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Thomas Wagner,1,2 Jakob Lauritsen,1 Mikkel Bandak,1 Linda Aagaard Rasmussen,3 Johannes Bakker,4 Hanna Birkbak Hovaldt,4 Heidi Larsson,4 Ib Jarle Christensen,1 Birgitte Grønkær Toft,2 Mads Agerbæk,5 Lars Dysager,6 Michael Kreiberg,1 Josephine Julie Rosenvilde,1 Birte Engvad,7 Daniel M Berney,8 Gedske Daugaard1 1Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 2Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 3Research Unit for General Practice, Aarhus, Denmark; 4The Danish Clinical Quality Program – National Clinical Registries (RKKP), Aarhus, Odense and Copenhagen, Denmark; 5Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Oncology, Odense University Hospital, Odense, Denmark; 7Department of Pathology, Odense University Hospital, Odense, Denmark; 8Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UKCorrespondence: Thomas Wagner, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, 2100, Denmark, Tel +45 35459682, Email thomas.wagner.nielsen@regionh.dkPurpose: The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer.Patients and Methods: Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record information on relapse data served as a gold standard. A pre-specified algorithm to identify relapse was tested and optimized on a random sample of 250 patients. Indicators of relapse were obtained from pathology codes in the Danish National Pathology Register and from diagnosis and procedure codes in the Danish National Patient Register. We applied the final algorithm to the remaining study population to validate its performance.Results: Of the 1377 included patients, 284 patients relapsed according to the gold standard during a median follow-up time of 5.9 years. The completeness of relapse data registered in the DaTeCa database was 97.2% (95% confidence interval (CI): 95.2– 99.1). The algorithm achieved a sensitivity of 99.6% (95% CI: 98.7– 100), a specificity of 98.9% (95% CI: 98.2– 99.6), and a positive predictive value of 95.9% (95% CI: 93.4– 98.4) in the validation cohort (n = 1127, 233 relapses).Conclusion: The registration of relapse data in the DaTeCa database is accurate, confirming the database as a reliable source for ongoing clinical quality assessments. Applying the provided algorithm to the DaTeCa database will optimize the accuracy of relapse data further, decrease time-consuming medical record review and contribute to important future clinical research.Keywords: testicular cancer, relapse, algorithm, validation, registries

Linda Aagaard Rasmussen,1 Niels Lyhne Christensen,2 Anne Winther-Larsen,3 Susanne Oksbjerg Dalton,4,5 Line Flytkjær Virgilsen,1 Henry Jensen,1 Peter Vedsted1 1Research Unit for General Practice, Aarhus, Denmark; 2Department of Pulmonary Medicine and Allergy, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 4Survivorship and Inequality in Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark; 5Department of Clinical Oncology & Palliative Care, Zealand University Hospital, Næstved, DenmarkCorrespondence: Linda Aagaard Rasmussen, Research Unit for General Practice, Bartholins Allé 2, Aarhus C, 8000, Denmark, Tel +45 8716 8365, Email linda.rasmussen@ph.au.dkIntroduction: Recurrence of cancer is not routinely registered in Danish national health registers. This study aimed to develop and validate a register-based algorithm to identify patients diagnosed with recurrent lung cancer and to estimate the accuracy of the identified diagnosis date.Material and Methods: Patients with early-stage lung cancer treated with surgery were included in the study. Recurrence indicators were diagnosis and procedure codes recorded in the Danish National Patient Register and pathology results recorded in the Danish National Pathology Register. Information from CT scans and medical records served as the gold standard to assess the accuracy of the algorithm.Results: The final population consisted of 217 patients; 72 (33%) had recurrence according to the gold standard. The median follow-up time since primary lung cancer diagnosis was 29 months (interquartile interval: 18– 46). The algorithm for identifying a recurrence reached a sensitivity of 83.3% (95% CI: 72.7– 91.1), a specificity of 93.8% (95% CI: 88.5– 97.1), and a positive predictive value of 87.0% (95% CI: 76.7– 93.9). The algorithm identified 70% of the recurrences within 60 days of the recurrence date registered by the gold standard method. The positive predictive value of the algorithm decreased to 70% when the algorithm was simulated in a population with a recurrence rate of 15%.Conclusion: The proposed algorithm demonstrated good performance in a population with 33% recurrences over a median of 29 months. It can be used to identify patients diagnosed with recurrent lung cancer, and it may be a valuable tool for future research in this field. However, a lower positive predictive value is seen when applying the algorithm in populations with low recurrence rates.Keywords: lung neoplasms, recurrence, algorithms, validation study, registries, Denmark

Linda Aagaard Rasmussen,1 Henry Jensen,1 Line Flytkjaer Virgilsen,1 Lisbet Rosenkrantz Hölmich,2,3 Peter Vedsted1 1Research Centre for Cancer Diagnosis in Primary Care (CaP), Research Unit for General Practice, Aarhus, Denmark; 2Department of Plastic Surgery, Herlev and Gentofte Hospital, Herlev, Denmark; 3Department of Clinical Medicine, Copenhagen University, Copenhagen, DenmarkCorrespondence: Linda Aagaard RasmussenResearch Unit for General Practice, Aarhus, DenmarkTel +45 8716 8369Fax +45 8612 4788Email linda.rasmussen@ph.au.dkPurpose: Information on cancer recurrence is rarely available outside clinical trials. Wide exclusion criteria used in clinical trials tend to limit the generalizability of findings to the entire population of people living beyond a cancer disease. Therefore, population-level evidence is needed. The aim of this study was to develop and validate a register-based algorithm to identify patients diagnosed with recurrence after curative treatment of malignant melanoma.Patients and Methods: Indicators of recurrence were diagnosis and procedure codes recorded in the Danish National Patient Register and pathology results recorded in the Danish National Pathology Register. Medical records on recurrence status and recurrence date in the Danish Melanoma Database served as the gold standard to assess the accuracy of the algorithm.Results: The study included 1747 patients diagnosed with malignant melanoma; 95 (5.4%) were diagnosed with recurrence of malignant melanoma according to the gold standard. The algorithm reached a sensitivity of 93.7% (95% confidence interval (CI) 86.8– 97.6), a specificity of 99.2% (95% CI: 98.6– 99.5), a positive predictive value of 86.4% (95% CI: 78.2– 92.4), and negative predictive value of 99.6% (95% CI: 99.2– 99.9). Lin’s concordance correlation coefficient was 0.992 (95% CI: 0.989– 0.996) for the agreement between the recurrence dates generated by the algorithm and by the gold standard.Conclusion: The algorithm can be used to identify patients diagnosed with recurrence of malignant melanoma and to establish the timing of recurrence. This can generate population-level evidence on disease-free survival and diagnostic pathways for recurrence of malignant melanoma.Keywords: melanoma, recurrence, algorithms, validation study, registries, Denmark

Linda Aagaard Rasmussen,1 Henry Jensen,1 Line Flytkjær Virgilsen,1 Jørgen Bjerggaard Jensen,2,3 Peter Vedsted1 1Research Centre for Cancer Diagnosis in Primary Care (CaP), Research Unit for General Practice, Department of Public Health, Aarhus University, 8000 Aarhus C, Denmark; 2Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark; 3Department of Urology, Aarhus University Hospital, 8200 Aarhus N, Denmark Purpose: Recurrence of cancer is not routinely registered in the national registers in Denmark. The aim of this study was to develop and validate a register-based algorithm to identify patients diagnosed with recurrence of invasive bladder cancer (BC). Materials and methods: We performed a cohort study based on data from Danish national health registers. Diagnosis codes and procedural codes in the Danish National Patient Register and Systematized Nomenclature of Medicine codes in the Danish National Pathology Register were used as indicators of cancer recurrence. Status and date of recurrence as registered in the Danish Bladder Cancer Database (DaBlaCa-data) were used as the gold standard of BC recurrence to ascertain the accuracy of the algorithm. Results: The algorithm reached a sensitivity of 85% (95% CI: 78–91), a specificity of 90% (95% CI: 79–96), and a positive predictive value of 95% (95% CI: 89–98). The algorithm demonstrated superior performance in patients undergoing cystectomy compared to patients undergoing radiotherapy as primary BC treatment. The concordance correlation coefficient for the agreement between the recurrence dates generated by the algorithm and the gold standard was 0.96 (95% CI: 0.95–0.98), and the estimated date was set within 90 days of the gold standard date for 90% of patients. Conclusion: The proposed algorithm to identify patients diagnosed with BC recurrence from Danish national registries showed excellent performance in terms of ascertaining occurrence and the timing of BC recurrence. Keywords: urinary bladder neoplasms, recurrence, algorithms, validation studies, registers, Denmark

