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The University of Toronto is a public research university in Toronto, Ontario, Canada, situated on the grounds that surround Queen's Park. It was founded by royal charter in 1827 as King's College, the first institution of higher learning in Upper Canada. Originally controlled by the Church of England, the university assumed the present name in 1850 upon becoming a secular institution. Wikipedia.


Hannah-Moffat K.,University of Toronto
Psychology, Crime and Law | Year: 2016

Recent calls for ‘evidence-based’ approaches have firmly positioned risk assessment as a promising path towards more efficient, unbiased, and empirically based offender management, in custody and in the community. Simultaneously, sociological and critical legal scholars have questioned the focus on individual needs at the expense of wider structural factors’. I will demonstrate the need to reconceptualise risk/need logics and the use of ‘evidence’. I will argue that various criminal justice processes are themselves dynamic criminogenic risks that produce systemic conditions for recidivism and which, if modified, could make a measurable difference in recidivism and other correctional efficiencies. Finally, I will argue that the logic of dynamic risk is transferable to an analysis of socio-structural factors, and that this characterisation can alter the framing of penal subjects, governmental responsibilities, and potentially interrupt the systemically produced criminogenic pathways that perpetuate criminal involvement and marginalisation. © 2016 Taylor & Francis.


Duffin J.,University of Toronto
Journal of Physiology | Year: 2014

This paper presents a personal view of research into the exercise drive to breathe that can be observed to act immediately to increase breathing at the start of rhythmic exercise. It is based on a talk given at the Experimental Biology 2013 meeting in a session entitled 'Recent advances in understanding mechanisms regulating breathing during exercise'. This drive to breathe has its origin in a combination of central command, whereby voluntary motor commands to the exercising muscles produce a concurrent respiratory drive, and afferent feedback, whereby afferent information from the exercising muscles affects breathing. The drive at the start and end of rhythmic exercise is proportional to limb movement frequency, and its magnitude decays as exercise continues so that the immediate decrease of ventilation at the end of exercise is about 60% of the immediate increase at the start. With such evidence for the effect of this fast drive to breathe at the start and end of rhythmic exercise, its existence during exercise is hypothesised. Experiments to test this hypothesis have, however, provided debatable evidence. A fast drive to breathe during both ramp and sine wave changes in treadmill exercise speed and grade appears to be present in some individuals, but is not as evident in the general population. Recent sine-wave cycling experiments show that when cadence is varied sinusoidally the ventilation response lags by about 10 s, whereas when pedal loading is varied ventilation lags by about 30 s. It therefore appears that limb movement frequency is effective in influencing ventilation during exercise as well as at the start and end of exercise. © 2013 The Physiological Society.


Lee H.W.,University of Toronto
The International journal of oral & maxillofacial implants | Year: 2013

To report the complications encountered during 100 consecutive maxillary sinus augmentations via the lateral window approach and to propose solutions to manage these complications. Pretreatment residual bone heights and the presence of septa were recorded. The incidences of any intraoperative or postoperative sinus complications such as excessive bleeding, membrane perforation, infection, wound dehiscence, sinusitis, loss of bone graft, and implant success were reported. results: This study evaluated 42 men and 44 women requiring 100 consecutive sinus elevation procedures between March 2008 and February 2011. Five intraoperative membrane perforations were noted, and one subsequently developed an active infection (2 weeks after surgery). Eight instances of suppuration were noted, while 10 sites presented with wound dehiscence 1 to 2 weeks after surgery. One example of partial loss of the bone graft 6 months after surgery was identified. Of a total of 151 implants placed in 97 sinuses (one patient with bilateral sinuses and one with unilateral sinus did not complete implant placement), 2 implants presented excessive bone loss prior to uncovering. One implant was removed and one was left submerged. conclusions: Sinus floor elevation utilizing the lateral window approach is a predictable approach to manage bone volume deficiency in the posterior maxilla for patients seeking dental implant-based treatment. However, complications may include membrane tear, infection, wound dehiscence, loss of graft, and implant failure. It is vital for the clinician to understand how to recognize and solve these complications.


