Aarhus University Hospital

Accurate normalization is an absolute prerequisite for correct measurement of gene expression. For quantitative real-time reverse transcription-PCR (RT-PCR), the most commonly used normalization strategy involves standardization to a single constitutively expressed control gene. However, in recent years, it has become clear that no single gene is constitutively expressed in all cell types and under all experimental conditions, implying that the expression stability of the intended control gene has to be verified before each experiment. We outline a novel, innovative, and robust strategy to identify stably expressed genes among a set of candidate normalization genes. The strategy is rooted in a mathematical model of gene expression that enables estimation not only of the overall variation of the candidate normalization genes but also of the variation between sample subgroups of the sample set. Notably, the strategy provides a direct measure for the estimated expression variation, enabling the user to evaluate the systematic error introduced when using the gene. In a side-by-side comparison with a previously published strategy, our model-based approach performed in a more robust manner and showed less sensitivity toward coregulation of the candidate normalization genes. We used the model-based strategy to identify genes suited to normalize quantitative RT-PCR data from colon cancer and bladder cancer. These genes are UBC, GAPD, and TPT1 for the colon and HSPCB, TEGT, and ATP5B for the bladder. The presented strategy can be applied to evaluate the suitability of any normalization gene candidate in any kind of experimental design and should allow more reliable normalization of RT-PCR data.

BACKGROUND: Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. METHODS: In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. RESULTS: At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. CONCLUSIONS: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is thatthere is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the completeprocess including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increasedautophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in manycases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as forreviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multipleassays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagyrelated protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. METHODS: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. RESULTS: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). CONCLUSIONS: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

... ... ... ... In the late 19th century, post-mortem examinations demonstrated a possible relationship between thrombotic occlusion of a coronary artery and myocardial infarction (MI).1 However, it was not until the beginning of the 20th century that the first clinical descriptions appeared describing a connection between the formation of a thrombus in a coronary artery and its associated clinical features.2 , 3 Despite these landmark observations, considerable time elapsed before general clinical acceptance of this entity was achieved, in part due to one autopsy study that showed no thrombi in the coronary arteries of 31% of deceased patients with an MI.4 The clinical entity was referred to as coronary thrombosis, although use of the term ‘MI’ ultimately prevailed. Over the years, several different definitions of MI have been used, leading to controversy and confusion. Hence, a general and worldwide definition for MI was needed. This occurred for the first time in the 1950–70s, when working groups from the World Health Organization (WHO) established a primarily electrocardiographic (ECG)-based definition of MI intended for epidemiological use.5 The original description, with minor modifications, is still used in epidemiological surveys (Figure 1).6–8

BACKGROUND: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

ABSTRACT: The current International Association for the Study of Pain (IASP) definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a reevaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain, to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year.

OBJECTIVE: To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS: A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20-79 years. RESULTS: A total of 35 studies (1980-2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5-34.8) for any DR, 6.96% (6.87-7.04) for proliferative DR, 6.81% (6.74-6.89) for diabetic macular edema, and 10.2% (10.1-10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A(1c), and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS: There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

BACKGROUND: The Danish National Patient Registry (DNPR) is one of the world's oldest nationwide hospital registries and is used extensively for research. Many studies have validated algorithms for identifying health events in the DNPR, but the reports are fragmented and no overview exists. OBJECTIVES: To review the content, data quality, and research potential of the DNPR. METHODS: We examined the setting, history, aims, content, and classification systems of the DNPR. We searched PubMed and the Danish Medical Journal to create a bibliography of validation studies. We included also studies that were referenced in retrieved papers or known to us beforehand. Methodological considerations related to DNPR data were reviewed. RESULTS: During 1977-2012, the DNPR registered 8,085,603 persons, accounting for 7,268,857 inpatient, 5,953,405 outpatient, and 5,097,300 emergency department contacts. The DNPR provides nationwide longitudinal registration of detailed administrative and clinical data. It has recorded information on all patients discharged from Danish nonpsychiatric hospitals since 1977 and on psychiatric inpatients and emergency department and outpatient specialty clinic contacts since 1995. For each patient contact, one primary and optional secondary diagnoses are recorded according to the International Classification of Diseases. The DNPR provides a data source to identify diseases, examinations, certain in-hospital medical treatments, and surgical procedures. Long-term temporal trends in hospitalization and treatment rates can be studied. The positive predictive values of diseases and treatments vary widely (<15%-100%). The DNPR data are linkable at the patient level with data from other Danish administrative registries, clinical registries, randomized controlled trials, population surveys, and epidemiologic field studies - enabling researchers to reconstruct individual life and health trajectories for an entire population. CONCLUSION: The DNPR is a valuable tool for epidemiological research. However, both its strengths and limitations must be considered when interpreting research results, and continuous validation of its clinical data is essential.

