Showing papers by "McMaster University published in 2014"
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TL;DR: A prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials offered clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.
3,729 citations
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University of Southampton1, Imperial College London2, University of Washington3, Nippon Medical School4, University of Colorado Denver5, University of Duisburg-Essen6, University of Lyon7, University of Ulsan8, McMaster University9, Cedars-Sinai Medical Center10, Boehringer Ingelheim11, University of California, San Francisco12
TL;DR: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintinganib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.
Abstract: Background Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. Methods We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George’s Respiratory Questionnaire, both assessed over a 52-week period. Results A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was −114.7 ml with nintedanib versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P = 0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P = 0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. Conclusions In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)
2,936 citations
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National Institutes of Health1, University of Pittsburgh2, McMaster University3, University of Washington4, University of Cape Town5, Wake Forest University6, University of Leicester7, Karolinska Institutet8, University of Southampton9, Boston Children's Hospital10, John Hunter Hospital11, McGill University12, University of Wisconsin-Madison13, University of Virginia14
TL;DR: Recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults and coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy are provided.
Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
2,795 citations
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Icahn School of Medicine at Mount Sinai1, Carnegie Mellon University2, Harvard University3, University of Toronto4, Wellcome Trust Sanger Institute5, University of Pittsburgh6, Nagoya University7, University of Freiburg8, King's College London9, Vanderbilt University10, King Abdulaziz University11, University of Santiago de Compostela12, University of Utah13, Duke University14, Memorial University of Newfoundland15, Trinity College, Dublin16, University of Pennsylvania17, University of Illinois at Chicago18, Boston Children's Hospital19, Columbia University20, German Cancer Research Center21, University College London22, Kaiser Permanente23, Broad Institute24, Cardiff University25, Complutense University of Madrid26, Newcastle University27, Baylor College of Medicine28, University of California, San Francisco29, RWTH Aachen University30, National Health Service31, McMaster University32, Saarland University33, Karolinska Institutet34, National Institutes of Health35, University of Helsinki36, Emory University37
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
2,228 citations
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TL;DR: The current article will present the four types of triangulation followed by a discussion of the use of focus groups and in-depth individual interviews as an example of data source triangulations in qualitative inquiry.
Abstract: Triangulation refers to the use of multiple methods or data sources in qualitative research to develop a comprehensive understanding of phenomena (Patton, 1999). Triangulation also has been viewed as a qualitative research strategy to test validity through the convergence of information from different sources. Denzin (1978) and Patton (1999) identified four types of triangulation: (a) method triangulation, (b) investigator triangulation, (c) theory triangulation, and (d) data source triangulation. The current article will present the four types of triangulation followed by a discussion of the use of focus groups (FGs) and in-depth individual (IDI) interviews as an example of data source triangulation in qualitative inquiry.
2,180 citations
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Nicholas J Kassebaum1, Amelia Bertozzi-Villa1, Megan Coggeshall1, Katya Anne Shackelford1 +349 more•Institutions (179)
TL;DR: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015, with evidence of continued acceleration in the MMR, and MMR was highest in the oldest age groups in both 1990 and 2013.
1,383 citations
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Cleveland Clinic1, MedStar Washington Hospital Center2, University of Texas Health Science Center at Houston3, University of Pennsylvania4, Harvard University5, McMaster University6, McGill University7, University of Padua8, European Institute of Oncology9, University of Chicago10, Oslo University Hospital11, Temple University12, University of Liège13, Memorial Sloan Kettering Cancer Center14, Menzies Research Institute15, Mayo Clinic16
TL;DR: The noninvasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially car- diotoxic cancer treatment.
Abstract: Cardiac dysfunction resulting from exposure to cancer therapeutics
was first recognized in the 1960s, with the widespread introduction
of anthracyclines into the oncologic therapeutic armamentarium.
Heart failure (HF) associated with anthracyclines was then recognized
as an important side effect. As a result, physicians learned to limit their
doses to avoid cardiac dysfunction. Several strategies have been used
over the past decades to detect it. Two of them evolved over time
to be very useful: endomyocardial biopsies and monitoring of left ven-
tricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination
of endomyocardial biopsies proved to be the most sensitive and spe-
cific parameter for the identification of anthracycline-induced LV
dysfunction and became the gold standard in the 1970s. However,
the interest in endomyocardial biopsy has diminished over time
because of the reduction in the cumulative dosages used to treat ma-
lignancies, the invasive nature of the procedure, and the remarkable
progress made in noninvasive cardiac imaging. The noninvasive
evaluation of LVEF has gained importance, and notwithstanding the
limitations of the techniques used for its calculation, has emerged as
the most widely used strategy for monitoring the changes in cardiac
function, both during and after the administration of potentially car-
diotoxic cancer treatment.
1,316 citations
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TL;DR: A comparison with the existing concreteness norms indicates that participants, as before, largely focused on visual and haptic experiences.
Abstract: Concreteness ratings are presented for 37,058 English words and 2,896 two-word expressions (such as zebra crossing and zoom in), obtained from over 4,000 participants by means of a norming study using Internet crowdsourcing for data collection. Although the instructions stressed that the assessment of word concreteness would be based on experiences involving all senses and motor responses, a comparison with the existing concreteness norms indicates that participants, as before, largely focused on visual and haptic experiences. The reported data set is a subset of a comprehensive list of English lemmas and contains all lemmas known by at least 85 % of the raters. It can be used in future research as a reference list of generally known English lemmas.
1,237 citations
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TL;DR: Differences in assessment and low agreement between reviewers and authors suggest the need to contact authors for information not published in studies when applying the NOS in systematic reviews.
Abstract: Lack of appropriate reporting of methodological details has previously been shown to distort risk of bias assessments in randomized controlled trials. The same might be true for observational studies. The goal of this study was to compare the Newcastle-Ottawa Scale (NOS) assessment for risk of bias between reviewers and authors of cohort studies included in a published systematic review on risk factors for severe outcomes in patients infected with influenza. Cohort studies included in the systematic review and published between 2008–2011 were included. The corresponding or first authors completed a survey covering all NOS items. Results were compared with the NOS assessment applied by reviewers of the systematic review. Inter-rater reliability was calculated using kappa (K) statistics. Authors of 65/182 (36%) studies completed the survey. The overall NOS score was significantly higher (p < 0.001) in the reviewers’ assessment (median = 6; interquartile range [IQR] 6–6) compared with those by authors (median = 5, IQR 4–6). Inter-rater reliability by item ranged from slight (K = 0.15, 95% confidence interval [CI] = −0.19, 0.48) to poor (K = −0.06, 95% CI = −0.22, 0.10). Reliability for the overall score was poor (K = −0.004, 95% CI = −0.11, 0.11). Differences in assessment and low agreement between reviewers and authors suggest the need to contact authors for information not published in studies when applying the NOS in systematic reviews.
1,171 citations
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TL;DR: In this article, the authors provide support to the bedside clinician regarding the diagnosis, management and monitoring of circulatory shock, which is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate.
Abstract: Objective
Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock.
1,142 citations
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TL;DR: It is shown that the quality of evidence supporting NMA estimates varies from high to very low across comparisons, and that quality ratings given to a whole network are uninformative and likely to mislead.
Abstract: Network meta-analysis (NMA), combining direct and indirect comparisons, is increasingly being used to examine the comparative effectiveness of medical interventions. Minimal guidance exists on how to rate the quality of evidence supporting treatment effect estimates obtained from NMA. We present a four-step approach to rate the quality of evidence in each of the direct, indirect, and NMA estimates based on methods developed by the GRADE working group. Using an example of a published NMA, we show that the quality of evidence supporting NMA estimates varies from high to very low across comparisons, and that quality ratings given to a whole network are uninformative and likely to mislead.
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TL;DR: Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease, and other therapies for motor and nonmotor features is less well established.
Abstract: Importance Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. Objective To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. Evidence Review References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. Results Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged Conclusions and Relevance Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.
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29 Sep 2014TL;DR: In this article, the authors present a concise review of developments on various continuous multivariate distributions and present some basic definitions and notations, and present several important continuous multi-dimensional distributions and their significant properties and characteristics.
Abstract: In this article, we present a concise review of developments on various continuous multivariate distributions. We first present some basic definitions and notations. Then, we present several important continuous multivariate distributions and list their significant properties and characteristics.
Keywords:
generating function;
moments;
conditional distribution;
truncated distribution;
regression;
bivariate normal;
multivariate normal;
multivariate exponential;
multivariate gamma;
dirichlet;
inverted dirichlet;
liouville;
multivariate logistic;
multivariate pareto;
multivariate extreme value;
multivariate t;
wishart translated systems;
multivariate exponential families
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University of Cambridge1, Nottingham University Hospitals NHS Trust2, University of Manchester3, St George's Hospital4, University of Southampton5, University of Warwick6, Cambridge University Hospitals NHS Foundation Trust7, University of Oxford8, Queen Alexandra Hospital9, University of Plymouth10, Northumbria Healthcare NHS Foundation Trust11, University of Nottingham12, University Hospital Coventry13, King's College London14, McMaster University15, University of Leicester16
TL;DR: These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia and suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria for the first time.
