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Annually resolved ice core records from different regions over the Greenland ice sheet (GrIS) are used to investigate the spatial and temporal variability of calcium (Ca2+, mainly from mineral dust) and sodium (Na+, mainly from sea salt) deposition. Cores of high common inter-annual variability are grouped with an EOF analysis, resulting in regionally representative Ca2+ and Na+ records for northeastern and central Greenland. Utilizing a regression and validation method with ERA-40 reanalysis data, these common records are associated with distinct regional atmospheric circulation patterns over the North American Arctic, Greenland, and Central to Northern Europe. These patterns are interpreted in terms of transport and deposition of the impurities. In the northeastern part of the GrIS sea salt records reflect the intrusion of marine air masses from southeasterly flow. A large fraction of the Ca2+ variability in this region is connected to a circulation pattern suggesting transport from the west and dry deposition. This pattern is consistent with the current understanding of a predominantly Asian source of the dust deposited over the GrIS. However, our results also indicate that a significant fraction of the inter-annual dust variability in NE and Central Greenland is determined by the frequency and intensity of wet deposition during the season of high atmospheric dust loading, rather than representing the variability of the Asian dust source and/or long-range transport to Greenland. The variances in the regional proxy records explained by the streamfunction patterns are high enough to permit reconstructions of the corresponding regional deposition regimes and the associated circulation patterns. © Springer-Verlag 2006.

Background & Aims: Thiopurine therapy is a cornerstone in the treatment of inflammatory bowel disease (IBD). We aimed to assess the effect of thiopurines on cancer risk in IBD according to drug exposure and age., Methods: Danish national registers were used to identify incident IBD patients, exposure to drugs, and status of cancers, in 1996 to 2018. Cox regressions were used to compare cancer risks in IBD and non-IBD individuals and to assess IBD patients' cumulative drug exposure and the association to first cancer, excluding non-melanoma skin cancer., Results: We followed 43,419 patients with IBD for a median of 8.2 years (interquartile range, 3.7-14.2 years) after IBD diagnosis. Cancer was reported in 3128 (7.2%) patients with IBD. The risk of cancer was increased in patients with IBD in all age categories compared with non-IBD individuals (<50 years: adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.43-1.77; 50-65 years: aHR, 1.31; 95% CI, 1.19-1.44; and >65 years: aHR, 1.14; 95% CI, 1.05-1.24). Monotherapy (aHR, 1.36; 95% CI, 1.17-1.57) and combination therapy (aHR, 2.49; 95% CI, 1.64-3.78) were associated with an increased risk of cancer compared to unexposed patients with IBD. Among elderly patients (>65 years), the aHR was 2.79 (95% CI, 1.24-6.28) in those receiving combination therapy. In patients discontinuing thiopurines, aHRs returned to the level of unexposed (aHR, 0.89; 95% CI, 0.78-1.01). The aHR was positively associated with cumulative thiopurine exposure and in patients with >5 years of exposure, reaching an aHR of 1.36 (95% CI, 1.15-1.61)., Conclusions: Thiopurines were associated with increased hazard of cancer, especially when used in combination therapy in the elderly. The hazard increased by 36% when patients were exposed to thiopurines for more than 5 years. Reassuringly, the hazard returned to baseline after discontinuation of thiopurines., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The commonly used combined hormonal contraceptives with progestins and ethinylestradiol are associated with an increased risk of ischemic stroke (IS). Progestin-only preparations, including levonorgestrel-releasing intrauterine devices (LG-IUDs), are not associated with an increased risk, and in smaller studies, the risk is even reduced. The risk of intracerebral hemorrhage (ICH) has never been investigated. We studied the risk of IS and ICH in women using LG-IUDs compared with women not using hormonal contraceptives., Methods: In this Danish historical cohort study (2004-2021), we followed nonpregnant women (18-49 years) registering incident IS and ICH in relation to use of LG-IUDs/nonuse of hormonal contraceptives utilizing Danish high-quality registries with nationwide coverage. Poisson regression models adjusting for age, ethnicity, education, calendar year, and medication use for risk factors were applied., Results: A total of 1 681 611 nonpregnant women contributed 11 971 745 person-years (py) of observation. Mean age at inclusion was 30.0 years; mean length of follow-up was 7.1 years; 2916 women (24.4 per 100 000 py) had IS; 367 (3.1 per 100 000 py) had ICH. Of these, 364 784 were users of LG-IUD contributing 1 720 311 py to the investigation; mean age at start of usage was 34.6 years. Nonusers of hormonal contraceptives contributed 10 251 434 py; mean age at inclusion was 30.0 years. The incidence rate of IS/ICH among LG-IUD users was 19.2/3.0 and among nonusers, it was 25.2/3.1 per 100 000 py. After adjustment, incidence rate ratio for IS was 0.78 (CI, 0.70-0.88), and for ICH it was 0.94 (CI, 0.69-1.28)., Conclusions: The use of LG-IUD was associated with a 22% lower incidence rate of IS without raising the incidence rate of ICH. The finding raises the question of whether levonorgestrel, in addition to its contraceptive properties, could have the potential to prevent IS., Competing Interests: Disclosures None.

Introduction: Familial adenomatous polyposis (FAP) is an autosomal, dominantly inherited disorder that predisposes to colorectal cancer. An increased risk of cancer may affect mental health, but the magnitude of this effect remains unknown. We assessed the psychosocial functioning, including the educational level attained and risk of psychiatric comorbidity, of patients with FAP by comparing them with matched nonexposed individuals., Methods: All Danish patients with FAP diagnosed before April 2021 were identified in the Danish Polyposis Register and paired with 4 matched nonexposed individuals. Educational history, psychiatric contacts or diagnoses ( International Classification of Disease, 10th Revision ), and treatment with antidepressants, anxiolytics, or antipsychotics were compared between patients with FAP and nonexposed individuals., Results: The analysis included 445 patients with FAP and 1,538 nonexposed individuals. The highest educational level reached was significantly lower for patients with FAP ( P < 0.001). When comparing patients with FAP and nonexposed and adjusting for a cancer diagnosis, an increased risk was observed for a psychiatric contact (1.69, 95% confidence interval [CI] 1.25-2.29, P < 0.001), any psychiatric prescription (1.39, 95% CI 1.17-1.66, P < 0.001), a psychiatric diagnosis (1.64, 95% CI 1.19-2.26, P = 0.002), and experiencing any psychiatric event (hazard ratio 1.42, 95% CI 1.20-1.68, P < 0.001). An increased risk was specifically seen for mood (affective) disorders (1.76, 95% CI 1.09-2.83, P = 0.02) and behavioral and emotional disorders (2.01, 95% CI 1.10-3.69, P = 0.02) and the need for antidepressants (1.59, 95% CI 1.24-2.03, P < 0.001) and antipsychotics (1.85, 95% CI 1.26-2.70, P = 0.002)., Discussion: Compared with nonexposed individuals, patients with had significantly less education and an increased risk of developing mood and behavioral disorders, with an increased likelihood of needing antidepressants and antipsychotics., (Copyright © 2023 by The American College of Gastroenterology.)

