZZ or PI*SZ) are high, 9% and 0.2%, respectively. Our primary aim was to examine the prevalence rate of AATD among hospitalized COVID-19-patients.Methods: In this prospective observational study, enrollment occurred from December 2020 to January 2021 in two COVID-19-units at Skåne University Hospital, Lund, Sweden. Case definition was a patient hospitalized due to COVID-19. Patients were screened for AATD with PI-typing and if results were inconclusive, PCR for the S- and Z-genes were performed. Patients were categorized as severe or moderate COVID-19 and 30-day-mortality data were collected. The primary outcome was prevalence rate of AATD. The secondary outcome investigated association between presence of mild AATD and severe COVID-19.Results: We enrolled 61 patients with COVID-19. Two patients out of 61 (3%) had mild AATD (PI*MZ) and none had moderate-to-severe AATD. 30/61 (49%) had severe COVID-19. Both patients with mild AATD developed severe COVID-19. Yet, presence of AATD was not significantly associated with severe COVID-19 (p=0.24).Conclusion: Mild AATD (PI*MS or PI*MZ) was rare in a small cohort of hospitalized patients with COVID-19 in a study setting with a high background prevalence of AATD.Keywords: alpha-1-antitrypsin, alpha-1-antitrypsin deficiency, COVID-19, SARS-CoV-2, PI-typing, SERPINA1

Christina Therkildsen,1,2 Lars Henrik Jensen,3 Maria Rasmussen,2 Inge Bernstein4,5 1Department of Surgical Gastroenterology, Copenhagen University Hospital, Copenhagen, Denmark; 2The Danish HNPCC Register, Department of Clinical Research, Copenhagen University Hospital, Amager and Hvidovre, Copenhagen, Denmark; 3Department of Oncology, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark; 4Department of Gastroenterology, Aalborg Hospital, Aalborg, Denmark; 5Faculty of Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Inge BernsteinDepartment of Gastroenterology, Aalborg Hospital, Hobrovej 18-22, Aalborg, 9100, DenmarkTel +45 97666805Email i.bernstein@rn.dkAbstract: During the recent years, immune checkpoint-based therapy has proven highly effective in microsatellite instable (MSI) solid tumors irrespective of organ site. MSI tumors are associated with a defective mismatch repair (MMR) system and a highly immune-infiltrative tumor microenvironment—both characteristics of Lynch syndrome. Lynch syndrome is a multi-tumor syndrome that not only confers a high risk of colorectal and endometrial cancer but also cancer in, eg the upper urinary tract, ovaries, and small bowel. Since the genetic predisposition for Lynch syndrome are pathogenic variants in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2, most of the Lynch syndrome cancers show MMR deficiency, MSI, and activation of the immune response system. Hence, Lynch syndrome cancer patients may be optimal candidates for immune checkpoint-based therapies. However, molecular differences have been described between sporadic MSI tumors (developed due to MLH1 promoter hypermethylation) and Lynch syndrome tumors, which may result in different treatment responses. Furthermore, the response profile of the rare Lynch syndrome cases may be masked by the more frequent cases of sporadic MSI tumors in large clinical trials. With this review, we systematically collected response data on Lynch syndrome patients treated with FDA- and EMA-approved immune checkpoint-based drugs (pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, and nivolumab) to elucidate the objective response rate and progression-free survival of cancer in Lynch syndrome patients. Herein, we report Lynch syndrome-related objective response rates between 46 and 71% for colorectal cancer and 14– 100% for noncolorectal cancer in unselected cohorts as well as an overview of the Lynch syndrome case reports. To date, no difference in the response rates has been reported between Lynch syndrome and sporadic MSI cancer patients.Keywords: hereditary colorectal cancer, HNPCC, Lynch syndrome, endometrial cancer, germline mismatch repair defect

