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Background and purpose: Bladder cancer (BC) is a common malignancy in the Western World with men being diagnosed almost four times as often as women. The etiology of bladder cancer may involve sex hormones. Prostate cancer (PCa) patients treated with chemical castration, such as androgen deprivation therapy, or surgical castration, may therefore have a lower risk of developing bladder cancer. Patients/material and methods: In a nation-wide population-based cohort study using national Danish registry data, we included a cohort of men with a first-time PCa diagnosis between 2002 and 2018 divided according to antihormonal treatment in the first year after PCa diagnosis and a comparison cohort consisting of 10 age-matched persons for each PCa patient. Each individual was followed from 1 year after PCa diagnosis until death or end of follow-up. We computed cumulative incidences (risk) and hazard ratios (HRs) for BC. In a second cohort analysis, we determined overall survival and BC-specific mortality, determined from date of BC diagnosis until death. Results and interpretation: We included 48,776 PCa patients of whom 13,592 were treated with chemical castration, 2,261 with surgical castration, and 32,923 received no antihormonal treatment. The 5-year risk of BC for each PCa group was 1.1%, 0.7%, and 1.3%, respectively, corresponding to an adjusted HR of 1.13 (95% CI 0.98; 1.31), 0.95 (95% CI 0.62; 1.47), and 1.18 (95% CI 1.09; 1.28) compared to individuals without PCa. Patients receiving antihormonal treatment had a slightly lower incidence of BC compared to individuals without PCa, however, this was not supported by the HRs. The treatment, however, was not associated with overall survival.

Abstract Aim To examine the risk of second primary cancer in patients with incident renal cell carcinoma (RCC). Methods We identified all patients diagnosed with incident RCC during 1995–2019, using population‐based Danish medical registries. Patients were followed from the date of RCC diagnosis until any second primary cancer diagnosis, death, emigration, or December 31, 2019, whichever came first. We computed the absolute risk, standardized incidence ratio (SIR), and excess absolute risk of second primary cancer, with 95% confidence intervals (CIs), among patients with RCC compared to the general population. Results The absolute 1‐ and 20‐year risks of any second primary cancer were 2.8% and 17.8%, respectively. Within 1 year after RCC diagnosis, we detected 20 excess cancer cases per 1000 person‐years (PY) (SIR, 2.3; 95% CI: 2.1–2.6). Moreover, we detected an additional four excess cancer cases per 1000 PY during 1 to

Abstract Background Physiotherapy appears as a promising therapy option for patients with Juvenile Idiopathic Arthritis (JIA) [1, 2], but the effects of physiotherapy and jaw exercises on JIA-related orofacial symptoms remain unknown [3]. The aim of this proof-of-concept study was to assess the impact of orofacial physiotherapy and home-exercise programs in patients with JIA and temporomandibular joint (TMJ) involvement. Methods Twelve patients with JIA and TMJ involvement received a treatment of physiotherapy, complemented by prescribed home exercises spanning over eight weeks. Orofacial symptoms and dysfunction were monitored pre-treatment, during treatment, after treatment, and at a three-months follow-up. Results Orofacial pain frequency and intensity significantly decreased during the course of the treatment (p = 0.009 and p = 0.006), with further reductions observed at the three-month follow-up (p = 0.007 and p = 0.002). During treatment, the mandibular function improved significantly in terms of maximal mouth opening capacity, laterotrusion, and protrusion. Conclusions This proof-of-concept study shows favourable effects of physiotherapy and home excercises in the management of JIA-related orofacial symptoms and dysfunctions.

Background: Opioids may modulate the immune function through opioid receptors on immune cells. Long-term consequences of prenatal opioid exposure on the immune system, such as childhood asthma, are unknown.Objectives: To investigate whether prenatal opioid exposure is associated with the risk of childhood asthma.Methods: Cohort study using linked nationwide registers in Denmark (1996–2015), Norway (2005–2015), and Sweden (2006–2013). Children born by mothers who were chronic opioid analgesics users before pregnancy (n = 14,764) or who were receiving opioid maintenance therapy (OMT) before or during pregnancy (n = 1,595) were identified based on information from each of the medical birth registers and prescription registers. Long-term opioid analgesics exposed children were compared to short-term exposed or unexposed, whereas OMT exposed children were compared to OMT unexposed. Asthma among children ≥1 years of age was defined as two or more filled prescriptions of antiasthmatic medication within 365 days, or a diagnosis of asthma. Hazard ratios (HRs) were calculated using Cox proportional hazards regression with attained age as the time scale. Inverse probability of treatment weights based on propensity scores were applied to adjust for measured confounders. Individual level data from Norway and Sweden were pooled, whereas individual level data from Denmark were analyzed separately. For the opioid analgesics comparisons, adjusted HRs (aHR) from the combined Norwegian/Swedish data and the Danish data were pooled in a fixed-effects meta-analysis.Results: For the opioid analgesics cohort, no increased risk of asthma was observed in long-term exposed children neither compared with unexposed [aHR = 0.99 (95% CI 0.87-1.12)], nor compared with short-term exposed [aHR = 0.97 (0.86-1.10)]. No increased risk of asthma was observed in OMT exposed compared with OMT unexposed children [Norway/Sweden: aHR = 1.07 (0.60-1.92), Denmark: aHR = 1.25 (0.87-1.81)]. Results from sensitivity analyses, where potential misclassification of the outcome and misclassification of OMT exposure were assessed, as well as starting follow-up at 6 years of age, showed that the estimates of association were generally robust.Conclusion: We found no association between prenatal exposure to opioids and risk of childhood asthma. Results were consistent across two different opioid exposure groups with different confounder distributions.

Introduction Programmed cell death ligand-1 (PD-L1) expression may help identify patients with non-small cell lung cancer (NSCLC) who would benefit from immunotherapy. We assessed PD-L1 expression, and epidermal growth factor receptor (EGFR) and V-Ki-Ras2 Kirsten rat sarcoma (KRAS) mutations in NSCLC patients receiving adjuvant chemotherapy. Methods Data for stage IB/II/IIIA NSCLC patients (diagnosed: 2001–2012) were retrieved from Danish population-based registries. Tumor tissue samples were tested for PD-L1 expression using VENTANA PD-L1 (SP263) Assay in tumor cells (TC) at ≥25% cutoff and immune cells (IC) at ≥1% and ≥25% cutoffs. KRAS and EGFR mutations were tested using PCR-based assays. Follow-up began 120 days after diagnosis until death/emigration/January 1, 2015, whichever came first. Using Cox proportional hazard regression, hazard ratios (HRs) were computed for overall survival (OS) for each biomarker, adjusting for age, sex, histology, comorbidities, and tissue specimen age. Results Among 391 patients identified, 40.4% had stage IIIA disease, 49.9% stage II, and 8.7% stage IB. PD-L1-TC was observed in 38% of patients, EGFR mutations in 4%, and KRAS mutations in 29%. KRAS mutations were more frequent among patients with PD-L1 TC≥25% versus TCConclusion A prognostic impact for NSCLC patients receiving adjuvant chemotherapy was not associated with PD-L1 expression, or with EGFR and KRAS mutations.

Abstract Programmed cell death receptor ligand-1 (PD-L1) expression, KRAS (KRASm) and EGFR (EGFRm) mutations may influence non-small cell lung cancer (NSCLC) prognosis. We aimed to evaluate PD-L1 expression, KRASm, and EGFRm and survival among stage III unresected NSCLC patients. Using Danish registries, we collected data on stage III unresected NSCLC patients diagnosed 2001–2012 and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression in tumors and tumor-infiltrating immune cells (ICs) by immunohistochemistry ( $$\ge$$ ≥ 1% threshold for PD-L1+). We genotyped KRAS and EGFR. Follow-up extended from 120 days post-diagnosis to death, emigration, or 31/12/2014. We computed median survival using Kaplan–Meier methods, and hazard ratios (HRs) using Cox regression associating the biomarkers with death, adjusting for confounders. Among 305 patients, 48% had adenocarcinoma; 38% squamous cell carcinoma. Forty-nine percent had PD-L1+ tumors—51% stage IIIA and 26% KRASm. Few (2%) patients had EGFRm. Median survival in months was 14.7 (95% CI = 11.8–17.9) and 13.4 (95% CI = 9.5–16.3) in PD-L1+ and PD-L1− tumors, respectively. KRASm was not associated with death (HR = 1.06, 95% CI = 0.74–1.51 versus wildtype). PD-L1+ tumors yielded a HR = 0.83 (95% CI = 0.63–1.10); PD-L1+ ICs a HR = 0.51 (95% CI = 0.39–0.68). Tumor expression of PD-L1 did not influence survival. PD-L1+ ICs may confer survival benefit in stage III unresected NSCLC patients.