Despite recent improvements in early-stage non-small-cell lung cancer (NSCLC), disease relapse remains challenging. Moreover, real-world evidence on long-term follow-up of disease-free survival (DFS) and recurrence patterns in a large, unselected cohort of early-stage NSCLC patients is lacking. This cohort study aimed to assess clinical characteristics, diagnostic workup, treatment, survival, and risk of disease relapse among early-stage NSCLC patients. Adult patients with stage IB, II, or IIIA NSCLC diagnosed and/or treated at Aarhus University Hospital in Denmark from January 2010 to December 2020 were included and followed-up until May 2021. Comprehensive clinical data were collected from electronic medical records of eligible patients and linked to Danish register data. The study population comprised 1341 early-stage NSCLC patients: 22%, 40%, and 38% were diagnosed with stage IB, II, and IIIA disease, respectively. In total, 42% of patients were tested for epidermal growth factor receptor (EGFR), of whom 10% were EGFR-mutation-positive (EGFRm + ). Half of all patients received surgery, and nine percent of patients received stereotactic body radiation therapy (SBRT). Disease-free survival 5 years post-diagnosis was 49%, 42%, and 22% for stage IB, II, and stage IIIA patients, respectively. DFS improved over time both for patients treated with surgery and SBRT. However, disease relapse remained a challenge, with approximately 40% of stage IIIA having relapsed 3 years post-diagnosis. This study contributes important knowledge that puts clinical trials on new perioperative treatment modalities for early-stage NSCLC patients into perspective. Our findings cover an essential evidence gap on real-world DFS and recurrence dynamics, confirming that despite an improvement in DFS over time and across different treatment modalities, disease relapse remains a monumental challenge. Therefore, better treatment strategies are needed.

Background & Aims: Familial adenomatous polyposis (FAP) is a hereditary disorder that predisposes patients to colorectal cancer (CRC). Prophylactic colectomy has greatly reduced the risk of CRC. However, new associations between FAP and the risk of other cancers have subsequently emerged. In this study, we assessed the risk of specific primary and secondary cancers among patients with FAP compared with matched controls., Methods: All known patients with FAP up until April 2021 were identified in the nationwide Danish Polyposis Register and paired with 4 unique controls matched by birth year, sex, and postal code. The risk of overall cancers, specific cancer types, and risk of a second primary cancer was assessed and compared with controls., Results: The analysis included 565 patients with FAP and 1890 controls. The overall risk of cancer was significantly higher for patients with FAP than for controls (hazard ratio [HR], 4.12; 95% confidence interval [CI], 3.28-5.17; P < .001). The increased risk was mainly due to CRC (HR, 4.61; 95% CI, 2.58-8.22; P < .001), pancreatic cancer (HR, 6.45; 95% CI, 2.02-20.64; P = .002), and duodenal/small-bowel cancer (HR, 14.49; 95% CI, 1.76-119.47; P = .013), whereas no significant difference was observed for gastric cancer (HR, 3.29; 95% CI, 0.53-20.23; P = .20). Furthermore, the risk of a second primary cancer was significantly higher for patients with FAP (HR, 1.89; 95% CI, 1.02-3.50; P = .042). Between 1980 and 2020, the risk of cancer among patients with FAP decreased by ∼50%., Conclusions: Despite an absolute reduction in the risk of developing cancer among patients with FAP, the risk remained significantly higher than for the background population due to colorectal, pancreatic, and duodenal/small-bowel cancers., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Elevated serum bile acids (BA) are harmful to the heart and alterations in the BA composition have been suggested to cause cardiovascular disturbances in cirrhosis., Aim: To investigate any associations between specific groups or individual serum BA and structural and functional cardiac abnormalities in patients with cirrhosis., Methods: An explorative study in 86 patients with cirrhosis. All participants underwent extensive cardiac assessment, including cardiac MRI with quantification of myocardial extracellular volume (ECV), which is indicative of diffuse myocardial fibrosis. A panel of 15 individual serum BA and C4, a marker of de novo bile acid synthesis, were assessed., Results: Patients with advanced cirrhosis had higher levels of total BA and conjugated BA, as well as lower C4 levels (p < 0.001). Conjugated BA levels were higher in patients with a high cardiac index (p < 0.001), increased left atrial volume index (LAVI) (p < 0.001), and in those with an abnormal myocardial ECV (p < 0.05). We also found several strong correlations between conjugated BA, both as a group and individually, and parameters of cardiac dysfunction. In a model adjusted for sex, age, BMI and MELD, conjugated BA remained significantly associated with LAVI, septal e', left ventricular volumes and cardiac index. In addition, taurocholic acid correlated closely with hepatic venous pressure gradient (HVPG) (p = 0.01)., Conclusions: Increased serum concentrations of conjugated BA are associated with several cardiac parameters, indicating a potential role in the development of hyperdynamic circulation and cardiac dysfunction in cirrhosis. Moreover, taurine-conjugated BA are associated with portal hypertension., (© 2023 John Wiley & Sons Ltd.)

Background: Sex differences in brain structure and neurodevelopment occur in non-clinical populations. We investigated whether sex had a similar effect on developmental domains amongst boys and girls with a familial risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and controls., Methods: Through Danish registries, we identified 522 7-year-old children (242 girls) with FHR-SZ, FHR-BP, and controls. We assessed their performance within the domains of neurocognition, motor function, language, social cognition, social behavior, psychopathology, and home environment., Results: FHR-SZ boys compared with FHR-SZ girls had a higher proportion of disruptive behavior and attention-deficit hyperactivity disorder (ADHD) and exhibited lower performance in manual dexterity, balance, and emotion recognition. No sex differences were found between boys and girls within FHR-BP group. Compared with controls, both FHR-SZ boys and FHR-SZ girls showed impaired processing speed and working memory, had lower levels of global functioning, and were more likely to live in an inadequate home environment. Compared with control boys, FHR-SZ boys showed impaired manual dexterity, social behavior, and social responsiveness, and had a higher proportion of ADHD and disruptive behavior disorder diagnoses. Stress and adjustment disorders were more common in FHR-BP boys compared with control boys. We found no differences between FHR-BP girls and control girls., Conclusions: Impairment within neurodevelopmental domains associated within FHR-SZ boys v. FHR-SZ girls was most evident among boys, whereas no sex differences were found within the FHR-BP group (FHR-BP boys v. FHR-BP girls). FHR-SZ boys exhibited the highest proportion of early developmental impairments.

