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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.

Background Human saliva contains approximately 700 bacterial species. It has been reported that the salivary microbiome of a large family of closely related individuals consisting of multiple households is similar but the relatedness of salivary bacteria between generations of parents and their children has not yet been investigated. The objectives were to investigate the entirety of salivary bacterial DNA profiles and whether and how families share these profiles and also compare these communities between grandparents and their first daughter generations (F1) using 16S rRNA gene amplicon sequencing. Results The most abundant phyla in two separate families were Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria and Actinobacteria. Family ties explained 13% of the variance between individuals’ bacterial communities (R2 = 0.13; P = 0.001). Mothers shared more OTUs with adult children compared to fathers, but this linkage seemed to be weaker in the nuclear family with older adult children. We identified 29 differentially abundant genus level OTUs (FDR < 0.05) between families, which accounted for 31% of the total identified genus level OTUs. Conclusions Our results indicate that adult family members share bacterial communities and adult children were more similar to mothers than fathers. The observed similarity in oral microbiome between parent–child pairs seemed to weaken over time. We suggest that our analysis approach is suitable for relatedness study of multigenerational salivary bacteria microbiome.

ObjectivesThe objective of this study was to investigate the association of tooth brushing frequency and bacterial communities of gingival crevicular fluid in patients subjected to preoperative dental examination prior to operative treatment for unruptured intracranial aneurysms.MethodsGingival crevicular fluid samples were taken from their deepest gingival pocket from a series of hospitalized neurosurgical patients undergoing preoperative dental screening (n = 60). The patients were asked whether they brushed their teeth two times a day, once a day, or less than every day. Total bacterial DNA was isolated and the V3–V4 region of the 16S rRNA gene was amplificated. Sequencing was performed with Illumina’s 16S metagenomic sequencing library preparation protocol and data were analyzed with QIIME (1.9.1) and R statistical software (3.3.2).ResultsBacterial diversity (Chao1 index) in the crevicular fluid reduced along with reported tooth brushing frequency (p = 0.0002;R2 = 34%;p(adjusted with age and sex) = 0.09;R2 = 11%) showing that patients who reported brushing their teeth twice a day had the lowest bacterial diversity. According to the differential abundant analysis between the tooth brushing groups, tooth brushing associated with two phyla of fusobacteria [p = 0.0001; p = 0.0007], and one bacteroidetes (p = 0.004) by reducing their amounts.ConclusionsTooth brushing may reduce the gingival bacterial diversity and the abundance of periodontal bacteria maintaining oral health and preventing periodontitis, and thus it is highly recommended for neurosurgical patients.

Improved localization of emission and reduction of artefacts have been achieved in tomographic reconstructions of the tangentially viewing spectroscopic divertor cameras in JET by introducing the contribution of reflections from the metallic wall surfaces in the geometry definition of the tomography process. The reconstructions thus describe the plasma emission only without features arising from misinterpreted reflected light. Benchmarks with synthetic emission distributions showed accurate reproduction within 10% and 1–2% of the reference emission distributions and camera images, respectively, when the reflection correction was applied. Without the correction, the reconstructed emission was observed to concentrate from the divertor volume towards the wall surfaces together with bright emission artefacts appearing in front of the surfaces to reproduce the reflections seen in the camera images.

Background: Long-term outcome of the three categories of acute coronary syndrome (ACS) in real-life patient cohorts is not well known. The objective of this study was to survey the 10-year outcome of an ACS patient cohort admitted to a university hospital and to explore factors affecting the outcome. Methods: A total of 1188 consecutive patients (median age 73 years) with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI) or unstable angina pectoris (UA) in 2002–2003 were included and followed up for ≥ 10 years. Results: Mortality for STEMI, NSTEMI and UA patients during the follow-up period was 52.5%, 69.9% and 41.0% (p < 0.001), respectively. In multivariable Cox regression analysis, only age and creatinine level at admission were independently associated with patient outcome in all the three ACS categories when analyzed separately. Conclusions: All the three ACS categories proved to have high mortality rates during long-term followup in a real-life patient cohort. NSTEMI patients had worse outcome than STEMI and UA patients during the whole follow-up period. Our study results indicate clear differences in the prognostic significance of various demographic and therapeutic parameters within the three ACS categories.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9–4% of women and 0.3% of men2–4, with twin-based heritability estimates of 50–60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

Background Chronic infections have been reported to be risk factors for both coronary heart disease and ischemic stroke. DNA of oral bacteria, mainly from the viridans streptococci group, has been detected in coronary thrombus aspirates of myocardial infarction and cerebral aneurysms. Viridans streptococci are known to cause infective endocarditis and possess thrombogenic properties. We studied the presence of oral bacterial DNA in thrombus aspirates of patients with acute ischemic stroke treated with mechanical thrombectomy. Methods and Results Thrombus aspirates and arterial blood were taken from 75 patients (69% men; mean age, 67 years) with acute ischemic stroke. The presence of Streptococcus species, mainly the Streptococcus mitis group, belonging to viridans streptococci as well as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans in samples were determined using a quantitative polymerase chain reaction with specific primers and probes. The relative amount of bacterial DNA in a sample was determined with the comparative threshold cycle method. Bacterial DNA was detected in 84% (n=63) of aspired thrombi, and 16% (n=12) of samples were considered bacterial DNA negative. DNA of Streptococcus species, mainly the S mitis group, was found in 79% (n=59) of samples. The median relative amount of Streptococcus species DNA was 5.10‐fold higher compared with the control blood samples from the same patients. All thrombi were negative for both P gingivalis and A actinomycetemcomitans . Conclusions This is the first study showing the common presence of bacterial DNA from viridans streptococci in aspired thrombi of patients with acute ischemic stroke. Streptococcal bacteria, mostly of oral origin, may contribute to the progression and thrombotic events of cerebrovascular diseases.

Background: Integration of systems-level biomolecular information with electronic health records has led to recent interest in the glycoprotein acetyls (GlycA) biomarker—a serum- or plasma-derived nuclear magnetic resonance spectroscopy signal that represents the abundance of circulating glycated proteins. GlycA predicts risk of diverse outcomes, including cardiovascular disease, type 2 diabetes mellitus, and all-cause mortality; however, the underlying detailed associations of GlycA’s morbidity and mortality risk are currently unknown. Methods: We used 2 population-based cohorts totaling 11 861 adults from the Finnish general population to test for an association with 468 common incident hospitalization and mortality outcomes during an 8-year follow-up. Further, we utilized 900 angiography patients to test for GlycA association with mortality risk and potential utility for mortality risk discrimination during 12-year follow-up. Results: New associations with GlycA and incident alcoholic liver disease, chronic renal failure, glomerular diseases, chronic obstructive pulmonary disease, inflammatory polyarthropathies, and hypertension were uncovered, and known incident disease associations were replicated. GlycA associations for incident disease outcomes were in general not attenuated when adjusting for hsCRP (high-sensitivity C-reactive protein). Among 900 patients referred to angiography, GlycA had hazard ratios of 4.87 (95% CI, 2.45–9.65) and 5.00 (95% CI, 2.38–10.48) for 12-year risk of mortality in the fourth and fifth quintiles by GlycA levels, demonstrating its prognostic potential for identification of high-risk individuals. When modeled together, both hsCRP and GlycA were attenuated but remained significant. Conclusions: GlycA was predictive of myriad incident diseases across many major internal organs and stratified mortality risk in angiography patients. Both GlycA and hsCRP had shared and independent contributions to mortality risk, suggesting chronic inflammation as an etiological factor. GlycA may be useful in improving risk prediction in specific disease settings.

Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ4, ɛ2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax = 549) and elderly non-demented samples (nmax = 552). Where available, genotype data derived from Illumina's 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16-1.58, p =

Background Controversy surrounds the effect of alcohol consumption on the development of dementia and cognitive impairment. We investigated the association between consumption of different alcoholic beverages and β-amyloid (Aβ) aggregation in the brain, 1 of the neuropathological lesions of Alzheimer's disease. Methods In total, 125 males of the Helsinki Sudden Death autopsy Series were included with an age range at death 35 to 70 years. The consumption of alcohol, Aβ aggregation in the brain, and Apolipoprotein E (APOE) genotype were assessed. Relatives answered a questionnaire to gather alcohol consumption history, and Aβ was visualized by implementing immunohistochemical staining of brain sections. Aβ immunoreactivity (IR) was assessed in a dichotomized (yes/no) fashion and as a stained area fraction (%). APOE genotype was assessed in DNA extracted from paraffin-embedded cardiac muscle samples. Results Increased age (p = 0.001; odds ratio [OR] = 1.09, confidence interval [CI] = 1.04 to 1.15) was associated with higher prevalence of Aβ-IR. Beer drinking decreased (p = 0.024; OR = 0.35, CI = 0.14 to 0.87) the prevalence of Aβ-IR and was associated with a significantly lower extent of Aβ-IR (p = 0.022). The amount of alcohol consumed was not linked with Aβ aggregation and neither was spirit nor wine consumption. Conclusions Beer consumption may protect against Aβ aggregation in brain. Further studies are necessary to fully understand the effects of alcohol on Aβ pathology seen in brain tissue.

Background— The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non–human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. Methods and Results— We conducted a large-scale genetic analysis on a case–control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels ( r =0.760; P + FOXP3 + regulatory T cell proliferation significantly (blocking versus nonblocking; P Conclusions— In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3 + T cell proliferation, especially in patients homozygous for the risk alleles. Clinical Trial Registration— https://www.clinicaltrials.gov ; Unique Identifier: NCT00417534.

