Correction: Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1004238.].

Trigeminal neuralgia and risk of cancer: A population-based cohort study.

BACKGROUND: Evidence of an association between trigeminal neuralgia (TN) and subsequent cancer risk remains sparse. The present study aimed to examine the association between TN and cancer risk in the Danish population. METHODS: A nationwide population-based cohort study using hospital diagnoses collected routinely and prospectively from Danish population-based registries in 1994-2022. RESULTS: We identified 7846 individuals with a first-time diagnosis of TN. Within one year of diagnosis, we observed 193 cancer cases (standardized incidence rate (SIR) = 2.45, 95% confidence interval (CI) = 2.11-2.82). Absolute risk (AR) for all cancers within one year of TN diagnosis was 2.5% (95% CI = 2.2-2.9). Cancers of the head, neck and nervous system were most strongly associated with TN (AR 0.9% (95% CI = 0.7-1.1); SIR = 13.5 (95% CI = 10.5-17.0)) and the risk was persistently elevated one year after TN diagnosis. We observed 827 cancer diagnoses beyond one year after TN diagnosis, where smoking related cancers were associated with elevated cancer risk (SIR 1.13 = (95% CI = 0.98-1.29)). CONCLUSIONS: TN was associated with an elevated risk of cancers of the head, neck and nervous system including site-specific cancers in the area. Our results suggest the potential importance of smoking related tumors in TN, either as a symptom, cause or shared risk factor.

Maternal Smoking During Pregnancy and Risk of Appendicitis in the Offspring.

BACKGROUND: Existing evidence on the link between smoking and appendicitis is scarce and ambiguous. We therefore conducted a population-based cohort study in Denmark to investigate whether smoking during pregnancy is associated with an increased risk of appendicitis in offspring. METHODS: We used the Danish Birth Registry to include all singletons born during 1991-2017 and to identify maternal smoking status during pregnancy. We followed the children from birth until date of appendicitis, emigration, death, or administrative end of study (31 December 2018), whichever came first. We calculated crude and adjusted hazard ratios (HRs) of appendicitis with 95% confidence intervals (CIs) comparing children of mothers who smoked during pregnancy to children of nonsmokers. Further, we conducted a bias analysis and sibling analysis. RESULTS: We included 1,659,526 singletons of whom 19% were born to mothers who smoked during pregnancy. After maximum 28 years of follow-up, hazard rates for children of smokers were slightly higher than for children of nonsmokers [adjusted HR: 1.07 (95% CI = 1.04, 1.10)]. Stratification by sex revealed no association for males [adjusted HR: 1.02 (95% CI = 0.99, 1.06)], but a higher HR for females [adjusted HR: 1.13 (95% CI = 1.09, 1.18)]. This association increased with increasing length of follow-up, indicating that the association may be mediated by later-life exposures. The bias analysis indicated that misclassification of maternal smoking could attenuate a true association, while the sibling analysis showed no association. CONCLUSIONS: Maternal smoking during pregnancy and appendicitis in the offspring may be associated.

Cancer risk in patients with migraine: A population-based cohort study in Denmark.

OBJECTIVE: The purpose of this study was to examine overall and site-specific cancer risk among individuals diagnosed with migraine compared with the general population. BACKGROUND: Current evidence regarding migraine and risk of cancer is sparse and inconclusive. METHODS: We conducted a nationwide population-based cohort study with data collected routinely and prospectively from Danish population-based registries from 1995 to 2017. We computed the age- and sex-standardized incidence ratio (SIR) as the ratio of observed to expected cancers among patients diagnosed with migraine in the study population overall, and by encounter type of first diagnosis (inpatient, outpatient specialty clinic, and emergency department). Site-specific cancers were grouped according to etiology. RESULTS: We identified 72,826 patients with a first-time hospital migraine diagnosis. There were 3090 observed overall cancer cases among individuals diagnosed with migraine as compared with 3108 expected cases (SIR 0.99, 95% confidence interval [CI]: 0.96-1.03). The cumulative incidence of all cancers combined from 1995 to 2017 among those with a first-time migraine diagnosis was 9.47% (95% CI: 9.08-9.87). The SIRs for most cancers were consistent with absence of an association: 1.00 (95% CI: 0.94-1.06) for hormone-related cancers, 0.96 (95% CI: 0.88-1.03) for smoking-related cancers, 1.10 (95% CI: 0.98-1.24) for hematologic cancers, and 0.95 (95% CI: 0.85-1.06) for immune-related cancers. Exceptions were SIRs for gastrointestinal cancers (0.78, 95% CI: 0.70-0.87) and for cancers of neurological origin (1.57, 95% CI: 1.40-1.76). CONCLUSIONS: For most cancer groups, our results did not support an association with migraine. The exceptions were an increased risk for cancers of neurological origin and a decreased risk for gastrointestinal cancers. These findings may reflect a true difference in risk among individuals with migraine, or more plausibly they reflect other forces, such as differences in medication use, detection bias and reverse causation, or shared risk factors.