BACKGROUND: The 5-item World Health Organization Well-Being Index (WHO-5) is among the most widely used questionnaires assessing subjective psychological well-being. Since its first publication in 1998, the WHO-5 has been translated into more than 30 languages and has been used in research studies all over the world. We now provide a systematic review of the literature on the WHO-5. METHODS: We conducted a systematic search for literature on the WHO-5 in PubMed and PsycINFO in accordance with the PRISMA guidelines. In our review of the identified articles, we focused particularly on the following aspects: (1) the clinimetric validity of the WHO-5; (2) the responsiveness/sensitivity of the WHO-5 in controlled clinical trials; (3) the potential of the WHO-5 as a screening tool for depression, and (4) the applicability of the WHO-5 across study fields. RESULTS: A total of 213 articles met the predefined criteria for inclusion in the review. The review demonstrated that the WHO-5 has high clinimetric validity, can be used as an outcome measure balancing the wanted and unwanted effects of treatments, is a sensitive and specific screening tool for depression and its applicability across study fields is very high. CONCLUSIONS: The WHO-5 is a short questionnaire consisting of 5 simple and non-invasive questions, which tap into the subjective well-being of the respondents. The scale has adequate validity both as a screening tool for depression and as an outcome measure in clinical trials and has been applied successfully across a wide range of study fields.

Allergic rhinitis is a symptomatic disorder of the nose\ninduced after allergen exposure by an IgE-mediated\ninflammation of the membranes lining the nose. It is a\nglobal health problem that causes major illness and disability\nworldwide. Over 600 million patients from all\ncountries, all ethnic groups and of all ages suffer from\nallergic rhinitis. It affects social life, sleep, school and\nwork and its economic impact is substantial.\nRisk factors for allergic rhinitis are well identified.\nIndoor and outdoor allergens as well as occupational\nagents cause rhinitis and other allergic diseases.\nThe role of indoor and outdoor pollution is probably\nvery important, but has yet to be fully understood\nboth for the occurrence of the disease and its manifestations.\nIn 1999, during the Allergic Rhinitis and its Impact on\nAsthma (ARIA) WHO workshop, the expert panel\nproposed a new classification for allergic rhinitis which\nwas subdivided into _intermittent_ or _persistent_ disease.\nThis classification is now validated.\nThe diagnosis of allergic rhinitis is often quite easy, but\nin some cases it may cause problems and many patients\nare still under-diagnosed, often because they do not\nperceive the symptoms of rhinitis as a disease impairing\ntheir social life, school and work.\nThe management of allergic rhinitis is well established\nand the ARIA expert panel based its recommendations\non evidence using an extensive review of the literature\navailable up to December 1999. The statements of\nevidence for the development of these guidelines followed\nWHO rules and were based on those of Shekelle et al.\nA large number of papers have been published since 2000\nand are extensively reviewed in the 2008 Update using\nthe same evidence-based system. Recommendations for\nthe management of allergic rhinitis are similar in both the\nARIA workshop report and the 2008 Update. In the\nfuture, the GRADE approach will be used, but is not yet\navailable.\nAnother important aspect of the ARIA guidelines was\nto consider co-morbidities. Both allergic rhinitis and\nasthma are systemic inflammatory conditions and often\nco-exist in the same patients. In the 2008 Update, these\nlinks have been confirmed.\nTheARIAdocument is not intended to be a standard-ofcare\ndocument for individual countries. It is provided as a\nbasis for physicians, health care professionals and\norganizations involved in the treatment of allergic rhinitis\nand asthma in various countries to facilitate the\ndevelopment of relevant local standard-of-care documents\nfor patients.

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).