Barnaby N.,University of Toronto
Nuclear Physics B | Year: 2011

There are a number of reasons to entertain the possibility that locality is violated on microscopic scales, for example through the presence of an infinite series of higher derivatives in the fundamental equations of motion. This type of nonlocality leads to improved UV behavior, novel cosmological dynamics and is a generic prediction of string theory. On the other hand, fundamentally nonlocal models are fraught with complications, including instabilities and complications in setting up the initial value problem. We study the structure of the initial value problem in an interesting class of nonlocal models. We advocate a novel new formulation wherein the Cauchy surface is "smeared out" over the underlying scale of nonlocality, so that the usual notion of initial data at t=0 is replaced with an "initial function" defined over -M-1≤t≤0 where M is the underlying scale of nonlocality. Focusing on some specific examples from string theory and cosmology, we show that this mathematical re-formulation has surprising implications for the well-known stability problem. For D-brane decay in a linear dilaton background, we are able to show that the unstable directions in phase space cannot be accessed starting from a physically sensible initial function. Previous examples of unstable solutions in this model therefore correspond to unphysical initial conditions, an observation which is obfuscated in the old formulation of the initial value problem. We also discuss implication of this approach for nonlocal cosmological models. © 2010 Elsevier B.V.


Armstrong S.M.,University of Toronto
Virulence | Year: 2013

The development of severe influenza has been attributed, in part, to a heightened innate immune response. Recent evidence suggests that endothelial activation, loss of barrier function, and consequent microvascular leak may also serve important mechanistic roles in the pathogenesis of severe influenza. The aim of this review is to summarize the current evidence in support of endothelial activation and dysfunction as a central feature preceding the development of severe influenza. We also discuss the effect of influenza on platelet-endothelial interactions.


Floras J.S.,University of Toronto
Canadian Journal of Cardiology | Year: 2013

Blood pressure is a continuous, not a static, variable. Individuals exhibiting similar clinic or home blood pressure can differ considerably with respect to their average day and nighttime values, beat-by-beat blood pressure variation during wakefulness and sleep, responses to mental and physical stimuli, and intersession and seasonal variation. There now is evidence that several such representations of blood pressure variability, if augmented, increase cardiovascular risk independent of the average of conventionally acquired blood pressure readings. As well, recent retrospective analyses of published trial data have concluded that antihypertensive drug classes differ in their effects on intersession blood pressure variability and associated risk of stroke. If the goal of the hypertension community is to optimize personalized cardiovascular risk assessment and to attenuate fully such risk, future efforts should be directed at determining which representation of blood pressure variability estimates individual cardiovascular risk best, establishing "normal" and "high- risk" variability distributions, testing the hypothesis that attenuating such variability specifically through drug or device therapy reduces cardiovascular risk more than blood pressure reduction per se, and integrating such data into clinical practice. © 2013 Canadian Cardiovascular Society.


Hollister J.D.,University of Toronto
New Phytologist | Year: 2015

Genomic evidence of ancestral whole genome duplication (WGD) and polyploidy is widespread among eukaryotic species, and especially among plants. WGD is thought to provide the raw material for adaptation in the form of duplicated genes, and polyploids are thought to benefit from both physiological and genetic buffering. Comparatively little attention has focused on the genomic challenge of polyploidy, however, although much evidence exists that polyploidy severely perturbs important cellular functions. Here, I review recent progress in the study of the re-establishment of stable meiosis in recently evolved polyploids, focusing on four plant species. This work has yielded an insight into the mechanisms underlying stabilization of genome transmission in polyploids, and is revealing remarkable parallels among diverse taxa. Importantly, these studies also provide a road map for investigating how polyploids respond to the challenge of WGD. © 2014 New Phytologist Trust.


McIntyre K.,University of Toronto
Current Opinion in Pulmonary Medicine | Year: 2013

PURPOSE OF REVIEW: Survival for patients with cystic fibrosis (CF) continues to improve. The proportion of CF patients over the age of 18 years is nearly 50%, and care providers will need to better understand this patient population. Despite these improvements, young females continue to have a worse prognosis and lower median survival compared with their male counterparts. Contributing factors to the difference in survival remain uncertain. RECENT FINDINGS: The 'gender gap' remains an area of controversy. Recent data suggest that it still exists, though exact reasons remain unclear. For those patients diagnosed in adulthood, outcomes are also improving. Some evidence suggests persistence of the gender gap. Other data suggest a reversal of this effect. Additional work and study are needed. SUMMARY: This review finds supporting evidence for persistence of the gender gap and outlines the effect of age and sex on survival in CF. The majority of patients with CF will now be adults; thus, care providers must be aware of the impact this will have on ongoing patient management. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Campbell S.A.,University of Toronto
New Phytologist | Year: 2015

The diversity of flowering plants is evident in two seemingly unrelated aspects of life history: sexual reproduction, exemplified by the stunning variation in flower form and function, and defence, often in the form of an impressive arsenal of secondary chemistry. Researchers are beginning to appreciate that plant defence and reproduction do not evolve independently, but, instead, may have reciprocal and interactive (coevolutionary) effects on each other. Understanding the mechanisms for mating-defence interactions promises to broaden our understanding of how ecological processes can generate these two rich sources of angiosperm diversity. Here, I review current research on the role of herbivory as a driver of mating system evolution, and the role of mating systems in the evolution of defence strategies. I outline different ecological mechanisms and processes that could generate these coevolutionary patterns, and summarize theoretical and empirical support for each. I provide a conceptual framework for linking plant defence with mating system theory to better integrate these two research fields. © 2014 New Phytologist Trust.


We use N-body simulations as well as analytical techniques to study the long-term dynamical evolution of stellar black holes (BHs) at the Galactic center (GC) and to put constraints on their number and mass distribution. Starting from models that have not yet achieved a state of collisional equilibrium, we find that timescales associated with cusp regrowth can be longer than the Hubble time. Our results cast doubts on standard models that postulate high densities of BHs near the GC and motivate studies that start from initial conditions that correspond to well-defined physical models. For the first time, we consider the distribution of BHs in a dissipationless model for the formation of the Milky Way nuclear cluster (NC), in which massive stellar clusters merge to form a compact nucleus. We simulate the consecutive merger of 10 clusters containing an inner dense sub-cluster of BHs. After the formed NC is evolved for 5 Gyr, the BHs do form a steep central cusp, while the stellar distribution maintains properties that resemble those of the GC NC. Finally, we investigate the effect of BH perturbations on the motion of the GC S-stars as a means of constraining the number of the perturbers. We find that reproducing the quasi-thermal character of the S-star orbital eccentricities requires ≳ 1000 BHs within 0.1 pc of Sgr A∗. A dissipationless formation scenario for the GC NC is consistent with this lower limit and therefore could reconcile the need for high central densities of BHs (to explain the S-stars orbits) with the "missing-cusp" problem of the GC giant star population. © 2014. The American Astronomical Society. All rights reserved..


Odutayo A.,University of Toronto
Clinical journal of the American Society of Nephrology : CJASN | Year: 2012

Glomerular hyperfiltration, altered tubular function, and shifts in electrolyte-fluid balance are among the hallmark renal physiologic changes that characterize a healthy pregnancy. These adjustments are not only critical to maternal and fetal well being, but also provide the clinical context for identifying gestational aberrations in renal function and electrolyte composition. Systemic vasodilation characterizes early gestation and produces increments in renal plasma flow and GFR, the latter of which is maintained into the postpartum period. In addition, renal tubular changes allow for the accumulation of nutrients and electrolytes necessary for fetal growth such that wasting of proteins, glucose, and amino acids in urine is limited in pregnancy and total body stores of electrolytes increase throughout gestation. Substantial insight into the mechanisms underlying these complex adjustments can be gleaned from the available animal and human literature, but our understanding in many areas remains incomplete. This article reviews the available literature on renal adaptation to normal pregnancy, including renal function, tubular function, and electrolyte-fluid balance, along with the clinical ramifications of these adjustments, the limitations of the existing literature, and suggestions for future studies.