Abstract Background Non-obstetric surgery conducted during pregnancy may increase the risk of adverse birth outcomes like small for gestational age, preterm birth, and miscarriage. Mechanisms are unclear but possibly longer lasting. We examined whether appendectomy, cholecystectomy and diagnostic laparoscopy conducted before pregnancy affect these outcomes. Methods This nationwide Danish prevalence study included all pregnancies during 1996–2015 that had an appendectomy, cholecystectomy or diagnostic laparoscopy registered before last menstrual period in the years 1992–2015. We excluded pregnancies with surgery and categorized pre-pregnancy surgery according to timing (0–11, 12–23, and 24+ months before last menstrual period). Outcomes were small for gestational age, late preterm birth (32–37 weeks), early preterm birth (22–31 weeks) and miscarriage (7–21 weeks). We computed absolute risks and used logistic regression comparing pregnancies with surgery 0–11 or 12–23 to 24+ months before last menstrual period, computing odds ratios for each outcome, adjusting for maternal age and smoking. Results We identified 15,939 pregnancies with appendectomy, 12,869 pregnancies with cholecystectomy and 19,330 pregnancies with diagnostic laparoscopy. The absolute risk of small for gestational age was 2.2% for patients with appendectomy 0–11 months before last menstrual period, 3.2% 12–23 months before compared with 2.2% when appendectomy was conducted more than 24 months before (adjusted OR 0.95 (95% CI; 0.65 to 1.31) and 1.37(95% CI;1.00 to 1.86). For early preterm birth, the absolute risks were 0.7, 0.5 and 0.8%, for late preterm birth 4.8, 4.4 and 4.7% and for miscarriage 5.7, 6.2 and 5.4%.We observed similar results for cholecystectomy. For diagnostic laparoscopy 0–11 months before pregnancy we found increased risks of small for gestational age (4.0, 2.8 and 2.6%) and late preterm birth (5.9, 5.0 and 4.8%). Conclusions We found no increased risk of adverse birth outcomes among pregnancies with appendectomy or cholecystectomy conducted within 2 years before pregnancy compared to more than 2 years before pregnancy. The increased risks 0–11 months after diagnostic laparoscopy are likely explained by confounding by underlying indication. It appears safe to become pregnant any time following appendectomy and cholecystectomy, but, probably depending on indication, attention should be payed 0–11 months after diagnostic laparoscopy.

Background: Population-based cohorts of immune thrombocytopenia (ITP) are useful for understanding occurrence, clinical characteristics and long-term clinical course. This paper describes the content of the Nordic Country Patient Registry for Romiplostim (NCPRR) and provides prevalence and incidence estimates of chronic ITP (cITP). Methods: The NCPRR, a cohort study established in 2009, includes all adult (≥18 years) patients in Denmark, Sweden and Norway with cITP (defined as ITP lasting >12 months and platelet count

Background: Sleep disturbances may increase risks of Alzheimer's disease (AD) and other dementias. Benign prostatic hyperplasia (BPH) is usually associated with lower urinary tract symptoms, including nocturia, and thereby disturbed sleep. We examined if men with BPH are at increased risk of AD and all-cause dementia. Methods: In a Danish nationwide cohort (1996–2016), we identified 297,026 men with BPH, defined by inpatient or outpatient hospital diagnosis or by BPH-related surgical or medical treatment, and 1,107,176 men from the general population matched by birth year. We computed rates, cumulative incidences, and adjusted hazard ratios (HRs) of AD and all-cause dementia. Follow-up started 1 year after BPH diagnosis date/index date. Findings: Median follow-up was 6·9 years (Interquartile range (IQR), 3·6 – 11·6 years] in the BPH cohort and 6·4 years (IQR: 3·4 – 10·8 years) in the comparison cohort. The cumulative 1–10 year risk of AD was 1·15% [95% confidence interval (CI), 1·11–1·20], in the BPH cohort and 1·00% (95% CI, 0·98 – 1·02) in the comparison cohort. The adjusted 1–10–year hazard ratios were 1·16 (95% CI: 1·10–1·21) for AD and 1·21 (95% CI: 1·17–1·25) for all-cause dementia. From >10 years up to 21 years of follow-up, BPH remained associated with 10%- 20% increased risk of AD and all-cause dementia. Interpretation: During up to 21 years of follow-up, men with BPH had persistently higher risk of AD and all-cause dementia compared with men in the general population. Our results identify BPH as a common, potentially remediable disorder associated with dementia risk. Funding: Lundbeckfonden, Aarhus University Research Foundation, and the National Institutes of Health.

Background and objectivesOnly few smaller studies have examined if impaired kidney function increases the risk of acute kidney injury in patients with acute pyelonephritis. Therefore, we estimated 30-day risk of acute kidney injury by preadmission kidney function in patients with acute pyelonephritis. Furthermore, we examined if impaired kidney function was a risk factor for development of acute kidney injury in pyelonephritis patients.MethodsThis cohort study included patients with a first-time hospitalization with pyelonephritis from 2000 to 2017. Preadmission kidney function (estimated glomerular filtration rate (eGFR) ResultsAmong 8,760 patients with available data on preadmission kidney function, 25.8% had a preadmission eGFR ConclusionAcute kidney injury is a common complication in patients hospitalized with acute pyelonephritis. Preadmission impaired kidney function is a strong risk factor for development of acute kidney injury in pyelonephritis patients and more attention should be raised in prevention of pyelonephritis in patients with a low kidney function.