Eric Schiffman, DDS, MS/Richard Ohrbach, DDS, PhD/Edmond Truelove, DDS, MSD/John Look, DDS, PhD/Gary Anderson, DDS, MS/Jean-Paul Goulet, DDS, MSD/Thomas List, DDS, Odont Dr/Peter Svensson, DDS, PhD, Dr Odont/Yoly Gonzalez, DDS, MS, MPH/Frank Lobbezoo, DDS, PhD/Ambra Michelotti, DDS/Sharon L. Brooks, DDS, MS/Werner Ceusters, MD/Mark Drangsholt, DDS, PhD/Dominik Ettlin, MD, DDS/Charly Gaul, MD/Louis J. Goldberg, DDS, PhD/Jennifer A. Haythornthwaite, PhD/Lars Hollender, DDS, Odont Dr/Rigmor Jensen, MD, PhD/Mike T. John, DDS, PhD/Antoon De Laat, DDS, PhD/Reny de Leeuw, DDS, PhD/William Maixner, DDS, PhD/Marylee van der Meulen, PhD/Greg M. Murray, MDS, PhD/Donald R. Nixdorf, DDS, MS/Sandro Palla, Dr Med Dent/Arne Petersson, DDS, Odont Dr/Paul Pionchon, DDS, PhD/Barry Smith, PhD/Corine M. Visscher, PT, PhD/Joanna Zakrzewska, MD, FDSRCSI/Samuel F. Dworkin, DDS, PhD: Aims: The original Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I diagnostic algorithms have been demonstrated to be reliable. However, the Validation Project determined that the RDC/TMD Axis I validity was below the target sensitivity of ≥ 0.70 and specificity of ≥ 0.95. Consequently, these empirical results supported the development of revised RDC/TMD Axis I diagnostic algorithms that were subsequently demonstrated to be valid for the most common pain-related TMD and for one temporomandibular joint (TMJ) intra-articular disorder. The original RDC/TMD Axis II instruments were shown to be both reliable and valid. Working from these findings and revisions, two international consensus workshops were convened, from which recommendations were obtained for the finalization of new Axis I diagnostic algorithms and new Axis II instruments. Methods: Through a series of workshops and symposia, a panel of clinical and basic science pain experts modified the revised RDC/TMD Axis I algorithms by using comprehensive searches of published TMD diagnostic literature followed by review and consensus via a formal structured process. The panel’s recommendations for further revision of the Axis I diagnostic algorithms were assessed for validity by using the Validation Project’s data set, and for reliability by using newly collected data from the ongoing TMJ Impact Project—the follow-up study to the Validation Project. New Axis II instruments were identified through a comprehensive search of the literature providing valid instruments that, relative to the RDC/TMD, are shorter in length, are available in the public domain, and currently are being used in medical settings. Results: The newly recommended Diagnostic Criteria for TMD (DC/TMD) Axis I protocol includes both a valid screener for detecting any pain-related TMD as well as valid diagnostic criteria for differentiating the most common pain-related TMD (sensitivity ≥ 0.86, specificity ≥ 0.98) and for one intra-articular disorder (sensitivity of 0.80 and specificity of 0.97). Diagnostic criteria for other common intra-articular disorders lack adequate validity for clinical diagnoses but can be used for screening purposes. Inter-examiner reliability for the clinical assessment associated with the validated DC/TMD criteria for pain-related TMD is excellent (kappa ≥ 0.85). Finally, a comprehensive classification system that includes both the common and less common TMD is also presented. The Axis II protocol retains selected original RDC/TMD screening instruments augmented with new instruments to assess jaw function as well as behavioral and additional psychosocial factors. The Axis II protocol is divided into screening and comprehensive selfreport instrument sets. The screening instruments’ 41 questions assess pain intensity, pain-related disability, psychological distress, jaw functional limitations, and parafunctional behaviors, and a pain drawing is used to assess locations of pain. The comprehensive instruments, composed of 81 questions, assess in further detail jaw functional limitations and psychological distress as well as additional constructs of anxiety and presence of comorbid pain conditions. Conclusion: The recommended evidence-based new DC/TMD protocol is appropriate for use in both clinical and research settings. More comprehensive instruments augment short and simple screening instruments for Axis I and Axis II. These validated instruments allow for identification of patients with a range of simple to complex TMD presentations. J Oral Facial Pain Headache 2014;28:6–27. doi: 10.11607/jop.1151

Udgivelsesdato: 2007-Nov-27

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

Abbreviations and acronyms Definition of myocardial infarction Criteria for acute myocardial infarction Criteria for prior myocardial infarction Introduction Pathological characteristics of myocardial ischaemia and infarction Biomarker detection of myocardial injury with necrosis Clinical features of myocardial ischaemia and infarction Clinical classification of myocardial infarction Spontaneous myocardial infarction (MI type 1) Myocardial infarction secondary to an ischaemic imbalance (MI type 2) Cardiac death due to myocardial infarction (MI type 3) Myocardial infarction associated with revascularization procedures (MI types 4 and 5) Electrocardiographic detection of myocardial infarction Prior myocardial infarction Silent myocardial infarction Conditions that confound the ECG diagnosis of myocardial infarction Imaging techniques Echocardiography Radionuclide imaging Magnetic resonance imaging Computed tomography Applying imaging in acute myocardial infarction Applying imaging in late presentation of myocardial infarction Diagnostic criteria for myocardial infarction with PCI (MI type 4) Diagnostic criteria for myocardial infarction with CABG (MI type 5) Assessment of MI in patients undergoing other cardiac procedures Myocardial infarction associated with non-cardiac procedures Myocardial infarction in the intensive care unit Recurrent myocardial infarction Reinfarction Myocardial injury or infarction associated with heart failure Application of MI in clinical trials and quality assurance programmes Public policy implications of the adjustment of the MI definition Global perspectives of the definition of myocardial infarction Conflicts of interest Acknowledgements References American College of Cardiology Foundation acute coronary syndrome American Heart Association coronary artery disease coronary artery bypass grafting creatine kinase MB isoform cardiac troponin computed tomography coefficient of variation electrocardiogram European Society of Cardiology fluorodeoxyglucose hour(s) heart failure left bundle branch block left ventricle left ventricular hypertrophy myocardial infarction meta-iodo-benzylguanidine minute(s) Multinational MONItoring of trends and determinants in CArdiovascular disease) myocardial perfusion scintigraphy magnetic resonance imaging millivolt(s) nanogram(s) per litre non-Q wave myocardial infarction non-ST-elevation myocardial infarction percutaneous coronary intervention positron emission tomography pictogram(s) per millilitre Q wave myocardial infarction right bundle branch block second(s) single photon emission computed tomography ST elevation myocardial infarction ST-segment –T wave upper reference limit World Heart Federation World Health Organization Myocardial infarction (MI) can be recognised by clinical features, including electrocardiographic (ECG) findings, elevated values of biochemical markers (biomarkers) of myocardial necrosis, and by imaging, or may be defined by pathology. It is a major cause of death and disability worldwide. MI may be the first manifestation of coronary artery disease (CAD) or it may occur, repeatedly, in patients with established disease. Information on MI rates can provide useful information regarding the burden of CAD within and across populations, especially if standardized data are collected in a manner that distinguishes between incident and recurrent events. From the epidemiological point of view, the incidence of MI in a population can be used as a proxy for the prevalence of CAD in that population. The term ‘myocardial infarction’ may have major psychological and legal implications for the individual and society. It is an indicator of one of the leading health problems in the world and it is an outcome measure in clinical trials, observational studies and quality assurance programmes. These studies and programmes require a precise and consistent definition of MI. In the past, a general consensus existed for the clinical syndrome designated as MI. In studies of disease prevalence, the World Health Organization (WHO) defined MI from symptoms, ECG abnormalities and cardiac enzymes. However, the development of ever more sensitive and myocardial tissue-specific cardiac biomarkers and more sensitive imaging techniques now allows for detection of very small amounts of myocardial injury or necrosis. Additionally, the management of patients with MI has significantly improved, resulting in less myocardial injury and necrosis, in spite of a similar clinical presentation. Moreover, it appears necessary to distinguish the various conditions which may cause MI, such as ‘spontaneous’ and ‘procedure-related’ MI. Accordingly, physicians, other healthcare providers and patients require an up-to-date definition of MI. In 2000, the First Global MI Task Force presented a new definition of MI, which implied that any necrosis in the setting of myocardial ischaemia should be labelled as MI.1 These principles were further refined by the Second Global MI Task Force, leading to the Universal Definition of Myocardial Infarction Consensus Document in 2007, which emphasized the different conditions which might lead to an MI.2 This document, endorsed by the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation (WHF), has been well accepted by the medical community