New nomenclature is presented identifying two subsets of sexually abusive youths currently not defined in the literature or in existing models or risk assessment tools: sexually violent youth (YSV) and predatory sexually violent youth (YPSV). Distinctively and qualitatively different, these youths are more dangerous, manifest higher levels of coercion (e.g., threats of bodily injury, use of weapons), or are predatory sexually violent toward strangers or casual acquaintances. Discussed is the innovative, empirically guided risk assessment tool Multiplex Empirically Guided Inventory of Ecological Aggregates for Assessing Sexually Abusive Children and Adolescents (Ages 19 and Under) (MEGA) (Miccio-Fonseca, 2006a) for assessing the level of risk for all youths (male and female) under the age of19 years, including YSVs and YPSVs. [ABSTRACT FROM AUTHOR]

Previous definitions of sexually abusive behavior in children and adolescents were deficient in failing to (1) highlight salient neuropsychological elements and antisocial behaviors that may contribute to a youth's functioning; (2) discriminate among possible types of coercion (e.g., manipulation, threats, physical force, and use of weapons); and (3) include predatory elements of sexual abuse against strangers or casual acquaintances. This article discusses a new comprehensive assessment tool that assists in defining sexually abusive youth. This tool, the Multiplex Empirically Guided Inventory of Ecological Aggregates for Assessing Sexually Abusive Children and Adolescents (Ages 19 and under) (MEGA; Miccio-Fonseca, 2006b), encompasses neuropsychological elements, coercive aspects, and predatory elements as essential factors to consider in comprehensive assessments of sexually abusive youth. [ABSTRACT FROM AUTHOR]

This article presents intervention strategies based on the Trauma Outcome Process, an integrated treatment model for guiding clinical practice with children with sexually abusive behavior problems. The steps for completing a comprehensive assessment are reviewed, and strategies are presented to help clinicians create a therapeutic alliance and increase these children's self-awareness of their thoughts, feelings, and body sensations. Treatment techniques based on an integrated approach combining cognitive-behavioral and expressive therapy approaches are described. These exercises help children accept responsibility for sexually inappropriate behavior and select adaptive responses for coping with the effects of traumatic experiences. [ABSTRACT FROM AUTHOR]

This article presents the Trauma Outcome Process, an integrated treatment model for guiding clinical practice with children with sexually abusive behavior problems. Criteria for identifying children with sexually abusive behavior problems arc presented. The Trauma Outcome Process is presented and compared with other approaches commonly used in clinical practice with sexually abused children and juvenile sexual offenders. The application of the Trauma Outcome Process model in assessing children with sexually abusive behavior problems is discussed and specific steps are provided to guide the assessment process. The advantages of the Trauma Outcome Process model over victim-specific or offender-specific approaches are highlighted. [ABSTRACT FROM AUTHOR]

There are two schools of thought for providing play therapy to children: non-directive and focused. This paper reviews the rationale for both non-directive and focused approaches to play therapy. The authors discuss why non-directive therapy alone may be ineffective in treating sexually abused children and abuse-reactive children. A prescriptive approach is proposed that combines the rapport building component of non-directive play therapy with focused techniques (i.e., cognitive-behavioral therapy, metaphors, bibliotherapy, and art therapy). The authors discuss how this integrated approach can meet the therapeutic needs of sexually abused and abuse-reactive children. [ABSTRACT FROM AUTHOR]

Abstract Background Fibulin-1 is one of a few extracellular matrix proteins present in blood in high concentrations. We aimed to define the relationship between plasma fibulin-1 levels and risk markers of cardiovascular disease. Methods Plasma fibulin-1 was determined in subjects with chronic kidney disease (n = 32; median age 62.5, inter-quartile range 51 – 73 years) and 60 age-matched control subjects. Among kidney disease patients serological biomarkers related to cardiovascular disease (fibrinogen, interleukin 6, C-reactive protein) were measured. Arterial applanation tonometry was used to determine central hemodynamic and arterial stiffness indices. Results We observed a positive correlation of fibulin-1 levels with age (r = 0.38; p = 0.033), glycated hemoglobin (r = 0.80; p = 0.003), creatinine (r = 0.35; p = 0.045), and fibrinogen (r = 0.39; p = 0.027). Glomerular filtration rate and fibulin-1 were inversely correlated (r = −0.57; p = 0.022). There was a positive correlation between fibulin-1 and central pulse pressure (r = 0.44; p = 0.011) and central augmentation pressure (r = 0.55; p = 0.001). In a multivariable regression model, diabetes, creatinine, fibrinogen and central augmentation pressure were independent predictors of plasma fibulin-1. Conclusion Increased plasma fibulin-1 levels were associated with diabetes and impaired kidney function. Furthermore, fibulin-1 levels were associated with hemodynamic cardiovascular risk markers. Fibulin-1 is a candidate in the pathogenesis of cardiovascular disease observed in chronic kidney disease and diabetes.

Abstract Background Seasonal variation in the occurrence of cardiovascular diseases has been recognized for decades. In particular, incidence rates of hospitalization with atrial fibrillation (AF) and stroke have shown to exhibit a seasonal variation. Stroke in AF patients is common and often severe. Obtaining a description of a possible seasonal variation in the occurrence of stroke in AF patients is crucial in clarifying risk factors for developing stroke and initiating prophylaxis treatment. Methods Using a dynamic generalized linear model we were able to model gradually changing seasonal variation in hospitalization rates of stroke in AF patients from 1977 to 2011. The study population consisted of all Danes registered with a diagnosis of AF comprising 270,017 subjects. During follow-up, 39,632 subjects were hospitalized with stroke. Incidence rates of stroke in AF patients were analyzed assuming the seasonal variation being a sum of two sinusoids and a local linear trend. Results The results showed that the peak-to-trough ratio decreased from 1.25 to 1.16 during the study period, and that the times of year for peak and trough changed slightly. Conclusion The present study indicates that using dynamic generalized linear models provides a flexible modeling approach for studying changes in seasonal variation of stroke in AF patients and yields plausible results.

Abstract Background A high perioperative inspiratory oxygen fraction (FiO2) may reduce the frequency of surgical site infection. Perioperative atelectasis is caused by absorption, compression and reduced function of surfactant. It is well accepted, that ventilation with 100% oxygen for only a few minutes is associated with significant formation of atelectasis. However, it is still not clear if a longer period of 80% oxygen results in more atelectasis compared to a low FiO2. Our aim was to assess if a high FiO2 is associated with impaired oxygenation and decreased pulmonary functional residual capacity (FRC). Methods Thirty-five patients scheduled for laparotomy for ovarian cancer were randomized to receive either 30% oxygen (n = 15) or 80% oxygen (n = 20) during and for 2 h after surgery. The oxygenation index (PaO2/FiO2) was measured every 30 min during anesthesia and 90 min after extubation. FRC was measured the day before surgery and 2 h after extubation by a rebreathing method using the inert gas SF6. Results Five min after intubation, the median PaO2/FiO2 was 69 kPa [53-71] in the 30%-group vs. 60 kPa [47-69] in the 80%-group (P = 0.25). At the end of anesthesia, the PaO2/FiO2 was 58 kPa [40-70] vs. 57 kPa [46-67] in the 30%- and 80%-group, respectively (P = 0.10). The median FRC was 1993 mL [1610-2240] vs. 1875 mL [1545-2048] at baseline and 1615 mL [1375-2318] vs. 1633 mL [1343-1948] postoperatively in the 30%- and 80%-group, respectively (P = 0.70). Conclusion We found no significant difference in oxygenation index or functional residual capacity between patients given 80% and 30% oxygen for a period of approximately 5 hours. Trial registration ClinicalTrials.gov Identifier: NCT00637936.

Abstract Background Titin is a muscle-specific protein found in cardiac and skeletal muscles which is responsible for restoring passive tension. Levels and functioning of titin have been shown to be affected by cardiac damage. Due to the inherent difficulty of measuring titin levels in vivo in a clinical setting, we aimed to develop an assay that could reliably measure fragments of degraded titin in serum and potentially be used in the assessment of cardiac muscle damage. Methods A competitive ELISA was developed to specifically measure levels of the titin sequence 12670’ NVTVEARLIK 12679’, derived by the degradation of titin by matrix metalloproteinase (MMP)-12. Serum samples from 90 individuals were divided into 3 equally sized groups. One group had been diagnosed with acute myocardial infarction (AMI) while the remaining two were asymptomatic individuals either with CT-scan signs of coronary calcium (CT-plusCa) or without coronary calcium (CT-noCa). Results Mean geometric levels of the titin fragment in the CT-noCa group were 506.5 ng/ml (±43.88). The CT-plusCa group showed 50.6% higher levels of the marker [763 ng/ml (±90.14)] (P Conclusions The titin-12670 fragment is present in both individuals with undiagnosed and diagnosed CVD. The statistically significant increase in level of the marker in the AMI group is indicative that this neoepitope biomarker may be a useful serological marker in AMI.

Abstract Background Ambulance personnel play an essential role in the ‘Chain of Survival’. The prognosis after out-of-hospital cardiac arrest was dismal on a rural Danish island and in this study we assessed the cardiopulmonary resuscitation performance of ambulance personnel on that island. Methods The Basic Life Support (BLS) and Automated External Defibrillator (AED) skills of the ambulance personnel were tested in a simulated cardiac arrest. Points were given according to a scoring sheet. One sample t test was used to analyze the deviation from optimal care according to the 2005 guidelines. After each assessment, individual feedback was given. Results On 3 consecutive days, we assessed the individual EMS teams responding to OHCA on the island. Overall, 70% of the maximal points were achieved. The hands-off ratio was 40%. Correct compression/ventilation ratio (30:2) was used by 80%. A mean compression depth of 40–50 mm was achieved by 55% and the mean compression depth was 42 mm (SD 7 mm). The mean compression rate was 123 per min (SD 15/min). The mean tidal volume was 746 ml (SD 221 ml). Only the mean tidal volume deviated significantly from the recommended (p = 0.01). During the rhythm analysis, 65% did not perform any visual or verbal safety check. Conclusion The EMS providers achieved 70% of the maximal points. Tidal volumes were larger than recommended when mask ventilation was applied. Chest compression depth was optimally performed by 55% of the staff. Defibrillation safety checks were not performed in 65% of EMS providers.

Abstract Background Generalized arterial alterations, such as endothelial dysfunction, medial matrix accumulations, and calcifications are associated with type 2 diabetes (T2D). These changes may render the vessel wall more susceptible to injury; however, the molecular characteristics of such diffuse pre-atherosclerotic changes in diabetes are only superficially known. Methods To identify the molecular alterations of the generalized arterial disease in T2D, DNA microarrays were applied to examine gene expression changes in normal-appearing, non-atherosclerotic arterial tissue from 10 diabetic and 11 age-matched non-diabetic men scheduled for a coronary by-pass operation. Gene expression changes were integrated with GO-Elite, GSEA, and Cytoscape to identify significant biological pathways and networks. Results Global pathway analysis revealed differential expression of gene-sets representing matrix metabolism, triglyceride synthesis, inflammation, insulin signaling, and apoptosis. The network analysis showed a significant cluster of dysregulated genes coding for both intra- and extra-cellular proteins associated with vascular cell functions together with genes related to insulin signaling and matrix remodeling. Conclusions Our results identify pathways and networks involved in the diffuse vasculopathy present in non-atherosclerotic arterial tissue in patients with T2D and confirmed previously observed mRNA-alterations. These abnormalities may play a role for the arterial response to injury and putatively for the accelerated atherogenesis among patients with diabetes.

Abstract Background Abdominal aortic calcifications (AAC) predict cardiovascular mortality. A new scoring model for AAC, the Morphological Atherosclerotic Calcification Distribution (MACD) index may contribute with additional information to the commonly used Aortic Calcification Severity (AC24) score, when predicting death from cardiovascular disease (CVD). In this study we investigated associations of MACD and AC24 with traditional metabolic-syndrome associated risk factors at baseline and after 8.3 years follow-up, to identify biological parameters that may account for the differential performance of these indices. Methods Three hundred and eight healthy women aged 48 to 76 years, were followed for 8.3 ± 0.3 years. AAC was quantified using lumbar radiographs. Baseline data included age, weight, blood pressure, blood lipids, and glucose levels. Pearson correlation coefficients were used to test for relationships. Results At baseline and across all patients, MACD correlated with blood glucose (r2 = 0.1, P< 0.001) and to a lesser, but significant extent with traditional risk factors (p < 0.01) of CVD. In the longitudinal analysis of correlations between baseline biological parameters and the follow-up calcification assessment using radiographs we found LDL-cholesterol, HDL/LDL, and the ApoB/ApoA ratio significantly associated with the MACD (P< 0.01). In a subset of patients presenting with calcification at both baseline and at follow-up, all cholesterol levels were significantly associated with the MACD (P< 0.01) index. AC24 index was not correlated with blood parameters. Conclusion Patterns of calcification identified by the MACD, but not the AC24 index, appear to contain useful biological information perhaps explaining part of the improved identification of risk of cardiovascular death of the MACD index. Correlations of MACD but not the AC24 with glucose levels at baseline suggest that hyperglycemia may contribute to unique patterns of calcification indicated by the MACD.

Abstract Background Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes. Methods Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured. Results The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia. Conclusions Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown. Trial registration number at http://www.clinicaltrial.gov: NCT00298844

Abstract Objective Plasma osteoprotegerin (P-OPG) is an independent predictor of cardiovascular disease in diabetic and other populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells and increased P-OPG may reflect arterial damage. We investigated the correlation between P-OPG and coronary artery disease (CAD) in asymptomatic type 2 diabetic patients with microalbuminuria. Methods P-OPG was measured in 200 asymptomatic diabetic patients without known cardiac disease. Patients with P-NT-proBNP >45.2 ng/l and/or coronary calcium score (CCS) ≥400 were stratified as high risk of CAD (n = 133), and all other patients as low risk patients (n = 67). High risk patients were examined by myocardial perfusion imaging (MPI; n = 109), and/or CT-angiography (n = 20), and/or coronary angiography (CAG; n = 86). Significant CAD was defined by presence of significant myocardial perfusion defects at MPI and/or >70% coronary artery stenosis at CAG. Results Significant CAD was demonstrated in 70 of the high risk patients and of these 23 patients had >70% coronary artery stenosis at CAG. Among high risk patients, increased P-OPG was an independent predictor of significant CAD (adjusted odds ratio [CI] 3.11 [1.01-19.54] and 3.03 [1.00-9.18] for second and third tertile vs.first tertile P-OPG, respectively) and remained so after adjustments for NT-proBNP and CCS. High P-OPG was also associated with presence of >70% coronary artery stenosis(adjusted odds ratio 14.20 [1.35-148.92] for third vs. first tertile P-OPG), and 91% of patients with low (first tertile) P-OPG did not have >70% coronary artery stenosis. Conclusions Elevated P-OPG is an independent predictor of the presence of CAD in asymptomatic type 2 diabetic patients with microalbuminuria.

Abstract Background A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension. Two trials have shown that a high perioperative inspiratory oxygen fraction (FiO2 = 0.80) significantly reduced risk of surgical site infections after elective colorectal surgery, but a third trial was stopped early because the frequency of surgical site infections was more than doubled in the group receiving FiO2 = 0.80. It has not been settled if a high inspiratory oxygen fraction increases the risk of pulmonary complications, such as atelectasis, pneumonia and respiratory failure. The aim of our trial is to assess the potential benefits and harms of a high perioperative oxygen fraction in patients undergoing abdominal surgery. Methods and design The PROXI-Trial is a randomized, patient- and assessor blinded trial of perioperative supplemental oxygen in 1400 patients undergoing acute or elective laparotomy in 14 Danish hospitals. Patients are randomized to receive either 80% oxygen (FiO2 = 0.80) or 30% oxygen (FiO2 = 0.30) during surgery and for the first 2 postoperative hours. The primary outcome is surgical site infection within 14 days. The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit. The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power. Discussion This trial assesses benefits and harms of a high inspiratory oxygen fraction, and the trial may be generalizable to a general surgical population undergoing laparotomy. Trial registration ClinicalTrials.gov identifier: NCT00364741.

Objectives: Irreversible tissue damage is frequently present at the time of diagnosis in systemic sclerosis (SSc), which calls for earlier diagnosis. This study estimated healthcare utilization three years before the diagnosis of SSc., Methods: We conducted a population-based cohort study using data from Danish national registries. Incident patients diagnosed with SSc between January 1, 2005, and December 31, 2018, were matched by age and gender with 10 references without SSc. The date of diagnosis was the index date. We estimated quarterly rates and adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CI) of healthcare utilization in the three years preceding the diagnosis for patients with SSc and their references., Results: A total of 1,650 SSc patients (1,255 women and 395 men) and 16 500 non-SSc references were included. The mean age was 58 years (interquartile range 48-68). Three years before diagnosis, patients with SSc had more contacts with general practice (IRRwomen= 1.43 [95% CI: 1.33; 1.53], IRRmen= 1.47 [95% CI: 1.26; 1.71]) and hospitals (IRRwomen= 1.86 [95% CI: 1.62; 2.14], IRRmen= 2.70 [95% CI: 2.04; 3.58]) compared with their references. In the last three months before diagnosis, patients with SSc had significantly more contacts with general practice (IRRwomen= 2.30 [95% CI: 2.16; 2.44], IRRmen= 2.98 [95% CI: 2.64; 3.35]) and hospitals (IRRwomen= 5.62 [95% CI: 5.08; 6.20], IRRmen= 9.53 [95% CI: 7.81; 11.63])., Conclusion: The higher use of healthcare services in general practice and hospitals in the three years before diagnosis suggests an opportunity to facilitate earlier diagnosis and treatment of SSc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Multiple myeloma often presents with vague and non-specific symptoms. Many patients are diagnosed in unplanned rather than elective (planned) diagnostic pathways. This study investigates the diagnosis of multiple myeloma in unplanned pathways and the association with patient characteristics, disease profile, and survival., Methods: We conducted a nationwide register-based study, including all patients diagnosed with multiple myeloma in Denmark in 2014-2018. Patients were categorised as diagnosed in an unplanned pathway if registered with an acute admission within 30 days prior to the multiple myeloma diagnosis and no other previously registered pathway to this diagnosis. Unplanned pathways were compared to all other pathways combined., Results: We included 2,213 patients diagnosed with multiple myeloma, hereof 32% diagnosed in an unplanned pathway. Comorbidity, no prior cancer diagnosis, a history of few visits to the general practitioner (GP), multiple myeloma complications at diagnosis, high-risk cytogenetics, and advanced cancer stage were associated with a higher probability of being diagnosed in an unplanned pathway. For example, 24.4% (95% confidence interval (CI): 21.8-27.0) of patients with low comorbidity (Charlson Comorbidity Index (CCI) score 0) were diagnosed in an unplanned pathway as were 50.9% (95% CI: 45.6-56.1) of patients with high comorbidity (CCI score 3+). For patients with dialysis need at the time of diagnosis the probability was 66.0% (95% CI 54.2-77.8) and 30.9% (95% CI: 28.9-32.9) for patients with no dialysis need. Patients diagnosed in an unplanned pathway had inferior survival (hazard ratio 1.44 (95% CI: 1.26-1.64)). However, this association was not seen in analyses restricted to patients surviving for more than three years., Conclusions: High comorbidity level, few usual GP visits, advanced disease status at diagnosis, and complications were associated with diagnosis in an unplanned pathway. Further, patients diagnosed in an unplanned pathway had inferior survival. Promoting earlier diagnosis and preventing unplanned pathways may help improve survival in multiple myeloma., (© 2024. The Author(s).)

Stormwater runoff from urban areas contain a wide variety of pollutants which is typically managed using stormwater retention ponds. However, their performance with regards to emerging pollutants such as microplastics and tyre wear material remains unclear. In this study, samples of effluent water and sediments from four stormwater retention ponds were analysed for their content of microplastics and tyre wear material. Microplastics were analysed using state-of-the-art hyperspectral imaging technique while tyre wear material was analysed using pyrolysis-GC-MS. Microplastics were recovered in all samples and the mass balance revealed that on average 88% of small microplastics (<500 µm) were retain in the ponds while the removal efficiency for large microplastics (>500 µm) was 95%. Tyre wear material was identified in all sediment samples but found below the detection limit in three out of four effluent samples. On average 95% of the tyre wear material was removed by the retention ponds. The results from this study show that stormwater retention ponds are very effective in removing microplastics as well as tyre wear material from stormwater runoff., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: To investigate the association between fear of cancer recurrence (FCR) and healthcare use in general practice among cancer survivors., Methods: We linked nationwide register data to survey data on FCR in cancer survivors at 2.5 years after a cancer diagnosis. Multiple regression models were used to analyse the association between high FCR level and quartiles of healthcare use at 18-30 months before the cancer diagnosis (habitual healthcare use) and between high FCR level and healthcare use at 18-30 months after the cancer diagnosis (survivorship healthcare use)., Results: We included 1538 cancer survivors in the study. High habitual healthcare use was associated with a high level of FCR (odds ratio = 2.07 (95% confidence interval (CI): 1.36-3.15)) for the 4th quartile of healthcare use compared to the 1st quartile. A high FCR score was also associated with higher healthcare use during cancer survivorship (incidence rate ratio (IRR) = 1.26 (95% CI: 1.14-1.40)). This association remained statistically significant when adjusting for habitual healthcare use (IRR = 1.20 (95% CI: 1.09-1.33))., Conclusion: High healthcare use before the cancer diagnosis was associated with high FCR during survivorship. This indicates that FCR is partly explained by a general (pre-diagnostic) health concern. High FCR predicted high healthcare use during cancer survivorship, even when adjusting for habitual healthcare use., Implications for Cancer Survivors: Our results suggest that FCR in cancer survivors is triggered by a general high level of health concern, and the cancer diagnosis may further exacerbate this concern., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Shape matters for microplastics, but its definition, particularly for hyperspectral imaged microplastics, remains ambiguous and inexplicit, leading to incomparability across data. Hyperspectral imaging is a common approach for quantification, yet no unambiguous microplastic shape classification exists. We conducted an expert-based survey and proposed a set of clear and concise shapes ( fiber , rod , ellipse , oval , sphere , quadrilateral , triangle , free-form , and unidentifiable ). The categories were validated on images of 11,042 microplastics from four environmental compartments (seven matrices: indoor air; wastewater influent, effluent, and sludge; marine water; stormwater; and stormwater pond sediments), by inviting five experts to score each shape. We found that the proposed shapes were well defined, representative, and distinguishable to the human eye, especially for fiber and sphere . Ellipse , oval , and rod were though less distinguishable but dominated in all water and solid matrices. Indoor air held more unidentifiable , an abstract shape that appeared mostly for particles below 30 μm. This study highlights the need for assessing the recognizability of chosen shape categories prior to reporting data. Shapes with a clear and stringent definition would increase comparability and reproducibility across data and promote harmonization in microplastic research.