Basolateral cholesterol depletion alters Aquaporin-2 post-translational modifications and disrupts apical plasma membrane targeting.

Apical plasma membrane accumulation of the water channel Aquaporin-2 (AQP2) in kidney collecting duct principal cells is critical for body water homeostasis. Posttranslational modification (PTM) of AQP2 is important for regulating AQP2 trafficking. The aim of this study was to determine the role of cholesterol in regulation of AQP2 PTM and in apical plasma membrane targeting of AQP2. Cholesterol depletion from the basolateral plasma membrane of a collecting duct cell line (mpkCCD14) using methyl-beta-cyclodextrin (MBCD) increased AQP2 ubiquitylation. Forskolin, cAMP or dDAVP-mediated AQP2 phosphorylation at Ser269 (pS269-AQP2) was prevented by cholesterol depletion from the basolateral membrane. None of these effects on pS269-AQP2 were observed when cholesterol was depleted from the apical side of cells, or when MBCD was applied subsequent to dDAVP stimulation. Basolateral, but not apical, MBCD application prevented cAMP-induced apical plasma membrane accumulation of AQP2. These studies indicate that manipulation of the cholesterol content of the basolateral plasma membrane interferes with AQP2 PTM and subsequently regulated apical plasma membrane targeting of AQP2.

Evaluation of Left Truncation and Censoring When Changing the Use of the International Classification of Diseases Eighth Revision Codes to Tenth Revision Codes in the Danish National Patient Registry.

Purpose: In the Danish National Patient Registry (DNPR), covering all Danish hospitals and widely used in research, diseases have been recorded using International Classification of Diseases (ICD) codes, transitioning from the Eighth to the Tenth revision in 1994. Uncertainty exists regarding whether including ICD-8 codes alongside ICD-10 is needed for complete disease identification. We assessed the extent of left-truncation and left-censoring in the DNPR arising from omitting ICD-8 codes. Patients and Methods: We sampled 500,000 Danes ≥40 years of age in 1995, 2010, and 2018. From the DNPR, we identified cardiovascular, endocrine, gastrointestinal, neurological, pulmonary, rheumatic, and urogenital diseases as well as fractures. We obtained the number of people with a disease recorded with ICD-8 codes only (ie, the ICD-8 record would be left-truncated by not using ICD-8 codes), ICD-8 plus ICD-10 codes (ie, the ICD-8 record would be left-censored by not using ICD-8 codes), and ICD-10 codes only. For each ICD group, we calculated the proportion of people with the disease relative to the total sample (ie, 500,000 people) and the total number of people with the disease across all ICD groups. Results: Overall, the left-truncation issue decreased over the years. Relative to all people with a disease, the left-truncated proportion was for example 59% in 1995 and <2% in 2018 for diabetes mellitus; 93% in 1995, and 54% in 2018 for appendicitis. The left-truncation issue increased with age group for most diseases. The proportion of disease records left-censored by not using ICD-8 codes was generally low but highest for chronic diseases. Conclusion: The left-truncation issue diminished over sample years, particularly for chronic diseases, yet remained rather high for selected surgical diseases. The left-truncation issue increased with age group for most diseases. Left-censoring was overall a minor issue that primarily concerned chronic diseases.

Combined Impact of Migraine and Pregnancy-Induced Hypertension on Long-term Risk of Premature Myocardial Infarction and Stroke.