Hodnett E.D.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2011

Historically, women have been attended and supported by other women during labour. However in hospitals worldwide, continuous support during labour has become the exception rather than the routine. Primary: to assess the effects of continuous, one-to-one intrapartum support compared with usual care. Secondary: to determine whether the effects of continuous support are influenced by: (1) routine practices and policies; (2) the provider's relationship to the hospital and to the woman; and (3) timing of onset. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2010). All published and unpublished randomized controlled trials comparing continuous support during labour with usual care. We used standard methods of the Cochrane Collaboration Pregnancy and Childbirth Group. Two authors independently evaluated methodological quality and extracted the data. We sought additional information from the trial authors. We used random-effects analyses for comparisons in which high heterogeneity was present, and we reported results using the risk ratio for categorical data and mean difference for continuous data. Twenty-one trials involving 15061 women met inclusion criteria and provided usable outcome data. Results are of random-effects analyses, unless otherwise noted. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (RR 1.08, 95% CI 1.04 to 1.12) and less likely to have intrapartum analgesia (RR 0.90, 95% CI 0.84 to 0.97) or to report dissatisfaction (RR 0.69, 95% CI 0.59 to 0.79). In addition their labours were shorter (mean difference -0.58 hours, 95% CI -0.86 to -0.30), they were less likely to have a caesarean (RR 0.79, 95% CI 0.67 to 0.92) or instrumental vaginal birth (fixed-effect, RR 0.90, 95% CI 0.84 to 0.96), regional analgesia (RR 0.93, 95% CI 0.88 to 0.99), or a baby with a low 5-minute Apgar score (fixed-effect, RR 0.70, 95% CI 0.50 to 0.96). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, or on breastfeeding. Subgroup analyses suggested that continuous support was most effective when provided by a woman who was neither part of the hospital staff nor the woman's social network, and in settings in which epidural analgesia was not routinely available. No conclusions could be drawn about the timing of onset of continuous support. Continuous support during labour has clinically meaningful benefits for women and infants and no known harm. All women should have support throughout labour and birth.


Yogeswaran K.,University of Toronto
The Korean journal of hepatology | Year: 2011

Chronic hepatitis B (CHB) affects 350 million individuals worldwide. Perinatal transmission leads to high rates of chronic infection and complications, including cirrhosis and hepatocellular carcinoma. It is important to recognize and appropriately treat CHB in pregnancy, thereby reducing the risk of neonatal transmission and HBV-associated morbidity and mortality. Screening for CHB is recommended in all pregnant mothers as is universal vaccination of infants with hepatitis B virus (HBV) vaccine with or without hepatitis B immunoglobulin (HBIG). This has resulted in a lower incidence of HBsAg seropositivity and HCC in regions where universal infant vaccination has been endorsed. Mode of delivery and breastfeeding do not appear to affect HBV transmission rates based on available data. Overall, CHB does not increase perinatal maternal-fetal mortality. Administration of oral antiviral therapy during the third trimester to HBsAg-positive mothers with HBV DNA≥7 log IU/mL may be useful in preventing breakthrough infection. Treatment may be considered earlier in pregnancy for persistently active liver disease shown by high ALT, HBV DNA levels and/or significant hepatic fibrosis. Lamivudine, tenofovir and telbivudine are safe and effective and are the agents of choice in pregnancy. However, further clinical studies are necessary to elucidate the role of antiviral therapy in the pregnant HBV carrier.