Chronic inflammation has earlier been detected in ruptured intracranial aneurysms. A previous study detected both dental bacterial DNA and bacterial-driven inflammation in ruptured intracranial aneurysm walls. The aim of this study was to compare the presence of oral and pharyngeal bacterial DNA in ruptured and unruptured intracranial aneurysms. The hypothesis was that oral bacterial DNA findings would be more common and the amount of bacterial DNA would be higher in ruptured aneurysm walls than in unruptured aneurysm walls.A total of 70 ruptured (n = 42) and unruptured (n = 28) intracranial aneurysm specimens were obtained perioperatively in aneurysm clipping operations. Aneurysmal sac tissue was analysed using a real-time quantitative polymerase chain reaction to detect bacterial DNA from several oral species. Both histologically non-atherosclerotic healthy vessel wall obtained from cardiac by-pass operations (LITA) and arterial blood samples obtained from each aneurysm patient were used as control samples.Bacterial DNA was detected in 49/70 (70%) of the specimens. A total of 29/42 (69%) of the ruptured and 20/28 (71%) of the unruptured aneurysm samples contained bacterial DNA of oral origin. Both ruptured and unruptured aneurysm tissue samples contained significantly more bacterial DNA than the LITA control samples (p-values 0.003 and 0.001, respectively). There was no significant difference in the amount of bacterial DNA between the ruptured and unruptured samples.Dental bacterial DNA can be found using a quantitative polymerase chain reaction in both ruptured and unruptured aneurysm walls, suggesting that bacterial DNA plays a role in the pathogenesis of cerebral aneurysms in general, rather than only in ruptured aneurysms.

The purpose of the prospective research was to evaluate the benefit of urine specimen as a collection technique for biological forensic evidence in adult volunteers following consensual intercourse. For detecting Y-chromosomal material Buccal Swab Spin Protocol® was used in DNA extraction and purification and samples were analysed with Quantifiler Y Human Male DNA Quantification Kit®. The time frame for positive Y-DNA was evaluated. Immediate microscopy for detection of spermatozoa was performed. Y-DNA was detected in 173/205 (84.4%) urine samples. Of the 86 first post-coital void urine samples available, Y-DNA was detected in 83 (96.5%) specimens. Of the 119 urine samples from volunteers with post-coital activities Y-DNA was still measurable in 70 (58.8%) urine specimens. The male DNA amount was below 0.023 ng/μl in 28/153 (18.3%) urine samples. Of the 22 urine samples obtained after 24 post-coital hours, 9 (40.9%) were still Y-DNA positive. No associations were found between coital durance, coital frequency during the past two weeks prior to the study intercourse, post-coital activities, and the urine sample Y-DNA positivity. Of the 111 urine samples where the immediate microscopy was performed, in 66 (59.5%) samples spermatozoa were verified and one sample even contained motile spermatozoa. Microscopy detected 66 (67.3%) and failed to detect spermatozoa in 32 (32.7%) of Y-DNA positive samples. In addition to conventional invasive swab techniques, urine samples seem to be an effective biological trace collection method for Y-DNA and spermatozoa within 24 h following penile-vaginal penetration. Furthermore, it may be considered as a non-invasive collection method in suspected acute child sexual abuse cases to diminish time delay in forensic evidence collection and to improve patients' positive attitudes towards evidence collection.

Integration of systems-level biomolecular information with electronic health records has led to the discovery of robust blood-based biomarkers predictive of future health and disease. Of recent intense interest is the GlycA biomarker, a complex nuclear magnetic resonance (NMR) spectroscopy signal reflective of acute and chronic inflammation, which predicts long term risk of diverse outcomes including cardiovascular disease, type 2 diabetes, and all-cause mortality. To systematically explore the specificity of the disease burden indicated by GlycA we analysed the risk for 468 common incident hospitalization and mortality outcomes occurring during an 8-year follow-up of 11,861 adults from Finland. Our analyses of GlycA replicated known associations, identified associations with specific cardiovascular disease outcomes, and uncovered new associations with risk of alcoholic liver disease (meta-analysed hazard ratio 2.94 per 1-SD, P=5×10-6), chronic renal failure (HR=2.47, P=3×10-6), glomerular diseases (HR=1.95, P=1×10-6), chronic obstructive pulmonary disease (HR=1.58, P=3×10-5), inflammatory polyarthropathies (HR=1.46, P=4×10-8), and hypertension (HR=1.21, P=5×10-5). We further evaluated GlycA as a biomarker in secondary prevention of 12-year cardiovascular mortality in 900 angiography patients with suspected coronary artery disease. We observed hazard ratios of 4.87 and 5.00 for 12-year mortality in angiography patients in the fourth and fifth quintiles by GlycA levels demonstrating the prognostic potential of GlycA for identification of high mortality-risk individuals. Both GlycA and C-reactive protein had shared as well as independent contributions to mortality hazard, emphasising the importance of chronic inflammation in secondary prevention of cardiovascular disease.

Background Cerebral white matter lesions are one imaging surrogate for cerebral small vessel disease. These white matter lesions are associated with increased morbidity and mortality in both the general population and ischemic stroke patients. Aims To investigate whether severe white matter lesions in a cohort of ischemic stroke patients are associated with fewer days spent at home and earlier permanent institutionalization. Methods We included 391 consecutive patients aged 55–85 years with ischemic stroke admitted to the Helsinki University Central Hospital (the Stroke Aging Memory cohort) with a 21-year follow-up. Hospitalization and nursing home admissions were reviewed from national registers.white matter lesions were rated using magnetic resonance imaging performed three-months poststroke, dichotomized as none-to-moderate and severe. Kaplan–Meier plots log-rank and binary logistic regression (odds ratio) and Cox multivariable proportional hazards model were used to study the association of white matter lesions with days spent at home and the time of permanent institutionalization. Hazards and odds ratio with their 95% confidence intervals are reported. Results Severe white matter lesions were associated with fewer days spent at home, and more frequent, and earlier permanent institutionalization (1487 vs. 2354 days; log-rank P < 0·001). After adjusting for significant covariates from univariable analyses, severe white matter lesions were associated with fewer days spent at home (odds ratio 1·62; confidence interval 1·16–2·25), permanent institutionalization within five-years (odds ratio 2·29; confidence interval 1·23–4·29), and increased hazards ratio of permanent institutionalization during 21 years of follow-up (1·64; confidence interval 1·119–2·26). Conclusions After ischemic stroke, patients with severe white matter lesions spend fewer days at home and become permanently institutionalized earlier, especially within the first five-years.

We have studied the feasibility of arc-discharge and plasma-sputtering methods in removing deposited layers from ITER-relevant test samples. Prototype devices have been designed and constructed for the experiments and the cleaning process is monitored by a spectral detection system. The present version of the arc-discharge device is capable of removing 1-μm thick layers from 350-mm 2 areas in 4–8 s, but due to the increased roughness of the cleaned surfaces and signs of local melting, mirror-like surfaces cannot be treated by this technique. The plasma-sputtering approach, for its part, is some 5–10 times slower in removing the deposited layers but no changes in surface roughness or morphology of the samples could be observed after the cleaning phase. The arc-discharge technique could therefore be used for rapid cleaning of plasma-facing components during maintenance shutdowns of ITER while in the case of diagnostics mirrors plasma sputtering is preferred.

AIMS: Genome-wide association studies (GWAS) have identified many variants associating with an increased risk of coronary artery disease (CAD). We studied the possible association between these variants and the risk of sudden cardiac death (SCD). METHODS AND RESULTS: A weighted genetic risk score (GRSCAD) was formed from variants most strongly associating with CAD identified by the CARDIoGRAMplusC4D Consortium explaining 10.6% of the heritability of CAD [153 single-nucleotide polymorphisms with r(2) < 0.2]. The association between GRSCAD and the occurrence of SCD was studied in three independent autopsy series of consecutive cases combining altogether 1035 autopsies with 306 SCDs due to CAD (SCDCAD). The results were replicated in a prospective follow-up study of 2321 patients (mean follow-up time of 6.2 years with 48 incident SCDs of which 39 due to CAD) undergoing clinical exercise test at baseline. In a meta-analysis of the autopsy series, GRSCAD associated significantly with the risk of SCDCAD with age, body mass index, and sex adjusted odds ratio (OR) of 1.042 (1.023-1.061, P = 9.1 × 10(-6)) for one allele increase in GRSCAD. The same association was seen in both sexes. GRSCAD predicted significantly the risk of SCDCAD also in a prospective study setting (Cox regression analysis adjusted with all relevant clinical data): hazard ratio 1.049 (1.010-1.090, P = 0.014). In meta-analysis of all cohorts (adjusting further for other genetic markers related to traditional risk factors and QT-interval), the association was highly significant [OR 1.045 (1.028-1.063), P = 1.7 × 10(-7)]. CONCLUSION: Genetic risk estimate for CAD may also be used to predict SCD.

We compare the deposition of material on poloidal sets of divertor tiles that had been exposed in JET in 1998–2009 and 1998–2007. Post mortem analyses suggest toroidally integrated deposition being increased by 197.5 cm 3 during 2007–2009. The analysis of dust collected from the divertor indicates the amount accumulated during the same period to be 248.4 g. Converting the weight of dust to volume, the fraction of material entering the divertor that was converted to dust and flakes is 43 ± 10%. The size of most dust particles ranged from 10 to 100 μm. The integrated amount of deposition on the “marker” tiles exposed in 2007–9 was found to be more than twice the amount expected from film growth on other tiles plus the dust because the plasma responds differently to the new tiles.

A sample of pure bulk tungsten was studied by laser induced breakdown spectroscopy (LIBS) method with the aim to find out a set of W analytic lines allowing a reliable determination of main parameters of the laser-produced plasma. The background pressure as well as the recording direction of spectra were close with those occurring in fusion reactors. Varying the delay time between the laser pulse and the data acquisition time-gate, time-resolved LIBS spectra were recorded at two different laser wavelengths. On the basis of spectral lines with negligible overlapping and self-absorption, the laser-induced plasma temperature as a function of time has been found.

