Dissecting the etiology of atrial fibrillation:A population perspective on risk factors and sex differences

In this thesis we examined various risk factors and sex differences and their influence on the atrial fibrillation development in the general population. We found that vascular-, cardiac autonomic-, inflammatory-, traditional-, novel-, and sex-specific risk factors are implicated in the etiology of atrial fibrillation

Perspectives on Sex- and Gender-Specific Prediction of New-Onset Atrial Fibrillation by Leveraging Big Data

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, has a large impact on quality of life and is associated with increased risk of hospitalization, morbidity, and mortality. Over the past two decades advances regarding the clinical epidemiology and management of AF have been established. Moreover, sex differences in the prevalence, incidence, prediction, pathophysiology, and prognosis of AF have been identified. Nevertheless, AF remains to be a complex and heterogeneous disorder and a comprehensive sex- and gender-specific approach to predict new-onset AF is lacking. The exponential growth in various sources of big data such as electrocardiograms, electronic health records, and wearable devices, carries the potential to improve AF risk prediction. Leveraging these big data sources by artificial intelligence (AI)-enabled approaches, in particular in a sex- and gender-specific manner, could lead to substantial advancements in AF prediction and ultimately prevention. We highlight the current status, premise, and potential of big data to improve sex- and gender-specific prediction of new-onset AF

Circulating metabolites associated with kidney function decline and incident CKD:a multi-platform population-based study

Background. Investigation of circulating metabolites associated with kidney function and chronic kidney disease (CKD) risk could enhance our understanding of underlying pathways and identify new biomarkers for kidney function. Methods. We selected participants from the population-based Rotterdam Study with data on circulating metabolites and estimated glomerular filtration rate based on serum creatinine (eGFRcreat) available at the same time point. Data on eGFR based on serum cystatin C (eGFRcys) and urine albumin-to-creatinine ratio (ACR) were also included. CKD was defined as eGFRcreat &lt;60 ml/min per 1.73 m2. Data on circulating metabolites (ntotal = 1381) was obtained from the Nightingale and Metabolon platform. Linear regression, linear mixed, and Cox proportional-hazards regression analyses were conducted to study the associations between metabolites and kidney function. We performed bidirectional two-sample Mendelian randomization analyses to investigate causality of the identified associations. Results. We included 3337 and 1540 participants with data from Nightingale and Metabolon, respectively. A total of 1381 metabolites (243 from Nightingale and 1138 from Metabolon) were included in the analyses. A large number of metabolites were significantly associated with eGFRcreat, eGFRcys, ACR, and CKD, including 16 metabolites that were associated with all four outcomes. Among these, C-glycosyltryptophan (HR 1.50, 95%CI 1.31;1.71) and X-12026 (HR 1.46, 95%CI 1.26;1.68) were most strongly associated with CKD risk. We revealed sex differences in the associations of 11-ketoetiocholanolone glucuronide and 11-beta-glucuronide with the kidney function assessments. No causal associations between the identified metabolites and kidney function were observed. Conclusion. Our study indicates that several circulating metabolites are associated with kidney function which are likely to have potential as biomarkers, rather than as molecules involved in the pathophysiology of kidney function decline.</p

Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4

AbstractMast cells (MCs) are found abundantly in the central nervous system and play a complex role in neuroinflammatory diseases such as multiple sclerosis and stroke. In the present study, we show that MC-deficient KitW-sh/W-sh mice display significantly increased astrogliosis and T cell infiltration as well as significantly reduced functional recovery after spinal cord injury compared to wildtype mice. In addition, MC-deficient mice show significantly increased levels of MCP-1, TNF-α, IL-10 and IL-13 protein levels in the spinal cord. Mice deficient in mouse mast cell protease 4 (mMCP4), an MC-specific chymase, also showed increased MCP-1, IL-6 and IL-13 protein levels in spinal cord samples and a decreased functional outcome after spinal cord injury. A degradation assay using supernatant from MCs derived from either mMCP4−/− mice or controls revealed that mMCP4 cleaves MCP-1, IL-6, and IL-13 suggesting a protective role for MC proteases in neuroinflammation. These data show for the first time that MCs may be protective after spinal cord injury and that they may reduce CNS damage by degrading inflammation-associated cytokines via the MC-specific chymase mMCP4

Evidence for Regulated Interleukin-4 Expression in Chondrocyte-Scaffolds under In Vitro Inflammatory Conditions

OBJECTIVE: To elucidate the anti-inflammatory and anabolic effects of regulated expression of IL-4 in chondrocyte-scaffolds under in vitro inflammatory conditions. METHODS: Mature articular chondrocytes from dogs (n = 3) were conditioned through transient transfection using pcDNA3.1.cIL-4 (constitutive) or pCOX-2.cIL-4 (cytokine-responsive) plasmids. Conditioned cells were seeded in alginate microspheres and rat-tail collagen type I matrix (CaReS®) to generate two types of tissue-engineered 3-dimensional scaffolds. Inflammatory arthritis was simulated in the packed chondrocytes through exogenous addition of recombinant canine (rc) IL-1β (100 ng/ml) plus rcTNFα (50 ng/ml) in culture media for 96 hours. Harvested cells and culture media were analyzed by various assays to monitor the anti-inflammatory and regenerative (anabolic) properties of cIL-4. RESULTS: cIL-4 was expressed from COX-2 promoter exclusively on the addition of rcIL-1β and rcTNFα while its expression from CMV promoter was constitutive. The expressed cIL-4 downregulated the mRNA expression of IL-1β, TNFα, IL-6, iNOS and COX-2 in the cells and inhibited the production of NO and PGE(2) in culture media. At the same time, it up-regulated the expression of IGF-1, IL-1ra, COL2a1 and aggrecan in conditioned chondrocytes in both scaffolds along with a diminished release of total collagen and sGAG into the culture media. An increased amount of cIL-4 protein was detected both in chondrocyte cell lysate and in concentrated culture media. Neutralizing anti-cIL-4 antibody assay confirmed that the anti-inflammatory and regenerative effects seen are exclusively driven by cIL-4. There was a restricted expression of IL-4 under COX-2 promoter possibly due to negative feedback loop while it was over-expressed under CMV promoter (undesirable). Furthermore, the anti-inflammatory /anabolic outcomes from both scaffolds were reproducible and the therapeutic effects of cIL-4 were both scaffold- and promoter-independent. CONCLUSIONS: Regulated expression of therapeutic candidate gene(s) coupled with suitable scaffold(s) could potentially serve as a useful tissue-engineering tool to devise future treatment strategies for osteoarthritis

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI