Neurotrophic tyrosine receptor kinase gene fusions in adult and pediatric patients with solid tumors: a clinicogenomic biobank and record linkage study of expression frequency and patient characteristics from Finland.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers. Using the Auria Biobank in Finland, we aimed to identify and characterize patients with these gene fusions, and describe their clinical and tumor characteristics, treatments received, and outcomes. MATERIAL AND METHODS: We evaluated pediatrics with any solid tumor type and adults with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), sarcoma, or salivary gland cancer. We determined tropomyosin receptor kinase (TRK) protein expression by pan-TRK immunohistochemistry (IHC) staining of tumor samples from the Auria Biobank, scored by a certified pathologist. NTRK gene fusion was confirmed by next generation sequencing (NGS). All 2,059 patients were followed-up starting 1 year before their cancer diagnosis. RESULTS: Frequency of NTRK gene fusion tumors was 3.1% (4/127) in pediatrics, 0.7% (8/1,151) for CRC, 0.3% (1/288) for NSCLC, 0.9% (1/114) for salivary gland cancer, and 0% (0/379) for sarcoma. Among pediatrics there was one case each of fibrosarcoma (TPM3::NTRK1), Ewing's sarcoma (LPPR1::NTRK2), primitive neuroectodermal tumor (DAB2IP::NTRK2), and papillary thyroid carcinoma (RAD51B::NTRK3). Among CRC patients, six harbored tumors with NTRK1 fusions (three fused with TPM3), one harbored a NTRK3::GABRG1 fusion, and the other a NTRK2::FXN/LPPR1 fusion. Microsatellite instability was higher in CRC patients with NTRK gene fusion tumors versus wild-type tumors (50.0% vs. 4.4%). Other detected fusions were SGCZ::NTRK3 (NSCLC) and ETV6::NTRK3 (salivary gland cancer). Four patients (three CRC, one NSCLC) received chemotherapy; one patient (with CRC) received radiotherapy. CONCLUSION: NTRK gene fusions are rare in adult CRC, NSCLC, salivary tumors, sarcoma, and pediatric solid tumors.

Population-based study of long-term anticoagulation for treatment and secondary prophylaxis of venous thromboembolism in men with prostate cancer in Sweden.

BACKGROUND: Epidemiological data on anticoagulation for venous thromboembolism (VTE) in prostate cancer are sparse. We aimed to investigate associations between anticoagulation duration and risks of VTE recurrence after treatment cessation and major on-treatment bleeding in men with prostate cancer in Sweden. METHODS: Using nationwide prostate cancer registry and prescribing data, we followed 1413 men with VTE and an outpatient anticoagulant prescription following prostate cancer diagnosis. Men were followed to identify cases of recurrent VTE, and hospitalized major bleeding. We calculated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) to quantify the association between anticoagulation duration (reference ≤ 3 months) and recurrent VTE using Cox regression. We estimated 1-year cumulative incidences of major bleedings from anticoagulation initiation. RESULTS: The outpatient anticoagulation prescribed was parenteral (64%), direct oral anticoagulant (31%), and vitamin K antagonist (20%). Median duration of anticoagulation was 7 months. Adjusted HRs (95% CI) for off-treatment recurrent pulmonary embolism (PE) were 0.32 (0.09-1.15) for > 3-6 months' duration, 0.21 (0.06-0.69) for > 6-9 months and 0.16 (0.05-0.55) for > 9 months; corresponding HRs for deep vein thrombosis (DVT) were 0.67 (0.27-1.66), 0.80 (0.31-2.07), and 1.19 (0.47-3.02). One-year cumulative incidences of intracranial, gastrointestinal and urogenital bleeding were 0.9%, 1.7%, 3.0% during treatment, and 1.2%, 0.9%, 1.6% after treatment cessation. CONCLUSION: The greatest possible benefit in reducing recurrent VTE risk occurred with > 9 months anticoagulation for PE and > 3-6 months for DVT, but larger studies are needed to confirm this. Risks of major bleeding were low overall.