The aim of this work was to study the applicability of laser induced breakdown spectroscopy (LIBS) as an in situ method for monitoring plasma facing materials in fusion reactors. Tungsten coated samples were exposed to Magnum PSI plasma using two different regimes: the steady-state (the sequence of approximately 11 s pulses) and the ELM-like. Right after the plasma exposure samples were tested with LIBS in the Magnum PSI analyses and target exchange chamber. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) were used to characterize the surface morphology and crystallinity. These methods showed that changes at the sample surface caused by used ELM-like mode did not differ remarkably from those caused by steady-state mode. Surface temperature had significant effect on the surface structure. In addition post mortem LIBS measurements were performed that gave result similar to that of in situ LIBS.

Objective Increasing data supports the role of bacterial inflammation in adverse events of cardiovascular and cerebrovascular diseases. In our previous research, DNA of bacterial species found in coronary artery thrombus aspirates and ruptured cerebral aneurysms were mostly of endodontic and periodontal origin, where Streptococcus mitis group DNA was the most common. We hypothesized that the genomes of S mitis group could be identified in thrombus aspirates of patients with lower limb arterial and deep venous thrombosis. Methods Thrombus aspirates and control blood samples taken from 42 patients with acute or acute-on-chronic lower limb ischemia (Rutherford I-IIb) owing to arterial or graft thrombosis (n = 31) or lower limb deep venous thrombosis (n = 11) were examined using a quantitative real-time polymerase chain reaction to detect all possible bacterial DNA and DNA of S mitis group in particular. The samples were considered positive, if the amount of bacterial DNA in the thrombus aspirates was 2-fold or greater in comparison with control blood samples. Results In the positive samples the mean difference for the total bacterial DNA was 12.1-fold (median, 7.1), whereas the differences for S mitis group DNA were a mean of 29.1 and a median of 5.2-fold. Of the arterial thrombus aspirates, 57.9% were positive for bacterial DNA, whereas bacterial genomes were found in 75% of bypass graft thrombosis with 77.8% of the prosthetic grafts being positive. Of the deep vein thrombus aspirates, 45.5% contained bacterial genomes. Most (80%) of bacterial DNA-positive cases contained DNA from the S mitis group. Previous arterial interventions were significantly associated with the occurrence of S mitis group DNA ( P = .049, Fisher's exact test). Conclusions This is the first study to report the presence of bacterial DNA, predominantly of S mitis group origin, in the thrombus aspirates of surgical patients with lower limb arterial and deep venous thrombosis, suggesting their possible role in the pathogenesis of thrombotic events. Additional studies will, however, be needed to reach a final conclusion.

OBJECTIVE/BACKGROUND: Expression patterns and association with cell specific gene expression signatures of the epigenetic regulator histone deacetylase 9 (HDAC9) and matrix metalloproteinase 12 (MMP12) in human plaque are not known. METHODS: This was a prospective cohort study. Genome wide expression analysis was performed in carotid, femoral, aortic plaques (n=68) and left internal thoracic (LITA) controls (n=28) and plaque histological severity assessed. Correlation and hierarchical cluster analysis was utilised. RESULTS: HDAC9 was associated with MMP12 expression in carotid plaques (r=.46, p=.012) and controls (r=-.44, p=.034). HDAC9 and MMP12 clustered with inflammatory macrophage markers but not with smooth muscle cell (SMC) rich markers. In plaques from all arterial sites, MMP12 but not HDAC9 showed positive correlation (p&nbsp

Laser-induced breakdown spectroscopy (LIBS) is a promising method for quantifying the fuel content of the plasma-facing components of ITER both in between plasma discharges (in-situ) and after maintenance operations. The aim of the present study is to test the applicability of in-situ LIBS for monitoring deuterium (D) and helium (He) content of W samples exposed to fusion relevant plasma fluxes in the linear plasma device Pilot-PSI.The D loading was performed during 1000s of plasma exposure at low (200-300 °C) surface temperatures. Despite of low intensity and noisy LIBS spectra, H and D lines, at 656.1 and 656.3nm, respectively, could be fitted with Lorentzian contours and reliably resolved at 1.2 mbar background pressure of argon.In the case of He loading, the samples were also exposed to plasma during 1000s while the surface temperature reached values up to 720 °C at the center. Already at 10–2 mbar residual pressure of the device, the He I line at 587.6nm was visible for the first 2–3 laser shots.We demonstrated that in-situ LIBS is a reliable method for detection of He and D retention in ITER-relevant materials. Nevertheless, for measuring relative and absolute concentrations of D and He in the ITER-relevant samples, further studies are needed. Keywords: Plasma surface interaction, LIBS, Fuel retention, Tungsten