and adopted by the However, the development of more sensitive for markers of myocardial necrosis further such necrosis in the setting of the percutaneous coronary procedures or cardiac The Global MI Task Force has the by and new data the document, which now that very small amounts of myocardial injury or necrosis can be by biochemical markers MI is defined in as myocardial death due to the of myocardial death is a of to as or less in It myocardial necrosis can be by or necrosis of myocardial or on the of to the ischaemic or coronary the of the to and individual for and The leading to a infarction may the and Myocardial injury is of sensitive and biomarkers such as or the MB of creatine kinase are Cardiac troponin and are of the of myocardial and are in the of biomarkers in the injury leading to necrosis of myocardial the have been for of from the including of myocardial of troponin and of and of the myocardial necrosis due to myocardial ischaemia is designated as MI. of myocardial injury with necrosis may be in clinical conditions associated with myocardial amounts of myocardial injury with necrosis may be which are associated with heart failure or percutaneous or coronary These should be labelled as MI or a of the as myocardial as in It is that the of clinical may it to individual may within the of In it is to distinguish acute of which require a of from that to of such clinical associated with elevated values of is presented in The resulting in the myocardial injury should be in the This various clinical for heart or cardiac or non-cardiac procedures that can be associated with myocardial injury with death by cardiac troponin However, can be associated with myocardial infarction in of clinical of acute myocardial ischaemia with of cardiac of cardiac troponin values of myocardial injury of cardiac troponin values of myocardial injury The and for of or which has myocardial as well as clinical of a of the is to the diagnosis of acute is defined as a the of a reference population reference limit This is designated as the for the diagnosis of MI and be for with quality in The values for the defined by including for of the in can be in the for the or in should be presented as per litre or per millilitre to Criteria for the of values are can be defined from the of individual including as by coefficient of variation the for should be defined as allows for more sensitive and the detection of The of that have the of a more cause with the should be It is that and problems can elevated and values of for the of should be on first and are if further ischaemic occur, or the of the is the diagnosis of MI, a in values with one the is with a The of a is to distinguish from in that are associated with heart patients with failure or can have in These can be as in patients with MI, However, a or is necessary to the diagnosis of MI if a with a of MI late for the of the or on the of that a can be may elevated for or more the of values may be for troponin elevated with or a of values or in the of clinical of should a for other associated with myocardial such as or failure and other more disease that can be associated with elevated are in a is the is by with an is defined as a the which is designated as the for the diagnosis of values should be of myocardial ischaemia is the in the development of MI and from an imbalance between and Myocardial ischaemia in a clinical setting can be from the and from the ischaemic various of upper or or or an ischaemic such as or The associated with acute MI the is by of the it may be by or However, are for myocardial Accordingly, may be and to or MI may with as or cardiac for in the or and of patients is especially is a of cardiac the of such as it is to MI in patients with or other ischaemic that ST elevation in ECG as an elevation In patients ST elevation presentation are designated as a elevation patients with MI Q wave elevated values can be as In to MI is various on clinical and with different Universal classification of myocardial infarction Universal classification of myocardial infarction This is an to or with resulting in one or more of the coronary leading to myocardial or with necrosis. The may have CAD on to or CAD may be in In of myocardial injury with necrosis, a other CAD to an imbalance between myocardial the term type is In or in patients undergoing major elevated values of cardiac biomarkers may due to the of or coronary have the to cause between myocardial infarction (MI) types and to the of the coronary cardiac with of myocardial ischaemia by new ischaemic ECG or new a These may for biomarkers can be or elevated cardiac biomarkers can be patients with clinical features of myocardial or with new ischaemic ECG should be as a MI, if cardiac of MI is myocardial injury or infarction may in the of the heart that is revascularization by PCI or by coronary artery bypass grafting values may be various may that can lead to myocardial injury with It is that of such injury is to the a for a to an of cardiac values in the of is well of MI are to and that may the The ECG is an of the of patients with MI and should be and within clinical in the ECG acute myocardial ischaemic require of if the ECG presentation is in patients with an ECG should be if ECG of an are an for a in patients with ECG a ECG should be as a for or in the and Q the to the to the to the of as well as and to ST-segment or wave is associated with a of myocardial ischaemia and a ECG associated with acute myocardial ischaemia cardiac and and of wave artery and of and of coronary and prior myocardial necrosis can ECG of myocardial the ECG presentation should be to prior ECG The ECG by is to acute myocardial ischaemia or ST may be in other such as acute left ventricular hypertrophy left bundle branch block and new ST-segment elevation associated with ST-segment acute coronary and in myocardial injury with necrosis. in Q may due to myocardial in the of ECG abnormalities of myocardial ischaemia or infarction may be in the the the ST-segment or the The of myocardial ischaemia are wave and ST-segment wave with in is an that may the elevation of the Q may be an of acute ischaemia or acute MI with wave criteria for the diagnosis of acute myocardial ischaemia that may or may lead to MI. The point is used to the of the ST-segment or point elevation is in other and In elevation can be as as in or it with require different for point elevation in in and is less in to lead such as or such as and the of the right ventricle and the ECG of acute myocardial ischaemia of and ECG of acute myocardial ischaemia of and The criteria in require that the ST be in or more of ST elevation in lead and in lead the criteria of in a However, and of ST in in in may a It should be acute myocardial ischaemia may ST-segment to the criteria in one lead have less the ST in a of ST or wave acute myocardial ischaemia or MI, a single may the more ECG that might be with ST elevation or Q in lead are more ST in the of myocardial ischaemia or as well as ECG should be in patients that with ischaemic and a Electrocardiographic of myocardial ischaemia in the of a left artery is and is the the left the left and the left of is in patients with clinical for acute ECG or ST-segment in of ST elevation is in is a ST elevation and should be used in ST in may be of myocardial ischaemia especially the wave is elevation is In patients with and right ventricular right and should be ST elevation in criteria for the an of acute of may acute myocardial or may in abnormalities and should be in the The diagnosis of MI is more in the of However, ST-segment elevation or a ECG may be to the of acute MI in In patients with right bundle branch block abnormalities in are it to the of ischaemia in new ST elevation or Q are myocardial ischaemia or infarction should be in Q or in the of are of a prior MI in patients with ischaemic heart of The of the ECG diagnosis for MI is Q in or lead the Q are associated with ST or wave in the the of MI is for Q and that are are of prior MI if by in the lead MI such as the and have been used in epidemiological studies and clinical ECG associated with prior myocardial infarction criteria are used for ECG associated with prior myocardial infarction criteria are used for patients new Q wave criteria for MI ECG or of MI by cardiac imaging, that be to a coronary revascularization should be In Q wave MI for of MI and were associated with a significantly lead or may in to be new Q or as to a prior the diagnosis of a new Q wave MI should be by a ECG with lead or by an imaging and by ischaemic in lead is Q wave and of the wave in lead is if the is between and Q wave may be in if the is between and Q are Q and of the in and or cardiac left right ventricular acute or may be associated with Q or in the of MI. ECG abnormalities that myocardial ischaemia or MI are presented in ECG in myocardial infarction ECG in myocardial infarction imaging in patients with or MI, in the diagnosis and of MI. The is that myocardial and ischaemia lead to a of including myocardial death and by imaging are myocardial and and the of on the of or used imaging techniques in acute and infarction are myocardial perfusion scintigraphy single photon emission computed tomography and magnetic resonance imaging emission tomography and computed tomography are less is in and of the techniques to a or myocardial and the techniques provide a of of the of the techniques provide of myocardial such as to by or myocardial by The of is the of cardiac and in myocardial and can of the and can be used to myocardial perfusion and and imaging of and have been that techniques have been in the setting of to be including the and and the and The of the techniques is that are the of the of the a for small of MI. The are of myocardial perfusion and the techniques of MI and perfusion imaging a of myocardial and techniques that are to the of MI imaging of meta-iodo-benzylguanidine imaging of in ventricular and refined of myocardial The of an of myocardial and it has similar to in acute MI. can be used to myocardial perfusion and the in that is associated with the of prior MI. These techniques have been used in the setting of acute and imaging of myocardial by is to small of MI. It is of in myocardial disease that can MI, such as is as a of left ventricle imaging as with late imaging by This is may be for and with clinical features that with of acute the is used of myocardial perfusion is Imaging techniques can be useful in the diagnosis of acute MI of to abnormalities or of in the of elevated cardiac for biomarkers have been or may have of new of myocardial in the of the criteria for MI. and have a very and acute imaging techniques are useful for and of patients with MI. However, if biomarkers have been and are an acute MI and the imaging myocardial and may be by acute MI or by one or more of other including prior MI, acute or such as and or can lead to of or the of imaging for acute MI is conditions can be and a new is or can be to have in the setting of other features of acute MI. Echocardiography an of of acute such as heart or It is the imaging of for of acute MI, including myocardial acute ventricular and secondary to or Radionuclide imaging can be used to the of that is by acute is the of with imaging a measure of a a measure of and the between the to the that has been In of late presentation MI, the of or in the of of MI. The and of late for the detection of myocardial has a very In the to distinguish between and other of a between ischaemic heart disease and other myocardial Imaging techniques are useful for a diagnosis of MI. The detection of or ischaemia ventricular of PCI or it is by or Myocardial injury with necrosis may from or in as coronary of a major coronary artery or a of or and of or may be and or of the of myocardial of myocardial necrosis have been by The of myocardial injury with necrosis can be by of cardiac biomarkers the further can be as myocardial injury if the is or if are or In patients with elevation of cardiac values the PCI are of myocardial In values of cardiac especially were associated with However, are PCI and the the the an is well and it is such a a single is it is to further are due to the or to the the In it appears that the is by the These more for the new troponin In patients undergoing PCI with of within of the of ischaemia as by or ischaemic ST or new Q or of a such as of of of a or or imaging of new of or new defined as MI This of values is on clinical and implications of the of MI. a is PCI and the the the is in the of or imaging term ‘myocardial should be the values are elevated and are or a of is for the diagnosis of a type MI, as with data PCI is MI are or have and elevation of cardiac values may have However, data are to of MI is as by and a of values as MI type In to the of in to the of the PCI the of to to and to distinguish in the of the various of MI in the clinical setting of appears to be a is of on clinical can lead to myocardial injury with necrosis. These myocardial from or of the coronary or ischaemia to cardiac to myocardial injury by or failure to of the that are by studies that necrosis in setting is and in the In patients with values any of cardiac values CABG myocardial necrosis, that an of is to be to an This has been in clinical studies and the CABG were associated with outcome has been values were elevated to the or of the the of biomarkers for an MI to a in a or in the setting of In the is elevated of values are biomarkers in MI in In of the on in patients with elevation of Task Force by that values the first from a In new Q or new or new or new coronary artery or imaging of new of or new should be as of a MI Cardiac is with CABG with bypass and with CABG to The is more for for the principles from the definition of MI should be for the definition of MI abnormalities are in patients cardiac new Q in different MI or 2) should be if associated with elevated cardiac new abnormalities or procedures such as or may cause myocardial injury with necrosis, by to the and by ischaemia from coronary or It is to the more the elevation of the the the data on that are criteria have been for the diagnosis of MI However, that is it appears to the criteria for MI as for of myocardial injury with necrosis, by of or of the The of the injury with necrosis can be by an elevation of values in should be labelled as MI. MI is the major in major non-cardiac and is associated with a patients have a MI ischaemic MI is as associated with as is of cardiac biomarkers in prior to and major is of in that of patients have the and have an elevation and a of values of myocardial of patients undergoing major non-cardiac the that of the in are by a imbalance between myocardial and a of with a of MI type However, one of MI patients and leading to in of such that is to MI type the that in the to clinical and is of values are in patients in the intensive care unit and are associated with of the disease may MI type due to CAD and myocardial patients may have elevated values of cardiac due to myocardial injury with necrosis by or from Moreover, in MI type may It is a for the for a with single or to on a of the has elevated and the from the clinical should be to to for CAD or heart disease is is defined as the first MI. features of MI in the first an incident is as a new for epidemiological characteristics of MI an incident MI, it is to be a recurrent The term is used for an acute MI that within of an or recurrent The ECG diagnosis of the MI may be by the ECG Reinfarction should be ST elevation or new Q in associated with ischaemic for or of the ST-segment be in myocardial and should lead to ST or are and should be used to In patients in is from clinical or the MI, an of is should be the is or the of the diagnosis of a or of the in the the is the criteria for new acute MI on the elevated of myocardial injury with necrosis, may be in patients with may be in patients with with a the in with more such as in MI type is an cause of should be in the of an acute values in a with the diagnosis of MI type and be in with MI type have been to elevated in patients with MI type