ObjectiveKnee buckling, in which a knee gives way during weight-bearing, is common in people with knee pain and knee osteoarthritis (OA), but little is known about the prevalence of sensations of knee instability, slipping or shifting in which the knee does not actually buckle, or of the psychosocial and physical consequences of these symptoms.DesignWe asked participants in the Multicenter Osteoarthritis Study (MOST) separately about episodes of knee buckling and sensations of knee instability without buckling in the past 3 months, and assessed fear of falling, poor balance confidence (Activities-specific Balance Confidence (ABC) Scale ≤ 67/100), activity limitation due to concern about buckling, and poor physical function (Western Ontario and McMaster Universities Arthritis Index (WOMAC) physical function ≥ 28/68). We used Poisson regression to estimate prevalence ratios (PRs) for cross-sectional associations of buckling and sensations of instability without buckling with these outcomes, adjusting for confounders.ResultsOf 2120 participants (60% female, 40% ≥ 65 years, mean Body mass index (BMI): 31 kg/m258), 18% reported buckling, 27% had sensations of knee instability without buckling, and 9% reported both symptoms. Buckling and sensations of instability without buckling were each significantly associated with fear of falling, poor balance confidence, activity limitations, and poor WOMAC physical function. Subjects who reported both buckling and instability without buckling and those with at least two buckling episodes (15%) had the strongest association with poor outcomes.ConclusionsKnee buckling and especially sensations of knee instability without buckling were common and each was significantly associated with fear of falling, poor balance confidence, activity limitations, and poor physical function.

Lasse Kaalby,1,2 Morten Rasmussen,3 Erik Zimmermann-Nielsen,1 Magdalena Maria Buijs,1 Gunnar Baatrup1,21Department of Surgery, Odense University Hospital, Odense, Denmark; 2Department of Clinical Science, University of Southern Denmark, Odense, Denmark; 3Department of Digestive Diseases K, Bispebjerg Hospital, Copenhagen, DenmarkPurpose: The aim of this study was to investigate the effect of response time from the Fecal Immunochemical Test (FIT) based screening invitation to the conclusive screening Optical Colonoscopy (OC) on the risk of detecting colorectal cancer (CRC), advanced stage disease and precursor lesions.Patients and methods: We used a cross-sectional study design and included all 62,554 screening participants registered in the Danish Colorectal Cancer Screening Database who tested FIT-positive between March 2014 and December 2016. The main exposure was response time, measured as the time from initial invitation to the conclusive OC. Our main outcomes were the probability of being diagnosed with CRC, advanced stage disease or precursor lesions.Results: Of the 62,554 FIT-positive participants, 53,171 (85%) received an OC and were eligible for analysis (median age 63.7 years, 56% men). In this group, 3,639 cancers were registered, 2,890 of which were registered with a defined stage of disease (79%), and 1,042 (36%) of these were advanced stage (UICC III & IV). In addition, 17,732 high-risk and 10,605 low-risk adenomas were identified. Compared to participants receiving the conclusive examination within 30 days, those receiving the examination more than 90 days after initial invitation were 3.49 times more likely to be diagnosed with any CRC (OR 3.49 [95% CI, 3.13–3.89]) and 2.10 times more likely to have advanced stage disease (OR 2.10 [95% CI, 1.73–2.56]). Those waiting for the longest were also more likely to have one or more high-risk adenomas (OR 1.59 [95% CI, 1.50–1.68]).Conclusion: Increased screening response time was associated with a higher probability of detecting high-risk adenomas, any stage CRC and advanced stage cancer. More research is needed to explain what causes these associations.Keywords: colorectal cancer screening, screening response time, delayed participation, screening uptake