Abstract: These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barrett's oesophagus and related neoplasia.
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TL;DR: The IOC expert working group introduces a broader, more comprehensive term for the condition previously known as ‘Female Athlete Triad’, ‘Relative Energy Deficiency in Sport’ (RED-S), and recommends practical clinical models for the management of affected athletes.
Abstract: Protecting the health of the athlete is a goal of the International Olympic Committee (IOC). The IOC convened an expert panel to update the 2005 IOC Consensus Statement on the Female Athlete Triad. This Consensus Statement replaces the previous and provides guidelines to guide risk assessment, treatment and return-to-play decisions. The IOC expert working group introduces a broader, more comprehensive term for the condition previously known as ‘Female Athlete Triad’. The term ‘Relative Energy Deficiency in Sport’ (RED-S), points to the complexity involved and the fact that male athletes are also affected. The syndrome of RED-S refers to impaired physiological function including, but not limited to, metabolic rate, menstrual function, bone health, immunity, protein synthesis, cardiovascular health caused by relative energy deficiency. The cause of this syndrome is energy deficiency relative to the balance between dietary energy intake and energy expenditure required for health and activities of daily living, growth and sporting activities. Psychological consequences can either precede RED-S or be the result of RED-S. The clinical phenomenon is not a ‘triad’ of the three entities of energy availability, menstrual function and bone health, but rather a syndrome that affects many aspects of physiological function, health and athletic performance. This Consensus Statement also recommends practical clinical models for the management of affected athletes. The ‘Sport Risk Assessment and Return to Play Model’ categorises the syndrome into three groups and translates these classifications into clinical recommendations.
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Cleveland Clinic1, MedStar Washington Hospital Center2, University of Texas Health Science Center at Houston3, University of Pennsylvania4, Harvard University5, McMaster University6, McGill University7, University of Padua8, European Institute of Oncology9, University of Chicago10, Oslo University Hospital11, Temple University12, University of Liège13, Memorial Sloan Kettering Cancer Center14, Menzies Research Institute15, Mayo Clinic16
TL;DR: The non-invasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially cardiotoxic cancer treatment.
Abstract: ### A. Definition, classification, and mechanisms of toxicity
Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncological therapeutic armamentarium.1 Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction.2 Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ventricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and specific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat malignancies, the invasive nature of the procedure, and the remarkable progress made in non-invasive cardiac imaging. The non-invasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially cardiotoxic cancer treatment.3–5
The timing of LV dysfunction can vary among agents. In the case of anthracyclines, the damage occurs immediately after the exposure;6 for others, the time frame between drug administration and detectable cardiac dysfunction appears to be more variable. Nevertheless, the heart has significant cardiac reserve, and the expression of damage in the form of alterations in systolic or diastolic parameters may not be overt until a substantial amount of cardiac reserve has been exhausted. Thus, cardiac damage may not become apparent until years or even decades after receiving the cardiotoxic treatment. This is particularly applicable to …
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University of Wisconsin-Madison1, Radiation Therapy Oncology Group2, University of Phoenix3, Tel Aviv Sourasky Medical Center4, Main Line Health5, McMaster University6, University of Western Ontario7, Christiana Care Health System8, Thomas Jefferson University9, Willamette University10, Boston University11, University of Maryland, Baltimore12
TL;DR: Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.
Abstract: Purpose Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance.
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Icahn School of Medicine at Mount Sinai1, Pierre-and-Marie-Curie University2, French Institute of Health and Medical Research3, Centre national de la recherche scientifique4, University of Toronto5, Trinity College, Dublin6, University of Pittsburgh7, Utrecht University8, McMaster University9, Our Lady's Children's Hospital10, University College Dublin11, University of Oxford12, University of Lisbon13, Instituto Nacional de Saúde Dr. Ricardo Jorge14, University of California, Los Angeles15, University of Miami16, Goethe University Frankfurt17, University of Pennsylvania18, Vanderbilt University19, Temple University20, University of Bologna21, Cancer Care Ontario22, University of Southern California23, University of Alberta24, University of Birmingham25, Université de Montréal26, Rush University Medical Center27, University of Coimbra28, Kaiser Permanente29, Cornell University30, Newcastle University31, University of Illinois at Chicago32, University of Minnesota33, University of Gothenburg34, Memorial University of Newfoundland35, Duke University36, University of Paris37, King's College London38, Centre for Mental Health39, University of Washington40, Nationwide Children's Hospital41, Indiana University42, Tufts University43, German Cancer Research Center44, University of Utah45, Stanford University46
TL;DR: For example, the authors analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability.
Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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TL;DR: This review summarizes the current state of animal model translation to clinical practice, and offers some explanations for the general lack of success in this process.
Abstract: Due to practical and ethical concerns associated with human experimentation, animal models have been essential in cancer research. However, the average rate of successful translation from animal models to clinical cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression. Therefore the safety and efficacy identified in animal studies is generally not translated to human trials. Animal models can serve as an important source of in vivo information, but alternative translational approaches have emerged that may eventually replace the link between in vitro studies and clinical applications. This review summarizes the current state of animal model translation to clinical practice, and offers some explanations for the general lack of success in this process. In addition, some alternative strategies to the classic in vivo approach are discussed.
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TL;DR: These guidelines were developed by Canadian experts in anxiety and related disorders through a consensus process based on global impression of efficacy, effectiveness, and side effects, using a modified version of the periodic health examination guidelines.
Abstract: Anxiety and related disorders are among the most common mental disorders, with lifetime prevalence reportedly as high as 31%. Unfortunately, anxiety disorders are under-diagnosed and under-treated. These guidelines were developed by Canadian experts in anxiety and related disorders through a consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were obtained through MEDLINE, PsycINFO, and manual searches (1980–2012). Treatment strategies were rated on strength of evidence, and a clinical recommendation for each intervention was made, based on global impression of efficacy, effectiveness, and side effects, using a modified version of the periodic health examination guidelines. These guidelines are presented in 10 sections, including an introduction, principles of diagnosis and management, six sections (Sections 3 through 8) on the specific anxiety-related disorders (panic disorder, agoraphobia, specific phobia, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), and two additional sections on special populations (children/adolescents, pregnant/lactating women, and the elderly) and clinical issues in patients with comorbid conditions. Anxiety and related disorders are very common in clinical practice, and frequently comorbid with other psychiatric and medical conditions. Optimal management requires a good understanding of the efficacy and side effect profiles of pharmacological and psychological treatments.
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TL;DR: Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE.
Abstract: Background—Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings. Methods and Resu...
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TL;DR: An estimated sodium intake between 3g per day and 6 g per day was associated with a lower risk of death and cardiovascular events than was either a higher or lower estimated level of intake.
Abstract: BackgroundThe optimal range of sodium intake for cardiovascular health is controversial. MethodsWe obtained morning fasting urine samples from 101,945 persons in 17 countries and estimated 24-hour sodium and potassium excretion (used as a surrogate for intake). We examined the association between estimated urinary sodium and potassium excretion and the composite outcome of death and major cardiovascular events. ResultsThe mean estimated sodium and potassium excretion was 4.93 g per day and 2.12 g per day, respectively. With a mean follow-up of 3.7 years, the composite outcome occurred in 3317 participants (3.3%). As compared with an estimated sodium excretion of 4.00 to 5.99 g per day (reference range), a higher estimated sodium excretion (≥7.00 g per day) was associated with an increased risk of the composite outcome (odds ratio, 1.15; 95% confidence interval [CI], 1.02 to 1.30), as well as increased risks of death and major cardiovascular events considered separately. The association between a high esti...
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Fernando Botto1, Pablo Alonso-Coello1, Matthew T. V. Chan2, Matthew T. V. Chan3 +291 more•Institutions (25)
TL;DR: Among adults undergoing noncardiac surgery, MINS was an independent predictor of 30-day mortality and had the highest population-attributable risk of the perioperative complications.
Abstract: Background Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated "abnormal" laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors' diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96-5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6-41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.
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TL;DR: The ENIGMA Consortium has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected.
Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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Hamilton Health Sciences1, University of Western Ontario2, Royal Melbourne Hospital3, St. John's Medical College4, McMaster University5, University of Basel6, Université catholique de Louvain7, Cayetano Heredia University8, Medical University of Vienna9, University of Manitoba10, University of Alberta11, University of Oxford12, University of Sydney13
TL;DR: Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding.
Abstract: The primary outcome occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P = 0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P = 0.04). The primary and secondary outcome results were similar in the two aspirin strata. Conclusions Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.)
