Showing papers by "Medical University of Graz published in 2014"
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
1,872 citations
Valentina Escott-Price1, Céline Bellenguez2, Li-San Wang3, Seung Hoan Choi4 +191 more•Institutions (67)
TL;DR: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimers disease.
Abstract: Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This s ...
1,518 citations
Charité1, Medical University of Graz2, University of Southern Denmark3, Medical University of Silesia4, University of Genoa5, Federal University of São Paulo6, Autonomous University of Barcelona7, University of Coimbra8, St. John's University9, Hiroshima University10, Medical University of South Carolina11, Hannover Medical School12, Hospital Kuala Lumpur13, Johns Hopkins University14, University of Zurich15, University of Manitoba16, University of Mainz17, University of Toronto18, Technion – Israel Institute of Technology19, University of Bari20, Peking University21
TL;DR: This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms, and outlines evidence-based diagnostic and therapeutic approaches for the different subtypes ofUrticaria.
Abstract: This guideline is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The life-time prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).
1,150 citations
Pierre-and-Marie-Curie University1, Paris Descartes University2, French Institute of Health and Medical Research3, University of Bern4, University of Erlangen-Nuremberg5, Providence Portland Medical Center6, Radboud University Nijmegen7, Umeå University8, Karolinska Institutet9, Humanitas University10, Medical University of Graz11, Dorset County Hospital NHS Foundation Trust12, Charles University in Prague13, Cornell University14, University Health Network15, University of Toronto16, Keio University17, Yamaguchi University18, Kindai University19, Harvard University20, Royal Melbourne Hospital21, University of Melbourne22, Sapporo Medical University23, Kurume University24, Xi'an Jiaotong University25, University of Texas MD Anderson Cancer Center26, Mayo Clinic27, Grigore T. Popa University of Medicine and Pharmacy28, Oregon Health & Science University29
TL;DR: In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC or UICCTNM classification.
Abstract: The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named 'Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
1,128 citations
TL;DR: Strain imaging detects impaired systolic function despite preserved global LVEF inHFpEF that may contribute to the pathophysiology of the HFpEF syndrome.
577 citations
Karolinska Institutet1, University of Pisa2, University of Crete3, University College London4, University of Münster5, Dresden University of Technology6, University of Groningen7, University of Manchester8, McGill University9, University of Pécs10, University Medical Center Utrecht11, Charité12, University of Birmingham13, Medical University of Graz14, Université catholique de Louvain15, Istanbul University16, Copenhagen University Hospital17, Rio de Janeiro State University18, University of Paris-Sud19, University of Santo Tomas Hospital20, Medical University of Vienna21, VU University Amsterdam22, Odense University Hospital23, Moscow State University24, Hairmyres Hospital25, University of Düsseldorf26
TL;DR: Treating-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative and it is anticipated that ‘treating- to-target’ can and will be applicable to the care of patients with SLE.
Abstract: The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.
521 citations
University of Milan1, Medical University of Graz2, Harvard University3, Technische Universität München4, University of Cincinnati Academic Health Center5, University of Mainz6, Semmelweis University7, Medical University of South Carolina8, University of California, San Diego9, University of Salerno10
TL;DR: Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting.
Abstract: Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.
510 citations
TL;DR: It is shown that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern and may serve as therapeutic targets for metastatic spitzoids melanomas.
Abstract: Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas. Spitzoid neoplasms constitute a spectrum of melanocytic tumours, characterized by distinct clinical, pathological and genetic features. Here, Wiesner et al. show that kinase fusions represent the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanoma.
486 citations
University of Amsterdam1, University of Verona2, University of Milan3, Karolinska University Hospital4, Mayo Clinic5, Heidelberg University6, Trinity College, Dublin7, University of Barcelona8, Medical University of Graz9, National and Kapodistrian University of Athens10, Technische Universität München11, Harvard University12, University of Belgrade13, University of Liverpool14, Tata Memorial Hospital15, University of Pennsylvania16, Thomas Jefferson University17, Freeman Hospital18
TL;DR: Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1,12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b, for cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard.