Background: Current guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab and a chemotherapeutic agent for 3rd line or later treatments. This study aims to describe the treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a real-world setting., Material and Methods: This observational population-based study included all women diagnosed with HER2-positive mBC in Denmark, previously treated with T-DM1 in the metastatic setting. Patients were included on the date of progression leading to initiation of 3rd line treatment if the patient had received T-DM1 in 1st or 2nd line. If the patient received T-DM1 in 3rd line or later the inclusion was based on the date of progression on T-DM1. The primary end points were overall survival (OS) and progression-free survival (PFS)., Results: The study included 272 women with a mean age of 59 (27-86) and a median of 3 (2-11) treatment lines prior to inclusion. At index, all patients had received T-DM1 and 167 (62%) patients had received pertuzumab in the metastatic setting. During follow-up 183 patients received chemotherapy. Of these patients, 120 received chemotherapy combined with trastuzumab, 50 received chemotherapy combined with other HER2-targeted therapy, and 13 received chemotherapy as monotherapy. The remaining 89 patients received either HER2-targeted monotherapy (41), endocrine therapy (31), experimental treatment (10), or no treatment (7). Median PFS was 5.5 months (95% CI, 4.8-6.5) and median OS was 18.5 months (95% CI, 16.2-21.3)., Conclusion: In this real-world study, we found that patients were treated with a wide variety of anti-cancer agents with modest efficacy. However, patients in this study did not have access to newer therapies like tucatinib and T-DXd.

Background: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark., Methods: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions., Results: Risk for depression increased by 35% with each standard deviation increase in polygenic liability ( p < 0.0001), and 36% ( p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs ( β = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15., Conclusions: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.

Children with neurofibromatosis 1 (NF1) may have a high burden of somatic disease and cognitive impairments, which can lead to poor academic performance. We evaluated school grades from exams ending mandatory schooling (usually around age 15 or 16 years) of children with NF1 in a population-based registry study using a within-school matched design. The study included 285 children with NF1 and 12,000 NF1-free peers who graduated from the same school and year during 2002-2015. We estimated overall and gender-specific grades by subject and compared the grades of children with NF1 with those of NF1-free peers in linear regression models. We also examined the effect of social and socioeconomic factors (immigration status and parental education, income and civil status) on grades and age at finalizing ninth grade. School grades varied considerably by socioeconomic stratum for all children; however, children with NF1 had lower grades by an average of 11-12% points in all subjects. In the adjusted models, children with NF1 had significantly lower grades than their NF1-free peers, with largest negative differences in grades observed for girls with NF1. Finally, children with NF1 were 0.2 (CI 0.1-0.2) years older than their peers on graduating from ninth grade, but only maternal educational modified the age at graduating. In conclusion, students with NF1 perform more poorly than their peers in all major school subjects. Gender had a strong effect on the association between NF1 and school grades; however, socioeconomic factors had a similar effect on grades for children with NF1 and their peers., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: Longitudinal, real-world data on the management of metastatic breast cancer is increasingly relevant to understand breast cancer care in routine clinical practice. Yet such data are scarce, particularly beyond second- and third-line treatment strategies. This study, therefore, examined both the long-term treatment patterns and overall survival (OS) in a regional Swedish cohort of female patients with metastatic breast cancer stratified by subtype in routine clinical practice during a recent eight-year period and correlation to current treatment guidelines., Methods: Consecutive female patients with metastatic breast cancer  clinically managed at Uppsala University Hospital, Uppsala, Sweden, during 2009-2016 and followed until the end of September, 2017 (n = 370) were included and, where possible, classified as having one of five, intrinsic subtypes: Luminal A; Luminal B; human epidermal growth factor receptor 2-positive (HER2+)/ estrogen receptor-positive (ER+); HER2+/estrogen receptor-negative (ER-); or triple negative breast cancer (TNBC). Treatment patterns and OS were estimated by subtype using time-to-event methods., Results: A total of 352/370 patients with metastatic breast cancer (mean age 67.6 years) could be subtyped: 118 (34%) were Luminal A, 119 (34%) Luminal B, 31 (8%) HER2+/ER-, 38 (11%) HER2+/Luminal, and 46 (13%) TNBC. The median number of metastatic treatment lines was 3. Most patients were on active treatment during follow-up (80% of the observation period), except for patients with TNBC who were on treatment for 60% of the observation time. Overall, 67% of patients died whilst on treatment. Among all patients (n = 370), median OS was 32.5 months (95% CI = 28.2-35.7). The 5-year survival rate was highest for HER2+/Luminal (46%) patients, followed by Luminal B (29%), Luminal A (28%), HER2+/ER- (21%), and TNBC (7%). Increasing age and number of metastatic sites also predicted worse survival., Conclusions: Metastatic breast cancer patients in Sweden, irrespective of subtype, generally receive active treatment until time of death. Survival varies considerably across subtypes and is also associated with patient characteristics. Regardless of differences in treatment patterns for Luminal A and B patients, long-term OS was the same., (© 2022. The Author(s).)

