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Shrier I.,Lady Davis Institute for Medical Research
British Journal of Sports Medicine | Year: 2015

The sport medicine clinician is faced with return-to-play (RTP) decisions for every patient who wants to return to activity. The complex interaction of factors related to history, physical examination, testing, activity and baseline characteristics can make RTP decision-making challenging. Further, when reasoning is not explicit, unnecessary conflict can arise among clinicians themselves, or among clinicians and patients. This conflict can have negative health consequences for the patient. In 2010, a transparent framework for RTP decisions was proposed. However, some have identified limitations to the framework and found difficulties in its implementation. This paper presents a revised framework that addresses the limitations, and provides concrete examples of how to apply it in simple and complex cases. Source


Schiffrin E.L.,Lady Davis Institute for Medical Research
Canadian Journal of Cardiology | Year: 2013

Over the past 20 years it has become recognized that low-grade inflammation plays a role in cardiovascular disease. More recently, participation of the innate and the adaptive immune response in mechanisms that contribute to inflammation in cardiovascular disease has been reported in atherosclerosis and hypertension. Different subsets of lymphocytes and their cytokines are involved in vascular remodelling and hypertensive renal disease as well as heart disease. Effector T cells including T-helper (Th) 1 (interferon-γ-producing) and Th2 lymphocytes (interleukin-4 producing), as well as Th17 (which produce interleukin-17), and T suppressor lymphocytes such as T regulatory cells, which express the transcription factor forkhead box P3, participate respectively as pro- and anti-inflammatory cells, and mediate effects of angiotensin II and mineralocorticoids. Involvement of immune mechanisms in cardiac, vascular, and renal changes in hypertension has been demonstrated in many experimental models, an example being the Dahl-salt sensitive rat and the spontaneously hypertensive rat. How activation of immunity is triggered remains unknown, but neoantigens could be generated by elevated blood pressure through damage-associated molecular pattern receptors or other mechanisms. When activated, Th1 may contribute to blood pressure elevation by affecting the kidney, vascular remodelling of blood vessels directly via effects of the cytokines produced, or through their effects on perivascular fat. T regulatory cells protect from blood pressure elevation acting on similar targets. These novel findings may open the way for new therapeutic approaches to improve outcomes in hypertension and cardiovascular disease in humans. © 2013 Canadian Cardiovascular Society. Source


Schiffrin E.L.,Lady Davis Institute for Medical Research
Clinical Science | Year: 2014

Over the last 20 years it has become recognized that low-grade inflammation plays a role in cardiovascular disease. More recently, participation of the innate and the adaptive immune response in mechanisms that contribute to inflammation in cardiovascular disease has been reported in atherosclerosis and hypertension. Different subsets of lymphocytes and their cytokines are involved in vascular remodelling in hypertension, chronic kidney disease and heart disease. Effector T-cells include Th1 (interferon-γ -producing) and Th2 (interleukin-4 producing) lymphocytes, as well as Th17 (which produce interleukin-17) and T-suppressor lymphocytes such as Treg-cells (regulatory T-cells), which express the transcription factor Foxp3 (forkhead box P3) and participate respectively as pro- and anti-inflammatory cells. Pro-inflammatory T-lymphocytes participate in mechanisms of cardiovascular disease in part by mediating the effects of angiotensin II and mineralocorticoids. Involvement of immune mechanisms in cardiac, vascular and renal changes in hypertension has been demonstrated in many experimental models, an example being the Dahl-salt sensitive rat and the spontaneously hypertensive rat. How activation of immunity is triggered remains unknown, but neo-antigens could be generated by elevated blood pressure through damage-associated molecular pattern receptors or other mechanisms. Once activated, Th1 cells may contribute to blood pressure elevation by affecting the kidney, vascular remodelling of blood vessels directly via the effects of the cytokines produced or through their effects on perivascular fat. Treg-cells protect from blood pressure elevation by acting upon similar targets. Recent data suggests that participation of these mechanisms that have been demonstrated already in murine models also occurs in humans. These novel findings may open the way for new therapeutic approaches to improve outcomes in hypertension and cardiovascular disease in humans. © 2014 Biochemical Society. Source


Hoffer L.J.,Lady Davis Institute for Medical Research | Bistrian B.R.,Beth Israel Deaconess Medical Center
American Journal of Clinical Nutrition | Year: 2012

Background: Widely varying recommendations have been published with regard to the appropriate amount of protein or amino acids to provide in critical illness. Objective: We carried out a systematic review of clinical trials that compared the metabolic or clinical effects of different protein intakes in adult critical illness and comprehensively reviewed all of the available evidence pertinent to the safe upper limit of protein provision in this setting. Design: MEDLINE was searched for clinical trials published in English between 1948 and 2012 that provided original data comparing the effects of different levels of protein intake on clinically relevant outcomes and evidence pertinent to the safe upper limit of protein provision to critically ill adults. Results: The limited amount and poor quality of the evidence preclude conclusions or clinical recommendations but strongly suggest that 2.0-2.5 g protein substrate · kg normal body weight -1 · d -1 is safe and could be optimum for most critically ill patients. At the present time, most critically ill adults receive less than half of the most common current recommendation, 1.5 g protein · kg -1 · d -1, for the first week or longer of their stay in an intensive care unit. Conclusion: There is an urgent need for well-designed clinical trials to identify the appropriate level of protein provision in critical illness. © 2012 American Society for Nutrition. Source


Eggermont A.M.M.,French Institute of Health and Medical Research | Eggermont A.M.M.,Erasmus Medical Center | Spatz A.,Lady Davis Institute for Medical Research | Robert C.,French Institute of Health and Medical Research
The Lancet | Year: 2014

In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to aff ect survival. The eff ect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns diff er substantially anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefi t of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs. Source

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