E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. OBJECTIVE: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion. METHODS AND RESULTS: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells. CONCLUSION: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.

FFR-Guided Complete or Culprit-Only PCI in Patients with Myocardial Infarction.

BACKGROUND: The benefit of fractional flow reserve (FFR)-guided complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear. METHODS: In this multinational, registry-based, randomized trial, we assigned patients with STEMI or very-high-risk non-STEMI (NSTEMI) and multivessel disease who were undergoing primary percutaneous coronary intervention (PCI) of the culprit lesion to receive either FFR-guided complete revascularization of nonculprit lesions or no further revascularization. The primary outcome was a composite of death from any cause, myocardial infarction, or unplanned revascularization. The two key secondary outcomes were a composite of death from any cause or myocardial infarction and unplanned revascularization. RESULTS: A total of 1542 patients underwent randomization, with 764 assigned to receive FFR-guided complete revascularization and 778 assigned to receive culprit-lesion-only PCI. At a median follow-up of 4.8 years (interquartile range, 4.3 to 5.2), a primary-outcome event had occurred in 145 patients (19.0%) in the complete-revascularization group and in 159 patients (20.4%) in the culprit-lesion-only group (hazard ratio, 0.93; 95% confidence interval [CI], 0.74 to 1.17; P = 0.53). With respect to the secondary outcomes, no apparent between-group differences were observed in the composite of death from any cause or myocardial infarction (hazard ratio, 1.12; 95% CI, 0.87 to 1.44) or unplanned revascularization (hazard ratio, 0.76; 95% CI, 0.56 to 1.04). There were no apparent between-group differences in safety outcomes. CONCLUSIONS: Among patients with STEMI or very-high-risk NSTEMI and multivessel coronary artery disease, FFR-guided complete revascularization was not shown to result in a lower risk of a composite of death from any cause, myocardial infarction, or unplanned revascularization than culprit-lesion-only PCI at 4.8 years. (Funded by the Swedish Research Council and others; FULL REVASC ClinicalTrials.gov number, NCT02862119.).

Bivalirudin versus heparin in ST and non-ST-segment elevation myocardial infarction-Outcomes at two years.

BACKGROUND: The registry-based randomized VALIDATE-SWEDEHEART trial (NCT02311231) compared bivalirudin vs. heparin in patients undergoing percutaneous coronary intervention (PCI) for myocardial infarction (MI). It showed no difference in the composite primary endpoint of death, MI, or major bleeding at 180 days. Here, we report outcomes at two years. METHODS: Analysis of primary and secondary endpoints at two years of follow-up was prespecified in the study protocol. We report the study results for the extended follow-up time here. RESULTS: In total, 6006 patients were enrolled, 3005 with ST-segment elevation MI (STEMI) and 3001 with Non-STEMI (NSTEMI), representing 70 % of all eligible patients with these diagnoses during the study. The primary endpoint occurred in 14.0 % (421 of 3004) in the bivalirudin group compared with 14.3 % (429 of 3002) in the heparin group (hazard ratio [HR] 0.97; 95 % confidence interval [CI], 0.85-1.11; P = 0.70) at one year and in 16.7 % (503 of 3004) compared with 17.1 % (514 of 3002), (HR 0.97; 95 % CI, 0.96-1.10; P = 0.66) at two years. The results were consistent in patients with STEMI and NSTEMI and across major subgroups. CONCLUSIONS: Until the two-year follow-up, there were no differences in endpoints between patients with MI undergoing PCI and allocated to bivalirudin compared with those allocated to heparin. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02311231.

C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project.

BACKGROUND AND AIMS: Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. METHODS: Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). RESULTS: Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). CONCLUSIONS: While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.

If you can make it, you can share it - Perspectives on the first DIY-fair at the European congress of medical physics (ECMP, DUBLIN 2022).