Background: This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC)., Methods: This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for ≥20 months., Results: Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After ≥20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01)., Conclusions: Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population., Lay Summary: Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Hypothesis: Lipases are widely used in the detergent industry and must withstand harsh conditions involving both anionic and zwitterionic surfactants at alkaline pH. Thermomyces lanuginosus lipase (TlL) is often used and stays active at high concentrations of the anionic surfactant sodium dodecyl sulfate (SDS) at pH 8.0, but is sensitive to SDS at pH 6.0 and below. We propose that enhanced stability at pH 8.0 results from a structurally distinct complex formation with SDS., Experiments: We use small-angle X-ray scattering (SAXS) to elucidate structures of TlL:SDS at pH 4.0, 6.0, and 8.0 and further investigate the complexes at pH 8.0 using hydrogen/deuterium exchange mass spectrometry (HDX-MS)., Findings: At pH 4.0, large dense aggregates are formed at low [SDS], which become gradually less dense at higher [SDS], resulting in a core-shell structure. At pH 6.0, SDS induces a TlL dimer and forms a hemi-micelle along the side of the dimer. At higher [SDS], TlL adopts a core-shell structure. At pH 8.0, TlL forms a dimer with a SDS hemi-micelle but avoids a core-shell structure and maintains activity. Three helices are identified as SDS anchor points. This study provides important structural insight into the stability of TlL towards SDS under alkaline conditions., 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Uncertainty exists for the absolute risk of ischemic and hemorrhagic stroke in users of oral contraceptives (OCs). Estimates greatly vary between countries. In Denmark, absolute risk of ischemic stroke (IS) is estimated to be 21 per 100,000 person-years. Risk of cerebral hemorrhage (CH) is unknown. Using the Danish Stroke Registry, we investigated absolute risk of IS and CH in users of OC., Material and Methods: For the Danish female population aged 15-49 years during 2003-2011, we obtained information on hospital admission for IS and CH and current use of OC from Danish nationwide registries. We defined current use of OC as redeeming at least two OC prescriptions within the previous year., Results: The Danish female population years 2003-2011 consisted mean of 1,246,142 women per year. Of these, 29.6% were OC users. In the study period, OC users had 291 IS and 14 CH. Absolute risk of IS in OC users was 8.8 per 100,000 person-years and of CH it was 0.4 per 100,000 person-years., Conclusions: In OC users, absolute risk of IS was 8.8 per 100,000 person-years. This is more than half that of the risk previously assumed in Denmark. Risk of CH in OC users was very low and 0.4 per 100,000 person-years., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Children with familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) are frequently affected in a range of domains known to be precursors of severe mental illness. No previous studies have gathered known precursors to examine whether they distribute evenly across familial high risk (FHR) children or if they cluster among a smaller group. Since such examination holds the potential to identify high and low risk of severe mental illness groups, we aimed to cluster FHR and control children affected to various degrees., Method: In The Danish High Risk and Resilience Study VIA 7, a clinical cohort study, 514 7-year-old children with FHR-SZ or FHR-BP and matched controls were assessed in domains of motor function, neurocognition, emotional control, behavior, social cognition, self-perception, language, psychotic experiences, and psychopathology, and grouped using cluster analysis. Associations between clusters and parents' level of education, functioning, caregiver status, child's level of stimulation and support in the home, and polygenic risk scores were examined., Results: A total of four groups including one of broadly affected children were identified. The broadly affected group was represented 4-5-fold (18.1%) amongst FHR-SZ children and 2-3-fold (10.2%) amongst FHR-BP children, compared to controls (4.1%) ( P < .001), and the broadly affected group had lower levels of caregiver functioning ( P < .001) and stimulation and support at home ( P < .001)., Conclusion: Precursors of severe mental illness distribute unevenly among FHR children; while approximately half are not affected in any domains, the other half are affected to various degrees. Targeted support towards the affected groups is indicated., (© The Author(s) 2022. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Background: Studies on the risk of new primary cancer in patients with posterior uveal melanoma (UM) have produced conflicting results, and the role of socioeconomic status (SES) is unknown. The purpose of this population-based matched cohort study was to determine the risk of new primary cancer following the diagnosis of posterior UM., Methods: 2179 patients with posterior UM 1968-2016 and 22,717 matched controls without cancer were included. Incidence and time-dependent hazard ratio (HR) of new primary cancer were described, and the effect of SES was emphasized in a sub-cohort., Results: The incidence of new primary cancer was increased in patients with posterior UM, rate ratio (RR) 1.21 (95% CI: 1.08; 1.35), but the specific cancer types did not differ compared to the controls. The rate of new primary cancer following the diagnosis of posterior UM was significantly increased 2-5 years (HR 1.49 (95% CI: 1.23; 1.80)) and 11-15 years (HR: 1.49 (95% CI: 1.12; 1.99)), and adjusting for SES did not change the rate (HR 1.35 (95% CI:1.20; 1.55))., Conclusions: Patients with posterior UM have an increased risk of new primary cancer independent of SES. No difference in incidence of specific cancer type was observed compared to the control group.

Background: Testing for epidermal growth factor receptor mutation (EGFRm) status is a prerequisite to identify eligible patients for tyrosine kinase inhibitors (TKI) treatment. However, EGFR testing of patients with non-small cell lung cancer (NSCLC) is suboptimal in many parts of the world. The aim of this study was to describe real-world EGFR testing practice, EGFRm prevalence, and subsequent TKI treatment patterns in Norway., Patients and Methods: This retrospective, observational, cohort study included all incident locally advanced and metastatic non-squamous NSCLC patients registered in the Norwegian Cancer Registry during 2010-2017. A cohort with follow-up through 2018 was formed with linkage to nationwide registries on comorbidities, prescribed drugs and causes-of-death., Results: A total of 10,717 patients were included, of which 35% (3782) with locally advanced NSCLC and 65% (6935) with metastatic disease. Mean age at diagnosis was 71 years and 47% were female. EGFR testing among patients with metastatic NSCLC increased from 41% to >64% between 2010 and 2017, with a relative stable incidence of EGFRm+ (∼9%). More than 85% of EGFRm+ patients received TKI treatment. Patients with the most dismal prognosis (>80 age, comorbidities) and with diagnosis based on cytology/imaging were less likely to be tested. Differences in testing were observed between regions., Conclusion: Despite increased test rates over the study period, in Norway, a significant proportion of patients with non-squamous metastatic NSCLC are still not tested for EGFR. To maximize the identification of eligible patients for targeted therapies, increased testing is recommended, regardless of age, comorbidity rate and place of residence., Competing Interests: Declaration of Competing Interest AH: advisory/consultancy role/presentations – AbbVie, AstraZeneca, BMS, Pfizer, Pierre Fabre and Takeda. Research grant Roche, BMS, Ultimovacs with honorarium to own institution. Have received research grants / study drug /diagnostic assays from Roche, AstraZeneca, Ultimovacs, BMS, Novartis, InCyte, EliLilly, Illumina. KAA: Employee of Astrazeneca at the time of study TÅM: Nothing to declare TBJ: Nothing to declare JA: Employee of Astrazeneca EE: Research funding from AstraZeneca AB to own institution., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: While early treatment of posterior uveal melanoma can save the eye, the effect of early treatment on survival remains unknown. Therefore, we aimed to determine whether the tumour size at diagnosis has changed over time, and if this has affected survival rates of patients with posterior uveal melanoma in Denmark., Methods: Nationwide retrospective cohort study linking data from registry-based resources to data from clinical charts and pathology records. Including all Danish patients diagnosed with posterior uveal melanoma from 1943 to 2017. Incidence rates were estimated as annual percentage change (APC) overall and by American Joint Committee on Cancer (AJCC) tumour sizes. The age-period-cohort model was applied to estimate the relative risk of calendar period. The cox proportional hazards model, relative survival Kaplan-Meier curves and cumulative incidence curves were applied to estimate the effect of calendar period on survival., Results: An overall increase in incidence rate of uveal melanoma was found (APC = 0.25%, 0.08-0.42; 95% CI). This was due to increasing incidence rate of AJCC T1 + T2 tumours (APC = 0.97%, 0.57-1.37; 95% CI), whereas no increase in incidence rates of AJCC T3 + T4 tumours was found (APC = -0.01%, -0.26 to 0.25; 95% CI). The disease-specific survival improved with calendar period for all tumour sizes (HR = 0.988; 0.984-0.993; 95% CI)., Conclusion: Increasing incidence rate and improved survival rate for uveal melanoma was found concordantly with a decrease in tumour size during a 70-year period., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results., Methods: We conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank., Results: The GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide-significant ( p < 5 × 10 -8 ) loci located in the ABCC1 gene (rs56076205, p = 3.7 × 10 -10 ), the AKAP6 gene (rs3784187, p = 1.2 × 10 -8 ), and near the MFSD1 gene (rs340315, p = 4.5 × 10 -8 ). No hits replicated in the UK Biobank (rs56076205: p = .87; rs3784187: p = .93; rs340315: p = .71)., Conclusions: In this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power., (© 2021 The Authors.)