To Treat or Not to Treat: Anticoagulants as Secondary Preventives to the Oldest Old With Atrial Fibrillation.

BACKGROUND AND PURPOSE: Anticoagulant treatment is effective for preventing recurrent ischemic strokes in patients who have atrial fibrillation. This benefit is paid by a small increase of hemorrhages. Anticoagulant-related hemorrhages seem to increase with age, but there are few studies showing whether the benefits of treatment persist in old age. METHODS: For this observational study, 4 different registers were used, among them Riksstroke, the Swedish Stroke Register. Patients who have had a recent ischemic stroke, were 80 to 100 years of age, and had atrial fibrillation, were included from 2006 through 2013. The patients were stratified into 3 age groups: 80 to 84, 85 to 89, and ≥90 years of age. Information on stroke severity, risk factors, drugs, and comorbidities was gathered from the registers. The patients were followed with respect to ischemic or hemorrhagic stroke, other hemorrhages, or death. RESULTS: Of all 23 356 patients with atrial fibrillation, 6361 (27%) used anticoagulants after an ischemic stroke. Anticoagulant treatment was associated with less recurrent ischemic stroke in all age groups. Hemorrhages increased most in the ≥90-year age group, but this did not offset the overall beneficial effect of the anticoagulant. Apart from age, no other cardiovascular risk factor or comorbidity was identified that influenced the risk of anticoagulant-associated hemorrhage. Drugs other than anticoagulants did not influence the incidence of major hemorrhage. CONCLUSIONS: Given the patient characteristics in this study, there is room for more patients to be treated with anticoagulants, without hemorrhages to prevail. In nonagenarians, hemorrhages increased somewhat more, but this did not affect the overall outcome in this age stratum.

Differences in diagnostic process, treatment and social Support for Alzheimer's dementia between primary and specialist care: resultss from the Swedish Dementia Registry.

Background: the increasing prevalence of Alzheimer's dementia (AD) has shifted the burden of management towards primary care (PC). Our aim is to compare diagnostic process and management of AD in PC and specialist care (SC). Design: cross-sectional study. Subjects: a total of, 9,625 patients diagnosed with AD registered 2011-14 in SveDem, the Swedish Dementia Registry. Methods: descriptive statistics are shown. Odds ratios are presented for test performance and treatment in PC compared to SC, adjusted for age, sex, Mini-Mental State Examination (MMSE) and number of medication. Results: a total of, 5,734 (60%) AD patients from SC and 3,891 (40%) from PC. In both, 64% of patients were women. PC patients were older (mean age 81 vs. 76; P < 0.001), had lower MMSE (median 21 vs. 22; P < 0.001) and more likely to receive home care (31% vs. 20%; P < 0.001) or day care (5% vs. 3%; P < 0.001). Fewer diagnostic tests were performed in PC and diagnostic time was shorter. Basic testing was less likely to be complete in PC. The greatest differences were found for neuroimaging (82% in PC vs. 98% in SC) and clock tests (84% vs. 93%). These differences remained statistically significant after adjusting for MMSE and demographic characteristics. PC patients received less antipsychotic medication and more anxiolytics and hypnotics, but there were no significant differences in use of cholinesterase inhibitors between PC and SC. Conclusion: primary and specialist AD patients differ in background characteristics, and this can influence diagnostic work-up and treatment. PC excels in restriction of antipsychotic use. Use of head CT and clock test in PC are areas for improvement in Sweden.

Cerebrospinal fluid tau and amyloid-ß1-42 in patients with dementia.

Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-ß1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-ß1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-ß1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-ß1-42 and amyloid-ß1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-ß1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-ß1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-ß1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-ß1-42, total tau, phosphorylated tau and the amyloid-ß1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-ß1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.

Medial temporal lobe atrophy and depressive symptoms in elderly patients with and without Alzheimer disease.