Background: Patients with multimorbidity are frequent users of healthcare, but fragmented care may lead to suboptimal treatment. Yet, this has never been examined across healthcare sectors on a national scale. We aimed to quantify care fragmentation using various measures and to analyze the associations with patient outcomes., Methods: We conducted a register-based nationwide cohort study with 4.7 million Danish adult citizens. All healthcare contacts to primary care and hospitals during 2018 were recorded. Clinical fragmentation indicators included number of healthcare contacts, involved providers, provider transitions, and hospital trajectories. Formal fragmentation indices assessed care concentration, dispersion, and contact sequence. The patient outcomes were potentially inappropriate medication and all-cause mortality adjusted for demographics, socioeconomic factors, and morbidity level., Results: The number of involved healthcare providers, provider transitions, and hospital trajectories rose with increasing morbidity levels. Patients with 3 versus 6 conditions had a mean of 4.0 versus 6.9 involved providers and 6.6 versus 13.7 provider transitions. The proportion of contacts to the patient's own general practice remained stable across morbidity levels. High levels of care fragmentation were associated with higher rates of potentially inappropriate medication and increased mortality on all fragmentation measures after adjusting for demographic characteristics, socioeconomic factors, and morbidity. The strongest associations with potentially inappropriate medication and mortality were found for ≥ 20 contacts versus none (incidence rate ratio 2.83, 95% CI 2.77-2.90) and ≥ 20 hospital trajectories versus none (hazard ratio 10.8, 95% CI 9.48-12.4), respectively. Having less than 25% of contacts with your usual provider was associated with an incidence rate ratio of potentially inappropriate medication of 1.49 (95% CI 1.40-1.58) and a mortality hazard ratio of 2.59 (95% CI 2.36-2.84) compared with full continuity. For the associations between fragmentation measures and patient outcomes, there were no clear interactions with number of conditions., Conclusions: Several clinical indicators of care fragmentation were associated with morbidity level. Care fragmentation was associated with higher rates of potentially inappropriate medication and increased mortality even when adjusting for the most important confounders. Frequent contact to the usual provider, fewer transitions, and better coordination were associated with better patient outcomes regardless of morbidity level., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Abstract: We developed an animal model of activity-induced muscle pain that is dependent on local macrophage activation and release of interleukin-1β (IL-1β). Activation of purinergic type 2X (P2X) 7 receptors recruits the NOD-like receptor protein (NLRP) 3 and activates Caspase-1 to release IL-1β. We hypothesized that pharmacological blockade of P2X7, NLRP3, and Caspase-1 would prevent development of activity-induced muscle pain in vivo and release of IL-1β from macrophages in vitro. The decrease in muscle withdrawal thresholds in male, but not female, mice was prevented by the administration of P2X7, NLRP3, and Caspase-1 inhibitors before induction of the model, whereas blockade of IL-1β before induction prevented muscle hyperalgesia in both male and female mice. Blockade of P2X7, NLRP3, Capsase-1, or IL-1β 24 hours, but not 1 week, after induction of the model alleviated muscle hyperalgesia in male, but not female, mice. mRNA expression of P2X7, NLRP3, Caspase-1, and IL-1β from muscle was increased 24 hours after induction of the model in both male and female mice. Using multiplex, increases in IL-1β induced by combining adenosine triphosphate with pH 6.5 in lipopolysaccharide-primed male and female macrophages were significantly lower with the presence of inhibitors of P2X7 (A740003), NLRP3 (MCC950), and Caspase-1 (Z-WEHD-FMK) when compared with the vehicle. The current data suggest the P2X7/NLRP3/Caspase-1 pathway contributed to activity-induced muscle pain initiation and early maintenance phases in male but not female, and not in late maintenance phases in male mice., (Copyright © 2023 International Association for the Study of Pain.)

In this study, seven roads and parking lots were sampled by a road surface cleaning truck and approximately 100 kg of particulate material was collected per site. Thereafter, the samples were analysed for microplastics, including tyre wear particles. The analyses revealed that tyre wear constituted 0.09 % of the dry mass of the samples on average. Other plastic types were also identified in the samples, but at on average 49 times lower concentrations compared to tyre wear particles. Although the roads and parking lots were used for residential, industrial, and commercial purposes, no correlation between land use and the total concentrations of microplastics was identified. Of microplastics other than tyre wear particles, polypropylene constituted an important fraction in all samples, whereas other polymers were present at various degrees. The contents of heavy metals, sulphur, and total organic carbon were also measured in the samples, but no correlation between them and microplastics was determined. A back-of-the-envelope estimation indicated that the tyre wear material retained by permeable pavements constituted a non-negligible fraction of the total mass of microplastics released on roads and parking lots. Therefore, permeable pavements can serve as a tool for the management of this pollutant., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To explore health-care use in the 12 months preceding a diagnosis of RA in Denmark., Methods: We conducted a population-based cohort study using data from national registries. Every patient diagnosed with RA in 2014-18 was matched to 10 reference individuals without RA from the Danish background population. Health-care use was defined as contacts to general practitioners, contacts to private practicing physiotherapists, and X-rays of hands and/or feet performed in primary or secondary care. We estimated the monthly contact rates for patients and references in the 12 months preceding the diagnosis, and we compared incidence rates for health-care use in each month between the two groups while adjusting for sociodemographic characteristics and comorbidity., Results: We included 7427 patients with RA and 74 270 references. Patients with RA had increasing contact rates with general practitioners and physiotherapists from 6 to 8 months before the diagnosis. Compared with references, women with RA had statistically significantly more contacts to general practitioners and physiotherapists during all 12 months. A similar contact pattern was seen in men, albeit less distinct. The number of X-rays increased slightly from 8 months before the diagnosis, with a steep increase in the last 3 months., Conclusion: Increased contacts to general practitioners and physiotherapists were seen in all 12 months preceding the RA diagnosis, intensifying in the last 6 to 8 months. Imaging increased from 3 months before the diagnosis. This indicates an opportunity to expedite referral to specialist care and ensure earlier diagnosis of RA., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The aim was to investigate the characteristics of cancer survivors with high levels of fear of cancer recurrence, and how such fear is associated with their needs for care., Methods: This cross-sectional study was based on survey data from Danish cancer survivors at 2.5 years after a cancer diagnosis. These data were linked to nationwide register data. We used the 7-item Fear of Cancer Recurrence Inventory (FCR7) to measure fear of cancer recurrence, focussing on emotional, cognitive and behavioural reactions to such fear. The FCR7 score was dichotomised at the 75th percentile. A logistic regression model was used to analyse the associations between a high level of fear of cancer recurrence and (1) characteristics of patient and primary cancer and (2) cancer survivors' statements concerning follow-up for cancer., Results: We included 1538 cancer survivors in the study. The median FCR7 score was 18 (interquartile interval: 13-21), and 366 (23.8%) respondents had an FCR7 score of > 21, defined as a high level of fear. In the adjusted analyses, a high level of fear was associated with female sex, younger age, comorbidity, advanced tumour stage and negative statements concerning follow-up, including feeling less safe in the follow-up programme. Fear was not related to the professional background of care providers involved in cancer follow-up., Conclusion: Fear of cancer recurrence was associated with female sex, younger age, comorbidity, advanced tumour stage and discontent with cancer follow-up., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: This study explores how women diagnosed with breast cancer may be supported by physicians and nurses during physical and existential changes related to oncoplastic breast surgery in Denmark. The following research questions were addressed: (a) how do women experience oncoplastic breast surgery, and (b) how does cancer treatment affect their body image?, Design: A descriptive qualitative study design with a six-step thematic analysis influenced by Braun and Clarke was applied in this study. This paper has been prepared in accordance with the consolidated criteria for reporting qualitative research., Methods: Fourteen in-depth interviews with seven women diagnosed with breast cancer were conducted from August 2018 to March 2019. In this qualitative study, data analysis was performed concurrent with data construction, recognizing that the process of analysis and making sense of data should start during the interviews. We explicitly frame the discussion of the findings in a theory of embodiment influenced by Merleau-Ponty, consistent with the construct of exploring human experiences to generate meaningful knowledge for applied practice., Results: Two overall themes with related subthemes were identified: (1) 'Treatment is required for life-threatening cancer', and (2) 'Striving for a new normal body'. Across both themes, women's experiences reflected a 'time pendulum' as they contemplated their past identity, their current rationale and their transition to a future beyond breast cancer with a changed body., Conclusion: Participants reflected on their past, present and future when facing an altered body image caused by their breast cancer diagnosis and oncoplastic breast surgery. The participants in the study expressed broad levels of satisfaction with the results of the oncoplastic breast surgery. The reconstructed breast helped them to live normally again, in particular maintaining interpersonal relationships. Breast reconstruction supported participants' embodiment experiences and redefinition of their 'new normal'., Impact: This study showed the dynamic changes in self-definition from receiving a breast cancer diagnosis and cancer treatment to oncoplastic breast surgery. The main finding of self-redefinition was from the perspective of breast cancer women who were in a period of transition between post-diagnosis and consultation for oncoplastic breast surgery. The findings indicate that advanced nurse specialists in the field of oncoplastic breast surgery can enhance psychosocial wellbeing and support women pre- and post-operatively by focusing on patient experiences of self-image and embodiment., (© 2022 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