Background: Colorectal cancer screening program using a fecal immunochemical test aims to reduce morbidity and mortality through early detection. Although screening participation is free-of-charge, almost 40% of the invited individuals choose not to participate. To bring new insight into how non-participation can be identified and targeted, we examined the association between marital status and screening participation; with a focus on partner concordance in participation and sex differences., Methods: This nationwide cross-sectional study included all Danish citizens aged 50-74 years, who were invited to colorectal cancer screening between 2014 and 2017. Logistic regression analysis was used to estimate odds ratio (OR) of participation while adjusting for sociodemographic variables., Results: A total of 1 909 662 individuals were included in the analysis of which 62.7% participated in the screening program. Participation was highest among women. Stratified by marital status, screening participation was markedly lower in widowed (61.5%), divorced (54.8%) and single (47.3%), while participation reached 68.4% in married individuals. This corresponded to ORs of 0.59 (95% CI 0.58-0.59) for widowed, 0.56 (95% CI 0.55-0.56) for divorced and 0.47 (95% CI 0.47-0.48) for single, compared to married individuals. Individuals married to a participating partner were five times more likely to participate than married individuals with a non-participating partner, regardless of gender., Conclusions: Marital status was strongly associated with participation in colorectal cancer screening, and participation was even higher in married individuals with a participating partner. Future efforts to increase participation in colorectal cancer screening could potentially benefit from considering the role of partner concordance., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: Treatment for disseminated testicular cancer increases the risk of secondary malignancy and cardiovascular disease. The risk of developing these serious adverse effects may be positively affected by healthy living. The purpose of this study was to identify health behaviours with possible influence on late effects that could be targets for intervention., Material and Methods: In this cross-sectional study, testicular cancer survivors diagnosed in the period 1984-2007 from the Danish Testicular Cancer database completed a questionnaire on health behaviours (2014-2016). We estimated prevalence of smoking, alcohol consumption, sedentary lifestyle and overweight. Prevalence ratios described with 95% confidence intervals of adverse health behaviours were stratified by treatment modalities and compared to a reference population by means of logistic regression with adjustment for sociodemographic confounders., Results: In total, 2395 testicular cancer survivors (surveillance, 1175; chemotherapy, 897; radiotherapy, 323), median time since diagnosis 19 years, and 65,289 noncancer males were included, questionnaire response rates were 60% and 54%, respectively. There were more current smokers (prevalence ratio; 1.14, 95% confidence interval (CI): 1.03-1.26) and patients with body mass index above 25 kg/m 2 (prevalence ratio; 1.10, 95% CI: 1.01-1.20) among testicular cancer survivors than in the reference population. Testicular cancer survivors reported less sedentary lifestyle (prevalence ratio; 95% CI: 0.74, 0.64-0.85) and everyday drinkers were fewer (prevalence ratio; 0.79, 95% CI: 0.68-0.92) than in the reference population., Conclusion: We identified smoking cessation as primary target for intervention studies in testicular cancer survivors. The effect of smoking cessation interventions as part of treatment should be investigated. Whether drug-based intervention is effective in minimising the risk of exposure to conventional risk factors for cardiovascular disease is also of interest.

Background and Purpose: To improve diagnoses of primary brain tumours, knowledge about early indicators is needed. Nationwide Danish health registries were used to conduct a population-based case-control study including all persons diagnosed with a primary brain tumour between 2005 and 2014 in Denmark., Methods: All 5135 adults diagnosed with a primary brain tumour in the Danish Cancer Registry were matched to 19 572 general population comparisons from the Danish Civil Registration System. Conditional logistic regression analyses were applied to estimate age- and multivariable-adjusted odds ratios (ORs) for the occurrence of a primary brain tumour up to 10 years after hospital diagnoses or prescription of medications related to nervous system diseases and mental and behavioural disorders., Results: Increased odds for primary brain tumour after nervous system diseases and mental and behavioural disorders manifested up to 10 years before tumour diagnosis were found. Increased odds were seen especially for hospital contacts for inflammatory nervous system diseases [OR 11.3; 95% confidence interval (CI) 6.5-19.7], epilepsy (OR 9.0; 95% CI 7.6-10.7) and antiepileptic medications (OR 3.6; 95% CI 3.2-4.0), whilst antidementia medications provided a strong, protective association for primary brain tumours (OR 0.5; 95% CI 0.3-0.8)., Conclusions: Sub-groups of patients diagnosed with or being prescribed certain medications targeting nervous system diseases and mental and behavioural disorders may be at increased risk of being diagnosed with a primary brain tumour. Further studies should disentangle the potential underlying common pathogenetic pathways. The results are important for the development of systematic clinical approaches to ensure early diagnosis of primary brain tumours., (© 2020 European Academy of Neurology.)

Background: We examined whether the apparent association between renal cell carcinoma (RCC) and use of dihydropyridine calcium channel blockers (CCBs) was explained by confounding by indication since hypertension, the main indication for CCBs, is a risk factor for RCC., Methods: Using Danish health registries, we conducted a nested case-control study including 7315 RCC cases during 2000-2015. We matched each case with up to 20 controls on age and sex using risk-set sampling. We estimated odds ratios (ORs) for long-term CCB use associated with RCC using conditional logistic regression. We addressed confounding by indication by (1) adjusting for hypertension severity indicators; (2) evaluating dose-response patterns; (3) examining whether other first-line anti-hypertensives were associated with RCC; and (4) using an active comparator new user design by nesting the study in new users of CCBs or angiotensin-converting enzyme inhibitors (ACEIs)., Results: The adjusted OR for RCC associated with long-term CCB use compared to non-use was 1.76 (1.63-1.90). After we additionally adjusted for hypertension severity indicators, the OR remained elevated (OR 1.37; confidence interval [CI] 1.25, 1.49) with evidence of a dose-response pattern. Other anti-hypertensives were also associated with RCC, for example, ACEIs (OR 1.27; 95% CI = 1.16, 1.39) and thiazides (OR 1.22; 95% CI = 1.12, 1.34). In the active comparator new user design, the OR was 1.21 (95% CI = 0.95, 1.53) for use of CCBs compared with ACEIs., Conclusions: In this population, confounding by indication appeared to explain at least part of the association between RCC and dihydropyridine CCBs.

Objectives: Stroke is associated with a higher risk of occult cancer. We studied the types of occult cancer most often associated with stroke., Materials and Methods: All patients with incident stroke in Denmark 2003-2015 were identified through the Danish Stroke Registry (n = 85 893) and matched 1:10 on age and sex to the Danish background population without history of stroke (n = 858 740). Linking data to the Danish Cancer Registry, we determined the prevalence of occult cancer in stroke defined as the event of previously unknown cancer during a one-year follow-up in the stroke and the background population. We stratified cancers into the 15 most common cancers and into cancers related to and not related to smoking., Results: Prevalence (per 1000 person-years; stroke/background population) of smoking-related occult cancers (lung, colon, bladder rectum, pancreas, kidney, stomach, and head and neck) was 13.3/8.1 (P < .01) and of cancers not related to smoking (prostate, breast, melanoma, non-Hodgkin lymphoma, ovary, endometrial) it was 6.6/6.2 (P > .05). Among men with stroke prostate (5.8), lung (5.7), and colon cancers (2.9) were most frequent; among women, it was lung (4.7), breast(3.5), and colon cancer(2.8). Among men in the background population, prostate(5.4), lung (3.0), and colon cancers (2.1) were most frequent. Among women, it was breast (3.7), lung(2.1), and colon cancers (1.9)., Conclusion: Stroke patients' increased risk of occult cancer was predominantly for smoking-related cancers while there was no higher risk for the most frequent cancers unrelated to smoking, that is, prostate and breast cancers. Lung cancer is the dominant type of occult cancer in stroke., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Opioids are the most potent analgesics in the treatment of postoperative pain. Respiratory depression is, however, a serious side effect. The aims of this study were to evaluate current practice and routines for post-operative administration of opioids in a Norwegian university hospital and to evaluate whether the clinical safeguards adequately protected patients' safety regarding risk of respiratory depression., Methods: The study had a retrospective cross-sectional design and included 200 patients, treated with opioids postoperatively. The patients were treated in a post-anesthesia care unit (PACU) before transferal to a surgical ward. Relevant data such as opioid dosages, routes of administration, sedation and respiratory function, routines for patient monitoring, and numbers of patients with opioid induced respiratory depression was collected., Results: Two patients (1%) developed respiratory depression that needed naloxone to reverse the effect, and 32 patients (16%) had a respiratory rate (RR) <10/min, which may have been caused by opioids. In the PACU, the patient's RR was evaluated on a routine base, but after transferal to a surgical ward RR documented in only 7% of the patients., Conclusions: The lack of routines for patient monitoring, especially RR, represented a risk of not detecting opioid induced respiratory depression., (© 2020 Karoline Kolås Andersen and Gunnvald Kvarstein, published by De Gruyter, Berlin/Boston.)

New ultrasound-mediated drug delivery systems, such as acoustic cluster therapy or combined imaging and therapy systems, require transducers that can operate beyond the bandwidth limitation (~100%) of conventional piezoceramic transducers. In this article, a dual-frequency coupled resonator transducer (CRT) comprised of a polymeric coupling layer with a low acoustic impedance (2-5 MRayl) sandwiched between two piezoceramic layers is investigated. Depending on the electrical configuration, the CRT exhibits two usable frequency bands. The resonance frequency of the high-frequency (HF) band can be tailored to be ~3-5 times higher than that of the low-frequency (LF) band using the stiffness in the coupling layer. The CRT's LF band was analyzed analytically, and we obtained the closed-form expressions for the LF resonance frequency. A dual-frequency CRT was designed, manufactured, and characterized acoustically, and comparisons with theory showed good agreement. The HF band exhibited a center frequency of 2.5 MHz with a -3-dB bandwidth of 70% and is suited to manipulate microbubbles or for diagnostic imaging applications. The LF band exhibited a center frequency of 0.5 MHz with a -3-dB bandwidth of 13% and is suited to induce biological effects in tissue, therein manipulation of microbubbles.

Background: In the 1960s only 1/3 of children with soft-tissue sarcomas survived, however with improved treatments survival today has reached 70%. Given the previous poor survival and the rarity of soft-tissue sarcomas, the risk of somatic late effects in a large cohort of Nordic soft-tissue sarcoma survivors has not yet been assessed., Methods: In this population-based cohort study we identified 985 five-year soft-tissue sarcoma survivors in Nordic nationwide cancer registries and late effects in national hospital registries covering the period 1964-2012. Information on tumour site and radiotherapy was available for Danish and Finnish survivors ( N  = 531). Using disease-specific rates of first-time hospital contacts for somatic diseases in survivors and in 4,830 matched comparisons we calculated relative rates (RR) and rate differences (RD)., Results: Survivors had a RR of 1.5 (95% CI 1.4-1.7) and an absolute RD of 23.5 (17.7-29.2) for a first hospital contact per 1,000 person-years. The highest risks in both relative and absolute terms were of endocrine disorders (RR = 2.5; RD = 7.6), and diseases of the nervous system (RR = 1.9; RD = 6.6), digestive organs (RR = 1.7; RD = 5.4) and urinary system (RR = 1.7; RD = 5.6). By tumour site, excess risk was lower after extremity tumours. Irradiated survivors had a 2.6 (1.2-5.9) times higher risk than non-irradiated., Conclusions: Soft-tissue sarcoma survivors have an increased risk of somatic late effects in 5 out of 10 main diagnostic groups of diseases, and the risk remains increased up to 40 years after cancer diagnosis. Risks were slightly lower for those treated for tumours in the extremities, and radiotherapy increased the risk by more than two-fold.