O'Brien K.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: Access to combination antiretroviral therapy has turned HIV into a chronic and manageable disease for many. This increased chronicity has been mirrored by increased prevalence of health-related challenges experienced by people living with HIV (Rusch 2004). Exercise is a key strategy for people living with HIV and by rehabilitation professionals to address these disablements; however, knowledge about the effects of exercise among adults living with HIV still is emerging. OBJECTIVES: To examine the safety and effectiveness of aerobic exercise interventions on immunologic and virologic, cardiopulmonary, psychologic outcomes and strength, weight, and body composition in adults living with HIV. SEARCH STRATEGY: Searches of MEDLINE, EMBASE, SCIENCE CITATION INDEX, CINAHL, HEALTHSTAR, PsycINFO, SPORTDISCUS and Cochrane Review Group Databases were conducted between 1980 and June 2009. Searches of published and unpublished abstracts and proceedings from major international and national HIV/AIDS conferences were conducted, as well as a handsearch of reference lists and tables of contents of relevant journals and books. SELECTION CRITERIA: We included studies of randomised controlled trials (RCTs) comparing aerobic exercise interventions with no aerobic exercise interventions or another exercise or treatment modality, performed at least three times per week for at least four weeks among adults (18 years of age or older) living with HIV. DATA COLLECTION AND ANALYSIS: Data on study design, participants, interventions, outcomes, and methodological quality were abstracted from included studies by two reviewers. Meta-analyses, using RevMan 5 computer software, were performed on outcomes when possible. MAIN RESULTS: A total of 14 studies met inclusion criteria for this review and 30 meta-analyses over several updates were performed. Main results indicated that performing constant or interval aerobic exercise, or a combination of constant aerobic exercise and progressive resistive exercise for at least 20 minutes at least three times per week for at least five weeks appears to be safe and may lead to significant improvements in selected outcomes of cardiopulmonary fitness (maximum oxygen consumption), body composition (leg muscle area, percent body fat), and psychological status (depression-dejection symptoms). These findings are limited to participants who continued to exercise and for whom there were adequate follow-up data. AUTHORS' CONCLUSIONS: Aerobic exercise appears to be safe and may be beneficial for adults living with HIV. These findings are limited by the small sample sizes and large withdrawal rates described in the studies. Future research would benefit from participant follow-up and intention-to-treat analysis. Further research is required to determine the optimal parameters in which aerobic exercise may be most beneficial for adults living with HIV.


Conroy A.L.,University of Toronto
Expert review of anti-infective therapy | Year: 2012

Despite increased malaria control efforts, recent reports indicate that over 1.2 million deaths due to malaria occurred in 2010. Pregnant women represent a particularly vulnerable risk group as malaria infection can lead to life-threatening disease for the mother and fetus. With 125 million women at risk of malaria in pregnancy every year, better diagnostic tools are needed for timely identification and treatment of malaria infection. Diagnostic surveillance tools are also needed to estimate disease burden and inform public health policies. In this review, the authors focus on malaria diagnostics in pregnancy and discuss considerations for different Plasmodium species and geographic regions. The authors also look at promising diagnostic modalities to monitor fetal and maternal health in pregnancy and discuss implementation barriers for low resource settings.


Franquesa J.,University of Toronto
Antipode | Year: 2011

The "mobility turn" claims that conceding analytical priority to the study of mobility is the best way to overcome methodological approaches based on fixed and stable categories argued to be unviable in a world that is increasingly mobile. In this paper I argue that the mobility approach, far from reaching this goal, in fact reifies the cleavage between mobility and immobility, relegating immobility to a passive, undertheorized position, and collapsing the complex workings of power, thus foreclosing a dialectical understanding of the contradictory albeit co-produced processes of mobilization and immobilization. Drawing on an ethnographic analysis of the impacts of changing patterns of accumulation of the tourist industry on the urban space of Palma (Majorca, Spain), I suggest a relational approach attentive to the dialectics of mobility and stability, continuity and change. © 2011 The Author Antipode © 2011 Editorial Board of Antipode.