BACKGROUND AND OBJECTIVES: Migraine and pregnancy-induced hypertension (PIH) are known to increase cardiovascular risk on their own. However, evidence is limited on the combined impact of migraine and PIH on risk of cardiovascular disease. The aim of this study was to examine the combined impact of migraine and PIH on risk of premature (age 60 years and younger) major adverse cardiovascular and cerebrovascular events (MACCE), a composite end point consisting of myocardial infarction, stroke, or death due to one of these diseases. METHODS: We conducted a population-based cohort study in Denmark (1996-2018) among women who had delivered at least one child. This population was stratified into 4 cohorts: women with neither migraine nor PIH, women with migraine, women with PIH, and women with both migraine and PIH. As a measure of absolute risk, we computed the 20-year cumulative incidence of premature MACCE, treating death by other causes than myocardial infarction and stroke as a competing risk. We used Cox regression to compute 20-year adjusted hazard ratios (HRs) of premature MACCE. Women with neither migraine nor PIH served as the comparison cohort. RESULTS: The 20-year absolute risk of premature MACCE was 1.3% (95% CI 1.2%; 1.3%) for women without migraine and without PIH (n = 1,288,541), 2.2% (95% CI 2.0%; 2.4%) for women with migraine (n = 54,827), 2.8% (95% CI 2.6%; 3.1%) for women with PIH (n = 49,008), and 3.1% (95% CI 2.1%; 4.4%) for women with both migraine and PIH (n = 3,140). The adjusted HR of premature MACCE was 1.66 (95% confidence interval [CI] 1.50-1.84) for women with migraine, 2.76 (95% CI 2.52-3.03) for women with PIH, and 2.41 (95% CI 1.61-3.61) for women with both migraine and PIH. DISCUSSION: Migraine and PIH separately increased the risk of premature MACCE. The risk of premature MACCE among women who had both migraine and PIH was similar to that among women with PIH only.

Mental Health Conditions in Partners and Adult Children of Stroke Survivors.

Importance: Family caregiving after critical illness has been associated with several adverse health outcomes, including various aspects of mental health, but research focusing specifically on family members of stroke survivors is limited. Objectives: To examine the associations of stroke in a partner or parent with the risk of depression, substance use disorders, anxiety disorders, and self-harm or suicide. Design, Setting, and Participants: This nationwide, population-based cohort study used data from Danish nationwide administrative and clinical registries (2004-2021). Participants included partners and adult children of survivors of stroke. Data analysis was performed from March to December 2023. Exposure: Having a partner or parent who survived stroke. Main Outcomes and Measures: The Aalen-Johansen estimator was used to compute propensity score-weighted 3-year absolute risks, risk differences, and risk ratios for depression, substance use disorders, anxiety disorders, and self-harm or suicide among partners or children of survivors of stroke compared with partners or children of survivors of myocardial infarction (MI) and matched individuals from the general population. Results: The study included a total of 1 923 732 individuals: 70 917 partners of stroke survivors (median [IQR] age, 68 [59-76] years; 46 369 women [65%]), 70 664 partners of MI survivors (median [IQR] age, 65 [55-73] years; 51 849 women [73%]), 354 570 partners of individuals from the general population (median [IQR] age, 68 [59-76] years; 231 833 women [65%]), 207 386 adult children of stroke survivors (median [IQR] age, 45 [36-52] years; 99 382 women [48%]), 183 309 adult children of MI survivors (median [IQR] age, 42 [33-49] years; 88 078 women [48%]), and 1 036 886 adult children of individuals from the general population (median [IQR] age, 45 [36-52] years; 496 875 women [48%]). Baseline characteristics were well balanced across cohorts after propensity score weighting. Among partners of stroke survivors, the 3-year absolute risk was 1.0% for depression, 0.7% for substance use disorders, 0.3% for anxiety disorders, and 0.04% for self-harm or suicide. Risk ratio point estimates for the assessed outcomes ranged from 1.14 to 1.42 compared with the general population and from 1.04 to 1.09 compared with partners of MI survivors. The elevated risk of depression in partners of stroke survivors was more pronounced after severe or moderate stroke than after mild stroke. Among adult children of stroke survivors, the 3-year absolute risk was 0.6% for depression, 0.6% for substance use disorders, 0.2% for anxiety disorders, and 0.05% for self-harm or suicide. Both absolute risks and risk ratios for adult children of stroke survivors were smaller than those reported in the partner analyses. Conclusions and Relevance: In this cohort study of partners and adult children of stroke survivors, risks of several mental health conditions and self-harm or suicide were moderately higher compared with the general population and, to a lesser extent, partners and adult children of MI survivors. These findings highlight the potential consequences of stroke among family members, particularly partners, and its findings may possibly serve as a quantitative foundation for the development of future stroke rehabilitation services.