The medical physics and engineering community is known for being active in conjuring do-it-yourself (DIY) -solutions to support their clinical and research work. To facilitate the exchange of solutions and ideas, a DIY-fair was held for the first time at the European Congress of Medical Physics (ECMP) in August 2022 in Dublin, Ireland. Altogether 32 contributions were presented, consisting of software, scripts, 3D-printed customized solutions, devices, gadgets and phantoms. All contributions were published in video format on a dedicated YouTube channel, and most were also presented in person at the conference. The fair demonstrated that there is an unmet need for sharing and distributing information on self-created solutions in the medical physics community. The authors propose the creation of a dedicated platform for sharing such content within our community, as well as a continuity of DIY-fairs at future ECMP meetings.

The influence of dual-energy computed tomography image noise in proton therapy treatment planning.

Background and purpose: In proton therapy, a 3.5% margin is often used to account for proton range uncertainties, of which computed tomography (CT) image noise is assumed to contribute 0.5%. This work evaluates the noise-sensitivity of three dual-energy computed tomography (DECT)-based methods for mapping proton stopping power relative to water (SPR): Näsmark & Andersson (N&A), Landry-Saito (L-S), and the commercial application DirectSPR. Methods and materials: DECT image data of a CIRS-062M phantom was acquired with CT scanners from two different vendors. Acquisitions were repeated 30 times to account for intra- and inter-scan variations. SPR maps were generated with the three DECT-based methods and range simulated in a commercial treatment planning system. Results: Noise in input data was amplified in L-S SPR maps, kept level with DirectSPR, while N&A compressed noise overall but displayed sensitivity to the choice of input data, potentially leading to increased noise levels. In our simulations, only N&A improved upon the assumed 0.5% noise contribution to range uncertainty on one scanner. On the other scanner, uncertainties exceeded 0.5% for all three methods. Mitigation of this issue was demonstrated by using a method employing virtual mono-energetic images as input. Increasing imaging radiation dose, as expected, alleviates the problem, while applying noise reduction only helped to a lesser extent. Conclusions: While range uncertainty due to noise is small compared to other contributions, it becomes more important as we move towards smaller treatment margins and the noise-sensitivity of SPR mapping methods should be carefully estimated and considered before clinical implementation.

Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol.

Defective LDL-C clearance and hence its elevation in the circulation is an established risk factor for cardiovascular diseases (CVDs) such as myocardial infarction (MI). A soluble LDL-receptor (sLDL-R) has been detected in human plasma which correlates strongly with circulating LDL-C and classical conditions that promote chronic inflammation. However, the mechanistic interplay between sLDL-R, inflammation, and CVDs remains to be investigated. Here, we report that stimulation of HepG2 cells with TNF-α induces the release of sLDL-R into culture supernatants. In addition, TNF-α induces gene expression of peptidases ADAM-17 and MMP-14 in HepG2 cells, and inhibiting these peptidases using TMI 1 significantly reduces the TNF-α induced sLDL-R release. We found that a soluble form of recombinant LDL-R (100 nM) can strongly bind to LDL-C and form a stable complex (KD = E-12). Moreover, incubation of HepG2 cells with this recombinant LDL-R resulted in reduced LDL-C uptake in a dose-dependent manner. In a nested case-control study, we found that baseline sLDL-R in plasma is positively correlated with plasma total cholesterol level. Furthermore, a twofold increase in plasma sLDL-R was associated with a 55% increase in the risk of future MI [AOR = 1.55 (95% CI = 1.10-2.18)]. Nevertheless, mediation analyses revealed that a significant proportion of the association is mediated by elevation in plasma cholesterol level (indirect effect ß = 0.21 (95% CI = 0.07-0.38). Collectively, our study shows that sLDL-R is induced by a pro-inflammatory cytokine TNF-α via membrane shedding. Furthermore, an increase in sLDL-R could inhibit hepatic clearance of LDL-C increasing its half-life in the circulation and contributing to the pathogenesis of MI. KEY MESSAGES: TNF-α causes shedding of hepatocytic LDL-R through induction of ADAM-17 and MMP-14. sLDL-R binds strongly to LDL-C and inhibits its uptake by hepatocytic cells. Plasma sLDL-R is positively correlated with TNF-α and cholesterol. Plasma sLDL-R is an independent predictor of myocardial infarction (MI). Plasma cholesterol mediates the association between sLDL-R and MI.

Barriers and Enablers for Implementation of an Artificial Intelligence-Based Decision Support Tool to Reduce the Risk of Readmission of Patients With Heart Failure: Stakeholder Interviews.

BACKGROUND: Artificial intelligence (AI) applications in health care are expected to provide value for health care organizations, professionals, and patients. However, the implementation of such systems should be carefully planned and organized in order to ensure quality, safety, and acceptance. The gathered view of different stakeholders is a great source of information to understand the barriers and enablers for implementation in a specific context. OBJECTIVE: This study aimed to understand the context and stakeholder perspectives related to the future implementation of a clinical decision support system for predicting readmissions of patients with heart failure. The study was part of a larger project involving model development, interface design, and implementation planning of the system. METHODS: Interviews were held with 12 stakeholders from the regional and municipal health care organizations to gather their views on the potential effects implementation of such a decision support system could have as well as barriers and enablers for implementation. Data were analyzed based on the categories defined in the nonadoption, abandonment, scale-up, spread, sustainability (NASSS) framework. RESULTS: Stakeholders had in general a positive attitude and curiosity toward AI-based decision support systems, and mentioned several barriers and enablers based on the experiences of previous implementations of information technology systems. Central aspects to consider for the proposed clinical decision support system were design aspects, access to information throughout the care process, and integration into the clinical workflow. The implementation of such a system could lead to a number of effects related to both clinical outcomes as well as resource allocation, which are all important to address in the planning of implementation. Stakeholders saw, however, value in several aspects of implementing such system, emphasizing the increased quality of life for those patients who can avoid being hospitalized. CONCLUSIONS: Several ideas were put forward on how the proposed AI system would potentially affect and provide value for patients, professionals, and the organization, and implementation aspects were important parts of that. A successful system can help clinicians to prioritize the need for different types of treatments but also be used for planning purposes within the hospital. However, the system needs not only technological and clinical precision but also a carefully planned implementation process. Such a process should take into consideration the aspects related to all the categories in the NASSS framework. This study further highlighted the importance to study stakeholder needs early in the process of development, design, and implementation of decision support systems, as the data revealed new information on the potential use of the system and the placement of the application in the care process.

Diabetes, prediabetes, and atrial fibrillation-A population-based cohort study based on national and regional registers.

BACKGROUND: Previous studies have shown an increased risk for atrial fibrillation and atrial flutter (AF) in people with type 2 diabetes and prediabetes. It is unclear whether this increase in AF risk is independent of other risk factors for AF. OBJECTIVE: To investigate the association between diabetes and different prediabetic states, as independent risk factors for the onset of AF. METHODS: We performed a population-based cohort study in Northern Sweden, including data on fasting plasma glucose, oral glucose tolerance test, major cardiovascular risk factors, medical history, and lifestyle factors. Participants were divided into six groups depending on glycemic status and followed through national registers for AF diagnosis. Cox proportional hazard model was used to assess the association between glycemic status and AF, using normoglycemia as reference. RESULTS: The cohort consisted of 88,889 participants who underwent a total of 139,661 health examinations. In the model adjusted for age and sex, there was a significant association between glycemic status and development of AF in all groups except the impaired glucose tolerance group, with the strongest association for the group with known diabetes (p-value <0.001). In a model adjusted for sex, age, systolic blood pressure, body mass index, antihypertensive drugs, cholesterol, alcohol, smoking, education level, marital status, and physical activity, there was no significant association between glycemic status and AF. CONCLUSIONS/INTERPRETATION: The association between glycemic status and AF disappears upon adjustment for potential confounders. Diabetes and prediabetes do not appear to be independent risk factors for AF.

Diabetes and heart failure associations in women and men: Results from the MORGAM consortium.