Braverman M.,University of Toronto | Rao A.,University of Washington
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2011

We show that it is possible to encode any communication protocol between two parties so that the protocol succeeds even if a (1/4-ε) fraction of all symbols transmitted by the parties are corrupted adversarially, at a cost of increasing the communication in the protocol by a constant factor (the constant depends on epsilon). This encoding uses a constant sized alphabet. This improves on an earlier result of Schulman, who showed how to recover when the fraction of errors is bounded by 1/240. We also show how to simulate an arbitrary protocol with a protocol using the binary alphabet, a constant factor increase in communication and tolerating a (1/8-ε) fraction of errors. © 2011 ACM.


Kruglov S.I.,University of Toronto
Annalen der Physik | Year: 2015

A new model of nonlinear electrodynamics with three parameters is suggested and investigated. It is shown that if the external constant magnetic field is present the phenomenon of vacuum birefringence takes place. The indices of refraction for two polarizations of electromagnetic waves, parallel and perpendicular to the magnetic induction field are calculated. The electric field of a point-like charge is not singular at the origin and the static electric energy is finite. We have calculated the static electric energy of point-like particles for different parameters of the model. The canonical and symmetrical Belinfante energy-momentum tensors and dilatation current are obtained. We demonstrate that the dilatation symmetry and dual symmetry are broken in the model suggested. A new model of nonlinear electrodynamics with three parameters is suggested and investigated. It is shown that if the external constant magnetic field is present the phenomenon of vacuum birefringence takes place. The indices of refraction for two polarizations of electromagnetic waves, parallel and perpendicular to the magnetic induction field are calculated. The electric field of a point-like charge is not singular at the origin and the static electric energy is finite. The static electric energy of point-like particles for different parameters of the model is calculated. The canonical and symmetrical Belinfante energy-momentum tensors and dilatation current are obtained. It is demonstrated that the dilatation symmetry and dual symmetry are broken in the model suggested. © 2015 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kruglov S.I.,University of Toronto
Annals of Physics | Year: 2015

A new model of nonlinear electrodynamics with two parameters is investigated. We also consider a model with one dimensional parameter. It was shown that the electric field of a point-like charge is not singular at the origin and there is the finiteness of the static electric energy of point-like charged particle. We obtain the canonical and symmetrical Belinfante energy-momentum tensors and dilatation currents. It is demonstrated that the dilatation symmetry and dual symmetry are broken in the models suggested. We have calculated the static electric energy of point-like particles. © 2014.


Observations of modern sedimentation rates in nonmarine and shallow-marine clastic environments indicate that deposits formed in comparable settings in the ancient record could accumulate in a fraction of the time that would appear to be available according to conventional chronostratigraphic dating methods. Typically as little as 10% of elapsed time is represented by sediment, the remainder by breaks in sedimentation, many of which are inconspicuous. An examination of the chronostratigraphy and sedimentary history of the Mesaverde Group of the Book Cliffs, Utah, U.S.A., confirms this pattern. Shoreface, deltaic, and nonmarine successions are considered to be particularly fragmentary. Ravinement surfaces may each account for up to 105 years of missing time. In the sedimentary record of shallow-marine and nonmarine deposits stratigraphic continuity is not to be expected, and calculation of time-related issues, such as mass-balance transport rates and the trajectories of shoreline transgression and regression, must take this into account. Copyright © 2014, SEPM (Society for Sedimentary Geology).