Mette Kielsholm Thomsen,1 Morten Rasmussen,2 Sisse Helle Njor,1,3 Ellen Margrethe Mikkelsen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Digestive Diseases K, Bispebjerg Hospital, Copenhagen, Denmark; 3Department of Public Health Programs, Randers Regional Hospital, Randers, Denmark Background: Predictors of participation in colorectal cancer screening with a stool sample screening modality have been widely studied, but adherence to subsequent diagnostic colonoscopy after a positive screening test has received less attention. We aimed to determine predictors of adherence to diagnostic colonoscopy in the Danish Colorectal Cancer Screening Program.Methods: We conducted a cross-sectional study using data from National Health Service registries. We included 8,112 individuals invited to screening between March 3, 2014, and August 31, 2014, who had a positive immunochemical fecal occult blood test. Potential predictors were gender, age, region of residence, Charlson Comorbidity Index (CCI) score, specific diseases (cardiovascular disease, chronic pulmonary disease, diabetes, and cancer), and number of prior hospital stays. We estimated prevalence proportion differences (PPDs) for the associations between potential predictors and adherence.Results: Overall, adherence to diagnostic colonoscopy was 88.6%. Adherence was lower in individuals aged 75 years compared with those aged

Ellen M Mikkelsen,1 Mette Kielsholm Thomsen,1 Julie Tybjerg,2 Lennart Friis-Hansen,3 Berit Andersen,4,5 Jens Christian Riis Jørgensen,6 Gunnar Baatrup,7,8 Sisse H Njor,2,4,5 Frank Mehnert,1 Morten Rasmussen9 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2RKKP, The Danish Clinical Registries, A National Quality Improvement Programme, Aarhus, Denmark; 3Department of Clinical Biochemistry, Nordsjællands Hospital, Hillerød, Denmark; 4Department of Public Health Programmes, Randers Regional Hospital, The Central Denmark Region, Randers, Denmark; 5Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 6Department of Surgery, Vejle Hospital, Vejle, Denmark; 7Department of Surgery, Odense University Hospital, Odense, Denmark; 8Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 9Department of Digestive Diseases K, Bispebjerg Hospital, Copenhagen, Denmark Background: The Danish national screening program for colorectal cancer (CRC) consists of an immunochemical fecal occult blood test (iFOBT) followed by colonoscopy. The Danish Colorectal Cancer Screening Database (DCCSD) records data on the incidence of hospital-registered complications after colonoscopy. However, the validity of these data is unknown, and the incidence of complications is potentially underreported.Objective: To evaluate the validity of the colonoscopy complications registered in the DCCSD by using medical records as the reference. Further, to evaluate the incidence of complications leading to hospital contact.Methods: Among 14,671 individuals with a positive iFOBT result and a colonoscopy procedure performed from March 3, 2014 to December 31, 2014, we selected 295 individuals for medical record review. We calculated sensitivity as the proportion of true complications registered in the DCCSD out of all complications found in the medical records, and the positive predictive value (PPV) as the number of true complications in the DCCSD out of all DCCSD-registered complications. On the basis of the medical record data, we calculated the incidence proportion of hospital-registered complications overall and by subtype.Results: In total, we reviewed 286 records and found 102 individuals with at least one complication. The sensitivity of the DCCSD for any complication was 29.4% (95% CI: 20.8–39.3) and the PPV was 88.2% (95% CI: 72.6–96.7). On the basis of the medical record data, the incidence proportion of any complication after colonoscopy was 0.70% (95% CI: 0.57–0.84) and that of perforation or lesion was 0.10% (95% CI: 0.06–0.17); bleeding, 0.41% (95% CI: 0.31–0.53); post-polypectomy syndrome, 0.16% (95% CI: 0.10–0.24); and other medical complications, 0.04 (95% CI: 0.02–0.09).Conclusion: The DCCSD has low sensitivity for complications, and improvements in data registration are warranted. The incidence proportion of any hospital-treated post-colonoscopy complication was 0.70% in 2014, which was the first year of the Danish national CRC screening program. This is within the range of complications reported by other studies. Keywords: prevention, public health, harms