484 citations
University of Helsinki1, Maastricht University2, University of Texas Southwestern Medical Center3, Columbia University4, University of Gothenburg5, Concord Repatriation General Hospital6, University of Manitoba7, University of Bonn8, Heidelberg University9, Medical University of Graz10, University of Bern11, Lille University of Science and Technology12, University of Milan13, Ghent University14, University College London15, University of Naples Federico II16, Hacettepe University17, French Institute of Health and Medical Research18
TL;DR: Functional foods with plant sterols/stanols may be considered in individuals with high cholesterol levels at intermediate or low global cardiovascular risk who do not qualify for pharmacotherapy and as an adjunct to pharmacologic therapy in high and very high risk patients who fail to achieve LDL-C targets on statins or are statin- intolerant.
406 citations
TL;DR: It is shown that nutrient starvation causes rapid depletion of AcCoA, and multiple distinct manipulations designed to increase or reduce cytosolic Ac CoA led to the suppression or induction of autophagy, respectively, both in cultured human cells and in mice, delineating Ac coenzyme A-centered pharmacological strategies that allow for the therapeutic manipulation ofautophagy.
TL;DR: This paper aims to provide a review of the history and status quo of Chinese, Indian, and Arabic herbal medicines in terms of their significant contribution to the health promotion in present-day over-populated and aging societies.
Abstract: In recent years, increasing numbers of people have been choosing herbal medicines or products to improve their health conditions, either alone or in combination with others. Herbs are staging a comeback and herbal "renaissance" occurs all over the world. According to the World Health Organization, 75% of the world's populations are using herbs for basic healthcare needs. Since the dawn of mankind, in fact, the use of herbs/plants has offered an effective medicine for the treatment of illnesses. Moreover, many conventional/pharmaceutical drugs are derived directly from both nature and traditional remedies distributed around the world. Up to now, the practice of herbal medicine entails the use of more than 53,000 species, and a number of these are facing the threat of extinction due to overexploitation. This paper aims to provide a review of the history and status quo of Chinese, Indian, and Arabic herbal medicines in terms of their significant contribution to the health promotion in present-day over-populated and aging societies. Attention will be focused on the depletion of plant resources on earth in meeting the increasing demand for herbs.
TL;DR: Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides are likely to emerge as neural and endocrine messengers in orchestrating the microbiota-gut-brain axis in health and disease.
Abstract: Neuropeptides are important mediators both within the nervous system and between neurons and other cell types. Neuropeptides such as substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. Current efforts in elucidating the implication of neuropeptides in the microbiota-gut-brain axis address four information carriers from the gut to the brain (vagal and spinal afferent neurons; immune mediators such as cytokines; gut hormones; gut microbiota-derived signalling molecules) and four information carriers from the central nervous system to the gut (sympathetic efferent neurons; parasympathetic efferent neurons; neuroendocrine factors involving the adrenal medulla; neuroendocrine factors involving the adrenal cortex). Apart from operating as neurotransmitters, many biologically active peptides also function as gut hormones. Given that neuropeptides and gut hormones target the same cell membrane receptors (typically G protein-coupled receptors), the two messenger roles often converge in the same or similar biological implications. This is exemplified by NPY and peptide YY (PYY), two members of the PP-fold peptide family. While PYY is almost exclusively expressed by enteroendocrine cells, NPY is found at all levels of the gut-brain and brain-gut axis. The function of PYY-releasing enteroendocrine cells is directly influenced by short chain fatty acids generated by the intestinal microbiota from indigestible fibre, while NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour. Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides are likely to emerge as neural and endocrine messengers in orchestrating the microbiota-gut-brain axis in health and disease.
Queen Elizabeth Hospital Birmingham1, Medical University of Vienna2, Leiden University3, University of La Laguna4, University of Copenhagen5, University of Pisa6, National Research Council7, University of Michigan8, Osaka University9, Charité10, Medical University of Graz11, Pompeu Fabra University12, University of Glasgow13, University of Groningen14, University of Oslo15
TL;DR: A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation as mentioned in this paper, where 24 transplant nephrologists, surgeons, diabetologists and clinical scientists met with the aim to review previous guidelines in light of emerging clinical data and research.
TL;DR: The process of idea generation can be generally understood as a state of focused internally-directed attention involving controlled semantic retrieval and left inferior parietal cortex and left prefrontal regions may subserve the flexible integration of previous knowledge for the construction of new and creative ideas.