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Institut Gustave Roussy1, University of São Paulo2, Katholieke Universiteit Leuven3, University of Burgundy4, Sapienza University of Rome5, Istituto Superiore di Sanità6, Vrije Universiteit Brussel7, University of Manchester8, University of Michigan9, National University of Cuyo10, Pierre-and-Marie-Curie University11, New York University12, University of Salento13, University of Crete14, Charles University in Prague15, University of Erlangen-Nuremberg16, University Hospital Heidelberg17, University of Pittsburgh18, University of Helsinki19, National Institutes of Health20, University of Bonn21, Providence Portland Medical Center22, National University of Singapore23, Ghent University24, University of Milan25, University of Graz26, University of Paris-Sud27, University College London28, Tuscia University29, McMaster University30, Technische Universität München31, Medical University of Vienna32, Karolinska Institutet33, University of Nice Sophia Antipolis34, University of Turin35, QIMR Berghofer Medical Research Institute36, Université de Montréal37, Dow University of Health Sciences38, French Institute of Health and Medical Research39, University of Colorado Denver40, University of Hawaii41, Stony Brook University42, Paris Descartes University43
TL;DR: Strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative I CD inducers are outlined, based on a high-content, high-throughput platform that was recently developed.
Abstract: Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.
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TL;DR: An open-source application, called BoxPlotR, and an associated web portal that allow rapid generation of customized box plots, which represent both the summary statistics and the distribution of the primary data in biomedical research.
Abstract: To the Editor
In biomedical research, it is often necessary to compare multiple data sets with different distributions. The bar plot, or histogram, is typically used to compare data sets on the basis of simple statistical measures, usually the mean with s.d. or s.e.m. However, summary statistics alone may fail to convey underlying differences in the structure of the primary data (Fig. 1a), which may in turn lead to erroneous conclusions. The box plot, also known as the box-and-whisker plot, represents both the summary statistics and the distribution of the primary data. The box plot thus enables visualization of the minimum, lower quartile, median, upper quartile and maximum of any data set (Fig. 1b). The first documented description of a box plot–like graph by Spear1 defined a range bar to show the median and interquartile range (IQR, or middle 50%) of a data set, with whiskers extended to minimum and maximum values. The most common implementation of the box plot, as defined by Tukey2, has a box that represents the IQR, with whiskers that extend 1.5 times the IQR from the box edges; it also allows for identification of outliers in the data set. Whiskers can also be defined to span the 95% central range of the data3. Other variations, including bean plots4 and violin plots, reveal additional details of the data distribution. These latter variants are less statistically informative but allow better visualization of the data distribution, such as bimodality (Fig. 1b), that may be hidden in a standard box plot.
Figure 1
Data visualization with box plots
Despite the obvious advantages of the box plot for simultaneous representation of data set and statistical parameters, this method is not in common use, in part because few available software tools allow the facile generation of box plots. For example, the standard spreadsheet tool Excel is unable to generate box plots. Here we describe an open-source application, called BoxPlotR, and an associated web portal that allow rapid generation of customized box plots. A user-defined data matrix is uploaded as a file or pasted directly into the application to generate a basic box plot with options for additional features. Sample size may be represented by the width of each box in proportion to the square root of the number of observations5. Whiskers may be defined according to the criteria of Spear1, Tukey2 or Altman3. The underlying data distribution may be visualized as a violin or bean plot or, alternatively, the actual data may be displayed as overlapping or nonoverlapping points. The 95% confidence interval that two medians are different may be illustrated as notches defined as ±(1.58 × IQR/√n) (ref. 5). There is also an op on to plot the sample means and their confidence intervals. More complex statistical comparisons may be required to ascertain significance according to the specific experimental design6. The output plots may be labeled; customized by color, dimensions and orientation; and exported as publication-quality .eps, .pdf or .svg files. To help ensure that generated plots are accurately described in publications, the application generates a description of the plot for incorporation into a figure legend.
The interactive web application is written in R (ref. 7) with the R packages shiny, beanplot4, vioplot, beeswarm and RColorBrewer, and it is hosted on a shiny server to allow for interactive data analysis. User data are held only temporarily and discarded as soon as the session terminates. BoxPlotR is available at http://boxplot.tyerslab.com/ and may be downloaded to run locally or as a virtual machine for VMware and VirtualBox.
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TL;DR: The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ≥100 kg, moderate renal insufficiency, an age ≥75 years, and cancer.
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TL;DR: Probiotics are effective treatments for IBS, although which individual species and strains are the most beneficial remains unclear, and the efficacy of all three therapies in CIC is also uncertain.
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TL;DR: A systematic review of the literature on the global burden of venous thromboembolism (VTE) in low-, middle-, and high-income countries was performed in this article.
Abstract: Background— Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. Objective— To review the literature on the global burden of disease caused by VTE. Approach and Results— We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. Conclusions— VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden.