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The aim of this population research was to find out the risk of arterial disease (defined as angina pectoris, myocardial infarction, peripheral occlusive arterial disease, and cerebrovascular disease) and hypertension in persons with varicose veins. A 5-year follow-up study was conducted in Tampere, Finland. A validated questionnaire was used in 3 middle-aged cohorts (40, 50, and 60 year olds) in a general population of 6,874. In the follow-up study, 71% (n = 4,903) replied. The incidence of arterial disease and hypertension was studied in those with varicose veins and those without at the entry to the study. During the follow-up, new arterial disease occurred significantly more often in individuals with varicose veins. The incidence odds ratio was 2.0 (95% confidence interval, 1.5-2.7; n = 3,032), but the incidence odds ratio of new hypertension was 1.0 (95% confidence interval, 0.8-1.3; n = 2,915). Varicose veins are a risk indicator of arterial disease but not of hypertension. Varicose veins likely do not cause arterial disease, but they may have common causes that, however, are not related with hypertension. [ABSTRACT FROM AUTHOR]

Background and Aims: Adenosine is a widely used potent cardioprotective drug, but the effect of an adenosine bolus in initial cardioplegia on cardioprotection in aortic valve replacement (AVR) patients has not been demonstrated. The aim of this double-blind randomized clinical trial was to compare intra-aortic adenosine bolus with saline on the postoperative myocardial function in patients undergoing AVR., Methods: Aortic valve stenosis patients scheduled for elective or urgent AVR surgery were randomized to receive either a 20 mg (4 mL) single dose of adenosine or a saline into the ascending aorta during the first cardioplegia infusion. The primary outcome was cardiac index (CI (L/min/m 2 ) at four timepoints (before incision, after weaning from cardiopulmonary bypass (CPB), at 7 p.m. on the operation day, and at 6 a.m. the next morning). Secondary outcomes included left ventricular stroke work index, right ventricular stroke work index, and myocardial biomarkers at the same timepoints., Results: Between November 2015 and March 2018, 45 patients were recruited, 23 in the adenosine group and 22 in the placebo group. The last follow-up date was 17 March 2018. There were no statistically significant differences in CI (mean differences with 95% confidence interval (95% CI): 0.09 L/min/m 2 at baseline (-0.20 to 0.38), -1.39 L/min/m 2 (-3.47 to 0.70) at post-CPB, -0.39 L/min/m 2 (-0.78 to 0.004) at 7 p.m., and -0.32 L/min/m 2 (-0.68 to 0.05) at 6 a.m., ( p  = 0.066)), right ventricular stroke work index, ( p  = 0.24), or cardiac biomarkers between the groups. Left ventricular stroke work index was lower in the adenosine group (-3.66 gm/m 2 (-11.13 to 3.81) at baseline, -17.42 gm/m 2 (-37.81 to 2.98) at post-CPB, -3.36 gm/m 2 (-11.10 to 4.38) at 7 p.m., and -3.77 gm/m 2 (-10.19 to 2.66) at 6 a.m. ( p  = 0.021))., Conclusions: There were no differences between 20 mg adenosine bolus and saline in the first cardioplegia infusion in CI improvement in AVR surgery for aortic valve stenosis.EudraCT number: 2014-001382-26., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The incidence of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), after lung cancer resections varies in the literature, and there is limited evidence regarding the optimal duration of thromboprophylaxis. This study aimed at determining the early and long-term occurrence of thromboembolic complications in patients who received in-hospital thromboprophylaxis and underwent resective surgery for lung cancer., Methods: The study included all patients who underwent lung cancer surgery at Tampere University Hospital between 2004 and 2016. Postoperative thromboprophylaxis was administered for the duration of the hospitalization. Data on subsequent episodes of VTE and survival were obtained from national registries. The results were compared to a demographically matched reference population., Results: The study comprised 435 patients and 4,338 individuals in the reference population. The overall occurrence of VTE in patients and the reference group was 0.3% vs. 0.2% at 90 days (P=0.56), 3.5% vs. 0.7% at 1 year (P<0.001), 9.2% vs. 2.2% at 3 years (P<0.001), and 18.7% and 3.9% at 5 years (P<0.001), respectively. The majority of cases represented PE. The overall mortality at 5 years was 44.4% vs. 11.6% (P<0.001). No associations between patient characteristics and the occurrence of VTE during follow-up were detected., Conclusions: Patients undergoing lung cancer surgery and who receive in-hospital medical thromboprophylaxis do not seem to be in high risk for symptomatic VTE during the early postoperative period. However, during long-term follow-up the occurrence of symptomatic VTE was significant., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-308/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background and Objective: In this clinical trial, we evaluated if a short-acting nucleoside, adenosine, as a high-dose bolus injection with blood cardioplegia induces faster arrest and provides better myocardial performance in patients after bypass surgery for coronary artery disease., Methods: Forty-three patients scheduled for elective or urgent coronary artery bypass grafting were prospectively recruited in two-arm 1:1 randomized parallel groups to either receive 20 mg of adenosine (in 21 patients) or saline (in 22 patients) into the aortic root during the first potassium-enriched blood cardioplegia infusion. The main outcomes of the study were ventricular myocardial performance measured with cardiac index, right ventricular stroke work index, and left ventricular stroke work index at predefined time points and time to asystole after a single bolus injection of adenosine. Conventional myocardial biomarkers were compared between the two groups at predefined time points as secondary endpoints. Electrocardiographic data and other ad hoc clinical outcomes were compared between the groups., Results: Compared with saline, adenosine reduced the time to asystole (68 (95% confidence interval (95% CI) = 37-100) versus 150 (95% CI = 100-210) seconds, p = 0.005). With myocardial performance, the results were inconclusive, since right ventricular stroke work index recovered better in the adenosine group (p = 0.008), but there were no significant overall differences in cardiac index and left ventricular stroke work index between the groups. Only the post-cardiopulmonary bypass cardiac index was better in the adenosine group (2.3 (95% CI = 2.2-2.5) versus 2.1 (95% CI = 1.9-2.2) L/min/m 2 , p = 0.016). There were no significant differences between the groups in cardiac biomarker values., Conclusions: A high dose adenosine bolus at the beginning of the first cardioplegia infusion resulted in significantly faster asystole in coronary artery bypass grafting patients but enhanced only partially the ventricular performance.EudraCT number: 2014-001382-26. https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001382-26/FI.

Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants ( n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged ≥65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline., Competing Interests: SL has received Roche funding for unrelated work; SJ has received grants from AstraZeneca, The Medicines Company; CH declares advisory board and speaker’s bureau for AstraZeneca, institutional research grants from Bristol Myers Squibb, Merck &Co, GlaxoSmithKline, Roche Diagnostics, and advisory board for Bayer and Boehringer Ingelheim; EH declares being an expert committee member, lecture fees, and institutional research grant from Sanofi and Amgen, institutional research grants from AstraZeneca and GlaxoSmithKline, as well as an expert committee member and lecture fees for Novo Nordisk and Behringer; BH has an institutional research grant from AstraZeneca for unrelated work and is an advisory board member for Opsis Health and Lab Me Analytics, and Intermountain Healthcare has licensed his intellectual property to CareCentra and Alluceo; NE declares institutional research grants from AstraZeneca and Pfizer. AXA has received institutional research grant and speaker fee from AstraZeneca and an institutional research grant from Roche Diagnostics; AXA has received an institutional research grant and speaker fee from AstraZeneca and an institutional research grant from Roche Diagnostics; BH has an institutional research grant from AstraZeneca for unrelated work and is an advisory board member for Opsis Health and Lab Me Analytics, and Intermountain Healthcare has licensed his intellectual property to CareCentra and Alluceo. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schillemans, Tragante, Maitusong, Gigante, Cresci, Laguzzi, Vikström, Richards, Pilbrow, Cameron, Foco, Doughty, Kuukasjärvi, Allayee, Hartiala, Tang, Lyytikäinen, Nikus, Laurikka, Srinivasan, Mordi, Trompet, Kraaijeveld, van Setten, Gijsberts, Maitland-van der Zee, Saely, Gong, Johnson, Cooper-DeHoff, Pepine, Casu, Leiherer, Drexel, Horne, van der Laan, Marziliano, Hazen, Sinisalo, Kähönen, Lehtimäki, Lang, Burkhardt, Scholz, Jukema, Eriksson, Åkerblom, James, Held, Hagström, Spertus, Algra, de Faire, Åkesson, Asselbergs, Patel and Leander.)

Background: Two respiratory physiotherapy modalities were compared in a randomized controlled trial on patients undergoing minor pleuro-pulmonary surgery., Methods: Forty-five patients were randomly allocated into positive expiratory pressure (PEP) therapy (n=23) and inspiratory muscle training (IMT) groups (n=22). Individualized group specific physiotherapeutic guidance was administered preoperatively, and once a day postoperatively. Patients also performed independent exercises and kept a logbook. Pain was assessed on a numerical reference scale (NRS). Volumetric pulmonary function values and walking distance were recorded preoperatively, and on first (POD1) and second postoperative days (POD2). Pre- and postoperative values were compared using two-way repeated measures analysis of variance., Results: Patient characteristics and pleuro-pulmonary interventions were similar between the groups. Thoracotomy was performed in 14/45 and video assisted surgery (VATS) in 31/45 of cases. Preoperative volumetric pulmonary functions were normal or slightly decreased in 29/45, and fell significantly (P<0.001) on the first postoperative day (POD1) and improved but remained significantly lower on the second postoperative day. The recovery of mean FEV1, FIV1 and FIVC values was greater in the IMT than in the PEP group between POD1 and POD2, but without significant difference. The corresponding relative to preoperative values were higher in the IMT group, with a significant difference in FEV1 (P=0.045). Also relative PEF and FIV1 values seemed to be slightly higher in the IMT compared to the PEP group, but not significantly. Average NRS values for pain were lower in the IMT group (P=0.010) but only on POD1. Air leak was noted in 4/45 patients, two in each group, on POD1, and two in PEP groups and one in IMT group on POD2. Mean measured walking distances between groups did not differ. Mean hospital stay was 4 days in the PEP group and 3 days in the IMT group. There was no hospital mortality., Conclusions: Pulmonary function values decreased significantly after minor lung resections, supporting rehabilitative respiratory physiotherapy to avoid postoperative pulmonary complications (PPCs). Both PEP and IMT training were well tolerated and equally efficient when comparing spirometry values at three time points. IMT appeared advantageous regarding relative FEV1 recovery and immediate postoperative pain., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jtd-21-473). Dr. SIL reports receiving funding from Tampere Tuberculosis Foundation and Pirkanmaa Cultural Foundation. The other authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Aims: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation., Methods and Results: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro., Conclusions: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objective: Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism (PE), is an infrequent but consequential and potentially preventable complication after major surgical procedures. The aim of the study was to describe the long-term occurrence of symptomatic VTE in patients undergoing abdominal aortic aneurysm (AAA) repair and to ascertain patient-specific risk factors as well as to compare the rate with that of a reference population., Methods: The study included all patients who had undergone endovascular or open AAA repair, both elective and urgent/acute cases, at the Tampere University Hospital (Finland) between February 2001 and December 2016; 59% of patients had undergone endovascular and 41% open repair, and 23% of all cases had required urgent or emergency treatment. Information about later treatment episodes for symptomatic VTE and survival data were obtained from national registries. The reference population was obtained from national registries with a random sample of inhabitants matched for age, sex, and location of residence with a 4:1 ratio and was analyzed similarly., Results: Altogether, 1021 patients and 4065 controls were included (88% male; median age, 74 years in both groups). The high-risk period for VTE lasted for approximately 3 months, and during that time, its occurrence was highest in patients with coronary disease (2.5%), after open repair (2.4%), and in an urgent or emergency setting (2.6%), whereas the rate was low after endovascular aneurysm repair (1.0%). The cumulative incidence of VTE at 3 months, 1 year, 3 years, and 5 years was 1.1%, 1.6%, 2.7%, and 4.5% in patients and 0.1%, 0.3%, 1.0%, and 1.8% in the reference population, respectively (P < .001 each). Most VTE events were PE in the patient group. The 5-year mortality rates were 37.9% in patients and 23.8% in controls (P < .001)., Conclusions: The incidence of symptomatic VTE, particularly PE, after AAA repair is significant, in both short-term and long-term follow-up. Open surgery, acute setting, and concomitant coronary disease appear to increase the risk., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Patients with pleural infections frequently have several comorbidities and inferior long-term survival. We hypothesized that these patients represent a vulnerable cohort with high rates of hospitalization and frequent use of healthcare services. This study aims to ascertain the need for and causes of treatment episodes after pleural infections during long-term follow-up., Methods: Patients treated for pleural infections at Tampere University Hospital between January 2000 and December 2008 (n = 191, 81% males, median age 58 years) were included and compared to a demographically matched population-based random sample of 1910 controls. Seventy percent of the pleural infections were caused by pneumonias and 80% of the patients underwent surgery. Information regarding later in-hospital periods and emergency room and out-patient clinic visits, as well as survival data, was obtained from national registries and compared between patients and controls., Results: Patients treated for pleural infections had significantly higher rates of hospitalizations (8.19 vs 2.19), in-hospital days (88.5 vs 26.6), emergency room admissions (3.18 vs 1.45), out-patient clinic visits (41.1 vs 11.8) and procedures performed (1.26 vs 0.55) per 100 patient-months when compared to controls during 5-year follow-up, in addition to having increased mortality (30% vs 11%), P-value <0.00001 each. Particularly, episodes due to respiratory and digestive diseases, malignancies and mental disorders were more frequent. The patients' comorbidities, such as alcoholism or chronic pulmonary disease, were associated with more frequent use of healthcare services., Conclusions: Patients treated for pleural infections have high rates of hospitalizations, emergency room admissions and out-patient clinic visits during follow-up., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD., Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality., Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I 2 =28%; P -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity., Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Purpose: Pleural infections are associated with significant inflammation, long hospitalizations, frequent comorbidities, and are often treated operatively-all of which are consequential risk factors for thrombo-embolic complications. However, their occurrence following the treatment of pleural infection is still unknown. The aim of the study was to ascertain the early and long-term occurrence of thrombo-embolic events in patients treated for pleural infections., Methods: The study included all patients that were treated for pleural infections in Tampere University Hospital between January 2000 and December 2016. Data regarding later treatment episodes due to pulmonary embolisms and/or deep vein thromboses as well as survival data were requested from national registries. The rates were also compared to a demographically matched reference population adjusted for age, sex, and the location of residence., Results: The final study population comprised 536 patients and 5318 controls (median age 60, 78% men). The most common etiology for pleural infection was pneumonia (73%) and 85% underwent surgical treatment for pleural infection. The occurrence of thrombo-embolic complications in patients and controls was 3.8% vs 0.1% at three months, 5.0% vs 0.4% at one year, 8.8% vs 1.0% at three years, and 12.4% vs 1.8% at five years, respectively, p < 0.001 each. Female sex, advanced age, chronic lung disease, immunosuppression, video-assisted surgery, and non-pneumonic etiology were associated with a higher incidence of thrombo-embolism., Conclusions: The occurrence of thrombo-embolic events-particularly pulmonary embolism but also deep vein thrombosis-was significant in patients treated for pleural infections, both initially and during long-term follow-up.