Objective To assess whether metformin use affects risk of benign prostatic hyperplasia (BPH) by comparing the risk of BPH in men with type 2 diabetes who initiated first-line treatment with either metformin or sulfonylurea monotherapy between 2000 or 2006 in Northern Denmark. In this period, sulfonylurea and metformin were both frequently used as first-line glucose-lowering drug (GLD) treatment.Design A population-based cohort study.Setting Northern Denmark.Participants All men who filled at least two prescriptions for metformin or for sulfonylurea, respectively, during their first 6 months of GLD treatment. Follow-up started 6 months after treatment start.Primary outcome measures Rates of subsequent BPH, identified based on community prescriptions for BPH-related treatment or hospital BPH diagnoses, and rates of transurethral resection of the prostate (TURP). Rates in metformin and sulfonylurea users were compared overall and stratified by 6-month haemoglobin A1c (HbA1c) using Cox regression and an intention-to-treat (ITT) approach and an as-treated analysis.Results During follow-up, less than five persons were lost to follow-up due to emigration. In 3953 metformin initiators with a median follow-up of 10 years, the 10-year cumulative BPH incidence was 25.7% (95% CI 24.2 to 27.1). Compared with 5958 sulfonylurea users (median follow-up 8 years, 10-year cumulative incidence 27.4% (95% CI 26.2 to 28.6)), the crude HR for BPH was 0.83 (95% CI 0.77 to 0.89) and adjusted HR in the ITT analyses was 0.97 (95% CI 0.88 to 1.06). For TURP, the adjusted HR was 0.96 (95% CI 0.63 to 1.46). In the as-treated analysis, adjusted HR for BPH was 0.91 (95% CI 0.81 to 1.02).Conclusions Compared with sulfonylurea, metformin did not substantially reduce the incidence of BPH in men with diabetes.

Objective Little is known about the prognosis of infections in patients with ankylosing spondylitis (AS) compared with patients without AS. The purpose of this study was to examine whether AS is associated with poorer outcomes in patients who are hospitalised with pneumonia.Methods In a population-based cohort study including patients with hospitalised pneumonia with and without AS, we compared 90-day rates of mortality, all-cause readmission (90 days post-discharge) and pulmonary complications including pulmonary embolism, empyema and pulmonary abscess. We used Cox regression analyses to compute crude and adjusted HRs while adjusting for sex, age and level of comorbidity.Results A total of 387 796 patients (median age 71 years) were hospitalised for pneumonia in Denmark between 1997 and 2017. Among these, 842 (0.2%) had AS (median age 65 years). The 90-day mortality was 12.5% in patients with AS and 15.5% in patients with non-AS pneumonia, with crude and adjusted 90-day HRs of 0.79 (95% CI 0.66 to 0.96) and 0.95 (95% CI 0.79 to 1.16), respectively. The 90-day post-discharge readmission rate was 27.3% in patients with AS and 25.4% in patients without AS, with a corresponding adjusted readmission HR of 1.12 (95% CI 0.98 to 1.27). Relative risk of pulmonary complications among patients with AS compared with patients without AS decreased over the study period, with adjusted HRs of 1.63 (95% CI 0.82 to 3.27) in 1997–2006 falling to 0.62 (95% CI 0.31 to 1.23) in 2007–2017.Conclusions AS is not associated with increased mortality following hospitalisation for pneumonia. Furthermore, no increased risk of readmission or pulmonary complications in patients with AS was detected in recent study years.

Objective Patients with rheumatoid arthritis (RA) experience an increased risk of infections, but the prognosis of infections is unclear. We examined if patients with RA have worse outcomes from pneumonia than non-RA individuals.Methods In a population-based cohort study, we computed 90-day mortality rates and crude and adjusted HRs comparing pneumonia patients with and without RA. Among patients with RA, we evaluated prognostic effects of RA medications including prednisolone and disease activity as assessed by C reactive protein (CRP) or platelet levels measured 30–180 days before admission to avoid any influence from the subsequent infection.Results Among 52 577 patients hospitalised for the first time with pneumonia, 1220 (2.3%) had RA. The 90-day mortality was 19.9% for patients with RA and 18.9% for non-RA patients (adjusted 90-day HR of 1.05 (95% CI 0.92 to 1.19)). Compared with CRP levels

Abstract Background Among cancer patients, prior antidepressant use has been associated with impaired survival. This could be due to differences in stage at diagnosis, in receipt of treatment, or in treatment complications. The purpose of this study was, therefore, to examine if preadmission antidepressant use in patients with bladder cancer is associated with tumor stage at diagnosis, rate of cystectomy, and surgical outcomes, including survival. Methods We performed a registry-based cohort study including all patients with incident invasive bladder cancer in Denmark 2005–2015. Exposure was defined as redemption of two or more antidepressant prescriptions one year before cancer diagnosis. We compared tumor stage using logistic regression, postsurgical inpatient length of stay using linear regression, and other outcomes using Cox regression. All results were adjusted for age, sex, comorbidity, and marital status. Results Among 10,427 bladder cancer patients, 10% were antidepressant users. At diagnosis, 51% of users and 52% of non-users had muscle-invasive disease. However, upon adjustment for age, sex, comorbidity, and marital status, users had lower odds of muscle-invasive disease (adjusted odds ratio 0.86 (95% confidence interval (CI) 0.74–0.99)). Among patients with muscle-invasive disease, fewer users than non-users had surgery within three months (15% vs. 24%, adjusted hazard ratio (aHR) 0.75 (95% CI 0.59–0.95)). Of 2532 patients undergoing surgery, 6% were antidepressant users. Postsurgical inpatient length of stay did not differ between users and non-users. The 30-day cumulative incidence of readmission was higher for users (41% vs. 33%, aHR 1.33 (95% CI 1.05–1.67)), while the 90-day incidence of postoperative procedures was 44% for users and 38% for non-users (aHR 1.18 (95% CI 0.93–1.51)). One-year mortality was comparable in users (15%) and non-users (14%). Conclusions Antidepressant use in bladder cancer patients was associated with less advanced stage at diagnosis and lower rate of cystectomy. After cystectomy, users had higher rate of readmission and postoperative procedures than non-users, but we found no difference in length of stay or one-year mortality. The results point to the importance of differentiated clinical care according to individual patient characteristics.