Background: Diabetes and its cardiovascular complications are a growing concern worldwide. Recently, some studies have demonstrated that relative risk of heart failure (HF) is higher in women with type 1 diabetes (T1DM) than in men. This study aims to validate these findings in cohorts representing five countries across Europe. Methods: This study includes 88,559 (51.8% women) participants, 3,281 (46.3% women) of whom had diabetes at baseline. Survival analysis was performed with the outcomes of interest being death and HF with a follow-up time of 12 years. Sub-group analysis according to sex and type of diabetes was also performed for the HF outcome. Results: 6,460 deaths were recorded, of which 567 were amongst those with diabetes. Additionally, HF was diagnosed in 2,772 individuals (446 with diabetes). A multivariable Cox proportional hazard analysis showed that there was an increased risk of death and HF (hazard ratio (HR) of 1.73 [1.58-1.89] and 2.12 [1.91-2.36], respectively) when comparing those with diabetes and those without. The HR for HF was 6.72 [2.75-16.41] for women with T1DM vs. 5.80 [2.72-12.37] for men with T1DM, but the interaction term for sex differences was insignificant (p for interaction 0.45). There was no significant difference in the relative risk of HF between men and women when both types of diabetes were combined (HR 2.22 [1.93-2.54] vs. 1.99 [1.67-2.38] respectively, p for interaction 0.80). Conclusion: Diabetes is associated with increased risks of death and heart failure, and there was no difference in relative risk according to sex.

Education and training in radiation protection in Europe: results from the EURAMED Rocc-n-Roll project survey.

PURPOSE: To analyse the existing radiation protection (RP) education and training (E&T) capabilities in the European Union and identify associated needs, problems and challenges. METHOD: An online survey was disseminated via the EURAMED Rocc-n-Roll consortium network and prominent medical societies in the field of radiological research. The survey sections analyse the RP E&T during undergraduate, residency/internship and continuous professional development; RP E&T problems and legal implementation. Differences were analysed by European geographic regions, profession, years of professional experience and main area of practice/research. RESULTS: The majority of the 550 respondents indicated that RP topics are part of undergraduate curricula in all courses for their profession and country (55%); however, hands-on practical training is not included according to 30% of the respondents. The lack of E&T, practical aspects in current E&T, and mandatory continuing E&T were considered the major problems. The legal requirement that obtained higher implementation score was the inclusion of the practical aspects of medical radiological procedures on education (86%), and lower score was obtained for the inclusion of RP E&T on medical and dental school curriculums (61%). CONCLUSIONS: A heterogeneity in RP E&T during undergraduate, residency/internship and continuous professional development is evident across Europe. Differences were noted per area of practice/research, profession, and European geographic region. A large variation in RP E&T problem rating was also obtained.

Prognostic value of early sustained ventricular arrhythmias in ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: A substudy of VALIDATE-SWEDEHEART trial.

Background: Prognostic assessment of ventricular tachycardia (VT) or ventricular fibrillation (VF) in ST-segment elevation myocardial infarction (STEMI) is based mainly on distinguishing between early (<48 hours) and late arrhythmias, and does not take into account its time distribution with regard to reperfusion, or type of arrhythmia. Objective: We analyzed the prognostic value of early ventricular arrhythmias (VAs) in STEMI with regard to their type and timing. Methods: The prespecified analysis of the multicenter prospective Bivalirudin versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarctionin Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease evaluated according to Recommended Therapies Registry Trial included 2886 STEMI patients undergoing primary percutaneous coronary intervention (PCI). VA episodes were characterized regarding their type and timing. Survival status at 180 days was assessed through the population registry. Results: Nonmonomorphic VT or VF was observed in 97 (3.4%) and monomorphic VT in 16 (0.5%) patients. Only 3 (2.7%) early VA episodes occurred after 24 hours from symptom onset. VA was associated with higher risk of death (hazard ratio 3.59; 95% confidence interval [CI] 2.01-6.42) after adjustment for age, sex, and STEMI localization. VA after PCI was associated with an increased mortality compared with VA before PCI (hazard ratio 6.68; 95% CI 2.90-15.41). Early VA was associated with in-hospital mortality (odds ratio 7.39; 95% CI 3.68-14.83) but not with long-term prognosis in patients discharged alive. The type of VA was not associated with mortality. Conclusion: VA after PCI was associated with an increased mortality compared with VA before PCI. Long-term prognosis did not differ between patients with monomorphic VT and nonmonomorphic VT or VF, but events were few. VA incidence during 24 to 48 hours of STEMI is negligibly low, thus precluding assessment of its prognostic importance.

CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women.

OBJECTIVES: Cystathionine-gamma-lyase (CSE) in the transsulfuration pathway generates hydrogen sulfide (H2S), suggested regulating cardiovascular function. The G1208T polymorphism in the CTH gene, rs1021737, has, in addition to MTHFR, been found to increase homocysteine, related to myocardial infarction (MI) risk. This study aimed, for the first time, to investigate the associations of the polymorphisms CTH G1208T, MTHFR C677T, and A1298C with the prospective risk of developing a fatal or non-fatal first MI. METHODS: This case-referent study included 545 cases later developing a first-ever MI and 1,054 referents from the Northern Sweden Health and Disease Study. Fatal MI was defined as death within 28 days after MI symptoms. RESULTS: Women, but not men, had a positive association between fatal MI and the CTH G1208T, odds ratio [95% confidence interval] 3.14 [1.16-8.54] for heterozygotes, and the dominant model 3.22 [1.22-8.51], and for the MTHFR A1298C heterozygotes 3.24 [1.26-8.34] and the dominant model 2.63 [1.06-6.50]. The MTHFR C677T polymorphism was not related to MI. CONCLUSIONS: This study indicates that the minor alleles of CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk for a fatal MI among women but not for non-fatal MI. No association was found in men.

Education and training in radiation protection in Europe: an analysis from the EURAMED rocc-n-roll project.

BACKGROUND: A Strengths, weaknesses, opportunities and threats analysis was performed to understand the status quo of education and training in radiation protection (RP) and to develop a coordinated European approach to RP training needs based on stakeholder consensus and existing activities in the field. Fourteen team members represented six European professional societies, one European voluntary organisation, two international healthcare organisations and five professions, namely: Medical Physicists; Nuclear Medicine Physicians; Radiologists; Radiation Oncologists and Radiographers. Four subgroups analysed the "Strengths", "Weaknesses", "Opportunities" and "Threats" related to E&T in RP developed under previous European Union (EU) programmes and on the Guidelines on Radiation Protection Education and Training of Medical Professionals in the EU. RESULTS: Consensus agreement identified four themes for strengths and opportunities, namely: (1) existing structures and training recommendations; (2) RP training needs assessment and education & training (E&T) model(s) development; (3) E&T dissemination, harmonisation, and accreditation; (4) financial supports. Weaknesses and Threats analysis identified two themes: (1) awareness and prioritisation at a national/global level and (2) awareness and prioritisation by healthcare professional groups and researchers. CONCLUSIONS: A lack of effective implementation of RP principles in daily practice was identified. EuRnR strategic planning needs to consider processes at European, national and local levels. Success is dependent upon efficient governance structures and expert leadership. Financial support is required to allow the stakeholder professional agencies to have sufficient resources to achieve a pan European radiation protection training network which is sustainable and accredited across multiple national domains.

An observational pilot study: Prevalence and cost of high frequency emergency department users at Örebro University Hospital, Sweden.

BACKGROUND: There is little research on high frequency emergency department users (HEDU) in Sweden. We aim to determine the prevalence and costs of HEDU compared to non-HEDU at Örebro University Hospital (ÖUH). Additionally, we will determine the factors and outcomes associated with being a HEDU. METHODS: This was a retrospective, observational cohort study of ED patients presenting to ÖUH, Sweden between 2018-19. Analyses used electronic registry, ambulance, and cost data. The definition for HEDU was ≥4 visits/year. HEDUs were categorized further into Repeat, High and Super HEDU with 4-7, 8-18 and ≥19 visits/year, respectively. We used multivariable logistic regression to determine the adjusted odds ratios for factors and outcomes between HEDU and non-HEDU. FINDINGS: Of all ÖUH ED patients, 6.1% were HEDU and accounted for 22.4% of ED visits and associated costs. Compared to the mean cost of non-HEDU, the Repeat, High and Super HEDU were more costly by factors of 4, 8 and 27, respectively. The HEDUs were more likely to be male, self-referred, present with abdominal pain, arrive by ambulance, at night and from the Örebro municipal region. Super HEDU were more likely to be of adult age and assigned lower acuity scores. HEDU were more likely to be directed to the surgical zone, less likely to receive radiologic imaging or achieve a 4-hr time target. In contrast to the Repeat and High HEDU, Super HEDU were less likely to be admitted, but more likely to leave without being seen. CONCLUSION: ÖUH has a HEDU population with associated factors and outcomes. They account for a substantial proportion of ED costs compared to non-HEDU.

Leukotriene A4 Hydrolase and Hepatocyte Growth Factor Are Risk Factors of Sudden Cardiac Death Due to First-Ever Myocardial Infarction.

Patients at a high risk for sudden cardiac death (SCD) without previous history of cardiovascular disease remain a challenge to identify. Atherosclerosis and prothrombotic states involve inflammation and non-cardiac tissue damage that may play active roles in SCD development. Therefore, we hypothesized that circulating proteins implicated in inflammation and tissue damage are linked to the future risk of SCD. We conducted a prospective nested case-control study of SCD cases with verified myocardial infarction (N = 224) and matched controls without myocardial infarction (N = 224), aged 60 ± 10 years time and median time to event was 8 years. Protein concentrations (N = 122) were measured using a proximity extension immunoassay. The analyses revealed 14 proteins significantly associated with an increased risk of SCD, from which two remained significant after adjusting for smoking status, systolic blood pressure, BMI, cholesterol, and glucose levels. We identified leukotriene A4 hydrolase (LTA4H, odds ratio 1.80, corrected confidence interval (CIcorr) 1.02-3.17) and hepatocyte growth factor (HGF; odds ratio 1.81, CIcorr 1.06-3.11) as independent risk markers of SCD. Elevated LTA4H may reflect increased systemic and pulmonary neutrophilic inflammatory processes that can contribute to atherosclerotic plaque instability. Increased HGF levels are linked to obesity-related metabolic disturbances that are more prevalent in SCD cases than the controls.

An experimental and theoretical characterization of the electronic structure of doubly ionised disulfur.

Using time-of-flight multiple electron and ion coincidence techniques in combination with a helium gas discharge lamp and synchrotron radiation, the double ionisation spectrum of disulfur (S[Formula: see text]) and the subsequent fragmentation dynamics of its dication are investigated. The S[Formula: see text] sample was produced by heating mercury sulfide (HgS), whose vapour at a suitably chosen temperature consists primarily of two constituents: S[Formula: see text] and atomic Hg. A multi-particle-coincidence technique is thus particularly useful for retrieving spectra of S[Formula: see text] from ionisation of the mixed vapour. The results obtained are compared with detailed calculations of the electronic structure and potential energy curves of S[Formula: see text] which are also presented. These computations are carried out using configuration interaction methodology. The experimental results are interpreted with and strongly supported by the computational results.

Rationale and design of switch Swedeheart: A registry-based, stepped-wedge, cluster-randomized, open-label multicenter trial to compare prasugrel and ticagrelor for treatment of patients with acute coronary syndrome.