Objectives: Postoperative atrial fibrillation is the most frequent complication after cardiac surgery, and the use of statins in preventing them is being extensively studied. The aim of this study was to investigate whether a pause in the administration of statins affects the occurrence of atrial fibrillation after cardiac surgery in a prospective randomized and controlled setting., Methods: A total of 301 patients without chronic atrial fibrillation with prior statin medication scheduled for elective or urgent cardiac surgery involving the coronary arteries and/or heart valves were prospectively recruited and randomized for statin re-initiation on either the first (immediate statin group) or the fifth (late statin group) postoperative day, using the original medication and dosage. The immediate statin group comprised 146 patients and the late statin group 155 patients. Except for a somewhat higher rate of males (85% vs 73%, P = 0.016) in the immediate statin group, the baseline characteristics and the distribution of procedures performed within the groups were comparable. The occurrence of postoperative atrial fibrillation and the clinical course of the patients were compared between the groups., Results: The incidence of atrial fibrillation was 46% and the median delay after surgery before the onset of atrial fibrillation was 3 days in both groups (P = NS). No differences were observed in the frequency of the arrhythmia in any subgroup analyses or in other major complications or clinical parameters. No adverse effects related to early statin administration were detected., Conclusions: Early re-initiation of statins does not appear to affect the occurrence of postoperative atrial fibrillation., Clinical Trial Registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT)-2016-001655-44., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Motivation: Selecting the optimal machine learning (ML) model for a given dataset is often challenging. Automated ML (AutoML) has emerged as a powerful tool for enabling the automatic selection of ML methods and parameter settings for the prediction of biomedical endpoints. Here, we apply the tree-based pipeline optimization tool (TPOT) to predict angiographic diagnoses of coronary artery disease (CAD). With TPOT, ML models are represented as expression trees and optimal pipelines discovered using a stochastic search method called genetic programing. We provide some guidelines for TPOT-based ML pipeline selection and optimization-based on various clinical phenotypes and high-throughput metabolic profiles in the Angiography and Genes Study (ANGES)., Results: We analyzed nuclear magnetic resonance-derived lipoprotein and metabolite profiles in the ANGES cohort with a goal to identify the role of non-obstructive CAD patients in CAD diagnostics. We performed a comparative analysis of TPOT-generated ML pipelines with selected ML classifiers, optimized with a grid search approach, applied to two phenotypic CAD profiles. As a result, TPOT-generated ML pipelines that outperformed grid search optimized models across multiple performance metrics including balanced accuracy and area under the precision-recall curve. With the selected models, we demonstrated that the phenotypic profile that distinguishes non-obstructive CAD patients from no CAD patients is associated with higher precision, suggesting a discrepancy in the underlying processes between these phenotypes., Availability and Implementation: TPOT is freely available via http://epistasislab.github.io/tpot/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press.)

