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Stress-induced release of the S100A8/A9 alarmin is elevated in coronary artery disease patients with impaired cortisol response

Psychological stress is thought to be an important trigger of cardiovascular events, yet the involved pathways and mediators are largely unknown. Elevated systemic levels of the pro-inflammatory alarmin S100A8/A9 correlate with poor prognosis in coronary artery disease (CAD) patients. Here, we investigated the links between S100A8/A9 release and parameters of anti-inflammatory glucocorticoid secre

Re-evaluation of HER2 status in 606 breast cancers—gene protein assay on tissue microarrays versus routine pathological assessment

Human epidermal growth factor receptor 2 (HER2) status in breast cancer is routinely determined through immunohistochemistry (IHC) and/or in situ hybridisation (ISH) performed on whole tissue sections (WS). The purpose was to evaluate whether a gene protein assay (GPA) combining IHC with ISH, performed on breast cancer tissue microarray (TMA), is suitable for large-scale retrospective HER2 status

Desloratadine and loratadine stand out among common H1-antihistamines for association with improved breast cancer survival

Background: As tumors maintain an inflammatory microenvironment, anti-inflammatory medication can be useful in cancer therapy. We have previously shown an association with improved survival in melanoma for use of the H1-antihistamines desloratadine and loratadine, and here we examine use of H1-antihistamines and breast cancer mortality.Material and methods: We investigated use of the six major H1-

Echocardiographic predictors of recoarctation following surgical repair – a Swedish national study

Background Following surgical repair of aortic coarctation (CoA) there is a risk for restenosis (reCoA), particularly in the first year of life. It was the aim of this study to identify reCoA risk factors by analyzing postoperative pre-discharge echocardiograms. Methods Retrospective analysis of echocardiograms of children born operated for CoA in Sweden 2011-2017. Results 253 children were includ

Probabilistic Quantification Of Bias to Combine the Strengths Of Population-Based Register Data and Clinical Cohorts - Studying Mortality in Osteoarthritis

We propose to combine population-based register data, with a nested clinical cohort to correct misclassification and unmeasured confounding through probabilistic quantification of bias. We illustrate this approach by estimating the association between knee osteoarthritis and mortality. We used the Swedish Population Register to include all persons resident in the Skåne region in 2008 and assessed

The effect of LRRK2 loss-of-function variants in humans

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, su

Evaluating drug targets through human loss-of-function genetic variation

Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants

Transcript expression-aware annotation improves rare variant interpretation

The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of puta

A structural variation reference for medical and population genetics

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide v

The mutational constraint spectrum quantified from variation in 141,456 humans

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors,

The effect of clinical features and glucocorticoids on biopsy findings in giant cell arteritis

Background: To investigate the effect of baseline clinical characteristics and glucocorticoid treatment on temporal artery biopsy (TAB) findings in patients with giant cell arteritis (GCA). Methods: Individuals who developed GCA after inclusion in two population-based health surveys were identified through linkage to the local and the national patient registers. In addition, other patients diagnos

Variations in pain and function before and after total knee arthroplasty : A comparison between Swedish and Australian cohorts

Objective: Preoperative pain and function is viewed as an important predictor of total knee arthroplasty (TKA) outcomes. We examined whether variations in pain and function outcomes existed at 12 months between two centres in Sweden and Australia, and whether this was explained by variations in patient presentation for TKA. Methods: This was a retrospective analysis of prospectively collected data

A law and economics analysis of corporate opportunities doctrines from a comparative perspective

Business opportunities are a chance for a company to grow its activity and to further the aggregate welfare of the society as a whole. Corporate opportunities rules and their functional equivalents should enable companies to develop their business activities when directors discover those business opportunities. Companies need to be certain that they can legally appropriate those business opportuni

A new approach for ratiometric in vivo calcium imaging of microglia

Microglia, resident immune cells of the brain, react to the presence of pathogens/danger signals with a large repertoire of functional responses including morphological changes, proliferation, chemotaxis, production/release of cytokines, and phagocytosis. In vitro studies suggest that many of these effector functions are Ca2+-dependent, but our knowledge about in vivo Ca2+ signalling in microglia

Small airway involvement in the late allergic response in asthma

Background: Allergy and asthma are closely linked. Inhalation of allergen induces an early allergic response (EAR) within the airways of allergic asthmatic subjects, which is followed by a late allergic response (LAR) in approximately 50% of the subjects. The LAR is defined as a drop in forced expiratory volume in 1 second (FEV1) from baseline usually occurring 4-8 hours after exposure and is beli

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we

Work disability in non-radiographic axial spondyloarthritis patients before and after start of anti-TNF therapy : A population-based regional cohort study from southern Sweden

Objective. The aim was to assess work-loss days before and after commencement of anti-TNF treatment in patients with non-radiographic axial spondylarthritis (nr-axSpA). Methods. Bionaïve nr-axSpA patients (n = 75), aged 17-62 years, fulfilling the Assessment of SpondyloArthritis international Society criteria for axial spondyloarthritis and starting anti-TNF treatment during 2004-11, were retrieve

The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease : a population based cohort study

BACKGROUND: Chromosome 9p21 variants are associated with cardiovascular disease (CVD) but not with any of its known risk markers. However, recent studies have suggested that the risk associated with 9p21 variation is modified by a prudent dietary pattern and smoking. We tested if the increased risk of CVD by the 9p21 single nucleotide polymorphism rs4977574 is modified by intakes of vegetables, fr

Deposition efficiency of inhaled particles (15-5000 nm) related to breathing pattern and lung function : An experimental study in healthy children and adults

Background: Exposure to airborne particles has a major impact on global health. The probability of these particles to deposit in the respiratory tract during breathing is essential for their toxic effects. Observations have shown that there is a substantial variability in deposition between subjects, not only due to respiratory diseases, but also among individuals with healthy lungs. The factors d