Gorczynski P.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: The health benefits of physical activity and exercise are well documented and these effects could help people with schizophrenia. OBJECTIVES: To determine the mental health effects of exercise/physical activity programmes for people with schizophrenia or schizophrenia-like illnesses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (December 2008) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. We also inspected references within relevant papers. SELECTION CRITERIA: We included all randomised controlled trials comparing any intervention where physical activity or exercise was considered to be the main or active ingredient with standard care or other treatments for people with schizophrenia or schizophrenia-like illnesses. DATA COLLECTION AND ANALYSIS: We independently inspected citations and abstracts, ordered papers, quality assessed and data extracted. For binary outcomes we calculated a fixed-effect risk ratio (RR) and its 95% confidence interval (CI). Where possible, the weighted number needed to treat/harm statistic (NNT/H) and its 95% confidence interval (CI), was also calculated. For continuous outcomes, endpoint data were preferred to change data. We synthesised non-skewed data from valid scales using a weighted mean difference (WMD). MAIN RESULTS: Three randomised controlled trials met the inclusion criteria. Trials assessed the effects of exercise on physical and mental health. Overall numbers leaving the trials were similar. Two trials (Beebe 2005 and Marzaloni 2008) compared exercise to standard care and both found exercise to significantly improve negative symptoms of mental state (Mental Health Inventory Depression: 1RCT, n=10, MD 17.50 CI 6.70 to 28.30, PANNS negative: 1RCT, n=10, MD -8.50 CI -11.11 to -5.89). No absolute effects were found for positive symptoms of mental state. Physical health improved significantly in the exercise group compared to those in standard care (1RCT, n=13, MD 79.50 CI 33.82 to 125.18), but no effect on peoples' weight/BMI was apparent. Duraiswamy 2007 compared exercise with yoga and found that yoga had a better outcome for mental state (PANNS total: 1RCT, n=41, MD 14.95 CI 2.60 to 27.30). The same trial also found those in the yoga group had significantly better quality of life scores (WHOQOL Physical: 1RCT, n=41, MD -9.22 CI -18.86 to 0.42). Adverse effects (AIMS total scores) were, however, similar. AUTHORS' CONCLUSIONS: Results of this Cochrane review are similar to existing reviews that have examined the health benefits of exercise in this population (Faulkner 2005). Although studies included in this review are small and used various measures of physical and mental health, results indicated that regular exercise programmes are possible in this population, and that they can have healthful effects on both the physical and mental health and well-being of individuals with schizophrenia. Larger randomised studies are required before any definitive conclusions can be drawn.


Collard R.-C.,University of Toronto
Annals of the Association of American Geographers | Year: 2014

Each year ARCAS Wildlife Rehabilitation Center in northern Guatemala receives 200 to 700 animals: cardboard boxes stuffed with baby parrots, crates full of lizards, monkeys with leashes ringing their necks. Many of these animals were confiscated while being smuggled for the pet trade. Seized animals represent a fraction of overall trade (legal and illegal) in and out of Guatemala and of global trade, worth tens of billions of dollars annually. Forming wild animals into companion commodities in these bio-economic circuits involves severing them from their social, ecological, and familial networks and replacing these systems with human-provided supports: food, shelter, and diversion. Many of these commodities fail because the animals die. For the few animals that are confiscated alive, rehabilitation for return to the wild is a form of decommodification attempted through various misanthropic practices-actions and routines designed to instill in animals fear and even hatred of humans-that aim to divest animals of human ties. This article draws on participant observation and interview fieldwork and socioeconomic scholarship to critically examine the dual processes of making and unmaking lively companion commodities. It suggests that commodification and decommodification are not processes of "denaturing" and "renaturing," respectively. Rather, following Haraway and Smith, they are both productions of particular natures. This article considers the differential contours and subjects of these natures, as well as their ecological and ethical stakes, concluding by suggesting that the collapse of the culture-nature dualism should not preclude acknowledgment of nonhuman animals' wildness and the violence that can attend its attrition. © 2014 Copyright Taylor and Francis Group, LLC.