High-intensity versus moderate-intensity statin treatment for patients with ischemic stroke: Nationwide cohort study.

PURPOSE: Guidelines recommend high-intensity statin treatment after ischemic stroke, but evidence is sparse on the effectiveness and safety of different statin treatment intensities. We examined effectiveness and safety outcomes among patients initiating high-intensity versus moderate-intensity statins after ischemic stroke. METHODS: In this population-based new-user active-comparator cohort study, we used the Danish Stroke Registry, covering all Danish hospitals, to identify patients with a first-time ischemic stroke during 2012-2021. Using multiple Danish registries, patients who redeemed a statin prescription within 21 days after stroke admission were classified as high-intensity statin initiators or moderate-intensity statin initiators. Propensity score inverse probability of treatment weighting was used to balance patient characteristics. We used competing risk methods to compute 5 year risk differences (RDs) and Cox proportional hazards regression to compute 5 year hazard ratios (HRs) of stroke recurrence, myocardial infarction, heart failure, venous thromboembolism, and all-cause mortality (effectiveness outcomes) and diabetes, liver disease, and kidney disease (safety outcomes). RESULTS: High-intensity (n = 13,032) and moderate-intensity (n = 14,355) statin initiators were identified. Risks of most examined effectiveness outcomes were comparable between statin intensities. There was no clear association between statin intensity and stroke recurrence (RD: 0.8% [95% CI: 0.1, 1.4], HR: 1.08 [95% CI: 0.96, 1.22]). All-cause mortality was slightly reduced among high-intensity statin initiators (RD: -1.1% [95% CI: -0.1, -2.1], HR: 0.93 [95% CI: 0.85, 1.01]. Risks of most safety outcomes were comparable between statin intensities, but high-intensity statin use was associated with an increased risk of diabetes (RD: 1.2% [95% CI: 0.4, 1.9], HR: 1.10 [95% CI: 1.00, 1.21]). DISCUSSION AND CONCLUSION: Compared with initiation of moderate-intensity statins, initiation of high-intensity statins after ischemic stroke was associated with similar risks of most effectiveness and safety outcomes. However, mortality risk was reduced, and diabetes risk was increased.

Non-Traumatic Subdural Hematoma and Cancer: A Cohort Study.

Introduction: Cancer may increase the risk of bleeding. However, whether subdural hematoma is a marker of occult cancer remains unknown. We examined the association between non-traumatic subdural hematoma and cancer risk in a cohort study. Materials and Methods: Using Danish nationwide health registries, we identified 2713 patients with non-traumatic subdural hematoma and no previous cancer diagnosis, who were hospitalized between April 1, 1996 and December 31, 2019. We computed age-, sex-, and calendar year-standardized incidence ratios (SIRs) as the ratio of the observed to expected number of patients with cancer by using national incidence rates as reference as a measure of relative risk. Results: We identified 77 cancer cases within the first year of follow-up and 272 cancer cases thereafter. The one-year risk of cancer was 2.8% (95% confidence interval: 2.2-3.5), and the one-year SIR was 1.7 (95% confidence interval: 1.3-2.1). During the subsequent years, the SIR was 1.0 (95% confidence interval: 0.9-1.1). The relative risk was elevated for some hematological and liver cancers. Conclusion: The risk of a new cancer diagnosis was clearly increased in patients with non-traumatic subdural hematoma compared with the general population during the first year of follow-up. However, the absolute risk was low, thus limiting the clinical relevance of pursuing early cancer detection in these patients.

A Review of Major Danish Biobanks: Advantages and Possibilities of Health Research in Denmark.

Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health - Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.