Abstract Background Several frequently used prescription drugs may affect bleeding risk. We investigated use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and statins and risk of postoperative red blood cell transfusion in breast cancer patients. Methods Using Danish population-based registries, we identified a cohort of women who underwent surgery for primary breast cancer (n = 22,238) during 2005–2012 and ascertained their use of aspirin, NSAIDs, SSRIs, and statins. For each drug, patients were categorized as users if they filled ≥1 prescription in the 60 days prior to surgery. We calculated the 14-day risk of red blood cell transfusion and relative risks (RRs) with 95% confidence intervals (CIs), comparing users with nonusers for each drug and adjusting for age, cancer stage, and Charlson Comorbidity Index score. Results In our cohort, 1385 (6.2%) women were aspirin users, 1794 (8.0%) were NSAID users, 1110 (4.9%) were SSRI users, and 2053 (9.1%) were statin users. The overall risk of red blood cell transfusion was 1.3%. The 14-day risk of RBC transfusion was 3.5% among aspirin users versus 1.1% among aspirin nonusers (adjusted RR = 1.9, 95% CI: 1.4–2.7), and 1.8% among SSRI users versus 1.2% among SSRI nonusers (adjusted RR = 1.2, 95% CI: 0.7–1.9). Red blood cell transfusion risk was increased among NSAID users, but not in a sensitivity analysis with a 30-day exposure window. Red blood cell transfusion risk was not increased among SSRI and statin users. Conclusions Primary breast cancer surgery confers a low risk of RBC transfusion. Still, use of aspirin and possibly NSAIDs, but not SSRIs and statins, is associated with increased red blood cell transfusion. This increased risk is not explained by differences in age, stage, or comorbidity level.

Introduction Staphylococcus aureus bacteremia (SAB) is an invasive infection with high mortality and morbidity. Rheumatoid arthritis (RA) is associated with increased risk of infections due to the disease per se and the use of antirheumatic treatments. Few minor studies have previously investigated risk of SAB in patients with RA and indicated increased risk compared with the general population. This nationwide observational study aims to investigate incidence of and risk factors for SAB in adult patients with RA compared with the general population. The effect of disease characteristics (eg, joint erosions, disease duration and activity), different antirheumatic treatments and smoking on SAB risk will be evaluated.Methods and analysis All adults (>18 years of age) alive and living in Denmark in 1996–2017 will be identified in The Danish Civil Registration System. Incident patients with RA are identified in the Danish National Patient Registry (DNPR) and the nationwide rheumatology registry, DANBIO, in which information on, for example, antirheumatic treatments, disease characteristics and smoking is collected prospectively in routine care. Information on comorbidities, invasive procedures and prescribed drugs are identified in the DNPR and in The Register of Medicinal Product Statistics. Socioeconomic status is evaluated in national registers on income and education. Incident cases of first-time SAB are identified in The Danish National SAB Database. All registers are linked on an individual level by unique civil registration numbers. Incidence rates and incidence rate ratios will be analysed using Poisson regression models and the impact of possible risk factors will be evaluated.Ethics and dissemination All data will be handled in accordance with the General Data Protection Regulation (EU) 2016/679. No ethical approval is necessary in Denmark when handling registry data only. The results will be presented in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology initiative in international peer-reviewed journals and at medical conferences.Trial registration number NCT03908086.

Objectives Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder. Sleep disturbance may interfere with clearance of abnormal proteins that aggregate in neurodegenerative diseases. The objective of this study was to examine the association between benign prostatic hyperplasia (BPH), a common disorder causing nocturia and sleep disturbance, and risk of ALS and other motor neuron disease (MND). We hypothesised that men with BPH, in comparison to men in the general population, would be at increased risk.Design This is a nationwide, population-based cohort study.Setting This study was conducted among the population of Denmark.Participants We used linked Danish medical databases to identify all men with a first-time diagnosis of BPH between 1 January 1980 and 30 November 2013 and no prior diagnosis of MND (BPH cohort, n=223 131) and an age-matched general population comparison cohort of men without BPH or MND (n=1 115 642).Primary outcome measure The primary outcome is diagnosis of MND after the BPH diagnosis (index) date, with follow-up until MND diagnosis, emigration, death or 30 November 2013.Results We used Cox regression to compute adjusted HR, comparing men with and without BPH. After 34 years of follow-up, there were 227 cases of MND in the BPH cohort (incidence rate 0.13/1000 person-years) and 1094 MND cases in the comparison cohort (0.12/1000 person-years; HR 1.05, 95% CI 0.90 to 1.22). Risk did not vary by follow-up time.Conclusions BPH is not associated with an increased risk of ALS and other MND. Future studies should examine the relation between other disorders that disrupt sleep and MND risk in men and women.

Background: Streptococcus pneumoniae and Neisseria meningitidis are frequent pathogens in life-threatening infections. Genetic variation in the immune system may predispose to these infections. Nuclear factor-κB is a key component of the TLR-pathway, controlled by inhibitors, encoded by the genes NFKBIA, NFKBIE and NFKBIZ. We aimed to replicate previous findings of genetic variation associated with invasive pneumococcal disease (IPD), and to assess whether similar associations could be found in invasive meningococcal disease (IMD). Methods: Cases with IPD and IMD and controls were identified by linking Danish national registries. DNA was obtained from the Danish Neonatal Screening Biobank. The association between SNPs and susceptibility to IPD and IMD, mortality and pneumococcal serotypes was investigated. Results: 372 children with pneumococcal meningitis, 907 with pneumococcal bacteremia and 1273 controls were included. We included 406 cases with meningococcal meningitis, 272 with meningococcal bacteremia, and 672 controls. The NFKBIE SNP was associated with increased risk of pneumococcal meningitis (aOR 1.68; 95% CI: 1.20–2.36), but not bacteremia (aOR 1.08; 95% CI: 0.86–1.35). The remaining SNPs were not associated with susceptibility to invasive disease. None of the SNPs were associated with risk of IMD or mortality. Conclusions: A NFKBIE polymorphism was associated with increased risk of pneumococcal meningitis.

BACKGROUND:Cerebral palsy (CP) is the most common physical developmental disability in childhood with a prevalence of 2 to 3 per 1000 live births. β2-adrenoreceptor agonist (β2AA) are widely used for the treatment of asthma. Maternal use of β2AAs may increase the risk of adverse neuro-psychiatric health outcomes in the offspring. No study, however, has evaluated the effect of prenatal exposure to β2AAs on the risk of CP. OBJECTIVE:To examine the association between prenatal exposure to β2AAs and the risk of childhood cerebral palsy. METHODS:This population-based cohort study included all live singleton births in Denmark from January 1, 1997 to December 31, 2003. The information on outpatient prescriptions of β2AAs was extracted from Danish National Prescription Registry. Children born to mothers who used β2AAs from 30 days before pregnancy until delivery were categorized as the exposed. To differentiate the effect of β2AAs from the underlying indications, the exposure window was further extended to 2 years before pregnancy and the exposed groups were re-defined to represent different periods of exposure to maternal use of β2AAs (use only before pregnancy, use only during pregnancy, and use both before and during pregnancy). Cases of CP were identified from the Danish Cerebral Palsy Register. Logistic regression was used to estimate incidence odds ratio (OR) of CP. RESULTS:Among all the 442,278 singletons, 19,616 (4.44%) were exposed to β2AAs in utero (from 30 days before pregnancy until delivery). The risk of childhood CP was 0.21% in exposed and 0.19% in unexposed group, yielding an adjusted OR (aOR) 1.12 (95% confidence interval (CI): 0.82, 1.53). When extending the exposure time window to 2 years prior to pregnancy, no overall significant association was observed regardless of the exposure period. However, an increased risk of CP (aOR = 1.41, 95%CI: 0.92, 2.18) for maternal β2AAs use during pregnancy was observed in female offspring, especially in those born at term (aOR = 1.65, 95%CI: 1.02, 2.67). This increase was mainly attributed to an increased risk in those born to mothers who used β2AAs both before and during pregnancy (aOR = 1.81, 95%CI: 0.99, 3.33). CONCLUSIONS:We observed an association between maternal β2AAs use during pregnancy and an increased risk of CP in female offspring, but we could not rule out confounding by the underlying indications for β2AAs.