UCL Institute of Child Health1, University of Reading2, University of Tromsø3, German Cancer Research Center4, Boston University5, University of Oulu6, Imperial College London7, University of Groningen8, University of Helsinki9, Sahlgrenska University Hospital10, University College London11, King's College London12, George Washington University13, Wake Forest University14, University of Copenhagen15, Gentofte Hospital16, University of Exeter17, Trinity College, Dublin18, University of Edinburgh19, Ludwig Maximilian University of Munich20, University of Oxford21, Wellcome Trust Centre for Human Genetics22, Oulu University Hospital23, National Institutes of Health24, Finnish Institute of Occupational Health25, Heidelberg University26, University of Southampton27, Turku University Hospital28, University of Turku29, VU University Amsterdam30, Aarhus University Hospital31, University of Bristol32, Uppsala University33, Science for Life Laboratory34, University of Split35, Lund University36, Frederiksberg Hospital37, Harvard University38, University of Tampere39, Synlab Group40, Medical University of Graz41, Vanderbilt University42, GlaxoSmithKline43, University of South Australia44
TL;DR: In this article, the authors used a mendelian randomisation approach to test whether low plasma 25-hydroxyvitamin D (25[OH]D) concentration is causally associated with blood pressure and hypertension risk.
TL;DR: The results of the primary analysis constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC, and a 10-year metastasis risk of <3.5% makes it unlikely that additional chemotherapy would improve this outcome.
University of Oslo1, Norwegian University of Science and Technology2, University of East Anglia3, University of Gothenburg4, University of Toronto5, Medical University of Lublin6, University of Geneva7, Boston Children's Hospital8, University of Belgrade9, Royal Hospital for Women10, Ljubljana University Medical Centre11, Medical University of Graz12, Norwegian Institute of Public Health13
TL;DR: The majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy, and there was a substantial inter-region variability in the types of medication used.
Abstract: Objectives Intercountry comparability between studies on medication use in pregnancy is difficult due to dissimilarities in study design and methodology. This study aimed to examine patterns and factors associated with medications use in pregnancy from a multinational perspective, with emphasis on type of medication utilised and indication for use. Design Cross-sectional, web-based study performed within the period from 1 October 2011 to 29 February 2012. Uniform collection of drug utilisation data was performed via an anonymous online questionnaire. Setting Multinational study in Europe (Western, Northern and Eastern), North and South America and Australia. Participants Pregnant women and new mothers with children less than 1 year of age. Primary and secondary outcome measures Prevalence of and factors associated with medication use for acute/short-term illnesses, chronic/long-term disorders and over-the-counter (OTC) medication use. Results The study population included 9459 women, of which 81.2% reported use of at least one medication (prescribed or OTC) during pregnancy. Overall, OTC medication use occurred in 66.9% of the pregnancies, whereas 68.4% and 17% of women reported use of at least one medication for treatment of acute/short-term illnesses and chronic/long-term disorders, respectively. The extent of self-reported medicated illnesses and types of medication used by indication varied across regions, especially in relation to urinary tract infections, depression or OTC nasal sprays. Women with higher age or lower educational level, housewives or women with an unplanned pregnancy were those most often reporting use of medication for chronic/long-term disorders. Immigrant women in Western (adjusted OR (aOR): 0.55, 95% CI 0.34 to 0.87) and Northern Europe (aOR: 0.50, 95% CI 0.31 to 0.83) were less likely to report use of medication for chronic/long-term disorders during pregnancy than non-immigrants. Conclusions In this study, the majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy. There was a substantial inter-region variability in the types of medication used.
VU University Medical Center1, Cardiff University2, University of Navarra3, Brigham and Women's Hospital4, University of Oslo5, University of Milan6, University Health System7, Charité8, University of Brescia9, University of Michigan10, University of Göttingen11, University of Perugia12, University of Warwick13, Monash University14, Athens State University15, Northwestern University16, Boston University17, Campbell University18, Medical University of Graz19
TL;DR: To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials.
Abstract: The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.
Emory University1, University of California, Los Angeles2, Medical University of South Carolina3, University Health System4, Bayer Corporation5, University of Pittsburgh6, Northwestern University7, University of Alabama at Birmingham8, Castle Hill Hospital9, Janssen Pharmaceutica10, Vanderbilt University11, Center for Drug Evaluation and Research12, Athens State University13, Novartis14, British Heart Foundation15, University of Brescia16, Duke University17, Harvard University18, Medical University of Graz19, University of Michigan20, Henry Ford Hospital21, University of California, San Francisco22
TL;DR: To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies.
Abstract: The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.
Leipzig University1, Odense University Hospital2, Université libre de Bruxelles3, Universidade Federal do Estado do Rio de Janeiro4, University Health Network5, Nottingham University Hospitals NHS Trust6, Ege University7, Ankara University8, Université de Montréal9, Universidade Federal do Rio Grande do Sul10, Federal University of Rio de Janeiro11, Hannover Medical School12, University of Plymouth13, University of New South Wales14, Cairo University15, Örebro University16, Ain Shams University17, Dokuz Eylül University18, Karolinska University Hospital19, Federal University of São Paulo20, Carlos III Health Institute21, University of Copenhagen22, State University of Campinas23, University of São Paulo24, Medical University of Vienna25, Masaryk University26, University of Manitoba27, Istanbul University28, University of British Columbia29, Aalborg University30, Katholieke Universiteit Leuven31, University of Western Ontario32, University of Düsseldorf33, University of Zurich34, University of Calgary35, Geneva College36, Queen Elizabeth II Health Sciences Centre37, Dalhousie University38, Monash University39, University College London40, Goethe University Frankfurt41, University of St. Gallen42, Université catholique de Louvain43, Medical University of Graz44, University of Melbourne45, Charles University in Prague46, Ghent University Hospital47, University of Hasselt48, Ghent University49, Copenhagen University Hospital50, University of Antwerp51, Karolinska Institutet52
TL;DR: In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use, and Diagnosis, treatment and transplant levels also differed considerably between countries.
Abstract: Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6,358,000 cases in 2008 and Brazil with 2,106,000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.
TL;DR: Additional determination of NO metabolites, BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.
Abstract: Core tip: Crosstalk between a number of pathways involved in the regulation of immune and endothelial homeostasis is strongly coordinated by redox processes. Underlying molecular mechanisms of atherogenesis include metabolic imbalances that are linked to the onset and progression of endothelial dysfunction and inflammation, finally leading to a status of heightened oxidative stress. Decrease of plasma antioxidants may develop secondarily due to an increased demand for oxidation-sensitive vitamins during inflammation. Antioxidant and vitamin supplementation therapy is controversially discussed and success might depend of an individual patient’s demand.
TL;DR: The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients and the results suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy.
Abstract: The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer
TL;DR: Assessment of the effects of intensive versus conventional glycaemic targets in patients with type 1 diabetes in terms of long-term complications and whether very low, near normoglycaemic values are of additional benefit found evidence for an initial worsening of retinopathy.
Abstract: Background
Clinical guidelines differ regarding their recommended blood glucose targets for patients with type 1 diabetes and recent studies on patients with type 2 diabetes suggest that aiming at very low targets can increase the risk of mortality.
Objectives
To assess the effects of intensive versus conventional glycaemic targets in patients with type 1 diabetes in terms of long-term complications and determine whether very low, near normoglycaemic values are of additional benefit.
Search methods
A systematic literature search was performed in the databases The Cochrane Library, MEDLINE and EMBASE. The date of the last search was December 2012 for all databases.
Selection criteria
We included all randomised controlled trials (RCTs) that had defined different glycaemic targets in the treatment arms, studied patients with type 1 diabetes, and had a follow-up duration of at least one year.
Data collection and analysis
Two review authors independently extracted data, assessed studies for risk of bias, with differences resolved by consensus. Overall study quality was evaluated by the 'Grading of Recommendations Assessment, Development, and Evaluation' (GRADE) system. Random-effects models were used for the main analyses and the results are presented as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes.
Main results
We identified 12 trials that fulfilled the inclusion criteria, including a total of 2230 patients. The patient populations varied widely across studies with one study only including children, one study only including patients after a kidney transplant, one study with newly diagnosed adult patients, and several studies where patients had retinopathy or microalbuminuria at baseline. The mean follow-up duration across studies varied between one and 6.5 years. The majority of the studies were carried out in the 1980s and all trials took place in Europe or North America. Due to the nature of the intervention, none of the studies could be carried out in a blinded fashion so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the studies. Fifty per cent of the studies were judged to have a high risk of bias in at least one other category.