OBJECTIVE: To determine whether depressive symptoms are associated with medial temporal lobe atrophy in older people with and without Alzheimer disease (AD). METHOD: A total of 368 memory clinic patients with AD, mild cognitive impairment, and subjective cognitive impairment (SCI) were included. Depressive symptoms were defined as a score of 8 or higher on Cornell Scale for Depression in Dementia or use of antidepressant medications. Magnetic resonance imaging and computer tomography scans were rated for medial temporal lobe atrophy (MTA), using the Scheltens scale. For a subsample (n = 57 patients), hippocampal volume was manually traced. RESULTS: Based on visual assessment, AD patients with depressive symptoms had less atrophy of the right medial temporal lobe (odds ratio [OR] for having MTA: 0.39; 95% confidence interval [CI] 0.16-0.99) and decreased scores on Scheltens scale for the left medial temporal lobe (OR: 0.43, 95% CI 0.19-0.96) in comparison to AD patients without depressive symptoms. In the subgroup where manual tracing was used to measure hippocampal volume, people with SCI experiencing depressive symptoms had smaller right (mean difference: 0.28 cm(3); P = .005) and left (mean difference 0.32 cm(3); P = .002) hippocampal volumes compared to people with SCI who did not have depressive symptoms. CONCLUSION: Hippocampal atrophy was more pronounced among patients having SCI with depressive symptoms, while the medial temporal lobe was less atrophic in patients having AD with depressive symptoms than those without depressive symptoms. These findings suggest that different mechanisms underlie depression in older people with and without AD and may explain some of the inconsistent observations in previous studies.

Benchmarking biomarker-based criteria for Alzheimer's disease: Data from the Swedish Dementia Registry, SveDem.

INTRODUCTION: New research guidelines for the diagnosis of Alzheimer's disease (AD) include biomarker evidence of amyloid-ß (Aß) and tau pathology. The aim of this study was to investigate what proportion of AD patients diagnosed in clinical routine in Sweden that had an AD-indicative cerebrospinal fluid (CSF) biomarker profile. METHODS: By cross-referencing a laboratory database with the Swedish Dementia Registry (SveDem), 2357 patients with data on CSF Aß and tau biomarkers and a clinical diagnosis of AD with dementia were acquired. RESULTS: Altogether, 77.2% had pathologic Aß42 and total tau or phosphorylated tau in CSF. These results were stable across age groups. Female sex and low mini-mental state examination score increased the likelihood of pathologic biomarkers. DISCUSSION: About a quarter of clinically diagnosed AD patients did not have an AD-indicative CSF biomarker profile. This discrepancy may partly reflect incorrect (false positive) clinical diagnosis or a lack in sensitivity of the biomarker assays.

Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study.

AIMS: We aimed to investigate the association of number of completed races and finishing time with risk of arrhythmias among participants of Vasaloppet, a 90 km cross-country skiing event. METHODS AND RESULTS: All the participants without cardiovascular disease who completed Vasaloppet during 1989-98 were followed through national registries until December 2005. Primary outcome was hospitalization for any arrhythmia and secondary outcomes were atrial fibrillation/flutter (AF), bradyarrhythmias, other supraventricular tachycardias (SVT), and ventricular tachycardia/ventricular fibrillation/cardiac arrest (VT/VF/CA). Among 52 755 participants, 919 experienced arrhythmia during follow-up. Adjusting for age, education, and occupational status, those who completed the highest number of races during the period had higher risk of any arrhythmias [hazard ratio (HR)1.30; 95% CI 1.08-1.58; for ≥5 vs. 1 completed race], AF (HR 1.29; 95% CI 1.04-1.61), and bradyarrhythmias (HR 2.10; 95% CI 1.28-3.47). Those who had the fastest relative finishing time also had higher risk of any arrhythmias (HR 1.30; 95% CI 1.04-1.62; for 100-160% vs. >240% of winning time), AF (1.20; 95% CI 0.93-1.55), and bradyarrhythmias (HR 1.85; 95% CI 0.97-3.54). SVT or VT/VF/CA was not associated with finishing time or number of completed races. CONCLUSIONS: Among male participants of a 90 km cross-country skiing event, a faster finishing time and a high number of completed races were associated with higher risk of arrhythmias. This was mainly driven by a higher incidence of AF and bradyarrhythmias. No association with SVT or VT/VF/CA was found.

Neurotrophic-tyrosine receptor kinase gene fusion in papillary thyroid cancer: A clinicogenomic biobank and record linkage study from Finland.

Selective tropomyosin receptor kinase (TRK) inhibitors are approved targeted therapies for patients with solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Country-specific estimates of NTRK gene fusion frequency, and knowledge on the characteristics of affected patients, are limited. We identified patients with histologically-confirmed papillary thyroid cancer (PTC) from Finland's Auria Biobank. TRK protein expression was determined by pan-TRK immunohistochemistry. Immuno-stained tumor samples were scored by a certified pathologist. Gene fusions and other co-occurring gene alterations were identified by next generation sequencing. Patient characteristics and vital status were determined from linked hospital electronic health records (EHRs). Patients were followed from 1 year before PTC diagnosis until death. 6/389 (1.5%) PTC patients had an NTRK gene fusion (all NTRK3); mean age 43.8 years (and none had comorbidities) at PTC diagnosis. Gene fusion partners were EML4 (n = 3), ETV6 (n = 2), and RBPMS (n = 1). Of 3/6 patients with complete EHRs, all received radioactive iodine ablation only and were alive at end of follow-up (median observation, 9.12 years). In conclusion, NTRK gene fusion is infrequent in patients with PTC. Linkage of biobank samples to EHRs is feasible in describing the characteristics and outcomes of patients with PTC and potentially other cancer types.

Risk of venous thromboembolism in men with prostate cancer compared with men in the general population: a nationwide population-based cohort study in Sweden.

OBJECTIVE: To estimate the additional risk of venous thromboembolism (VTE) in men with prostate cancer compared with men without prostate cancer in Sweden. DESIGN: Nationwide cohort study following 92 105 men with prostate cancer and 466 241 men without prostate cancer (comparison cohort) matched 5:1 by birth year and residential region. SETTING: The male general population of Sweden (using the Nationwide Prostate Cancer data Base Sweden). PRIMARY AND SECONDARY OUTCOME MEASURES: Crude incidence proportion ratios (IPRs) comparing the incidence of VTE in men with prostate cancer and men in the comparison cohort. Cox regression was used to calculate HRs for VTE adjusted for confounders. RESULTS: 2955 men with prostate cancer and 9774 men in the comparison cohort experienced a first VTE during a median of 4.5 years' follow-up. Deep vein thrombosis (DVT) accounted for 52% of VTE cases in both cohorts. Median time from start of follow-up to VTE was 2.5 years (IQR 0.9-4.7) in the prostate cancer cohort and 2.9 years (IQR 1.3-5.0) in the comparison cohort. Crude incidence rates of VTE per 1000 person-years were 6.54 (95% CI 6.31 to 6.78) in the prostate cancer cohort (n=2955 events) and 4.27 (95% CI 4.18 to 4.35) in the comparison cohort (n=9774 events). The IPR decreased from 2.53 (95% CI 2.26 to 2.83) at 6 months to 1.59 (95% CI 1.52 to 1.67) at 5 years' follow-up. Adjusted HRs were 1.48 (95% CI 1.39 to 1.57) for DVT and 1.47 (95% CI 1.39 to 1.56) for pulmonary embolism after adjustment for patient characteristics. CONCLUSIONS: Swedish men with prostate cancer had a mean 50% increased risk of VTE during the 5 years following their cancer diagnosis compared with matched men free of prostate cancer. Physicians should be mindful of this marked increase in VTE risk in men with prostate cancer to help ensure timely diagnosis.

Characteristics, treatment patterns, and residual cardiovascular risk of patients with a first acute myocardial infarction: A nationwide population-based cohort study in Norway.

There are few nationwide descriptive studies of longitudinal drug use and residual cardiovascular risk in patients with myocardial infarction (MI) in contemporary clinical practice. The objectives of this work were to describe characteristics and longitudinal cardiovascular drug use of patients with a first acute MI in Norway, and to quantify residual risks of cardiovascular events and death. Using nationwide health registries in Norway, we identified 43 750 adults with a first MI (2010 to 2015) and ≥1 prescription for antiplatelet medication. We described cardiovascular medication post-MI and calculated residual cardiovascular risks. Between 3 months and 13-15 months post MI, medication use dropped from 93.3% to 75.1% for low-dose aspirin, 78.1% to 11.0% for dual antiplatelet therapy, 91.6% to 78.7% for antihypertensives, and 88.0% to 70.7% for lipid-lowering therapy. Incidence rate ratios (IRRs) for recurrent MI were similar between subpopulations at 12 months and notably different at 12-36 months. IRRs (95% CIs) at 12-36 months were 1.52 (1.26-1.82) for 65-74 years, 2.26 (1.88-2.71) for 75-84 years, and 3.97 (3.29-4.79) for ≥85 years (vs. 18-49 years), 2.42 (2.18-2.69) for those with ischaemic heart disease (IHD), 2.26 (1.97-2.59) for peripheral artery disease (PAD), 2.17 (1.98-2.36) for hypertension, and 1.82 (1.65-2.01) for diabetes. In conclusion, secondary prevention medication use 13-15 months following a first MI is suboptimal among patients in Norway. The elderly and those with IHD, PAD, diabetes, or hypertension are at high-risk for recurrent MI/stroke/death and should be managed closely beyond the first year.

Diagnostic and prognostic factors in patients with prostate cancer: a systematic review.

OBJECTIVES: As part of the PIONEER Consortium objectives, we have explored which diagnostic and prognostic factors (DPFs) are available in relation to our previously defined clinician and patient-reported outcomes for prostate cancer (PCa). DESIGN: We performed a systematic review to identify validated and non-validated studies. DATA SOURCES: MEDLINE, Embase and the Cochrane Library were searched on 21 January 2020. ELIGIBILITY CRITERIA: Only quantitative studies were included. Single studies with fewer than 50 participants, published before 2014 and looking at outcomes which are not prioritised in the PIONEER core outcome set were excluded. DATA EXTRACTION AND SYNTHESIS: After initial screening, we extracted data following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of prognostic factor studies (CHARMS-PF) criteria and discussed the identified factors with a multidisciplinary expert group. The quality of the included papers was scored for applicability and risk of bias using validated tools such as PROBAST, Quality in Prognostic Studies and Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: The search identified 6604 studies, from which 489 DPFs were included. Sixty-four of those were internally or externally validated. However, only three studies on diagnostic and seven studies on prognostic factors had a low risk of bias and a low risk concerning applicability. CONCLUSION: Most of the DPFs identified require additional evaluation and validation in properly designed studies before they can be recommended for use in clinical practice. The PIONEER online search tool for DPFs for PCa will enable researchers to understand the quality of the current research and help them design future studies. ETHICS AND DISSEMINATION: There are no ethical implications.

Age in relation to comorbidity and outcome in patients with high-risk TIA or minor ischemic stroke: A Swedish national observational study.

INTRODUCTION: Recent trials report positive results for preventing vascular events with dual antiplatelet therapy (DAPT) in patients with high-risk TIA or minor ischemic stroke. We aimed to investigate this population regarding influence of age on vascular risk factors, hospital stay and mortality. PATIENTS AND METHODS: Data on patients aged 40-100 years with TIA or ischemic stroke in the Swedish Stroke Register during 2012-13 were linked with national registers. To identify patients with high-risk TIA (ABCD2 ≥6) or minor ischemic stroke (NIHSS ≤5) eligible for DAPT, we excluded patients with atrial fibrillation, anticoagulant use, prior major bleeding, or unknown stroke severity. FINDINGS: We identified 10,053 potential DAPT-candidates (mean age 72.6 years, 45.2% female, 16.4% with TIA). With advancing age, most vascular risk factors increased. Antiplatelet treatment increased from 31.9% before the event to 95.5% after discharge. Within 1 year following index event, the proportion of patients with ≥1 re-admission increased with age (29.2% in 40-64 year-olds; 47.2% in 85-100 year-olds). All-cause death per 100 person-years was 6.9 (95% CI 6.4-7.4) within 1 year, and highest in the first 30 days (15.2; 95% CI 12.8-18.2). For each year of increased age, the risk of death increased with 3.5% (p = 0.128) in patients 40-64 years and with 11.8% (p < 0.001) in those ≥85 years. CONCLUSIONS: While in theory representing a subset of patients with mild injury, our observational study highlights substantial use of health-care resources and high mortality rates among patients with high-risk TIA or minor ischemic stroke assumed eligible for DAPT.