may from coronary or MI type or and due to has been to as well as and may with and and the diagnosis of MI, the and of elevation in is accepted to be an of in acute and of and should be as In the of an or should be and ECG with the of or MI type as the In elevated values should be with a of for MI type if a of the are or if it is by ischaemic symptoms, new ischaemic ECG or of myocardial on artery may be such may be used to troponin coronary are a type MI or a for troponin may be the other coronary is the of a in of the is to a diagnosis of acute MI due to is it to the for the In further such as myocardial perfusion coronary or is to the cause of the However, it may be to the for such In clinical trials, MI may be an or an definition for MI is of for clinical it a standardized for and across different The definition of MI as an MI type and MI type characteristics in the MI is the This MI type might be designated as an type defined as coronary or a associated with a of values and other CAD of or of a coronary artery with In different MI have been as and between and with to the definition of MI used as an in clinical is of of the definition to an individual clinical may be in and should have a should that a data for the various types of MI and the of or other biomarkers of the may be as in This of trials and in clinical trials of MI types to of the upper reference limit of the cardiac MI myocardial PCI percutaneous coronary CABG coronary artery bypass values are of death are defined values the MI limit PCI or is defined as coronary or a associated with a of values and other CAD of or of a coronary artery with in clinical trials of MI types to of the upper reference limit of the cardiac MI myocardial PCI percutaneous coronary CABG coronary artery bypass values are of death are defined values the MI limit PCI or is defined as coronary or a associated with a of values and other CAD of or of a coronary artery with different may be including in clinical trials, it is to the This troponin values across different the of the In patients undergoing cardiac the incidence of MI may be used as a measure of that a consistent definition is by in the quality assurance be and to type of to a to the different across of the definition of MI has a of implications for as well as for or diagnosis is the for further and for the The of patients with a diagnosis is the for health care and policy and of the of clinical is to a and which is by The to the definition of MI in In the of the term ‘myocardial infarction’ has sensitive have been to the diagnosis of acute MI is a clinical diagnosis on symptoms, ECG and sensitive biochemical as well as information from various imaging It is to the type of MI as well as the of the and the of CAD and other a diagnosis of MI. The information the and to more the that the has an MI. The are that and can be of have been to the MI. The classification of the various other associated with MI should lead to a of the clinical for patients with the conditions that can lead to myocardial necrosis, with elevation of It should be that the of the definition of MI may be associated with for the patients and in of psychological as well as and The diagnosis is associated with implications as to health and disability In to be of the to be and be and healthcare should to the of the definition to physicians, other health care and the general disease is a health the burden and of CAD in is of clinical criteria and biomarkers to and to the health of the The definition of MI for has and the data are consistent are for and The in are for However, to trends it is to have consistent and to biomarkers or other criteria the of the of for In with cardiac biomarkers and imaging techniques may be in a and the of ECG may be In the that or other are for as The the of the Universal MI Definition in more in and problems in the different of the world in the diagnosis and of acute MI require It is that the between and be in of disease. The of the Task Force of the the the and the have in the of document, on and clinical and an and clinical of have are in with and or health providers such have The of is in the quality of and However, to with and health providers are on the for the Task and of were by the are very to the of the of the

The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). Among the PRRs, the Toll-like receptors have been studied most extensively. Upon PAMP engagement, PRRs trigger intracellular signaling cascades ultimately culminating in the expression of a variety of proinflammatory molecules, which together orchestrate the early host response to infection, and also is a prerequisite for the subsequent activation and shaping of adaptive immunity. In order to avoid immunopathology, this system is tightly regulated by a number of endogenous molecules that limit the magnitude and duration of the inflammatory response. Moreover, pathogenic microbes have developed sophisticated molecular strategies to subvert host defenses by interfering with molecules involved in inflammatory signaling. This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response. Moreover, medical implications are discussed, including the role of PRRs in primary immunodeficiencies and in the pathogenesis of infectious and autoimmune diseases, as well as the possibilities for translation into clinical and therapeutic applications.