Objective: To describe the use of healthcare prior to a diagnosis of pancreatic cancer in Denmark., Design: A population-based cohort study using prospectively recorded data from Danish National Health Registries., Setting: Danish general practice and hospitals., Subjects: A total of 5926 patients diagnosed with pancreatic cancer in 2012-2018 and 59,260 matched references without pancreatic cancer from the Danish general population., Main Outcome Measures: The monthly frequency of healthcare use (contacts and tests in general practice and contacts and diagnostic investigations in hospitals) during the 12 months preceding the pancreatic cancer diagnosis and a corresponding index date assigned to the references., Results: Compared to the references, the patients had increased contacts and diagnostic tests, especially blood glucose testing, in general practice from 7 to 12 months before diagnosis. Hospital contacts and diagnostic imaging increased from 5 months before the diagnosis., Conclusions: The pattern of increasing healthcare contacts before a diagnosis of pancreatic cancer may represent a window of opportunity to diagnose pancreatic cancer earlier. The increased use of blood glucose test in general practice may represent an important sign of an underlying disease. Key pointsPancreatic cancer is a rapidly progressing and highly lethal disease. Focus on early diagnosis is essential to improve the prognosis.Patients with pancreatic cancer had increased number of healthcare contacts from 7 months before the diagnosis.Patients with pancreatic cancer had increased number of blood glucose tests taken throughout almost the entire year before the diagnosis.The results may indicate that a window of opportunity exists to diagnose pancreatic cancer earlier.

Objective: This study aimed to investigate the first point of contact in patients diagnosed with pancreatic cancer, and to study factors associated with the GP's suspicion of cancer, Cancer Patient Pathway (CPP) referral and long diagnostic interval., Design: Cross-sectional study combining register and survey data., Patients: Patients with incident pancreatic cancer recorded in the Danish National Patient Register (n = 303)., Main Outcome Measures: The patient's first point of symptoms presentation, GP's cancer suspicion, CPP referral and diagnostic interval., Results: General practice was the first point of contact for 85.5% of the population. At the first consultation, cancer was suspected in 32.7% and 22.9% were referred to a CPP. The GPs were more likely to suspect cancer or serious illness in patients aged >70 years (prevalence rate ratio (PRR) 1.34, 95% CI 1.09-1.66) and among patients with high comorbidity (PRR 1.23, 95% CI 1.04-1.47). A CPP referral was less likely among patients with low education. The median diagnostic interval was 39 days (interquartile range: 15-72). When the GP initially did not suspect cancer, the likelihood of longer diagnostic interval increased., Conclusion: The majority of patients with pancreatic cancer began their diagnostic route in general practice. Diagnosing pancreatic cancer swiftly in general practice was challenging; the GP did often not initially suspect cancer or refer to a CPP and several of the patient characteristics were associated with the GPs initial suspicion of cancer or CPP referral. Thus, there may be room for improvements in the diagnostics of pancreatic cancer in general practice.Key pointsPatients with pancreatic cancer have a poor prognosis, as pancreatic cancer is often diagnosed in late stage.The majority of patients with pancreatic cancer began their diagnostic process in general practice.General practitioners (GPs) suspected cancer at the first consultation in one out of three patients with pancreatic cancer; more often in older and comorbid patients.The GPs suspicion of cancer was associated with urgent referral and shorter time to diagnosis.

The mesophilic digester of a wastewater treatment plant serving 790,000 inhabitants was analyzed for incoming and outgoing microplastics (MPs). The annual MP load on the digester was 7326 kg y -1 and 1.20 × 10 14 N y -1 , while the digested sludge contained 4885 kg y -1 and 0.85 × 10 14 N y -1 . The corresponding mean reduction of approximately 30% was though within the variability of the analyzed samples, and size distributions and polymer composition before and after the digester could similarly neither confirm nor deny if MPs were lost in the digester. The load on the digester corresponded to a per capita load of 0.025 g capita -1 day -1 or 4.14 × 10 5 N capita -1 day -1 . In terms of MP numbers, the values were high compared to most previous studies, which most likely was due to differences in analytical methods, where the present study applied FPA-μFTIR hyperspectral imaging with automatized MP recognition in the size range 10-500 μm and ATR-FTIR on all particles in the range 500-5000 μm. The polymer composition was quite diverse, with 15 identified polymer types, of which polyethylene and polyester were the most common in the sludge, while the variation in composition was larger in the grease that came from the plant's grease trap and the fatty slurries which came from grease traps in the drainage area. The load on the digester was finally used to demonstrate how especially the determined mass loads can be used to set upper boundaries for specific sources, for example human excretion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To analyse healthcare utilisation in colorectal cancer (CRC) survivors in the 12 months preceding a diagnosis of CRC recurrence., Methods: This register-based cohort study included curatively treated survivors of CRC diagnosed in 2008-2018. Survivors with CRC recurrence were matched 1:5 with recurrence-free survivors. We estimated the monthly frequency of healthcare utilisation before the recurrence diagnosis and a corresponding index date assigned to the matched population. A regression model was used to compare healthcare utilisation between groups., Results: We included 3045 survivors with recurrence and 15,225 recurrence-free survivors. At study entry, both groups had on average one contact per month to general practice. Compared with recurrence-free survivors, survivors with recurrence had more contacts to general practice from 10 months before the diagnosis and more haemoglobin measurements from 4 months before the diagnosis. They had more contacts to hospitals and follow-up clinics from 7 months before the diagnosis and more diagnostic investigations from 2 months before the diagnosis., Conclusion: General practitioners have regular contact with CRC survivors and are involved in detecting recurrence. The increased number of contacts in the months before the rise in diagnostic investigations indicates an opportunity to expedite referral to diagnostics and the diagnosis of CRC recurrence., (© 2021 John Wiley & Sons Ltd.)

Engaging with ethical issues is central to the management of neonatal encephalopathy (NE). As treatment for these neonates evolves, new ethical issues will arise and many existing challenges will remain. We highlight three key ethical issues that arise in the care of neonates with NE treated with therapeutic hypothermia: facilitating shared decision making, understanding futility, and defining the boundaries between standard of care and research. Awareness of these issues will help clinicians counsel families in light of evolving treatments and outcomes., (Copyright © 2021. Published by Elsevier Ltd.)

A complete plastic particle mass balance was established at Sweden's second-largest wastewater treatment plant. It comprised material collected at its two bar screens, a 20 mm and a 2 mm one, in the influent water after the 20 mm screen, the effluent water, and the digested sludge. Macro- and microplastics above 500 µm were analysed individually applying ATR-FTIR, while microplastics of 10-500 µm were analysed by µFTIR imaging with automated particle recognition. Masses of plastics >500 µm were determined by weighting, while the mass of the smaller microplastics was estimated from the imaging. The total plastic load on the plant was 202.2 kg d -1 , of which the two screens retained 73%. The remaining plastic mass was found in the sludge (13.6%) and the effluent (0.4%). The missing 12.7% could be caused by sampling and measuring uncertainties and potentially also fragmentation below the size detection limit of the analytical approach, or by degradation. The bar screens furthermore retained plastics smaller than the screen size, indicating that this material should be taken into account also when solely looking at smaller particles. The overall treatment efficiency of the plant was high: 99.6% considering both macro- and microplastics, and 98.8% considering only microplastics <500 µm., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Recurrence of endometrial cancer is not routinely registered in the Danish national health registers. The aim of this study was to develop and validate a register-based algorithm to identify women diagnosed with endometrial cancer recurrence in Denmark to facilitate register-based research in this field., Material and Methods: We conducted a cohort study based on data from Danish health registers. The algorithm was designed to identify women with recurrence and estimate the accompanying diagnosis date, which was based on information from the Danish National Patient Registry and the Danish National Pathology Registry. Indicators of recurrence were pathology registrations and procedure or diagnosis codes suggesting recurrence and related treatment. The gold standard for endometrial cancer recurrence originated from a Danish nationwide study of 2612 women diagnosed with endometrial cancer, FIGO stage I-II during 2005-2009. Recurrence was suspected in 308 women based on pathology reports, and recurrence suspicion was confirmed or rejected in the 308 women based on reviews of the medical records. The algorithm was validated by comparing the recurrence status identified by the algorithm and the recurrence status in the gold standard., Results: After relevant exclusions, the final study population consisted of 268 women, hereof 160 (60%) with recurrence according to the gold standard. The algorithm displayed a sensitivity of 91.3% (95% confidence interval (CI): 85.8-95.1), a specificity of 91.7% (95% CI: 84.8-96.1) and a positive predictive value of 94.2% (95% CI: 89.3-97.3). The algorithm estimated the recurrence date within 30 days of the gold standard in 86% and within 60 days of the gold standard in 94% of the identified patients., Discussion: The algorithm demonstrated good performance; it could be a valuable tool for future research in endometrial cancer recurrence and may facilitate studies with potential impact on clinical practice.

Background: The organisation of cancer follow-up is under scrutiny in many countries, and general practice is suggested to become more involved. A central focus is timely detection of recurring previous cancer and new second primary cancer. More knowledge on the patient pathway before cancer recurrence and second primary cancer is warranted to ensure the best possible organisation of follow-up. We aimed to describe the healthcare utilisation in the year preceding a diagnosis of cancer recurrence or second primary cancer., Methods: This nationwide register study comprises patients diagnosed with bladder, breast, colorectal, endometrial, lung, malignant melanoma and ovarian cancer in Denmark in 2008-2016. The frequency of healthcare contacts during the 12 months preceding a cancer recurrence or second primary cancer was estimated and compared to the frequency of cancer survivors in cancer remission. The main analyses were stratified on sex and healthcare setting. Furthermore, two sub-analyses were stratified on 1) sex, healthcare setting and age group and on 2) sex, healthcare setting and comorbidity status., Results: The study population consisted of 7832 patients with recurrence and 2703 patients with second primary cancer. On average, the patients were in contact with general practice one time per month in the 12th month preceding a new cancer diagnosis (recurrence or second primary cancer). Increasing contact rates were seen from 7 months before diagnosis in general practice and from 12 months before diagnosis in hospitals. This pattern was more pronounced in patients with cancer recurrence, younger patients and patients with no comorbidity. For instance, the contact rate ratios for hospital contacts in non-comorbid women with recurrence demonstrated 30% more contacts in the 12th month before recurrence and 127% more contacts in the 2nd month before recurrence., Conclusions: The results show that cancer survivors are already seen in general practice on a regular basis. The increasing contact rates before a diagnosis of cancer recurrence or second primary cancer indicate that a window of opportunity exists for more timely diagnosis; this is seen in both general practice and in hospitals. Thus, cancer survivors may benefit from improvements in the organisation of cancer follow-up.

Background: The benefits of extensive lymph node dissection as performed in complete mesocolic excision are still debated, although recent studies have shown an association with improved long-term outcomes. However, none of these studies had an intention-to-treat design or aimed to show a causal effect; therefore in this study, we aimed to estimate the causal oncological treatment effects of complete mesocolic excision on right-sided colon cancer., Methods: We did a population-based cohort study involving prospective data collected from four hospitals in Denmark. We compared the oncological outcome data of patients at one centre performing central lymph node dissection and vascular division after almost complete exposure of the proximal part of the superior mesenteric vein (ie, the complete mesocolic excision group) with three other centres performing conventional resections with unstandardised and limited lymph node dissection (ie, non-complete mesocolic excision; control group). We included data for all patients in the Capital Region of Denmark undergoing elective curative-intent right-sided colon resections for stages I-III colon cancer, as categorised by the Union for International Cancer Control (UICC; 5th edition), from June 1, 2008, to Dec 31, 2013. Patients were followed-up for 5·2 years after surgery. The primary outcome was the cumulative incidence of recurrence after 5·2 years of surgery. Inverse probability of treatment weighting and competing risk analyses were used to estimate the possible causal effects of complete mesocolic excision. This study is registered with ClinicalTrials.gov, number NCT03754075., Findings: 1069 patients (813 in the control group and 256 in the complete mesocolic excision group) underwent curative-intent elective surgery for right-sided colon cancer during the study period. None of the patients were lost to follow-up regarding survival or recurrence status, and consequently no patient was censored in the analyses. The 5·2-year cumulative incidence of recurrence was 9·7% (95% CI 6·3-13·1) in the complete mesocolic excision group compared with 17·9% (15·3-20·5) in the control group, and the absolute risk reduction of complete mesocolic excision after 5·2 years was 8·2% (95% CI 4·0-12·4; p=0·00015). In the control group, 145 (18%) of 813 patients were diagnosed with a recurrence and 281 (35%) died during follow-up, whereas in the complete mesocolic excision group 25 (10%) of 256 patients were diagnosed with a recurrence and 75 (29%) died during follow-up., Interpretation: This study shows a causal treatment effect of central mesocolic lymph node excision on risk of recurrence after resection for right-sided colon adenocarcinoma. Complete mesocolic excision has the potential to reduce the risk of recurrence and improve long-term outcome after resection for all UICC stages I-III of right-sided colon adenocarcinomas., Funding: The Tvergaard Fund, Helen Rude Fund, Krista and Viggo Petersen Fund, Olga Bryde Nielsen Fund, and Else and Mogens Wedell-Wedellsborg Fund., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Specialised follow-up care after cancer treatment is changing towards increased involvement of general practice. To ensure timely detection of new cancer events, knowledge is warranted on the timing of cancer recurrence (CR) and second primary cancer (SPC), including risk factors for CR., Methods: This population-based register study included 67,092 patients diagnosed with malignant melanoma, bladder, lung, ovarian, endometrial, colorectal and breast cancer in Denmark in 2008-2016. The time from primary cancer to CR or SPC and risk factors for prolonged time to CR were analysed and stratified on sex and primary cancer type., Results: Cancer recurrence proportions ranged from 6% to 35%. The risk of CR increased profoundly within the first 3 years and then levelled off, except for breast cancer. A total of 3%-6% of patients had SPC, with monotonously increasing cumulative incidence proportions. Besides primary tumour characteristics, lower educational level, living alone and comorbidity were associated with earlier CR. For example, in female malignant melanoma, HRs and 95% confidence intervals were 0.47 (0.37-0.61) for high educational level, 1.40 (1.16-1.68) for living alone and 2.38 (1.53-3.70) for high comorbidity., Conclusion: The results may inform stratified risk assessment in decision of frequency, location and duration of post-cancer follow-up care., (© 2019 John Wiley & Sons Ltd.)