Diagnostic and prognostic factors in patients with prostate cancer: a systematic review protocol.

INTRODUCTION: As part of the PIONEER (Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe) Consortium, we will explore which diagnostic and prognostic factors (DPFs) are currently being researched to previously defined clinical and patient-reported outcomes for prostate cancer (PCa). METHODS AND ANALYSIS: This research project will follow the following four steps: (1) a broad systematic literature review of DPFs for all stages of PCa, covering evidence from 2014 onwards; (2) discussion of systematic review findings by a multidisciplinary expert panel; (3) risk of bias assessment and applicability with Prediction model Risk Of Bias Assessment Tool criteria, Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and the Quality In Prognosis Studies tool (QUIPS) and (4) additional quantitative assessments if required. ETHICS AND DISSEMINATION: We aim to develop an online tool to present the DPFs identified in this research and make them available across all stakeholders. There are no ethical implications.

Ischemic stroke and secondary prevention in clinical practice: a cohort study of 14,529 patients in the Swedish Stroke Register.

BACKGROUND AND PURPOSE: Secondary prevention is recommended after stroke, but adherence to guidelines is unknown. We studied the prescription of antiplatelet drugs, angiotensin-converting enzyme inhibitors, statins, and anticoagulant drugs and their relation to risk of death. METHODS: Patients with first-ever ischemic stroke in 2005 were registered in the Swedish Stroke Register. Odds ratios, hazard ratios, and 95% CIs were calculated using logistic and Cox proportional hazard regression models. Adjustments were performed for age, sex, cardiovascular risk factors, other drug therapies, and activities of daily living function. RESULTS: In total, 14,529 patients with a mean age of 75.0 (+/-11.6) years were included. They were followed for 1.4 (+/-0.5) years: 52% had hypertension, 26% atrial fibrillation, 19% diabetes, and 15% were smokers. The odds ratio for prescription of antiplatelet was 2.20 (95% CI, 1.86 to 2.60) among the oldest patients (>or=85 years of age) compared with the youngest (18 to 64 years of age). The corresponding odds ratio was 0.38 (0.32 to 0.45) for prescriptions of angiotensin-converting enzyme inhibitors, 0.09 (0.08 to 0.11) for statins, and 0.07 (0.05 to 0.09) for anticoagulant therapy. Prescription of statin and anticoagulant therapy was associated with reduced risk of death (hazard ratio, 0.78 [0.65 to 0.91] and hazard ratio, 0.58 [0.44 to 0.76], respectively) but not the prescription of antiplatelet drugs or angiotensin-converting enzyme inhibitors. CONCLUSIONS: The prescription of antiplatelet, angiotensin-converting enzyme inhibitors, statins, and anticoagulant therapy was strongly age related. Statin and anticoagulant therapy was associated with reduced risk of death and seemed to be underused among elderly patients. These findings should encourage physicians to follow today's guidelines for stroke care.

Incidence of urinary tract infection in patients with type 2 diabetes. Experience from adverse event reporting in clinical trials.