Splenectomized patients are at increased risk of cardiovascular events, but it remains unclear whether this is due to lack of the spleen or due to the underlying disease leading to splenectomy. We aimed to assess the risk of myocardial infarction, pulmonary hypertension, and stroke following splenectomy. We identified patients splenectomized in Denmark between 1996 and 2012. We constructed two comparison cohorts: an age- and sex-matched general population cohort and a disease-matched cohort based on the splenectomy-related underlying disease. We computed 5-year cumulative incidences and adjusted hazard ratios of myocardial infarction, pulmonary hypertension, and stroke for the three cohorts. The study included 5,306 splenectomized patients, 53,060 members of the general population, and 11,651 disease-matched patients. During the 5-year follow-up, 1.3% of splenectomized patients had a myocardial infarction versus 1.8% of the population cohort. The adjusted hazard ratio for myocardial infarction in splenectomized patients versus the population cohort was 1.24 (95% confidence interval: 1.01–1.52). The 5-year cumulative incidence of pulmonary hypertension was 0.4% among splenectomized subjects and 0.2% in the population cohort [adjusted hazard ratio 3.25 (95% confidence interval: 1.93–5.45)], while that of stroke was 3.3% among splenectomized patients versus 2.6% in the population cohort [adjusted hazard ratio 2.04 (95% confidence interval: 1.78–2.35)]. When comparing splenectomized subjects with the disease-matched cohort, only stroke risk was elevated, with 5-year risks of 3.0% and 2.3%, respectively [adjusted hazard ratio 1.56 (95% confidence interval: 1.26–1.92)]. In conclusion, splenectomized patients were at increased risk of stroke. Additionally, we found that underlying splenectomy-related diseases explained the increased risk of myocardial infarction and pulmonary hypertension following splenectomy.

Annette Østergaard Jensen1, Mette Nørgaard1, Mellissa Yong2, Jon P Fryzek2, Henrik Toft Sørensen11Department of Clinical Epidemiology, Aarhus University hospital, Århus, Denmark; 2Global Epidemiology, Amgen inc., Thousands Oaks, CA, USAObjective: The clinical history of bone metastases and skeletal-related events (SREs) secondary to cancers is not well understood. In support of studies of the natural history of bone metastases and SREs in Danish prostate and breast cancer patients, we estimated the sensitivity and specificity of hospital diagnoses for bone metastases and SREs (ie, radiation therapy to the bone, pathological or osteoporotic fractures, spinal cord compression and surgery to the bone) in a nationwide medical registry in Denmark.Study design and setting: In North Jutland County, Denmark, we randomly sampled 100 patients with primary prostate cancer and 100 patients with primary breast cancer diagnoses from the National Registry of Patients (NRP), during the period January 1st, 2000 to December 31st, 2000 and followed them for up to five years after their cancer diagnosis. We used information from medical chart reviews as the reference for estimating sensitivity, and specificity of the NRP International Classification of Diseases, 10th edition (ICD-10) coding for bone metastases and SRE diagnoses. Results: For prostate cancer, the overall sensitivity of bone metastases or SRE coding in the NRP was 0.54 (95% confidence interval [CI]: 0.39–0.69), and the specificity was 0.96 (95% CI: 0.87–1.00). For breast cancer, the overall sensitivity of bone metastases or SRE coding in the NRP was 0.58 (95% CI: 0.34–0.80), and the specificity was 0.95 (95% CI: 0.88–0.99). Conclusion: We measured the validity of ICD-10 coding in the Danish NRP for bone metastases and SREs in prostate and breast cancer patients and found it has adequate sensitivity and high specificity. The NRP remains a valuable tool for clinical epidemiological studies of bone metastases and SREs.Keywords: bone metastases, skeletal-related events (SRE), sensitivity, specificity

Katrine Edith Klith Heden, Annette Østergaard Jensen, Dora Körmendiné Farkas, Mette NørgaardDepartment of Clinical Epidemiology, Aarhus University Hospital, DenmarkBackground: Administrative data may be useful for epidemiological studies of chronic idiopathic thrombocytopenic purpura (ITP). However, the quality of the recorded diagnoses needs evaluation.Aim: We evaluated the validity in predicting chronic ITP of the International Classifi cation of Diseases (ICD)-10 diagnoses of ITP in the Danish National Registry of Patients (NRP).Methods: We used the NRP to identify patients with ITP, according to code D69.3, from January 1, 1996 to December 31, 2007. We defined chronic ITP as lasting longer than 6 months by including only patients with 2 or more hospital ITP diagnoses over longer than 6 months. We confirmed diagnoses by evaluating each candidate chronic ITP patient’s medical chart and estimating the positive predictive value (PPV) and 95% confidence interval (CI) of the recorded NRP diagnostic code.Results: We identified 513 patients with chronic ITP in the NRP. We were able to retrieve the charts of 439. After evaluation of the charts, 410 patients were deemed to have a valid diagnosis of chronic ITP, yielding a PPV of 0.93 (95% CI: 0.91–0.96).Conclusion: The validity of this procedure to identify chronic ITP patients was high. The NRP is valid for epidemiological studies of patients with chronic ITP.Keywords: validity, idiopathic thrombocytopenic purpura, National Registry of Patients