Background: Biological therapies have established efficacy in psoriasis vulgaris. However, palmoplantar pustulosis (PPP) has proven difficult to treat, and data on drug survival in these patients remain scarce. Objective: To investigate drug survival of biological treatments in a nationwide cohort of patients with PPP. Methods: We included all patients treated for PPP with a biologic from a prospective Danish nationwide registry between 2007 and 2019. Descriptive statistics were reported. Drug survival was calculated for all patients and specified for the most frequently used biologics. Drug survival was reported as median time to discontinuation. Kaplan–Meier plots were used to visualize drug survival. Trajectories of Dermatology Life Quality Index (DLQI) scores were plotted by interpolating between the different visits with a dermatologist for each treatment course. Results: We identified 85 individual patients who received biological therapy for PPP across 194 treatment courses during follow‐up. Of the included treatment courses, 151 (77.8%) were discontinued. The most frequent cause of discontinuation was ineffective response to treatment (54.3%), while 18.5% of courses were discontinued due to adverse events. The median drug survival across all therapies for PPP was 9.3 (Inter quartile range (IQR), 3.9–25.6) months. Ustekinumab demonstrated the longest median time to discontinuation of 14.6 (IQR, 9.1–51.8) months. The proportion of bio‐naive patients in treatment at 12 months were according to drug 47.9% for adalimumab, 64.3% for ustekinumab and 40.0% for secukinumab. For bio‐experienced, it was 58.2% adalimumab, 54.5% for ustekinumab and 51.4% for secukinumab. Conclusions: The treatment of PPP poses significant challenges, with limited drug survival observed across all therapies regardless of prior experience with biologics. Ustekinumab demonstrated the longest median drug survival. Notably, patients discontinuing therapy due to inefficacy exhibited higher DLQI scores, highlighting the importance of personalized treatment selection and timely consideration of therapy changes when inefficacy is established. [ABSTRACT FROM AUTHOR]

Summary: We conducted a systematic review of the literature reporting phenylephrine‐induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue oxygen saturation as measured by near‐infrared spectroscopy in humans. We used the proportion change of the group mean values reported by the original studies in our analysis. Phenylephrine elevates blood pressure whilst concurrently inducing a reduction in cardiac output. Furthermore, despite increasing cerebral blood flow, it decreases cerebral tissue oxygen saturation. The extent of phenylephrine's influence on cardiac output (r = ‐0.54 and p = 0.09 in awake humans; r = ‐0.55 and p = 0.007 in anaesthetised humans), cerebral blood flow (r = 0.65 and p = 0.002 in awake humans; r = 0.80 and p = 0.003 in anaesthetised humans) and cerebral tissue oxygen saturation (r = ‐0.72 and p = 0.03 in awake humans; r = ‐0.24 and p = 0.48 in anaesthetised humans) appears closely linked to the magnitude of phenylephrine‐induced blood pressure changes. When comparing the effects of phenylephrine in awake and anaesthetised humans, we found no evidence of a significant difference in cardiac output, cerebral blood flow or cerebral tissue oxygen saturation. There was also no evidence of a significant difference in effect on systemic and cerebral circulations whether phenylephrine was given by bolus or infusion. We explore the underlying mechanisms driving the phenylephrine‐induced cardiac output reduction, cerebral blood flow increase and cerebral tissue oxygen saturation decrease. Individualised treatment approaches, close monitoring and consideration of potential risks and benefits remain vital to the safe and effective use of phenylephrine in acute care. [ABSTRACT FROM AUTHOR]