The 2014–2016 JET results are reviewed in the light of their significance for optimising the ITER research plan for the active and non-active operation. More than 60 h of plasma operation with ITER first wall materials successfully took place since its installation in 2011. New multi-machine scaling of the type I-ELM divertor energy flux density to ITER is supported by first principle modelling. ITER relevant disruption experiments and first principle modelling are reported with a set of three disruption mitigation valves mimicking the ITER setup. Insights of the L–H power threshold in Deuterium and Hydrogen are given, stressing the importance of the magnetic configurations and the recent measurements of fine-scale structures in the edge radial electric. Dimensionless scans of the core and pedestal confinement provide new information to elucidate the importance of the first wall material on the fusion performance. H-mode plasmas at ITER triangularity (H = 1 at ßN ~ 1.8 and n/nGW ~ 0.6) have been sustained at 2 MA during 5 s. The ITER neutronics codes have been validated on high performance experiments. Prospects for the coming D–T campaign and 14 MeV neutron calibration strategy are reviewed. This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 under grant agreement No 633053. Peer Reviewed Article signat per 1.173 autors/es: X. Litaudon35, S. Abduallev39, M. Abhangi46, P. Abreu53, M. Afzal7, K.M. Aggarwal29, T. Ahlgren101, J.H. Ahn8, L. Aho-Mantila112, N. Aiba69, M. Airila112, R. Albanese105, V. Aldred7, D. Alegre93, E. Alessi45, P. Aleynikov55, A. Alfier12, A. Alkseev72, M. Allinson7, B. Alper7, E. Alves53, G. Ambrosino105, R. Ambrosino106, L. Amicucci90, V. Amosov88, E. Andersson Sundén22, M. Angelone90, M. Anghel85, C. Angioni62, L. Appel7, C. Appelbee7, P. Arena30, M. Ariola106, H. Arnichand8, S. Arshad41, A. Ash7, N. Ashikawa68, V. Aslanyan64, O. Asunta1, F. Auriemma12, Y. Austin7, L. Avotina103, M.D. Axton7, C. Ayres7, M. Bacharis24, A. Baciero57, D. Baião53, S. Bailey7, A. Baker7, I. Balboa7, M. Balden62, N. Balshaw7, R. Bament7, J.W. Banks7, Y.F. Baranov7, M.A. Barnard7, D. Barnes7, M. Barnes27, R. Barnsley55, A. Baron Wiechec7, L. Barrera Orte34, M. Baruzzo12, V. Basiuk8, M. Bassan55, R. Bastow7, A. Batista53, P. Batistoni90, R. Baughan7, B. Bauvir55, L. Baylor73, B. Bazylev56, J. Beal110, P.S. Beaumont7, M. Beckers39, B. Beckett7, A. Becoulet8, N. Bekris35, M. Beldishevski7, K. Bell7, F. Belli90, M. Bellinger7, É. Belonohy62, N. Ben Ayed7, N.A. Benterman7, H. Bergsåker42, J. Bernardo53, M. Bernert62, M. Berry7, L. Bertalot55, C. Besliu7, M. Beurskens63, B. Bieg61, J. Bielecki47, T. Biewer73, M. Bigi12, P. Bílková50, F. Binda22, A. Bisoffi31, J.P.S. Bizarro53, C. Björkas101, J. Blackburn7, K. Blackman7, T.R. Blackman7, P. Blanchard33, P. Blatchford7, V. Bobkov62, A. Boboc7, G. Bodnár113, O. Bogar18, I. Bolshakova60, T. Bolzonella12, N. Bonanomi97, F. Bonelli56, J. Boom62, J. Booth7, D. Borba35,53, D. Borodin39, I. Borodkina39, A. Botrugno90, C. Bottereau8, P. Boulting7, C. Bourdelle8, M. Bowden7, C. Bower7, C. Bowman110, T. Boyce7, C. Boyd7, H.J. Boyer7, J.M.A. Bradshaw7, V. Braic87, R. Bravanec40, B. Breizman107, S. Bremond8, P.D. Brennan7, S. Breton8, A. Brett7, S. Brezinsek39, M.D.J. Bright7, M. Brix7, W. Broeckx78, M. Brombin12, A. Brosławski65, D.P.D. Brown7, M. Brown7, E. Bruno55, J. Bucalossi8, J. Buch46, J. Buchanan7, M.A. Buckley7, R. Budny76, H. Bufferand8, M. Bulman7, N. Bulmer7, P. Bunting7, P. Buratti90, A. Burckhart62, A. Buscarino30, A. Busse7, N.K. Butler7, I. Bykov42, J. Byrne7, P. Cahyna50, G. Calabrò90, I. Calvo57, Y. Camenen4, P. Camp7, D.C. Campling7, J. Cane7, B. Cannas17, A.J. Capel7, P.J. Card7, A. Cardinali90, P. Carman7, M. Carr7, D. Carralero62, L. Carraro12, B.B. Carvalho53, I. 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Dalgliesh7, S. Dalley7, J. Dankowski47, D. Darrow76, O. Davies7, W. Davis55,76, C. Day56, I.E. Day7, M. De Bock55, A. de Castro57, E. de la Cal57, E. de la Luna57, G. De Masi12, J. L. de Pablos57, G. De Temmerman55, G. De Tommasi105, P. de Vries55, K. Deakin7, J. Deane7, F. Degli Agostini12, R. Dejarnac50, E. Delabie73, N. den Harder38, R.O. Dendy7, J. Denis8, P. Denner39, S. Devaux62,104, P. Devynck8, F. Di Maio55, A. Di Siena62, C. Di Troia90, P. Dinca86, R. D’Inca62, B. Ding51, T. Dittmar39, H. Doerk62, R.P. Doerner9, T. Donné34, S.E. Dorling7, S. Dormido-Canto93, S. Doswon7, D. Douai8, P.T. Doyle7, A. Drenik62,81, P. Drewelow63, P. Drews39, Ph. Duckworth55, R. Dumont8, P. Dumortier58, D. Dunai113, M. Dunne62, I. Ďuran50, F. Durodié58, P. Dutta46, B. P. Duval33, R. Dux62, K. Dylst78, N. Dzysiuk22, P.V. Edappala46, J. Edmond7, A.M. Edwards7, J. Edwards7, Th. Eich62, A. Ekedahl8, R. El-Jorf7, C.G. Elsmore7, M. Enachescu84, G. Ericsson22, F. Eriksson16, J. Eriksson22, L.G. Eriksson36, B. Esposito90, S. Esquembri94, H.G. Esser39, D. Esteve8, B. Evans7, G.E. Evans7, G. Evison7, G.D. Ewart7, D. Fagan7, M. Faitsch62, D. Falie86, A. Fanni17, A. Fasoli33, J. M. Faustin33, N. Fawlk7, L. Fazendeiro53, N. Fedorczak8, R.C. Felton7, K. Fenton7, A. Fernades53, H. Fernandes53, J. Ferreira53, J.A. Fessey7, O. Février8, O. Ficker50, A. Field7, S. Fietz62, A. Figueiredo53, J. Figueiredo53,35, A. Fil8, P. Finburg7, M. Firdaouss8, U. Fischer56, L. Fittill7, M. Fitzgerald7, D. Flammini90, J. Flanagan7, C. Fleming7, K. Flinders7, N. Fonnesu90, J. M. Fontdecaba57, A. Formisano79, L. Forsythe7, L. Fortuna30, E. Fortuna-Zalesna19, M. Fortune7, S. Foster7, T. Franke34, T. Franklin7, M. Frasca30, L. Frassinetti42, M. Freisinger39, R. Fresa98, D. Frigione90, V. Fuchs50, D. Fuller35, S. Futatani6, J. Fyvie7, K. Gál34,62, D. Galassi2, K. Gałązka49, J. Galdon-Quiroga92, J. Gallagher7, D. Gallart6, R. Galvão10, X. Gao51, Y. Gao39, J. Garcia8, A. Garcia-Carrasco42, M. García-Muñoz92, J.-L. Gardarein3, L. Garzotti7, P. Gaudio95, E. Gauthier8, D.F. Gear7, S.J. Gee7, B. Geiger62, M. Gelfusa95, S. Gerasimov7, G. Gervasini45, M. Gethins7, Z. Ghani7, M. Ghate46, M. Gherendi86, J.C. Giacalone8, L. Giacomelli45, C.S. Gibson7, T. Giegerich56, C. Gil8, L. Gil53, S. Gilligan7, D. Gin54, E. Giovannozzi90, J.B. Girardo8, C. Giroud7, G. Giruzzi8, S. Glöggler62, J. Godwin7, J. Goff7, P. Gohil43, V. Goloborod’ko102, R. Gomes53, B. Gonçalves53, M. Goniche8, M. Goodliffe7, A. Goodyear7, G. Gorini97, M. Gosk65, R. Goulding76, A. Goussarov78, R. Gowland7, B. Graham7, M.E. Graham7, J. P. Graves33, N. Grazier7, P. Grazier7, N.R. Green7, H. Greuner62, B. Grierson76, F.S. Griph7, C. Grisolia8, D. Grist7, M. Groth1, R. Grove73, C.N. Grundy7, J. Grzonka19, D. Guard7, C. Guérard34, C. Guillemaut8,53, R. Guirlet8, C. Gurl7, H.H. Utoh69, L.J. Hackett7, S. Hacquin8,35, A. Hagar7, R. Hager76, A. Hakola112, M. Halitovs103, S.J. Hall7, S.P. Hallworth Cook7, C. Hamlyn-Harris7, K. 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Rubino12, L. Ruchko52, M. Ruiz94, C. Ruset86, J. Rzadkiewicz65, S. Saarelma7, R. Sabot8, E. Safi101, P. Sagar7, G. Saibene41, F. Saint-Laurent8, M. Salewski83, A. Salmi112, R. Salmon7, F. Salzedas53, D. Samaddar7, U. Samm39, D. Sandiford7, P. Santa46, M.I.K. Santala1, B. Santos53, A. Santucci90, F. Sartori41, R. Sartori41, O. Sauter33, R. Scannell7, T. Schlummer39, K. Schmid62, V. Schmidt12, S. Schmuck7, M. Schneider8, K. Schöpf102, D. Schwörer32, S.D. Scott76, G. Sergienko39, M. Sertoli62, A. Shabbir15, S.E. Sharapov7, A. Shaw7, R. Shaw7, H. Sheikh7, A. Shepherd7, A. Shevelev54, A. Shumack38, G. Sias17, M. Sibbald7, B. Sieglin62, S. Silburn7, A. Silva53, C. Silva53, P.A. Simmons7, J. Simpson7, J. Simpson-Hutchinson7, A. Sinha46, S.K. Sipilä1, A.C.C. Sips36, P. Sirén112, A. Sirinelli55, H. Sjöstrand22, M. Skiba22, R. Skilton7, K. Slabkowska49, B. Slade7, N. Smith7, P.G. Smith7, R. Smith7, T.J. Smith7, M. Smithies110, L. Snoj81, S. Soare85, E. R. Solano35,57, A. Somers32, C. Sommariva8, P. Sonato12, A. Sopplesa12, J. Sousa53, C. Sozzi45, S. Spagnolo12, T. Spelzini7, F. Spineanu86, G. Stables7, I. Stamatelatos71, M.F. Stamp7, P. Staniec7, G. Stankūnas59, C. Stan-Sion84, M.J. Stead7, E. Stefanikova42, I. Stepanov58, A.V. Stephen7, M. Stephen46, A. Stevens7, B.D. Stevens7, J. Strachan76, P. Strand16, H.R. Strauss44, P. Ström42, G. Stubbs7, W. Studholme7, F. Subba75, H.P. Summers21, J. Svensson63, Ł. Świderski65, T. Szabolics113, M. Szawlowski49, G. Szepesi7, T.T. Suzuki69, B. Tál113, T. Tala112, A.R. Talbot7, S. Talebzadeh95, C. Taliercio12, P. Tamain8, C. Tame7, W. Tang76, M. Tardocchi45, L. Taroni12, D. Taylor7, K.A. Taylor7, D. Tegnered16, G. Telesca15, N. Teplova54, D. Terranova12, D. Testa33, E. Tholerus42, J. Thomas7, J.D. Thomas7, P. Thomas55, A. Thompson7, C.