Objective: Prognosis of Hypoxic-Ischemic Encephalopathy (HIE) remains challenging and uncertain. This paper investigates how physicians understand and address the ethical challenges of prognostic uncertainty in the case of neonatal HIE, contextualized within the social science literature., Study Design: Semi-structured interviews were conducted with 12 Canadian neurologists and neonatologists, addressing their perspectives and clinical experiences concerning neonatal HIE prognostication. Interviews were analyzed using thematic content analysis., Results: Participants unanimously recognized uncertainty in their prognostication. They identified several sources contributing to uncertainty in HIE prognostication, including etiology and underlying pathophysiologic mechanisms, statistical limitations, variable clinical data, the dynamic process of neurodevelopment, or the impact of hypothermia treatment. Unlike in some other literature, some physicians in this study talked about ways to render uncertainty explicit rather than hide it., Conclusion: Results from this study support the call for recognition of the ubiquitous uncertainty surrounding this act in medical education and training.

Introduction: During the past decade, the mandatory population-based healthcare database, the Western Denmark Heart Registry (WDHR), has provided the data for several research projects. As in most clinical registries, the data quality has not been validated thoroughly. This study was undertaken to evaluate the quality of registrations in the WDHR., Methods: The audit supervised procedures from involved departments that were performed in 2013. An experienced research nurse completed data collection, and an experienced consultant evaluated the agreement between the WDHR and patient records. Indistinct data from patient records were determined after consulting a specialist from the department in question. Patient files were double-checked in case of disagreements between the involved systems., Results: The total proportion of errors in the referral date was 16.4% in surgery, 9.8% in percutaneous invasive procedures (PCI), 16.1% in coronary angiography (CAG) and 19.5% in computed tomography (CT)-CAG, while the errors in inhospital dates were slightly lower. In the cardiac surgery registries, the proportion of errors was 3.3% in the history and EuroSCORE module, 1.0% in the procedure module and 2.8% in the discharge module. For PCI procedures, the errors were 3.8% in the history module, 2.2% in the procedure module and 1.6% in the discharge module. CAG and CT-CAG had slightly more errors., Conclusions: The quality control of the WDHR revealed that overall data errors were lower than 3% and for procedure-specific registrations including indications and complications, the error rate was below 1.5%. The WDHR is valid and may be used in contemporary epidemiological studies., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Regular physical activity prevents the development of chronic muscle pain through the modulation of central mechanisms that involve rostral ventromedial medulla (RVM). We tested if pharmacological blockade or genetic deletion of mu-opioid receptors in physically active mice modulates excitatory and inhibitory systems in the RVM in an activity-induced hyperalgesia model. We examined response frequency to mechanical stimulation of the paw, muscle withdrawal thresholds, and expression of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate receptor (p-NR1) and serotonin transporter (SERT) in the RVM. Mice that had performed 5 days of voluntary wheel running prior to the induction of the model were compared with sedentary mice. Sedentary mice showed significant increases in mechanical paw withdrawal frequency and a reduction in muscle withdrawal threshold; wheel running prevented the increase in paw withdrawal frequency. Naloxone-treated and MOR mice had increases in withdrawal frequency that were significantly greater than that in physically active control mice and similar to sedentary mice. Immunohistochemistry in the RVM showed increases in p-NR1 and SERT expression in sedentary mice 24 hours after the induction of the model. Wheel running prevented the increase in SERT, but not p-NR1. Physically active, naloxone-treated, and MOR mice showed significant increases in SERT immunoreactivity when compared with wild-type physically active control mice. Blockade of SERT in the RVM in sedentary mice reversed the activity-induced hyperalgesia of the paw and muscle. These results suggest that analgesia induced by 5 days of wheel running is mediated by mu-opioid receptors through the modulation of SERT, but not p-NR1, in RVM.

Introduction: It is generally believed that exercise produces its effects by activating central opioid receptors; there are little data that support this claim. The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are key nuclei in opioid-induced analgesia, and opioids interact with serotonin to produce analgesia., Objectives: The purpose was to examine central inhibitory mechanisms involved in analgesia produced by wheel running., Methods: C57/Black6 mice were given access to running wheels in their home cages before induction of chronic muscle hyperalgesia and compared with those without running wheels. Systemic, intra-PAG, and intra-RVM naloxone tested the role of central opioid receptors in the antinociceptive effects of wheel running in animals with muscle insult. Immunohistochemistry for the serotonin transporter (SERT) in the spinal cord and RVM, and pharmacological blockade of SERT, tested whether the serotonin system was modulated by muscle insult and wheel running., Results: Wheel running prevented the development of muscle hyperalgesia. Systemic naloxone, intra-PAG naloxone, and intra-RVM naloxone reversed the antinociceptive effect of wheel running in animals that had received muscle insult. Induction of chronic muscle hyperalgesia increased SERT in the RVM, and blockade of SERT reversed the hyperalgesia in sedentary animals. Wheel running reduced SERT expression in animals with muscle insult. The serotonin transporter in the superficial dorsal horn of the spinal cord was unchanged after muscle insult, but increased after wheel running., Conclusion: These data support the hypothesis that wheel running produced analgesia through central inhibitory mechanisms involving opioidergic and serotonergic systems., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Predicting neurological outcomes of neonates with acute brain injury is an essential component of shared decision-making, in order to guide the development of treatment goals and appropriate care plans. It can aid parents in imagining the child's future, and guide timely and ongoing treatment decisions, including shifting treatment goals and focusing on comfort care. However, numerous challenges have been reported with respect to evidence-based practices for prognostication such as biases about prognosis among clinicians. Additionally, the evaluation or appreciation of living with disability can differ, including the well-known disability paradox where patients self-report a good quality of life in spite of severe disability. Herein, we put forward a set of five practice principles captured in the "ouR-HOPE" approach (Reflection, Humility, Open-mindedness, Partnership, and Engagement) and related questions to encourage clinicians to self-assess their practice and engage with others in responding to these challenges. We hope that this proposal paves the way to greater discussion and attention to ethical aspects of communicating prognosis in the context of neonatal brain injury., (© 2016 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)