We suggest a regression approach to estimate the excess cumulative incidence function (CIF) when matched data are available. In a competing risk setting, we define the excess risk as the difference between the CIF in the exposed group and the background CIF observed in the unexposed group. We show that the excess risk can be estimated through an extended binomial regression model that actively uses the matched structure of the data, avoiding further estimation of both the exposed and the unexposed CIFs. The method naturally deals with two time scales, age and time since exposure and simplifies how to deal with the left truncation on the age time-scale. The model makes it easy to predict individual excess risk scenarios and allows for a direct interpretation of the covariate effects on the cumulative incidence scale. After introducing the model and some theory to justify the approach, we show via simulations that our model works well in practice. We conclude by applying the excess risk model to data from the ALiCCS study to investigate the excess risk of late events in childhood cancer survivors., (© 2020 John Wiley & Sons, Ltd.)

Introduction: Symptoms of occult brain cancer may mimic stroke. Misdiagnosis may lead to improper treatment and delayed diagnosis. We characterised strokes associated with occult primary brain cancer and determined risk that ischaemic and haemorrhagic strokes are associated with occult primary brain cancer., Patients and Methods: All patients with incident stroke in Denmark 2003-2015 were identified through the Danish Stroke Registry (n = 85,893) and matched 1:10 on age and sex to the Danish background population without a stroke history (n = 858,740). This cohort was linked to the Danish Cancer Registry and prevalence of occult primary brain cancer defined as the event of previously unknown primary brain cancer during a one-year follow-up was estimated. We used Cox regression models to study risk of occult primary brain cancer in comparison to the background population., Results: Of 77,484 patients with ischaemic strokes, 39 (1 in 2000) were associated with primary brain cancer; of 8409 with haemorrhagic strokes, it was 126 (1 in 66). In the background cohort, 205 (1 in 4000) had occult primary brain cancer. The multivariate stroke risk factor analysis showed that patients with occult primary brain cancer differed significantly from those without occult primary brain cancer indicating they might have stroke mimics rather than true strokes. Discussion and conclusions: Strokes associated with occult primary brain cancer tend to be stroke mimics rather than true strokes. Primary brain cancer is rare in patients with ischaemic stroke (1 in 2000); risk that misdiagnosis results in maltreatment is, therefore, very low. Occult primary brain cancers are mainly found among patients with haemorrhagic stroke; they are not uncommon (1 in 66) and should always be kept in mind., (© European Stroke Organisation 2020.)

Background: Lung cancer and stroke share smoking as a major cause of disease. We investigated prevalence and risk of occult lung cancer with manifestation during the first year after stroke., Methods: All patients >40 years of age with incident stroke in Denmark 2003-2015 were identified through the Danish Stroke Registry (n=85,893) and matched 1:10 on age and sex to the Danish background population without a history of stroke (n=858,740). Linking data to the Danish Cancer Registry we determined prevalence of occult primary lung cancer defined as the event of previously unknown lung cancer during a one-year follow-up in the stroke and the background population. Cox regression models with adjustments for demographics, co-morbidities and stroke risk factors were used to study risk compared to the background population., Results: Prevalence (per 1000 person-years) of occult lung cancer in the stroke cohort was 5.3; in the background cohort 2.6. Prevalence separately for current smokers (n=26,055) was 9.6; ex-smokers (n=20,035) 6.5; never-smokers (n=27,268) 1.4. Risk of occult lung cancer (adjusted) was increased HR 1.95 in the stroke population. In the stroke population adjusting for stroke risk factors age (HR 1.24 per 10 years) and smoking (HR 7.1 in current smokers; HR 1.6 in ex-smokers) were the only significant risk factors for occult lung cancer., Conclusions: Occult lung cancer is rarely found in stroke patients who have never smoked. It is not uncommon in smokers in whom 1% of current smokers had occult lung cancer that became manifest within the first year after stroke., Competing Interests: Declaration Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To investigate the effect of repeated transurethral procedures under general anesthesia on overall mortality in patients with non-invasive bladder cancer. Materials and methods: All Danish residents with non-invasive papillary urothelial carcinoma or primary urothelial carcinoma in situ diagnosed between 1 January 2000 and 1 January 2011 were included and followed until death or 31 March 2017. All transurethral procedures under general anesthesia, intravesical instillation therapy, recurrences and progression to invasive disease or cystectomy were recorded during follow-up. Associations between treatments and overall mortality were evaluated using multivariable regression analysis adjusted for age, gender, comorbidities and socioeconomic status. The effect of disease progression on mortality was removed by censoring patients at the time of progression or cystectomy. Results: Risk of death increased with the number of transurethral procedures under general anesthesia for Ta low- and high-grade tumors compared to patients who had only one procedure; after eight or more procedures the risk of death increased by 28% and 83%, respectively. There was no similar relationship for carcinomas in situ . In total, 36-52% of procedures under general anesthesia did not identify urothelial neoplasia. Conclusions: Repeated transurethral procedures under general anesthesia appear to be associated with increased risk of death in patients with primary non-invasive papillary urothelial carcinoma. Furthermore, a substantial number of procedures were without findings of neoplasia, indicating that too many patients are admitted for transurethral procedures under GA. Attempts should be taken to reduce unnecessary transurethral procedures under GA, e.g. by improved outpatient diagnosis of urothelial neoplasia.

Purpose: The aim was to assess lifetime risk for hospitalization in individuals with neurofibromatosis 1 (NF1)., Methods: The 2467 individuals discharged with a diagnosis indicating NF1 or followed in a clinical center for NF1 were matched to 20,132 general population comparisons. Based on diagnoses in 12 main diagnostic groups and 146 subcategories, we calculated rate ratios (RRs), absolute excess risks (AERs), and hazard ratios for hospitalizations., Results: The RR for any first hospitalization among individuals with NF1 was 2.3 (95% confidence interval 2.2-2.5). A high AER was seen for all 12 main diagnostic groups, dominated by disorders of the nervous system (14.5% of all AERs), benign (13.6%) and malignant neoplasms (13.4%), and disorders of the digestive (10.5%) and respiratory systems (10.3%). Neoplasms, nerve and peripheral ganglia disease, pneumonia, epilepsy, bone and joint disorders, and intestinal infections were major contributors to the excess disease burden caused by NF1. Individuals with NF1 had more hospitalizations and spent more days in hospital than the comparisons. The increased risk for any hospitalization was observed for both children and adults, with or without an associated cancer., Conclusion: NF1 causes an overall greater likelihood of hospitalization, with frequent and longer hospitalizations involving all organ systems throughout life.