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk., Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD., Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09)., Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD., Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events., Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints., Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Background and Aims: The development of pleural infection may imply a worse state of health and prognosis. The objective of this study was to ascertain the long-term survival and causes of death after pleural infections and to compare them to those of matched controls., Material and Methods: Altogether 191 patients treated for pleural infections at a single University Hospital between January 2000 and December 2008 and 1910 age- and gender-matched controls were included. Survival data and the causes of death for non-survivors were obtained from national databases and compared between the groups., Results: The etiology of pleural infection was pulmonary infection in 70%, procedural complication in 9%, trauma in 5%, malignancy in 4%, other in 7%, and unknown in 5% of patients. The course of treatment was surgical in 82%, drainage only in 12%, and conservative in 5% of included patients. The median follow-up time was 11 years. Mortality rates were 8.4% versus 0.8% during the first 90 days, p < 0.001, and 46.6% versus 24.5% overall, p < 0.001, in patients and controls, respectively. Mortality was significantly higher in patients with pulmonary infection, procedural complication, or malignancy as the etiology of pleural infection. In multivariable analysis, advanced age, previous malignancies, institutional care, alcoholism, and malignant etiology for the infection were associated with inferior survival. Deaths caused by malignancies, respiratory diseases, and digestive diseases were significantly more common in patients than in controls., Conclusion: Long-term survival in patients with pleural infections is significantly inferior to that of age and gender-matched controls.