-A. Thompson7, V.K. Thompson7, L. Thorne7, A. Thornton7, A.S. Thrysøe83, P.A. Tigwell7, N. Tipton7, I. Tiseanu86, H. Tojo69, M. Tokitani67, P. Tolias82, M. Tomeš50, P. Tonner7, M. Towndrow7, P. Trimble7, M. Tripsky58, M. Tsalas38, P. Tsavalas71, D. Tskhakaya jun102, I. Turner7, M.M. Turner32, M. Turnyanskiy34, G. Tvalashvili7, S.G.J. Tyrrell7, A. Uccello45, Z. Ul-Abidin7, J. Uljanovs1, D. Ulyatt7, H. Urano69, I. Uytdenhouwen78, A.P. Vadgama7, D. Valcarcel7, M. Valentinuzzi8, M. Valisa12, P. Vallejos Olivares42, M. Valovic7, M. Van De Mortel7, D. Van Eester58, W. Van Renterghem78, G.J. van Rooij38, J. Varje1, S. Varoutis56, S. Vartanian8, K. Vasava46, T. Vasilopoulou71, J. Vega57, G. Verdoolaege58, R. Verhoeven7, C. Verona95, G. Verona Rinati95, E. Veshchev55, N. Vianello45, J. Vicente53, E. Viezzer62,92, S. Villari90, F. Villone100, P. Vincenzi12, I. Vinyar74, B. Viola90, A. Vitins103, Z. Vizvary7, M. Vlad86, I. Voitsekhovitch34, P. Vondráček50, N. Vora7, T. Vu8, W.W. Pires de Sa52, B. Wakeling7, C.W.F. Waldon7, N. Walkden7, M. Walker7, R. Walker7, M. Walsh55, E. Wang39, N. Wang39, S. Warder7, R.J. Warren7, J. Waterhouse7, N.W. Watkins28, C. Watts55, T. Wauters58, A. Weckmann42, J. Weiland23, H. Weisen33, M. Weiszflog22, C. Wellstood7, A.T. West7, M.R. Wheatley7, S. Whetham7, A.M. Whitehead7, B.D. Whitehead7, A.M. Widdowson7, S. Wiesen39, J. Wilkinson7, J. Williams7, M. Williams7, A.R. Wilson7, D.J. Wilson7, H.R. Wilson110, J. Wilson7, M. Wischmeier62, G. Withenshaw7, A. Withycombe7, D.M. Witts7, D. Wood7, R. Wood7, C. Woodley7, S. Wray7, J. Wright7, J.C. Wright64, J. Wu89, S. Wukitch64, A. Wynn110, T. Xu7, D. Yadikin16, W. Yanling39, L. Yao89, V. Yavorskij102, M.G. Yoo80, C. Young7, D. Young7, I.D. Young7, R. Young7, J. Zacks7, R. Zagorski49, F.S. Zaitsev18, R. Zanino75, A. Zarins103, K.D. Zastrow7, M. Zerbini90, W. Zhang62, Y. Zhou42, E. Zilli12, V. Zoita86, S. Zoletnik113, I. Zychor65 and JET Contributorsa // EUROfusion Consortium JET, Culham Science Centre, Abingdon, OX14 3DB, United Kingdom / 1 Aalto University, PO Box 14100, FIN-00076 Aalto, Finland / 2 Aix Marseille Université, CNRS, Centrale Marseille, M2P2 UMR 7340, 13451, Marseille, France / 3 Aix-Marseille Université, CNRS, IUSTI UMR 7343, 13013 Marseille, France / 4 Aix-Marseille Université, CNRS, PIIM, UMR 7345, 13013 Marseille, France / 5 Arizona State University, Tempe, AZ, United States of America / 6 Barcelona Supercomputing Center, Barcelona, Spain / 7 CCFE, Culham Science Centre, Abingdon, Oxon, OX14 3DB, United Kingdom / 8 CEA, IRFM, F-13108 Saint Paul Lez Durance, France / 9 Center for Energy Research, University of California at San Diego, La Jolla, CA 92093, United States of America / 10 Centro Brasileiro de Pesquisas Fisicas, Rua Xavier Sigaud, 160, Rio de Janeiro CEP 22290-180, Brazil / 11 Consorzio CREATE, Via Claudio 21, 80125 Napoli, Italy / 12 Consorzio RFX, corso Stati Uniti 4, 35127 Padova, Italy / 13 Daegu University, Jillyang, Gyeongsan, Gyeongbuk 712-174, Republic of Korea / 14 Departamento de Física, Universidad Carlos III de Madrid, 28911 Leganés, Madrid, Spain / 15 Department of Applied Physics UG (Ghent University) St-Pietersnieuwstraat 41 B-9000 Ghent, Belgium / 16 Department of Earth and Space Sciences, Chalmers University of Technology, SE-41296 Gothenburg, Sweden / 17 Department of Electrical and Electronic Engineering, University of Cagliari, Piazza d’Armi 09123, Cagliari, Italy / 18 Department of Experimental Physics, Faculty of Mathematics, Physics and Informatics Comenius University Mlynska dolina F2, 84248 Bratislava, Slovakia / 19 Department of Materials Science, Warsaw University of Technology, PL-01-152 Warsaw, Poland / 20 Department of Nuclear and Quantum Engineering, KAIST, Daejeon 34141, Korea / 21 Department of Physics and Applied Physics, University of Strathclyde, Glasgow, G4 ONG, United Kingdom / 22 Department of Physics and Astronomy, Uppsala University, SE-75120 Uppsala, Sweden / 23 Department of Physics, Chalmers University of Technology, SE-41296 Gothenburg, Sweden / 24 Department of Physics, Imperial College London, London, SW7 2AZ, United Kingdom / 25 Department of Physics, SCI, KTH, SE-10691 Stockholm, Sweden / 26 Department of Physics, University of Basel, Basel, Switzerland / 27 Department of Physics, University of Oxford, Oxford, OX1 2JD, United Kingdom / 28 Department of Physics, University of Warwick, Coventry, CV4 7AL, United Kingdom / 29 Department of Pure and Applied Physics, Queens University, Belfast, BT7 1NN, United Kingdom / 30 Dipartimento di Ingegneria Elettrica Elettronica e Informatica, Università degli Studi di Catania, 95125 Catania, Italy / 31 Dipartimento di Ingegneria Industriale, University of Trento, Trento, Italy / 32 Dublin City University (DCU), Dublin, Ireland / 33 Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Plasma Center (SPC), CH-1015 Lausanne, Switzerland / 34 EUROfusion Programme Management Unit, Boltzmannstr. 2, 85748 Garching, Germany / 35 EUROfusion Programme Management Unit, Culham Science Centre, Culham, OX14 3DB, United Kingdom / 36 European Commission, B-1049 Brussels, Belgium / 37 Fluid and Plasma Dynamics, ULB—Campus Plaine—CP 231 Boulevard du Triomphe, 1050 Bruxelles, Belgium / 38 FOM Institute DIFFER, Eindhoven, Netherlands / 39 Forschungszentrum Jülich GmbH, Institut für Energie- und Klimaforschung—Plasmaphysik, 52425 Jülich, Germany / 40 Fourth State Research, 503 Lockhart Dr, Austin, TX, United States of America / 41 Fusion for Energy Joint Undertaking, Josep Pl. 2, Torres Diagonal Litoral B3, 08019, Barcelona, Spain / 42 Fusion Plasma Physics, EES, KTH, SE-10044 Stockholm, Sweden / 43 General Atomics, PO Box 85608, San Diego, CA 92186-5608, United States of America / 44 HRS Fusion, West Orange, NJ, United States of America / 45 IFP-CNR, via R. Cozzi 53, 20125 Milano, Italy / 46 Institute for Plasma Research, Bhat, Gandhinagar-382 428, Gujarat State, India / 47 Institute of Nuclear Physics, Radzikowskiego 152, 31-342 Kraków, Poland / 48 Institute of Physics, Opole University, Oleska 48, 45-052 Opole, Poland / 49 Institute of Plasma Physics and Laser Microfusion, Hery 23, 01-497 Warsaw, Poland / 50 Institute of Plasma Physics AS CR, Za Slovankou 1782/3, 182 00 Praha 8, Czechia / 51 Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031, People’s Republic of China / 52 Instituto de Física, Universidade de São Paulo, Rua do Matão Travessa R Nr.187 CEP 05508-090 Cidade Universitária, São Paulo, Brasil / 53 Instituto de Plasmas e Fusão Nuclear, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal / 54 Ioffe Physico-Technical Institute, 26 Politekhnicheskaya, St Petersburg 194021, Russian Federation / 55 ITER Organization, Route de Vinon, CS 90 046, 13067 Saint Paul Lez Durance, France / 56 Karlsruhe Institute of Technology, PO Box 3640, D-76021 Karlsruhe, Germany / 57 Laboratorio Nacional de Fusión, CIEMAT, Madrid, Spain / 58 Laboratory for Plasma Physics Koninklijke Militaire School—Ecole Royale Militaire, Renaissancelaan 30 Avenue de la Renaissance B-1000, Brussels, Belgium / 59 Lithuanian energy institute, Breslaujos g. 3, LT-44403, Kaunas, Lithuania / 60 Magnetic Sensor Laboratory, Lviv Polytechnic National University, Lviv, Ukraine / 61 Maritime University of Szczecin, Waly Chrobrego 1-2, 70-500 Szczecin, Poland / 62 Max-Planck-Institut für Plasmaphysik, D-85748 Garching, Germany / 63 Max-Planck-Institut für Plasmaphysik, Teilinsitut Greifswald, D-17491 Greifswald, Germany / 64 MIT Plasma Science and Fusion Centre, Cambridge, MA 02139, United States of America / 65 National Centre for Nuclear Research (NCBJ), 05-400 Otwock-Świerk, Poland / 66 National Fusion Research Institute (NFRI), 169-148 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea / 67 National Institute for Fusion Science, Oroshi, Toki, Gifu 509-5292, Japan / 68 National Institute for Fusion Science, Toki, 509-5292, Japan / 69 National Institutes for Quantum and Radiological Science and Technology, Naka, Ibaraki 311-0193, Japan / 70 National Technical University of Athens, Iroon Politechniou 9, 157 73 Zografou, Athens, Greece / 71 NCSR ‘Demokritos’, 153 10, Agia Paraskevi Attikis, Greece / 72 NRC Kurchatov Institute, 1 Kurchatov Square, Moscow 123182, Russian Federation / 73 Oak Ridge National Laboratory, Oak Ridge, TN 37831-6169, United States of America / 74 PELIN LLC, 27a, Gzhatskaya Ulitsa, Saint Petersburg, 195220, Russian Federation / 75 Politecnico di Torino, Corso Duca degli Abruzzi 24, I-10129 Torino, Italy / 76 Princeton Plasma Physics Laboratory, James Forrestal Campus, Princeton, NJ 08543, United States of America / 77 Purdue University, 610 Purdue Mall, West Lafayette, IN 47907, United States of America / 78 SCK-CEN, Nuclear Research Centre, 2400 Mol, Belgium / 79 Second University of Napoli, Consorzio CREATE, Via Claudio 21, 80125 Napoli, Italy / 80 Seoul National University, Shilim-Dong, Gwanak-Gu, Republic of Korea / 81 Slovenian Fusion Association (SFA), Jozef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia / 82 Space and Plasma Physics, EES, KTH SE-100 44 Stockholm, Sweden / 83 Technical University of Denmark, Department of Physics, Bldg 309, DK-2800 Kgs Lyngby, Denmark / 84 The ‘Horia Hulubei’ National Institute for Physics and Nuclear Engineering, Magurele-Bucharest, Romania / 85 The National Institute for Cryogenics and Isotopic Technology, Ramnicu Valcea, Romania / 86 The National Institute for Laser, Plasma and Radiation Physics, Magurele-Bucharest, Romania / 87 The National Institute for Optoelectronics, Magurele-Bucharest, Romania / 88 Troitsk Insitute of Innovating and Thermonuclear Research (TRINITI), Troitsk 142190, Moscow Region, Russian Federation / 89 University of Electronic Science and Technology of China, Chengdu, People’s Republic of China / 90 Unità Tecnica Fusione, ENEA C. R. Frascati, via E. Fermi 45, 00044 Frascati (Roma), Italy / 91 Universidad Complutense de Madrid, Madrid, Spain / 92 Universidad de Sevilla, Sevilla, Spain / 93 Universidad Nacional de Educación a Distancia, Madrid, Spain / 94 Universidad Politécnica de Madrid, Grupo I2A2, Madrid, Spain / 95 Università di Roma Tor Vergata, Via del Politecnico 1, Roma, Italy / 96 University College Cork (UCC), Ireland / 97 University Milano-Bicocca, piazza della Scienza 3, 20126 Milano, Italy / 98 University of Basilicata, Consorzio CREATE, Via Claudio 21, 80125 Napoli, Italy / 99 University of California, 1111 Franklin St., Oakland, CA 94607, United States of America / 100 University of Cassino, Consorzio CREATE, Via Claudio 21, 80125 Napoli, Italy / 101 University of Helsinki, PO Box 43, FI-00014 University of Helsinki, Finland / 102 University of Innsbruck, Fusion@Österreichische Akademie der Wissenschaften (ÖAW), Innsbruck, Austria / 103 University of Latvia, 19 Raina Blvd., Riga, LV 1586, Latvia / 104 University of Lorraine, CNRS, UMR7198, YIJL, Nancy, France / 105 University of Napoli ‘Federico II’, Consorzio CREATE, Via Claudio 21, 80125 Napoli, Italy / 106 University of Napoli Parthenope, Consorzio CREATE, Via Claudio 21, 80125 Napoli, Italy / 107 University of Texas at Austin, Institute for Fusion Studies, Austin, TX 78712, United States of America / 108 University of Toyama, Toyama, 930-8555, Japan / 109 University of Tuscia, DEIM, Via del Paradiso 47, 01100 Viterbo, Italy / 110 University of York, Heslington, York YO10 5DD, United Kingdom / 111 Vienna University of Technology, Fusion@Österreichische Akademie der Wissenschaften (ÖAW), Austria / 112 VTT Technical Research Centre of Finland, PO Box 1000, FIN-02044 VTT, Finland / 113 Wigner Research Centre for Physics, PO Box 49, H-1525 Budapest, Hungary

Samples with tungsten (W) and tungsten-yttrium (Y) coatings on molybdenum were exposed to plasmas simulating the divertor conditions of ITER. The exposed surfaces were studied using in-situ laser induced breakdown spectroscopy diagnostics (LIBS) and the results were compared to those obtained by other surface characterization methods. Our results show that LIBS is a reliable technique for in situ monitoring of erosion, deposition, and fuel retention processes under reactor-relevant conditions. In the regions of the highest gross erosion the thickness of the remaining tungsten layer is thinnest and at the central part of samples both mixing and deposition of components took place. LIBS also allowed reliable recording of D retention. D accumulation is influenced by the surface temperature as well as by the surface irregularities.

We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation. © 2017 The Author(s).

Background and Purpose— Cerebral white matter lesions (WMLs), a surrogate for cerebral small-vessel disease, have been shown to be associated with decreasing mobility, gait instability, and falls. The aim of this study was to investigate whether WMLs of the brain are associated with increased incidence of hospital admissions because of any trauma and hip-fractures in a cohort of patients with stroke. Methods— We included 383 consecutive patients aged 55 to 85 years with ischemic stroke admitted to the Helsinki University Central Hospital (The Stroke Aging Memory cohort) with a 12-year follow-up. National register data were reviewed for hip-fractures, other traumatic injuries, survival data, and causes of death. WMLs were rated using MRI and dichotomized as none to mild and moderate to severe. The data were analyzed using Kaplan–Meier plots (log-rank) and a complex Cox multivariable hazards models for multiple cases per subject to assess hazard ratios with their 95% confidence intervals. Results— During the 12-year follow-up, there were more hip-fractures (13.5% versus 6.5%; log-rank, P =0.01) and more hospital admissions because of traumatic injury (22.2% versus 16.7%; log-rank, P =0.04) in the moderate-to-severe than in the none-to-mild WMLs group. In the complex samples, Cox multivariable model adjusting for age, sex, National Institutes of Health Stroke Scale, infarct size, and poststroke dementia, moderate-to-severe WMLs were associated with increased incidences of hospital admissions because of hip-fractures (hazard ratio, 3.98; 95% confidence interval, 1.55–10.21) and traumatic injuries including hip-fractures (hazard ratio, 1.72; 95% confidence interval, 1.03–2.87). Conclusions— Patients with ischemic stroke and moderate-to-severe WMLs are at high risk, who experience serious traumatic injuries and especially hip-fractures requiring hospital treatment.

The purpose of the research was to evaluate gynecological evidence collection techniques; the benefit of cervical canal brush sample compared to vaginal fornix and cervical swab samples and the time frame for detecting Y-chromosomal material QiAmp DNA Mini Kit® and Quantifiler Y Human Male DNA Quantification Kit® in adult volunteers following consensual intercourse. Eighty-four adult female volunteers following consensual intercourse were recruited for the study. By combining all sample collecting techniques, 81.0% of the volunteers were Y-DNA positive. Up to 60 h the conventional swab sampling techniques detected more Y-DNA positive samples when compared to the brush technique. However, after 60 h, the cervical canal brush sample technique showed its benefit by detecting 27.3% (6/22) of Y-DNA positive samples, which were Y-DNA negative in both conventional swab sampling techniques. By combining swab and brush techniques, 75% of the volunteers were still Y-DNA positive in 72–144 post-coital hours. The rate of measurable Y-DNA decreased approximately 3% per hour. Despite reported consensual intercourse, 6.8% (3/44) of volunteers were Y-DNA negative within 48 h. Y-DNA was not detected after 144 post-coital hours (6 days). In conclusion, the brush as a forensic evidence collection method may provide additional biological trace evidence from the cervical canal, although the best biological trace evidence collection can be obtained by combining all three sampling techniques. The time frame for gynecological forensic evidence sample collection should be considered to be at least a week if sexual violence is suspected.

Objectives New clinical forensic examination techniques for sexual assaults have not been introduced over the last few decades. We evaluated the benefit of ultraviolet light compared to white light for detecting minor anogenital injuries and scars, following consensual sexual intercourse among adult volunteers. Design A prospective study comparing female genital findings utilising white and ultraviolet light. A colposcopy with photographic documentation was used. Setting Personal invitation to healthcare students, hospital employees or acquaintances to volunteer for a gynecological examination, with a focus on clinical forensic aspects. Participants Eighty-eight adult female volunteers were recruited for the study. The examination was performed after consensual intercourse. Age ranged from 20 to 52 years (median 26.5 years). Main outcome measures Presence of acute findings and scars in the genital area using white and UV-light. Results Acute genital injury rate was 14.8% under white light colposcopy and 23.0% using UV light. Submucosal hemorrhages in the genital area were documented significantly better under UV-light than white light (14.9% vs. 6.8%; p = 0.016), whereas petechiaes (4.5%) and abrasions (2.3%) were detected using either method. UV-light revealed significantly more often delivery-associated genital scars compared to white light (39.8% vs. 31.8%; p = 0.016). Furthermore, 10 out of 31 (33.3%) women had no residual anogenital skin or mucosal surface findings, despite a prior episiotomy or rupture of the vaginal outlet wall during delivery, supporting its enormous ability to heal even after major trauma. Conclusions UV-light may provide additional value for the evaluation of physical findings in clinical forensic examinations after sexual assault, and is especially useful in detecting otherwise invisible early submucosal hemorrhages and scars.

openaire: EC/H2020/633053/EU//EUROfusion Considering reflections from metallic wall surfaces in generation of tomographic reconstructions of the tangentially viewing, visible-range spectroscopic divertor cameras in JET has been observed to yield enhanced spatial accuracy and significant reduction of emission artifacts in experimentally resolved 2D line emission distributions. Neglection of reflections in the tomography process was found to lead to overestimation of the emission near the wall surfaces by up to a factor of 4, as well as to formation of bright emission artifacts between the main emission regions and the wall surfaces, comprising locally up to 50% of the emission. Mimicking divertor spectroscopy measurements by integrating the tomographic reconstructions along vertical lines-of-sight implies that reflections comprise 15%-25% of the observed line-integrated emission peaks. The spatial differences in the reflection contribution between the different lines-of-sight are less pronounced than in the 2D reconstructions due to the dominance of the brightest emission regions through which the spectroscopic lines-of-sight pass. However, postprocessing EDGE2D-EIRENE simulations using the CHERAB code and synthetic spectroscopy suggests a decrease of the spectroscopically inferred divertor electron temperature by up to 75%, when redistribution of the observed light due to reflections is considered.

Background Ageing is characteristically accompanied by changes in vascular endothelial markers and growth factor as well as increased cellular death. We analysed the associations of the plasma levels of vascular cell adhesion molecule-1 (VCAM-1), hepatocyte growth factor (HGF) and soluble Fas (sFAS), and their combinations, with 4-year mortality to identify new biomarkers. Methods A total of 238 individuals, both community-dwelling and institutionalised, aged 89‒91 years and participating in the Vitality 90 + study were included. Biomarkers of endothelial function (VCAM-1), growth factor (HGF) and a marker of apoptosis (sFAS) were determined from plasma using Luminex® technology. This newly-determined data was combined with earlier data, e.g., 4-year mortality and medical history. Results Subjects who died during the follow-up had higher baseline plasma levels of VCAM-1, sFas, and HGF. When other known risk factors were adjusted for, subjects in the highest concentration tertile for VCAM-1 (HR 1.85; 95% CI, 1.12–3.05) and HGF (HR 2.22; 95% CI, 1.33–3.71) had higher mortality compared to those in the lowest tertile. In the adjusted analyses, when compared to subjects with none of the biomarkers in the highest concentration tertile, mortality was also higher when sFas and VCAM-1 were simultaneously (HR 2.03; 95% CI, 1.13–3.64) or all three were simultaneously (HR 3.63; 95% CI, 1.65–7.97) in the highest concentration tertile. Conclusions Our results suggest that increased concentrations of these biomarkers, separately and in combination, associate with mortality among the aged and are prognostic markers of death.

Although excessive alcohol consumption plays a major role in fatal events, the role of alcohol use as a possible contributing factor at the time of death is not easy to establish due to lack of suitable biomarkers for postmortem analyses. We used an immunological approach to measure ethyl glucuronide (EtG) concentrations from vitreous humor (VH) and serum from 58 individuals representing a forensic autopsy population of cases with either a well-documented history of excessive alcohol use (n=37) or cases without such history (n=21), according to medical and police records and blood alcohol determinations (BAC). The immunoassay was based on the Microgenics DRI-EtG EIA reagents applied on an automated Abbott Architect c8000 clinical chemistry analyzer. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) determination of EtG and ethyl sulfate (EtS) was used as a reference method. At a cut-off of 0.3mg/l for VH-EtG, the immunoassay correctly identified 92% of the cases with a history of excessive alcohol use, whereas the BAC was positive (cut-off 10mg/dl) in 68% of the cases. A significant correlation emerged between VH-EtG and serum EtG (r=0.77, p

Background— Oxidized low-density lipoprotein may be a key factor in the development of atherosclerosis. We performed a genome-wide association study on oxidized low-density lipoprotein and tested the impact of associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis and cardiovascular events. Methods and Results— A discovery genome-wide association study was performed on a population of young healthy white individuals (N=2080), and the SNPs associated with a P –8 were replicated in 2 independent samples (A: N=2912; B: N=1326). Associations with cardiovascular endpoints were also assessed with 2 additional clinical cohorts (C: N=1118; and D: N=808). We found 328 SNPs associated with oxidized low-density lipoprotein. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B was the proxy SNP behind all associations ( P =4.3×10 –136 , effect size=13.2 U/L per allele). This association was replicated in the 2 independent samples (A and B, P =2.5×10 –47 and 1.1×10 –11 , effect sizes=10.3 U/L and 7.8 U/L, respectively). In the meta-analyses of cohorts A, C, and D (excluding cohort B without angiographic data), the top SNP did not associate significantly with the age of onset of angiographically verified coronary artery disease (hazard ratio=1.00 [0.94–1.06] per allele), 3-vessel coronary artery disease (hazard ratio=1.03 [0.94–1.13]), or myocardial infarction (hazard ratio=1.04 [0.96–1.12]). Conclusions— This novel genetic marker is an important factor regulating oxidized low-density lipoprotein levels but not a major genetic factor for the studied cardiovascular endpoints.

Postmortem bacteriology can be a valuable tool for evaluating deaths due to bacterial infection or for researching the involvement of bacteria in various diseases. In this study, time-dependent postmortem bacterial migration into liver, mesenteric lymph node, pericardial fluid, portal, and peripheral vein was analyzed in 33 autopsy cases by bacterial culturing and real-time quantitative polymerase chain reaction (RT-qPCR). None suffered or died from bacterial infection. According to culturing, pericardial fluid and liver were the most sterile samples up to 5 days postmortem. In these samples, multigrowth and staphylococci were not or rarely detected. RT-qPCR was more sensitive and showed higher bacterial positivity in all samples. Relative amounts of intestinal bacterial DNA (bifidobacteria, bacteroides, enterobacter, clostridia) increased with time. Sterility of blood samples was low during the studied time periods (1-7 days). The best postmortem microbiological sampling sites were pericardial fluid and liver up to 5 days after death.

Background: Depression and depression-executive dysfunction syndrome (DES) are common neuropsychiatric consequences of stroke. We hypothesized that if stroke as a cerebrovascular event causes depression, this so-called post-stroke depression will further increase the risk of recurrent stroke. The objective of the study was to investigate whether patients with post-stroke depression or DES have increased rates of stroke recurrence. Methods: We included 223 patients from the Helsinki Stroke Aging Memory cohort (n = 486) admitted to Helsinki University Central Hospital with a follow-up of 12 years. We included only patients with first-ever ischaemic stroke who were testable for depression and executive dysfunction. For follow-up, national register data were reviewed for all diagnosis codes of ischaemic stroke, survival data and causes of death. Neuropsychological and neuropsychiatric evaluations for depression and executive functions were performed 12-20 weeks after the index stroke. Univariate analysis was performed using χ2, Mantel-Haenszel, ANOVA, and Kaplan-Meier log rank analyses. A Cox multivariable model with forced entry was used to adjust for stroke risk factors (age, gender, smoking, atrial fibrillation, hypertension, diabetes, peripheral arterial disease, hypercholesterolaemia). Results: The mean time to first recurrent stroke was shorter for the depressed patient group (8.15, 95% CI 7.11-9.19 vs. 9.63, 8.89-10.38 years) and even shorter for patients with DES (7.15, 5.55-8.75 vs. 9.75, 9.09-10.41 years) compared to the remaining groups, respectively. The cumulative risk for recurrent ischaemic stroke in the 12-year follow-up was higher for the depression group (log rank p = 0.04) and for the DES group (log rank p = 0.01) compared to the remaining groups, respectively. Cox multivariable analyses revealed that the older age of the patient (1.05; 1.01-1.08/year), the absence of hypercholesterolaemia (0.24; 0.09-0.59), depression (1.68; 1.07-2.63), and DES (1.95; 1.14-3.33) were all associated with recurrent stroke. Conclusions: Depression and especially DES are associated with a shorter interval to recurrence of ischaemic stroke but executive dysfunction alone is not associated with a more rapid stroke recurrence. Diagnosis and treatment of depressive syndromes should be considered as a part of secondary prevention in patients with ischaemic stroke.

Objective: To investigate whether poststroke dementia diagnosed after ischemic stroke is associated with earlier permanent institutionalization. Methods: We included 410 consecutive patients aged 55 to 85 years with ischemic stroke admitted to the Helsinki University Central Hospital (The SAM cohort) with a 21-year follow-up. Hospitalization and nursing home admissions were reviewed from national registers. Dementia was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders 3rd edition (DSM-III) criteria. Kaplan-Meier plots log-rank and binary logistic regression (odds ratio, OR) and Cox multivariable proportional hazards model were used to study the association of poststroke dementia status and time of permanent institutionalization. HR and OR with their 95% confidence intervals (CI) are reported. Results: Poststroke dementia was associated with more frequent (OR 2.05; CI 1.29-3.24) permanent institutionalization (Mantel-Haenszel), and earlier permanent institutionalization (5.6 versus 13.6 years; log-rank p Conclusions: Poststroke dementia at 3 month after stroke is associated with earlier permanent institutionalization compared with stroke patient without poststroke dementia.

Introduction: Haptoglobin (Hb) is an acute phase plasma protein which binds free hemoglobin and protects tissues from heme-iron induced oxidative damage. Hp gene exists in two variant alleles, Hp1 and Hp2 giving rise to three protein isoforms, hp1-1, hp1-2 and hp2-2, which differ in their efficiency to limit oxidative stress. Previously, Hp variants have been associated with the risk of ischemic stroke subtypes, Hp1 variant with lacunar stroke and Hp2 with large-artery atherosclerotic stroke. Hypothesis: Our aim was to scrutinize previous associations to stroke subtypes and, further, to test association of Hp variants with the extent of white matter lesions (WML) and incidence of cardiovascular death after first-ever ischemic stroke. Methods: Hp was genotyped by PCR and gel electrophoresis in Helsinki Stroke Aging Memory Study (SAM, n=378 with DNA) and Cardiovascular diseases -subcohort of Health 2000 Survey (n=1426), who served as population controls. Results: Hp genotype frequencies were 15.6% (Hp1-1), 44.2% (Hp1-2) and 40.2% (Hp2-2), within Hardy-Weinberg equilibrium and equal to those described in other Caucasian populations. There were no significant differences in Hp genotypes between stroke subtypes classified according to TOAST within SAM or compared to population controls. Hp alleles did not associate with the extent of WML. In follow-up, the carriers of Hp2 allele (Hp1-2 and Hp2-2) had substantially higher rate of cardiac deaths (24.5% vs 8.5%, P=0.006) and a trend towards more fatal strokes (23.5% vs 13.6%, P=0.122). The combined risk of ischemic cardiovascular death was 2.4-fold increased in Hp2 carriers (95%CI 1.28-4.43) even after adjustment for major cardiovascular risk factors (age, gender, hypertension, diabetes, atrial fibrillation, smoking, high LDL cholesterol). Conclusions: Hp2 allele is associated with increased risk of ischemic cardiovascular death after first-ever ischemic stroke. This may result from the impaired capacity of Hp2-containing protein isoforms to alleviate oxidative stress in the vasculopathic arterial tree.

USF1 (upstream stimulatory factor 1) is a transcription factor associated with familial combined hyperlipidemia and coronary artery disease in humans. However, whether USF1 is beneficial or detrimental to cardiometabolic health has not been addressed. By inactivating USF1 in mice, we demonstrate protection against diet-induced dyslipidemia, obesity, insulin resistance, hepatic steatosis, and atherosclerosis. The favorable plasma lipid profile, including increased high-density lipoprotein cholesterol and decreased triglycerides, was coupled with increased energy expenditure due to activation of brown adipose tissue (BAT). Usf1 inactivation directs triglycerides from the circulation to BAT for combustion via a lipoprotein lipase-dependent mechanism, thus enhancing plasma triglyceride clearance. Mice lacking Usf1 displayed increased BAT-facilitated, diet-induced thermogenesis with up-regulation of mitochondrial respiratory chain complexes, as well as increased BAT activity even at thermoneutrality and after BAT sympathectomy. A direct effect of USF1 on BAT activation was demonstrated by an amplified adrenergic response in brown adipocytes after Usf1 silencing, and by augmented norepinephrine-induced thermogenesis in mice lacking Usf1. In humans, individuals carrying SNP (single-nucleotide polymorphism) alleles that reduced USF1 mRNA expression also displayed a beneficial cardiometabolic profile, featuring improved insulin sensitivity, a favorable lipid profile, and reduced atherosclerosis. Our findings identify a new molecular link between lipid metabolism and energy expenditure, and point to the potential of USF1 as a therapeutic target for cardiometabolic disease.

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (Aβ) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had Aβ aggregations, most of those with Aβ aggregations did not have HSV present in the brain tissue., Summary: We assessed the presence of HSV types 1 and 2 in the brain tissue of a large non-institutionalised autopsy cohort, providing evidence of asymptomatic access of HSV to the brain.

Introduction Puumala virus (PUUV) infection is a viral hemorrhagic fever with renal syndrome (HFRS) characterized by thrombocytopenia and acute impairment of renal function. We aimed to assess whether genetic polymorphisms of platelet antigens together with those of von Willebrand factor (VWF) and plasminogen activator inhibitor (PAI-1) correlate with disease severity. Patients and methods 172 consecutive hospital-treated patients with serologically confirmed acute PUUV infection were included. Platelet glycoprotein (GP) IIIa T > C (rs5918), GP Ia T > C (rs1126643), GP Ib C > T (rs6065), GP VI T > C (rs1613662), VWF A > G (rs1063856) and PAI-1 A > G (rs2227631) were genotyped. The associations of the rarer alleles with variables reflecting the severity of the disease were analyzed. Results PAI-1 G-carriers had higher maximum creatinine level compared with the non-carriers (median 213 μmol/l, range 60–1499 μmol/l vs. median 122 μmol/l, range 51–1156 μmol/l, p = 0.01). The GG-genotypes had higher creatinine levels than GA- and AA-genotypes (medians 249 μmol/l, 204 μmol/l and 122 μmol/l, respectively, p = 0.03). Polymorphisms of GP VI and VWF associated with lower creatinine levels during PUUV infection. The minor C-allele of GP Ia associated with lower platelet counts (median 44 × 109/l, range 20–90 × 109/l vs median 64 × 109/l, range 3–238 × 109/l; p = 0.02). Conclusions Polymorphism of PAI-1, a major regulator of fibrinolysis, has an adverse impact on the outcome of kidney function in PUUV-HFRS. Platelet collagen receptor GP Ia polymorphism associates with lower platelet count.

The apolipoprotein E (APOE) gene associates with Alzheimer's disease (AD) and cholesterol levels. Upstream transcription factor 1 (USF1) regulates lipid metabolism genes, including APOE, and the AD Aβ-precursor protein. We investigated associations between 6 haplotype-tagging USF1 single-nucleotide polymorphisms (and haplotypes) and AD-related neuropathological lesions [senile plaques (SP), neurofibrillary tangles (NFT) ] in an autopsy series comprising 603 cases (ages 0–97, mean 62 years, 215 women) that died out-of-hospital. In age- and APOE-adjusted analyses, the minor G-allele of rs2774276, previously linked to elevated cholesterol, associated with late-stage burnt out SP among women and early non-neuritic SP among men. The G-allele of the previously unreported rs10908821 showed significant risk of having SP, especially neuritic and burnt out SP, among women but not men. USF1 haplotype GCGCAC carriers (risk alleles of rs2774276 and rs10908821) associated with SP risk, especially neuritic and late-stage burnt out SP, among women but not men. Younger CCGCAC carriers (risk allele of rs2774276 and protective of rs10908821) were more likely to have non-neuritic and diffuse SP. Conversely, USF1 CCGCAC haplotype carriers had lower NFT prevalence among 65+ year-olds. These results suggest USF1 has an independent but gender- and age-associated effect on AD-related brain lesion development.

Aims High-throughput metabolite quantification holds promise for cardiovascular risk assessment. Here, we evaluated whether metabolite quantification by nuclear magnetic resonance (NMR) improves prediction of subclinical atherosclerosis in comparison to conventional lipid testing. Methods and results Circulating lipids, lipoprotein subclasses, and small molecules were assayed by NMR for 1595 individuals aged 24–39 years from the population-based Cardiovascular Risk in Young Finns Study. Carotid intima–media thickness (IMT), a marker of subclinical atherosclerosis, was measured in 2001 and 2007. Baseline conventional risk factors and systemic metabolites were used to predict 6-year incidence of high IMT (≥90th percentile) or plaque. The best prediction of high intima–media thickness was achieved when total and HDL cholesterol were replaced by NMR-determined LDL cholesterol and medium HDL, docosahexaenoic acid, and tyrosine in prediction models with risk factors from the Framingham risk score. The extended prediction model improved risk stratification beyond established risk factors alone; area under the receiver operating characteristic curve 0.764 vs. 0.737, P = 0.02, and net reclassification index 17.6%, P = 0.0008. Higher docosahexaenoic acid levels were associated with decreased risk for incident high IMT (odds ratio: 0.74; 95% confidence interval: 0.67–0.98; P = 0.007). Tyrosine (1.33; 1.10–1.60; P = 0.003) and glutamine (1.38; 1.13–1.68; P = 0.001) levels were associated with 6-year incident high IMT independent of lipid measures. Furthermore, these amino acids were cross-sectionally associated with carotid IMT and the presence of angiographically ascertained coronary artery disease in independent populations. Conclusion High-throughput metabolite quantification, with new systemic biomarkers, improved risk stratification for subclinical atherosclerosis in comparison to conventional lipids and could potentially be useful for early cardiovascular risk assessment.

The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI.To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk.Samples from the Finnish cardiovascular study (FINCAVAS, N=2156) and the angiography and genes study (ANGES, N=1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N=443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N=53) samples.A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P0.001 and OR=1.43, P0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations.The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential.

MicroRNAs are small non-coding RNAs that inversely regulate their target gene expression. The whole miRNA profile of human atherosclerotic plaques has not been studied previously. The aim of this study was to investigate the miRNA expression profile in human atherosclerotic plaques as compared to non-atherosclerotic left internal thoracic arteries (LITA), and to connect this expression to the processes in atherosclerosis.The miRNA expression profiles of six LITAs and 12 atherosclerotic plaques obtained from aortic, carotid, and femoral atherosclerotic arteries from Tampere Vascular Study were analyzed. The analyses were performed with Agilent's miRNA Microarray. The expression levels of over 4-fold up-regulated miRNAs were verified with qRT-PCR from a larger population (n=50). Messenger RNA levels were analyzed with Illumina's Expression BeadChip to study miRNA target expression.Ten miRNAs were found to be differently expressed in atherosclerotic plaques when compared to controls (p0.05). The expression of miR-21, -34a, -146a, -146b-5p, and -210 was verified and found to be significantly up-regulated in atherosclerotic arteries versus LITAs (p0.001, fold changes 4.61, 2.55, 2.87, 2.82, and 3.92, respectively). Several predicted targets of these miRNAs were down-regulated, and gene set enrichment analysis showed several pathways which could be differently expressed due to this miRNA profile.The microRNA expression profile differs significantly between atherosclerotic plaques and control arteries. The most up-regulated miRNAs are involved in processes known to be connected to atherosclerosis. Interfering with the miRNA expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development.

The aim of this study was to assess the relationship between short stature and coronary heart disease (CHD) morbidity and mortality.We performed a systematic search from MEDLINE, PREMEDLINE, and All EBM Reviews as well as from a reference list of relevant articles. We used SPICO (Study design, Patient, Intervention, Control-intervention, Outcome) criteria. The methodological quality of studies was analysed by modified Borghoust criteria. From a total of 1907 articles, we selected 52 studies comprising population-based follow-up studies and patient cohorts followed after a CHD event, as well as case-control studies with height either as a continuous or categorical variable, totalling 3 012 747 individuals. The short ones were below 160.5 cm and tall ones over 173.9 cm on average. Among the shortest height category, the relative risks were 1.35 (95% CI 1.25-1.44) for all-cause mortality, 1.55 (1.37-1.74) for all cardiovascular disease (CVD) mortality, 1.49 (1.33-1.67) for CHD, and 1.52 (1.28-1.81) for myocardial infarction when compared with those within the highest height category. The mean relative risk was 1.46 (1.37-1.55). Short stature was associated with increased cardiovascular morbidity and mortality in both genders.The relationship between short stature and CVD appears to be a real one. On the basis of comparison, adults within the shortest category had an approximately 50% higher risk of CHD morbidity and mortality than tall individuals.

Fly species that are commonly recovered on human corpses concealed in houses or other dwellings are often dependent on human created environments and might have special features in their biology that allow them to colonize indoor cadavers. In this study we describe nine typical cases involving forensically relevant flies on human remains found indoors in southern Finland. Eggs, larvae and puparia were reared to adult stage and determined to species. Of the five species found the most common were Lucilia sericata Meigen, Calliphora vicina Robineau-Desvoidy and Protophormia terraenovae Robineau-Desvoidy. The flesh fly Sarcophaga caerulescens Zetterstedt is reported for the first time to colonize human cadavers inside houses and a COI gene sequence based DNA barcode is provided for it to help facilitate identification in the future. Fly biology, colonization speed and the significance of indoors forensic entomological evidence are discussed.

Objective— USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined. Methods and Results— We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta ( P =0.0028), with TGs in dyslipidemic coronary artery disease subjects ( P =0.03), and with high-density lipoprotein cholesterol ( P =0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated. Conclusion— Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects.

Background: Cardiac troponin elevations are associated not only with acute coronary syndromes (ACS) but also with multiple other cardiac and non-cardiac conditions. Study Objectives: To investigate the etiology and clinical significance of cardiac troponin I elevations in an unselected Emergency Department (ED) patient cohort. Methods: The study population consisted of 991 consecutive troponin-positive patients admitted to the ED of a university hospital with ACS as the presumptive diagnosis. Cardiac troponin I was measured on admission and a follow-up sample was obtained at 6–12 h. Clinical diagnosis was ascertained retrospectively using all the available information including electrocardiogram, clinical data, laboratory tests, and available coronary angiograms. Results: At admission, 805 (81.2%) patients were already troponin positive; of these, the troponin elevation was related to myocardial infarction (MI) in 654 (81.2%) patients. Finally, 83.0% of the troponin elevations were due to MI, 7.9% were related to other cardiac causes, and 9.1% to non-cardiac diseases. The leading non-cardiac causes were pulmonary embolism, renal failure, pneumonia, and sepsis. Non-cardiac patients with elevated troponin I at admission showed significantly higher in-hospital mortality (26.7% vs. 13.4%, p = 0.002) compared to cardiac patients. Conclusion: Elevated troponin levels for reasons other than MI are common in the ED and are a marker of poor in-hospital prognosis.