BACKGROUND: European treatment guidelines recommend prasugrel over ticagrelor for treating patients with non-ST-elevation acute coronary syndrome (ACS), prompting several Swedish administrative regions to transition from ticagrelor to prasugrel as the preferred treatment for patients with ACS. We aim to systematically evaluate this transition to determine the relative efficacy of prasugrel versus ticagrelor in a real-world cohort of patients with ACS. STUDY DESIGN AND OBJECTIVES: The SWITCH SWEDEHEART trial is a prospective, multicenter, open-label, cross-sectional, stepped-wedge cluster-randomized clinical trial, in which administrative regions in Sweden will constitute the clusters. At the start of the study, all clusters will use ticagrelor as the P2Y12 inhibitor drug of choice for ACS. The order in which the clusters will implement the transition from ticagrelor to prasugrel will be randomly assigned. Every 9 months, 1 cluster will switch from ticagrelor to prasugrel as the P2Y12 inhibitor of choice for patients with ACS. The primary endpoint is the composite 1-year rate of the death, stroke, or myocardial infarction. CONCLUSIONS: The SWITCH SWEDEHEART study will provide an extensive randomized comparison between ticagrelor and prasugrel. Novel therapies are frequently costly and supported by evidence from few or small studies, and systematic evaluation after the introduction is rare. This study will establish an important standard for introducing and evaluating the effects of health care changes within our societies.

Physical activity attenuates but does not eliminate coronary heart disease risk amongst adults with risk factors: EPIC-CVD case-cohort study.

AIMS: This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. METHODS AND RESULTS: EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal).Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32-64%] and 21% (95%CI 2-44%), with hypercholesterolaemia were 80% (95%CI 55-108%) and 48% (95%CI 22-81%), with hypertension were 80% (95%CI 65-96%) and 49% (95%CI 28-74%), with diabetes were 142% (95%CI 63-260%), and 100% (95%CI 32-204%), and amongst smokers were 152% (95%CI 122-186%) and 109% (95%CI 74-150%). CONCLUSIONS: In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.

Interactions Between Heavy Trucks and Vulnerable Road Users-A Systematic Review to Inform the Interactive Capabilities of Highly Automated Trucks.

This study investigates interactive behaviors and communication cues of heavy goods vehicles (HGVs) and vulnerable road users (VRUs) such as pedestrians and cyclists as a means of informing the interactive capabilities of highly automated HGVs. Following a general framing of road traffic interaction, we conducted a systematic literature review of empirical HGV-VRU studies found through the databases Scopus, ScienceDirect and TRID. We extracted reports of interactive road user behaviors and communication cues from 19 eligible studies and categorized these into two groups: 1) the associated communication channel/mechanism (e.g., nonverbal behavior), and 2) the type of communication cue (implicit/explicit). We found the following interactive behaviors and communication cues: 1) vehicle-centric (e.g., HGV as a larger vehicle, adapting trajectory, position relative to the VRU, timing of acceleration to pass the VRU, displaying information via human-machine interface), 2) driver-centric (e.g., professional driver, present inside/outside the cabin, eye-gaze behavior), and 3) VRU-centric (e.g., racer cyclist, adapting trajectory, position relative to the HGV, proximity to other VRUs, eye-gaze behavior). These cues are predominantly based on road user trajectories and movements (i.e., kinesics/proxemics nonverbal behavior) forming implicit communication, which indicates that this is the primary mechanism for HGV-VRU interactions. However, there are also reports of more explicit cues such as cyclists waving to say thanks, the use of turning indicators, or new types of external human-machine interfaces (eHMI). Compared to corresponding scenarios with light vehicles, HGV-VRU interaction patterns are to a high extent formed by the HGV's size, shape and weight. For example, this can cause VRUs to feel less safe, drivers to seek to avoid unnecessary decelerations and accelerations, or lead to strategic behaviors due to larger blind-spots. Based on these findings, it is likely that road user trajectories and kinematic behaviors will form the basis for communication also for highly automated HGV-VRU interaction. However, it might also be beneficial to use additional eHMI to compensate for the loss of more social driver-centric cues or to signal other types of information. While controlled experiments can be used to gather such initial insights, deeper understanding of highly automated HGV-VRU interactions will also require naturalistic studies.