BACKGROUND:The purpose was to describe utilization of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including trends in prevalence, characteristics of users, drug switching and changes in prescribed doses in a large group of pregnant women across four Nordic countries. METHODS:A drug utilization study based on linked individual-level data from the nationwide prescription- and medical birth registers in Denmark, Iceland, Norway and Sweden. The study population comprised all pregnancies in these countries, resulting in a live birth or stillbirth after gestational week 22 from January 1st 2008 to December 31st 2012 (N = 1 162 470). In addition to the main study drugs SSRIs and SNRIs, we included (concurrent) use of other antidepressants, antipsychotics, anxiolytics and hypnotics. RESULTS:A total of 38 219 (3.3%) pregnancies were exposed to SSRIs and 5 634 (0.5%) to SNRIs. Prevalence of SSRI and SNRI use varied by country (1.8% in Norway to 7.0% in Iceland). Use and prescribed dosages decreased with each passing trimester of pregnancy; prevalence was 2.7% at conception, and 2.1%, 1.7% and 1.3% respectively in 1st, 2nd and 3rd trimester. In 0.6% of pregnancies women filled a prescription before pregnancy and in every trimester. In one third of exposed pregnancies, women were also dispensed anxiolytics, hypnotics or sedatives. CONCLUSION:Use of SSRI and SNRI use during pregnancy varied between the Nordic countries, but the overall prevalence remained low and relatively stable from 2008 to 2012. The low prevalence of use and high proportion of women who discontinue treatment in pregnancy raise questions about adequate treatment of depression in pregnant women.

Infections are common complications among patients on chronic hemodialysis. This population-based cohort study aims to estimate risk and case fatality of bloodstream infection among chronic hemodialysis patients.In this population-based cohort study we identified residents with end-stage renal disease in Central and North Jutland, Denmark who had hemodialysis as first renal replacement therapy (hemodialysis patients) during 1995-2010. For each hemodialysis patient, we sampled 19 persons from the general population matched on age, gender, and municipality. Information on positive blood cultures was obtained from regional microbiology databases. All persons were observed from cohort entry until first episode of bloodstream infection, emigration, death, or end of hemodialysis treatment, whichever came first. Incidence-rates and incidence-rate ratios were computed and risk factors for bloodstream infection assessed by Poisson regression. Case fatality was compared by Cox regression.Among 1792 hemodialysis patients and 33 618 matched population controls, we identified 461 and 1126 first episodes of bloodstream infection, respectively. Incidence rates of first episode of bloodstream infection were 13.7 (95% confidence interval (CI), 12.5-15.0) per 100 person-years among hemodialysis patients and 0.53 (95% CI, 0.50-0.56) per 100 person-years among population controls. In hemodialysis patients, the most common causative microorganisms were Staphylococcus aureus (43.8%) and Escherichia coli (12.6%). The 30-day case fatality was similar among hemodialysis patients and population controls 16% (95% CI, 13%-20%) vs. 18% (95% CI, 15%-20%).Hemodialysis patients have extraordinary high risk of bloodstream infection while short-term case fatality following is similar to that of population controls.

ObjectivesTo examine the effect of socioeconomic status (SES) on mortality in patients with bacteremia and the underlying factors that may mediate differences in mortality.MethodsWe conducted a population-based cohort study in two Danish regions. All patients 30 to 65 years of age with first time bacteremia from 2000 through 2008 were identified in a population-based microbiological bacteremia database (n = 8,653). Individual-level data on patients' SES (educational level and personal income) and comorbid conditions were obtained from public and medical registries. We used Cox regression to examine mortality within 30 days after bacteremia with and without cumulative adjustment for potential mediators.ResultsBacteremia patients of low SES were more likely to live alone and be unmarried than patients of high SES. They also had more pre-existing comorbidity, more substance abuse, more Staphylococcus aureus and nosocomial infections, and more admissions to small nonteaching hospitals. Overall, 1,374 patients (15.9%) died within 30 days of follow-up. Patients of low SES had consistently higher mortality after bacteremia than those of high SES crude hazard ratio for low vs. high education, 1.38 [95% confidence interval (CI), 1.18-1.61]; crude hazard ratio for low-income vs. high-income tertile, 1.58 [CI, 1.39-1.80]. Adjustment for differences in social support, pre-existing comorbidity, substance abuse, place of acquisition of the infection, and microbial agent substantially attenuated the effect of SES on mortality (adjusted hazard ratio for low vs. high education, 1.15 [95% CI, 0.98-1.36]; adjusted hazard ratio for low-income vs. high-income tertile, 1.29 [CI, 1.12-1.49]). Further adjustment for characteristics of the admitting hospital had minimal effect on observed mortality differences.ConclusionsLow SES was strongly associated with increased 30-day mortality after bacteremia. Less social support, more pre-existing comorbidity, more substance abuse, and differences in place of acquisition and agent of infection appeared to mediate much of the observed disparities in mortality.

BACKGROUND: Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection. METHODOLOGY/PRINCIPAL FINDINGS: To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191,383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100,000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22-1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count. CONCLUSIONS/SIGNIFICANCE: Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.