Under intensive glucose control, the risk of developing microvascular complications was reduced compared to conventional treatment for a) retinopathy: 23/371 (6.2%) versus 92/397 (23.2%); RR 0.27 (95% CI 0.18 to 0.42); P < 0.00001; 768 participants; 2 trials; high quality evidence; b) nephropathy: 119/732 (16.3%) versus 211/743 (28.4%); RR 0.56 (95% CI 0.46 to 0.68); P < 0.00001; 1475 participants; 3 trials; moderate quality evidence; c) neuropathy: 29/586 (4.9%) versus 86/617 (13.9%); RR 0.35 (95% CI 0.23 to 0.53); P < 0.00001; 1203 participants; 3 trials; high quality evidence. Regarding the progression of these complications after manifestation, the effect was weaker (retinopathy) or possibly not existent (nephropathy: RR 0.79 (95% CI 0.37 to 1.70); P = 0.55; 179 participants with microalbuminuria; 3 trials; very low quality evidence); no adequate data were available regarding the progression of neuropathy. For retinopathy, intensive glucose control reduced the risk of progression in studies with a follow-up duration of at least two years (85/366 (23.2%) versus 154/398 (38.7%); RR 0.61 (95% CI 0.49 to 0.76); P < 0.0001; 764 participants; 2 trials; moderate quality evidence), while we found evidence for an initial worsening of retinopathy after only one year of intensive glucose control (17/49 (34.7%) versus 7/47 (14.9%); RR 2.32 (95% CI 1.16 to 4.63); P = 0.02; 96 participants; 2 trials; low quality evidence).
Major macrovascular outcomes (stroke and myocardial infarction) occurred very rarely, and no firm evidence could be established regarding these outcome measures (low quality evidence).
We found that intensive glucose control increased the risk for severe hypoglycaemia, however the results were heterogeneous and only the 'Diabetes Complications Clinical Trial' (DCCT) showed a clear increase in severe hypoglycaemic episodes under intensive treatment. A subgroup analysis according to the baseline haemoglobin A1c (HbA1c) of participants in the trials (low quality evidence) suggests that the risk of hypoglycaemia is possibly only increased for patients who started with relatively low HbA1c values (< 9.0%). Several of the included studies also showed a greater weight gain under intensive glucose control, and the risk of ketoacidosis was only increased in studies using insulin pumps in the intensive treatment group (very low quality evidence).
Overall, all-cause mortality was very low in all studies (moderate quality evidence) except in one study investigating renal allograft as treatment for end-stage diabetic nephropathy. Health-related quality of life was only reported in the DCCT trial, showing no statistically significant differences between the intervention and comparator groups (moderate quality evidence). In addition, only the DCCT published data on costs, indicating that intensive glucose therapy control was highly cost-effective considering the reduction of potential diabetes complications (moderate quality evidence).
Authors' conclusions
Tight blood sugar control reduces the risk of developing microvascular diabetes complications. The evidence of benefit is mainly from studies in younger patients at early stages of the disease. Benefits need to be weighed against risks including severe hypoglycaemia, and patient training is an important aspect in practice. The effects of tight blood sugar control seem to become weaker once complications have been manifested. However, further research is needed on this issue. Furthermore, there is a lack of evidence from RCTs on the effects of tight blood sugar control in older patient populations or patients with macrovascular disease. There is no firm evidence for specific blood glucose targets and treatment goals need to be individualised taking into account age, disease progression, macrovascular risk, as well as the patient's lifestyle and disease management capabilities.
Cleveland Clinic1, University of KwaZulu-Natal2, Population Health Research Institute3, University Hospital of Basel4, McMaster University5, University of Virginia6, University of Perugia7, European Institute of Oncology8, University of Melbourne9, Pomeranian Medical University10, Sapienza University of Rome11, Medical University of Graz12, Wrightington, Wigan and Leigh NHS Foundation Trust13, Ewha Womans University14, University of Belgrade15, Ninewells Hospital16
TL;DR: Additional post-operative NP measurement enhanced risk stratification for the composite outcomes of death or nonfatal myocardial infarction at 30 days and ≥180 days after noncardiac surgery compared with a pre-operativeNP measurement alone.
TL;DR: It is demonstrated that hematogenous GBM spread is an intrinsic feature of GBM biology and should not be allowed to serve as organ donors.
Abstract: Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor in adults. The dogma that GBM spread is restricted to the brain was challenged by reports on extracranial metastases after organ transplantation from GBM donors. We identified circulating tumor cells (CTCs) in peripheral blood (PB) from 29 of 141 (20.6%) GBM patients by immunostaining of enriched mononuclear cells with antibodies directed against glial fibrillary acidic protein (GFAP). Tumor cell spread was not significantly enhanced by surgical intervention. The tumor nature of GFAP-positive cells was supported by the absence of those cells in healthy volunteers and the presence of tumor-specific aberrations such as EGFR gene amplification and gains and losses in genomic regions of chromosomes 7 and 10. Release of CTCs was associated with EGFR gene amplification, suggesting a growth potential of these cells. We demonstrate that hematogenous GBM spread is an intrinsic feature of GBM biology.
TL;DR: The general relevance of free radicals for the development and progression of both COPD and pulmonary emphysema is focused on as well as novel perspectives on therapeutic options.
Abstract: Oxidative stress occurs when free radicals and other reactive species overwhelm the availability of antioxidants. Reactive oxygen species (ROS), reactive nitrogen species, and their counterpart antioxidant agents are essential for physiological signaling and host defense, as well as for the evolution and persistence of inflammation. When their normal steady state is disturbed, imbalances between oxidants and antioxidants may provoke pathological reactions causing a range of nonrespiratory and respiratory diseases, particularly chronic obstructive pulmonary disease (COPD). In the respiratory system, ROS may be either exogenous from more or less inhalative gaseous or particulate agents such as air pollutants, cigarette smoke, ambient high-altitude hypoxia, and some occupational dusts, or endogenously generated in the context of defense mechanisms against such infectious pathogens as bacteria, viruses, or fungi. ROS may also damage body tissues depending on the amount and duration of exposure and may further act as triggers for enzymatically generated ROS released from respiratory, immune, and inflammatory cells. This paper focuses on the general relevance of free radicals for the development and progression of both COPD and pulmonary emphysema as well as novel perspectives on therapeutic options. Unfortunately, current treatment options do not suffice to prevent chronic airway inflammation and are not yet able to substantially alter the course of COPD. Effective therapeutic antioxidant measures are urgently needed to control and mitigate local as well as systemic oxygen bursts in COPD and other respiratory diseases. In addition to current therapeutic prospects and aspects of genomic medicine, trending research topics in COPD are presented.
TL;DR: This study identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients and revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes.
Abstract: The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients. Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points. Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57–4.83, P<0.001) that remained statistically significant in multivariable analysis (HR: 2.03, 95% CI: 1.03–4.02, P=0.042). An increased PLR was also significantly associated with decreased OS in univariable (HR: 2.45, 95% CI: 1.43–4.20, P=0.001) and in multivariable analysis (HR: 1.92, 95% CI: 1.01–3.67, P=0.047). Furthermore, univariable analysis showed a significant impact of increased PLR on DMFS (HR: 2.02, 95% CI: 1.18–3.44, P=0.010). Subgroup analysis revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes. This association retained its significance in multivariable analysis in patients with luminal B tumours (HR: 2.538, 95% CI: 1.043–6.177, P=0.040). In this study, we identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients. Independent validation of our findings is needed.
University of Cincinnati1, Broad Institute2, Harvard University3, Wake Forest University4, Cincinnati Children's Hospital Medical Center5, Jagiellonian University Medical College6, Medical University of Graz7, Lund University8, Autonomous University of Barcelona9, Pompeu Fabra University10, University of Miami11, University of Washington12, University of Michigan13, University of Florida14, University of Virginia15, Mayo Clinic16, University of Arizona17, Ludwig Maximilian University of Munich18, University of Oxford19
TL;DR: A genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry demonstrated biological heterogeneity across ICH subtypes and highlighted the importance of ascertaining ICH cases accordingly.
Abstract: Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
TL;DR: A significant and strong correlation of GDP, health expenditures and obesity prevalence with utilization of knee arthroplasty was found, and patients aged 64 years and younger show a two-fold higher growth rate in knee ar Throplasty compared to the older population.