Aim: Although patients with Lynch syndrome have an increased risk of developing colorectal cancer, surveillance can reduce morbidity and mortality. Whether or not affected individuals benefit from lifetime surveillance depends on individual factors and patient adherence, and these may vary, complicating risk modelling. The aim of this study was to identify individual factors which influence patient adherence to surveillance programmes and whether extended surveillance interval influenced their risk of developing colorectal cancer., Method: Demographics and survival data were obtained from patients (n = 1223) with Lynch syndrome, identified by interrogating the Danish Hereditary Non-Polyposis Colorectal Cancer Register. These data were linked to patient surveillance interval data which had been divided into three subsets (< 27 months, adherent to the recommended biennial programme; > 27 months, extended surveillance interval; and no surveillance) to estimate the cumulative risks and hazard ratios (HRs) for colorectal cancer., Results: In all, 147 colorectal cancers (99 first; 48 metachronous) were identified in 1223 patients. Factors associated with adherence to surveillance were female sex, a previous history of cancer and age < 75 years. The cumulative incidence for colorectal cancer was 38% (95% CI 27%-50%) for surveillance intervals < 27 months, 48% (95% CI 29%-67%) for intervals > 27 months and 72% (95% CI 61%-83%) with no surveillance. Adjusted HRs were 0.22 for surveillance intervals < 27 months and 0.32 for surveillance intervals > 27 months. Extended surveillance intervals > 27 months had a non-significant benefit with an HR of 1.51 (95% CI 0.83-2.75) compared to surveillance intervals < 27 months., Conclusion: This study demonstrates that adherence to colonoscopic surveillance in Lynch syndrome varies with age, sex and cancer history and demonstrates a consistent benefit from colorectal cancer surveillance, though it might be lower for individuals with extended intervals., (Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.)

Shotgun lipidomics is a powerful tool that enables simultaneous and fast quantification of diverse lipid classes through mass spectrometry based analyses of directly infused crude lipid extracts. We present here a shotgun lipidomics platform established to quantify 38 lipid classes belonging to four lipid categories present in mammalian samples and show the fine-tuning and comprehensive evaluation of its experimental parameters and performance. We first determined for all the targeted lipid classes the collision energy levels optimal for the recording of their lipid class- and species-specific fragment ions and fine-tuned the energy levels applied in the platform. We then performed a series of titrations to define the boundaries of linear signal response for the targeted lipid classes, and demonstrated that the dynamic quantification range spanned more than 3 orders of magnitude and reached sub picomole levels for 35 lipid classes. The platform identified 273, 261, and 287 lipid species in brain, plasma, and cultured fibroblast samples, respectively, at the respective optimal working sample amounts. The platform properly quantified the majority of these identified lipid species, while lipid species measured to be below the limit of quantification were efficiently removed from the data sets by the use of statistical analyses of data reproducibility or a cutoff threshold. Finally, we demonstrated that a series of parameters of cell culture conditions influence lipidomics outcomes, including confluency, medium supplements, and use of transfection reagents. The present study provides a guideline for setting up and using a simple and efficient platform for quantitatively exploring the mammalian lipidome.

Objectives: Cancer is associated with higher risk of stroke. Whether this translates into higher risk of cancer in stroke of an extent calling for cancer screening in stroke is unclear. We investigated prevalence and risk of occult cancer in stroke compared to the background population without history of stroke., Materials and Methods: All patients >40 years of age with incident stroke in Denmark 2003-2015 were identified through the Danish Stroke Registry (n = 85 893) and matched 1:10 on age and sex to the Danish background population without history of stroke (n = 858 740). Linking data to the Danish Cancer Registry, we determined prevalence of occult cancer in stroke defined as the event of previously unknown cancer during a 1-year follow-up in the stroke and in the background population. Cox regression models were used to study risk in comparison to the background population., Results: Prevalence (per 1000) of occult cancer in the stroke/background cohorts was 25.0/15.8 in women and 29.8/20.4 in men. Prevalence was dependent on age and sex. Highest among stroke patients aged 70-80 years (35.6 in women, 42.4 in men); lowest in patients aged 40-50 years (8.3 in women, 6.8 in men). Stroke was associated with an overall 54% higher risk of occult cancer but risk increased significantly with smoking, hazard ratio (HR) 1.47, age HR 1.27 per 10 years, male sex HR 1.25, and diabetes HR 1.25., Conclusions: Prevalence and risk of occult cancer in stroke is considerable and calls for attention when designing the stroke investigation program., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To analyze the risk of cardiovascular disease (CVD) after treatment of male germ cell cancer (GCC)., Methods: Clinical data were extracted from the Danish Testicular Cancer database. For each patient, 10 men matched on date of birth were identified in the Danish normal population by risk-set sampling. Cardiovascular risk factors, CVD, and associated deaths were identified in Danish registries. The association between treatment and outcomes was analyzed by separate Cox models for each outcome. Cancer treatment was included as a time-varying covariate., Results: We included 5,185 patients with GCC and 51,850 men in the normal population. Median follow-up was 15.8 years. Treatment with bleomycin-etoposide-cisplatin (BEP; n = 1,819) was associated with increased risks of hypertension and hypercholesterolemia. Hazard ratios (HRs) of CVD < 1 year after initiation of BEP treatment were as follows: myocardial infarction (HR, 6.3; 95% CI, 2.9 to 13.9), cerebrovascular accident (HR, 6.0; 95% CI, 2.6 to 14.1), and venous thromboembolism (HR, 24.7; 95% CI, 14.0 to 43.6). One year after BEP treatment, the risk of CVD decreased to normal levels, but after 10 years, increasing risks were found for myocardial infarction (HR, 1.4; 95% CI, 1.0 to 2.0) and cardiovascular death (HR, 1.6; 95% CI, 1.0 to 2.5). Radiotherapy (n = 780) increased the risk of diabetes at long-term follow-up (HR, 1.4; 95% CI, 1.0 to 2.0) but not that of other outcomes. With surveillance (n = 3,332), cardiovascular risk factors, CVD, and cardiovascular death data were comparable to that of the normal population., Conclusion: Treatment with BEP was associated with highly increased risks of CVD < 1 year after treatment start and mildly increased risks after 10 years of follow-up. Radiotherapy increased the risk of diabetes but not incident CVD. The risk of CVD in patients followed in a surveillance program was comparable to that of the normal population.