PURPOSE: Diabetes mellitus has long been widely considered to be associated with an increased risk of urinary tract infection (UTI), but information on incidence rates are scarce and risk factor data have been conflicting. The aim was to estimate UTI incidence and evaluate potential risk factors for UTI in patients with type 2 diabetes included in recent clinical trials. METHODS: Type 2 diabetes patients from 10 AstraZeneca phase III diabetes clinical trials (n=6016, mean 57.4 years, 50.7% female) conducted during 2004-2007 were included. Patients free of UTI at baseline were followed for up to 6 months after inclusion in the trials. UTI was considered present if any term sorting under the MedDRA high-level term "UTIs" was recorded as an adverse event. RESULTS: In all, 142 patients had an adverse event for UTI, corresponding to an incidence of 59.5/1000 person-years for all patients (91.5/1000 in women, 28.2/1000 in men) and a cumulative incidence of 2% during 6 months. Female gender was associated with an increased incidence [relative risk (RR) 3.4; 95% confidence interval (CI) 2.3-5.1] and also higher age (RR 2.5 [95% CI 1.4-4.8] for ages ≥ 70 years vs. 40-49 years). No increased incidence was associated with body mass index (25-29, 30+ vs. <25 kg/m(2) ), HbA1c (<8% vs. >8%), race (Black, Oriental vs. Caucasian) or drug treatment (study drug, comparator vs. placebo). A history of immune system disorder conveyed a twofold higher risk for UTI. CONCLUSION: UTI is common among female patients with type 2 diabetes and older patients of both genders.

Risk of stroke after new-onset seizures.

PURPOSE: Observational cohort studies have reported a potentially increased risk of stroke in patients with epileptic seizures. Whether late-onset seizures merit primary stroke prophylaxis is not known, and more information on stroke risk is needed for the planning of RCTs. We performed a case-control study based on Swedish national registers to quantify the risk of stroke after epileptic seizures. METHODS: Cases ≤100 years of age with a first-ever stroke 2001-2009 were identified through the Swedish Stroke Register, and stroke-free controls (matched for age and sex) were obtained from the Population Register. The National Patient Register provided information on diagnostic codes for seizures, epilepsy and comorbidities. 123 105 stroke cases and 250 506 controls were included. RESULTS: Epileptic seizures prior to index stroke date were detected in 1559 (1.27 %) cases and 1806 (0.72 %) controls, yielding an odds ratio (95 % confidence interval) for stroke of 1.77 (1.65-1.89). ORs were similar in men and women, but higher below the age of 75. An onset of seizures in the year preceding stroke date resulted in a higher risk for stroke (OR = 2.21, 95 % CI = 1.79-2.72) compared to when more than 5 years had passed since the first seizure (OR = 1.57, 95 % CI = 1.43-1.72). CONCLUSION: A history of epileptic seizures was associated with an increased risk of subsequent stroke. The risk seems to be particularly high in the first year following seizure diagnosis, which supports the notion that unexplained late-onset seizures may merit swift assessment of vascular risk profile. The nature of stroke prevention requires further study.

Statins as secondary preventives in patients with intracerebral hemorrhage.

BACKGROUND: Statins are important components of secondary stroke prevention, but there is a concern they may increase the risk of intracerebral hemorrhage. Although this risk may have been overestimated, there is still an open question whether statin therapy should be continued, or even initiated, in patients who have had a recent intracerebral hemorrhage. AIM: Our aim was to investigate the risk of statin use after an intracerebral hemorrhage with respect to recurrent intracerebral hemorrhage, stroke in general, and death. METHODS: This observational study was based on patients with a first intracerebral hemorrhage in 2004 through 2009. Clinical characteristics, index intracerebral hemorrhage, and recurrent intracerebral hemorrhages were identified by the Swedish Stroke Register; additional data on comorbidities and vital status were retrieved through record linkages to national registers. A propensity score for the likelihood of receiving statins at discharge was developed and used with other established risk factors in a multivariable analysis. RESULTS: Of 6082 intracerebral hemorrhage patients (mean age 69.6 years), 1097 (18%) were prescribed statins at discharge. During the follow-up (mean 3.1 years), 1434 (23.6%) deaths and 234 (3.8%) recurrent intracerebral hemorrhages were observed. Statin therapy was associated with a reduced risk of death (adjusted hazard ratio: 0.71; 95% confidence interval: 0.60-0.84) but not with the risk of recurrent intracerebral hemorrhage (adjusted hazard ratio: 0.82; 95% confidence interval: 0.55-1.22). CONCLUSIONS: This study provides some reassurance that statins may be safe to use, in at least some patients, after an intracerebral hemorrhage. In patients with intracerebral hemorrhage, statin use was associated with a reduced risk of death, without an increased risk of recurrent intracerebral hemorrhage.

Prognosis of patients with malignant mesothelioma by expression of programmed cell death 1 ligand 1 and mesothelin in a contemporary cohort in Finland.

OBJECTIVES: We aimed to describe mesothelin (MSLN) and programmed cell death 1 ligand 1 (PD-L1) tumour overexpression amongst patients with malignant mesothelioma (MM), and their associations with survival, amongst a cohort of patients with MM in Finland. METHODS: Between 2004 and 2017, 91 adults with histologically confirmed MM were identified from the Auria Biobank in Finland and followed-up using linked data from electronic health records and national statistics. Biomarker content in tumour cell membranes was determined using automated Immunohistochemistry on histological sections. Stained tumour sections were scored for MSLN and PD-L1 intensity. Adjusted associations between MSLN/PD-L1 co-expression and mortality were evaluated by estimating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression. RESULTS: Biomarker overexpression occurred in 52 patients for MSLN and 34 patients for PD-L1 and was associated with tumour histology and certain comorbidities. Fifteen per cent of patients had a tumour that overexpressed both biomarkers; r =-0.244, p-value: 0.02. Compared with MSLN+/PD-L1+ patients, HRs (95% CIs) for death were 4.18 (1.71-10.23) for MSLN-/PD-L1+ patients, 3.03 (1.35-6.77) for MSLN-/PD-L1- patients, and 2.13 (0.97-4.67) for MSLN+/PD-L1- patients. CONCLUSIONS: Both MSLN and PD-L1 markers were independent prognostic indicators in patients with MM. Overexpression of MSLN was associated with longer survival; yet their combined expression gave a better indication of survival. The risk of death was four times higher amongst MSLN-/PD-L1+ patients than in MSLN+/PD-L1+ patients.

Association between enrolment in a heart failure quality registry and subsequent mortality-a nationwide cohort study.

AIMS: Heart failure (HF) quality registries report quality of care but it is unknown whether they improve outcomes. The aims were to assess predictors of enrolment in a HF registry, test the hypothesis that enrolment in a HF registry is associated with reduced mortality, and assess potential explanatory factors for this reduction in mortality, if present. METHODS AND RESULTS: We conducted a nationwide prospective cohort study of patients with new-onset HF registered in the Swedish National Patient Registry (NPR, a mandatory registry of ICD-code diagnoses) with or without concurrent registration in the Swedish Heart Failure Registry (SwedeHF, a voluntary quality reporting registry) 2006-2013. The association between demographics, co-morbidities and medications, and enrolment in the SwedeHF, was assessed using multivariable logistic regression. The association between enrolment in the SwedeHF and all-cause mortality was assessed using multivariable Cox regression, with adjustment for demographics, co-morbidities and medications. A total of 231 437 patients were included, of which 21 888 (9.5%) were in the SwedeHF [age (mean ± standard deviation) 74 ± 13 years; 41% women; 68% inpatients] and 209 549 (90.5%) were not (age 78 ± 12 years, 50% women; 79% inpatients). Selected variables independently associated with enrolment in the SwedeHF were male sex, younger age, higher education, absent co-morbidities and co-morbidity-related medications, and use of HF and cardiovascular medications. Over a median (interquartile range) follow-up of 874 (247-1667) days, there were 13.0 vs. 20.8 deaths per 100 patient-years (P < 0.001). The hazard ratio (95% confidence interval) for death for the SwedeHF yes vs. no was 0.65 (0.63-0.66) crude, and increased to 0.80 (0.78-0.81) after adding demographics, to 0.82 (0.80-0.84) after adding co-morbidities and co-morbidity-related medications, to 0.95 (0.93-0.97) after adding cardiovascular medications, and to 1.04 (1.02-1.07) after adding HF-specific medications. CONCLUSION: Heart failure patients of male sex, younger age, and higher education were more likely to be enrolled in a HF quality registry. Enrolment was associated with reduced all-cause mortality that was explained by demographic differences and better utilization of cardiovascular and HF medications.