Mette Bach Larsen,1 Ellen M Mikkelsen,2 Morten Rasmussen,3 Lennart Friis-Hansen,4 Anders U Ovesen,5 Hans Bjarke Rahr,6 Berit Andersen1 1Department of Public Health Programmes, Randers Regional Hospital, Central Denmark Region, Randers NO, 2Department of Clinical Epidemiology, Aarhus University Hospital, Central Denmark Region, Aarhus N, 3Digestive Disease Center K, Bispebjerg Hospital, The Capital Region of Denmark, Copenhagen NV, 4Department of Clinical Biochemistry, Nordsjællands Hospital, The Capital Region of Denmark, Hillerød, 5Department of Surgical Gastroenterology, Aalborg University Hospital, North Denmark Region, Aalborg, 6Department of Surgery, Vejle Hospital, Region of Southern Denmark, Vejle, Denmark Introduction: Fecal occult blood tests are recommended for colorectal cancer (CRC) screening in Europe. Recently, the fecal immunochemical test (FIT) has come into use. Sociodemographic differences between participants and nonparticipants may be less pronounced when using FIT as there are no preceding dietary restrictions and only one specimen is required. The aim of this study was to examine the associations between sociodemographic characteristics and nonparticipation for both genders, with special emphasis on those who actively unsubscribe from the program. Methods: The study was a national, register-based, cross-sectional study among men and women randomized to be invited to participate in the prevalence round of the Danish CRC screening program between March 1 and December 31, 2014. Prevalence ratios (PRs) were used to quantify the association between sociodemographic characteristics and nonparticipation (including active nonparticipation). PRs were assessed using Poisson regression with robust error variance.Results: The likelihood of being a nonparticipant was highest in the younger part of the population; however, for women, the association across age groups was U-shaped. Female immigrants were more likely to be nonparticipants. Living alone, being on social welfare, and having lower income were factors that were associated with nonparticipation among both men and women. For both men and women, there was a U-shaped association between education and nonparticipation. For both men and women, the likelihood of active nonparticipation rose with age; it was lowest among non-western immigrants and highest among social welfare recipients. Conclusion: Social inequality in screening uptake was evident among both men and women in the Danish CRC screening program, even though the program is free of charge and the screening kit is based on FIT and mailed directly to the individuals. Interventions are needed to bridge this gap if CRC screening is to avoid aggravating existing inequalities in CRC-related morbidity and mortality. Keywords: colorectal neoplasms, mass screening, early detection of cancer, socioeconomic factors, demography

Mette Kielsholm Thomsen,1 Sisse Helle Njor,1 Morten Rasmussen,2 Dorte Linnemann,3 Berit Andersen,4 Gunnar Baatrup,5,6 Lennart Jan Friis-Hansen,7 Jens Christian Riis Jørgensen,8 Ellen Margrethe Mikkelsen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 2Department of Digestive Diseases K, Bispebjerg Hospital, Copenhagen, 3Department of Pathology, Herlev and Gentofte Hospital, Herlev, 4Department of Public Health Programs, Randers Regional Hospital, Randers, 5Department of Surgery, Odense University Hospital, 6Department of Clinical Science, University of Southern Denmark, Odense, 7Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, 8Department of Colorectal Cancer Surgery, Vejle Hospital, Vejle, Denmark Background: In Denmark, a nationwide screening program for colorectal cancer was implemented in March 2014. Along with this, a clinical database for program monitoring and research purposes was established. Objective: The aim of this study was to estimate the agreement and validity of diagnosis and procedure codes in the Danish Colorectal Cancer Screening Database (DCCSD). Methods: All individuals with a positive immunochemical fecal occult blood test (iFOBT) result who were invited to screening in the first 3 months since program initiation were identified. From these, a sample of 150 individuals was selected using stratified random sampling by age, gender and region of residence. Data from the DCCSD were compared with data from hospital records, which were used as the reference. Agreement, sensitivity, specificity and positive and negative predictive values were estimated for categories of codes “clean colon”, “colonoscopy performed”, “overall completeness of colonoscopy”, “incomplete colonoscopy”, “polypectomy”, “tumor tissue left behind”, “number of polyps”, “lost polyps”, “risk group of polyps” and “colorectal cancer and polyps/benign tumor”. Results: Hospital records were available for 136 individuals. Agreement was highest for “colorectal cancer” (97.1%) and lowest for “lost polyps” (88.2%). Sensitivity varied between moderate and high, with 60.0% for “incomplete colonoscopy” and 98.5% for “colonoscopy performed”. Specificity was 92.7% or above, except for the categories “colonoscopy performed” and “overall completeness of colonoscopy”, where the specificity was low; however, the estimates were imprecise. Conclusion: A high level of agreement between categories of codes in DCCSD and hospital records indicates that DCCSD reflects the hospital records well. Further, the validity of the categories of codes varied from moderate to high. Thus, the DCCSD may be a valuable data source for future research on colorectal cancer screening. Keywords: colorectal cancer screening, clinical database, data validity