Background and Aims: To describe the incidence of and risk factors for postoperative infections and the correlation between postoperative hyperglycemia despite tight blood glucose control with infectious and other complications after contemporary cardiac surgery., Material and Methods: The study comprised 1356 consecutive adult patients who underwent cardiac surgery between January 2013 and December 2014 and were followed up for 6 months. Patients surviving the first 2 days were included in the analysis. Preoperative demographic information, medical history, procedural details, and the postoperative course were recorded. The target range for blood glucose levels was 4-7 mmol/L and repeated arterial blood samples were obtained during the intensive care unit stay. The associations of blood glucose levels during the first postoperative day and the occurrence of postoperative infections and other significant complications were analyzed., Results: Of the study cohort, 9.8% developed infectious complications which were classified as major surgical site infections in 2.2%, minor surgical site infections in 1.1%, lung infections in 2.0%, unclear fever or bacteremia in 0.3%, cannula or catheter related in 2.6%, multiple in 1.5%, and other in 0.2%. The incidence of deep sternal wound infection was 2.0%. Repeated hyperglycemia occurred in 39.7% of patients and was associated with increased rates of postoperative infections, 12.1% versus 8.2%, p = 0.019; stroke, 4.9% versus 1.5%, p < 0.001; and mortality, 6.1% versus 2.1%, p < 0.001, when compared to patients with single or no hyperglycemia., Conclusion: Every 10th patient develops infectious complications after cardiac surgery. Repeated hyperglycemia is associated with increased rates of infectious complications, stroke, and mortality.

Objectives: Occurrence and risk factors of late postoperative pericardial effusions requiring invasive treatment, i.e. pretamponade and tamponade, following cardiac surgery are incompletely described in current literature. The purpose of this study was to define the incidence and presentation of late pretamponade and tamponade as well as to outline significant predisposing factors., Methods: A cohort of 1356 consecutive cardiac surgery patients treated in a tertiary academic centre between January 2013 and December 2014 was followed up for 6 months after surgery. Pericardial effusion was considered late when presenting after the 7th postoperative day. The incidence, timing and risk factors, as well as symptoms and clinical findings associated with late pretamponade and tamponade in patients surviving at least 7 days was analysed., Results: Of 1308 patients included in the analysis, 81 (6.2%) underwent invasive treatment for late postoperative pericardial effusion, 27 (2.1%) for pretamponade and 54 (4.1%) for tamponade, respectively, with a median delay of 11 (range 8-87) days after the primary operation. Haemodynamic instability was present in 34.6%, signs of cardiac chamber compression in 54.3% and subjective symptoms, mostly dyspnoea, in 56.8% of patients, respectively. Treated patients were younger, had lower EuroSCORE-II rating, less coronary disease, better cardiac function, higher preoperative haemoglobin values and had mostly undergone elective surgery involving cardiac valves. In multivariable analysis, independent risk factors were single valve surgery and high preoperative haemoglobin level, whereas age 60-69 years was associated with lower risk., Conclusions: Younger, generally healthier patients undergoing valve surgery are at greatest risk for developing late tamponade or pretamponade., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To assess whether smoking, alcohol drinking and dietary factors are linked with varicose veins., Methods: A middle-aged general population of 4903 was studied, and prevalence rates at entry and five-year incidence of varicose veins were assessed. Lifestyle habits were recorded at entry and at the end of the follow-up., Results: New varicose veins were significantly more common in individuals with regular alcohol intake, incidence odds ratio (OR) 1.5 (95% confidence interval [CI]: 1.05-2.3) in a multivariate analysis (of 2202 individuals). The association was particularly strong in women. Smokers had a higher incidence of varicose veins compared with non-smokers, OR 1.3 (95% CI: 0.9-1.8), but without statistical significance. Having daily meals of meat implied less new varicose veins than having 0-2 weekly meals of meat., Conclusion: Alcohol was likely to increase the risk of varicose veins in women and smoking in both genders. These findings were seen in the follow-up design, but not when the data of these risk factors were compared with varicose veins prevalent at entry.

Objective: We assessed differential misclassification in self-reported family history of varicose veins by comparing consistency of subject's own varicose vein status and the consistency of information on varicose veins in family members., Study Design and Setting: A population-based cohort study of 4,903 middle-aged residents of the city of Tampere, Finland. A questionnaire was used at entry and at the end of the 5-year follow-up., Results: The estimated prevalence of positive family history of varicose veins varied depending on subject's own varicose veins from odds ratio (OR) 0.14 (95% confidence interval [CI]=0.01-0.58), in those with varicose veins reported in the first but not the second survey to OR 6.0 (95% CI=2.0-47.8), in those with varicose veins reported in the second survey but not in the first. The incidence of varicose veins varied from 0.4 (95% CI=0.1-1.4) to 4.1 (95% CI=2.1-7.1) (per 100 person-years) depending how the proband memorized the family history., Conclusion: Results on the effect of family history on varicose veins are subject to bias, which reduces the credibility of the reports proposing a strong hereditary component of varicose veins.

Aim: Varicose veins are a common condition but their etiology and relationship with other cardiovascular diseases are not well established. The aim of the study was to find out if persons with varicose veins have a higher risk of congestive heart failure (CHF) than persons without varicose veins., Methods: The prevalence of CHF at entry and the incidence of CHF during a five-year follow-up period were studied in persons with and without varicose veins. A study was conducted with a questionnaire in a population of 4903 middle-aged residents in Tampere, Finland., Results: Marginally higher prevalence of CHF was found in persons with varicose veins than in those without (2.9% vs. 1.9%) with OR 1.6 (1.0-2.3) and sex and age adjusted OR 1.2 (0.8-1.9). The incidence of CHF was higher in subjects with varicose veins than in others (4.9 vs. 2.6 per 1000 person-years) with IDR 1.9 (1.1-2.9) and sex and age adjusted IOR 2.5 (1.4-4.6). The result was further adjusted for body mass index, arterial disease and hypertension; multi-adjusted IOR for the incidence of CHF by varicose veins was 2.1 (1.1-4.0)., Conclusions: Our longitudinal observation is consistent with the hypothesis that persons with varicose veins have a higher risk of CHF which is not mediated through sex, age, overweight, arterial disease or hypertension.

In the literature, the estimates of high risk of family history for varicose veins are based on prevalence rates from cross-sectional studies. The purpose of this study was to compare such prevalence rates with incidence rates from our longitudinal follow-up study to find out whether there is a difference due to the methodology. A validated questionnaire was used in 3 middle-aged cohorts (n = 6874) in Tampere, Finland. Positive family history was more common both in men (prevalence odds ratio 6.6; 95% confidence interval, 4.7-9.3) and women (4.9; 95% confidence interval, 4.0-6.0) with varicose veins compared to those without. However, positive family history was linked much less with the incidence of varicose veins than the prevalence of varicose veins in women (incidence odds ratio 1.8; 95% confidence interval, 1.1-2.8) and men 1.4 (95% confidence interval, 0.7-2.6). There is likely to be a hereditary component of varicose veins, but it is substantially less than usually proposed in literature.

Objectives: The aim of the study was to find out if persons with cardiovascular diseases (CVD) (arterial disease or hypertension) have additional risk of varicose veins (VV) compared with those without arterial disease (AD) or hypertension., Methods: We studied, using a validated questionnaire, the prevalence and incidence of VVs in those with and without CVD in a population of 4903 including 40-, 50- and 60-year-old men and women in Tampere, Finland. During the five years of follow-up, we had a special interest on the appearance of new VVs in those without VVs at entry (n = 3065)., Results: We found a higher prevalence of VVs in persons with CVD than in those without CVD (with sex and age adjusted odds ratio [OR] 1.3 [95% confidence interval, CI 1.1-1.5]). The prevalence of VVs was higher in persons with AD (OR 1.7 [CI 1.4-2.2]), but not in persons with hypertension (OR 1.1 [CI 0.9-1.2]) than in those who were free of AD or hypertension, respectively. Subjects with AD had higher incidence of VVs (incidence odds ratio, IOR 1.4 [CI 0.8-2.7]) than subjects without AD and the effect was statistically significant in women (IOR 2.2 [CI 1.1-4.5]). Also the incidence of VVs was more affected by AD than by hypertension (IOR 1.1 [CI 0.7-1.8])., Conclusion: There seems to exist a relatively strong additional risk of VVs in persons with AD and practically none in those with hypertension compared to those without.

Background: Incidence of varicose veins in the population is unknown. The study aimed at estimating the incidence of varicose veins in complete cohorts of 40-60 year-olds in a general population., Patients and Methods: The study was conducted in the city of Tampere, Finland. A validated questionnaire (with 93% sensitivity and 92% specificity) was used in a general population of 6874 individuals (aged 40, 50 or 60). Initially, 3065 of them had no varicose veins and 78% were followed-up for 5 years., Results: 157 individuals reported new varicose veins during the follow-up. The overall incidence was 13.5 per 1000 person years (8.5 for men and 19.2 for women). Female sex was an independent and statistically significant risk indicator of varicose veins (adjusted odds ratio, OR 2.4). The incidence was significantly higher at the age of 50-55 years (OR 1.6). Higher body mass index seemed to be related to higher risk of new varicose veins (OR 1.2-1.8), but the association failed to reach statistical significance. The level of education did not affect the incidence., Conclusions: New varicose veins appear also in the middle-aged population, and the rate is linked with the female gender, especially at the beginning of the 6th decade.

The objectives of the study were to discover the main determinants for the prevalence of varicose veins in a general population, and to assess the possibilities for prevention of this common surgical disease. Varicose veins were evaluated in three defined cohorts of 3284 men and 3590 women aged 40, 50, and 60 years by using a validated questionnaire. The response rate was 75% among men and 86% among women, and varicose veins were determined by self-assessment. Increasing age, female sex, childbirths, standing posture at work, higher weight or height, and positive family history were significantly associated with varicose veins in a univariate analysis. These factors were further taken into a multivariate logistic regression analysis, and female gender (adjusted odds ratio, OR 2.2), increasing age (OR 2.2-2.8), a reported positive family history for varicose veins (OR 4.9), increasing number of births (OR 1.2-2.8), standing posture at work (OR 1.6), and higher weight (OR 1.2) and height (OR 1.4) were found to independent and significant risk indicators of varicose veins. Increasing age, positive family history of varicose veins, and child-births in women were the most important factors in terms of population etiologic fractions. Familial predisposition and pregnancy-related factors bear important associations with varicose veins. Thus prevention of varicose veins appears to be difficult. Varicose veins are nonlethal and, therefore, higher age is related to higher prevalence.

Background: Recently we have reported a myoprotective protocol, adenosine-enhanced ischemic preconditioning, that extends the protection afforded by ischemic preconditioning in the isolated crystalloid-perfused heart. In this report the efficacy of adenosine-enhanced ischemic preconditioning in the in situ blood-perfused heart was investigated., Methods: Sheep were subjected to 60 minutes of regional ischemia and 120 minutes of reperfusion. Ischemic preconditioned hearts received 5 minutes of zero flow regional ischemia and 5 minutes of reperfusion before regional ischemia. Adenosine-enhanced ischemic preconditioned hearts received a bolus injection of 10 mmol adenosine at the immediate start of ischemic preconditioning. Adenosine-treated hearts received an adenosine bolus, 10 minutes before regional ischemia. The ratio of infarct size to area at risk and mechanical function were determined., Results: The infarct size to area at risk ratio in regional ischemia was 55.4%+/-2.1%. This ratio was significantly decreased with ischemic preconditioning and adenosine (22.2%+/-2.2% and 19.3%+/-1.4%, respectively; p < 0.001 versus regional ischemia) and adenosine-enhanced ischemic preconditioning (8.0%+/-2.0%, p < 0.001 versus regional ischemia and ischemic preconditioning, and p < 0.01 versus adenosine)., Conclusions: Adenosine-enhanced ischemic preconditioning significantly decreases infarct size in the in situ blood-perfused heart and provides superior protection compared with ischemic preconditioning.

A prospective study to evaluate the efficacy of a novel inflatable vest in supporting the sternotomy wound during the early period after coronary artery bypass grafting was carried out in 35 patients. The outcome variables were subjective pain score during cough, and peak expiratory flow (PEF) and vital capacity (VC) on postoperative days 2 and 3. The values without pressure in the vest were used as controls in the individual patients. Use of the vest significantly reduced the cough-associated subjective sternotomy pain score on days 2 and 3, when significant reduction of PEF and VC was also observed. The alleviation of pain by the inflatable vest may improve the efficacy of coughing and bronchial clearance in the immediate postoperative period.