Moore G.W.K.,University of Toronto
Journal of Climate | Year: 2014

Cape Farewell, Greenland's southernmost point, is characterized by a number of low-level jets that are the result of topographic flow distortion associated with passing extratropical cyclones. The heavy seas associated with these wind events are a hazard to maritime traffic in the region. In addition, the air-sea heat flux associated with these weather systems plays an important role in the climate system by contributing to the forcing of the lower limb of the Atlantic meridional overturning circulation. In this paper, the North American Regional Reanalysis will be used to generate a higher-resolution climatology of these mesoscale jets as compared to previous studies. Through the use of a diagnostic that partitions the occurrence frequency of high-speed wind events by wind direction, the author shows that there are four different types of Cape Farewell tips jets that are characterized as having either northwesterly, southwesterly, northeasterly, or southeasterly wind direction. All four types have distinct regions in the vicinity of Cape Farewell where their respective occurrence frequencies and air-sea heat fluxes are at a maximum. The southwesterly and northeasterly jets closely resemble the wind systems previously identified as being westerly and easterly tip jets. There are also instances where one type evolves into another and so it is possible to view westerly tip jets as a continuum with the northwesterly and southwesterly events identified in this paper representing end members with a similar picture for easterly tip jets. The position of a particular event along these continua will determine its impact on local weather and the coupled climate system. © 2014 American Meteorological Society.


Freedman J.,University of Toronto
Transfusion and Apheresis Science | Year: 2014

Blood conservation, or Patient Blood Management (PBM), is a paradigm shift in transfusion practice. Recognizing the potential adverse effects associated with blood transfusion, PBM emphasises the use of alternatives to transfusion in order to minimize unnecessary or inappropriate blood transfusion. The ONTraC program is a network of transfusion coordinators in 25 Ontario hospitals with the focus of implementing PBM. The program has been highly successful in reducing transfusion rates and improving clinical outcomes, and has proven very cost-effective. This paper summarizes results of the program from its inception in 2002-2011. © 2013 Elsevier Ltd.


Buys Y.M.,University of Toronto
Current Opinion in Ophthalmology | Year: 2013

Despite a large number of ExPRESS implant procedures worldwide, there is a paucity of high-quality studies comparing ExPRESS to trabeculectomy. From the available literature to date the outcomes (success and early complications) of ExPRESS are similar to trabeculectomy. Reports of late complications related to device extrusion and malposition are beginning to be published; however, the significantly increased cost for ExPRESS surgery is likely to be the main limitation to widespread adoption of this procedure. © 2013 Wolters Kluwer Health.


Langer J.C.,University of Toronto
Current Opinion in Pediatrics | Year: 2013

Purpose of review: Hirschsprung disease is relatively common in children. Surgical techniques are available to remove the aganglionic bowel and reconstruct the intestinal tract. Despite many advances, these children may still be difficult to diagnose, and may have ongoing functional problems after surgical correction. Recent findings: The genetic basis and cause of Hirschsprung disease are becoming increasingly clearer. Definitive diagnosis is based on rectal biopsy, but more sophisticated techniques are permitting earlier and more accurate diagnosis. Surgical correction has evolved from routine use of a colostomy and open laparotomy to one-stage transanal and laparoscopic approaches. The range of postoperative problems is reviewed so that the practicing pediatrician and primary care physician can effectively care for these children. Future advances may include better genotype-phenotype correlation and development of neuronal stem cell techniques. Summary: Pediatricians and primary care physicians have an important role to play in diagnosing and managing children with Hirschsprung disease. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Thomas S.C.,University of Toronto
Tree Physiology | Year: 2010

Studies of age-related changes in leaf functional biology have generally been based on dichotomous comparisons of young and mature individuals (e.g., saplings and mature canopy trees), with little data available to describe changes through the entire ontogeny of trees, particularly of broadleaf angiosperms. Leaf-level gas-exchange and morphological parameters were quantified in situ in the upper canopy of trees acclimated to high light conditions, spanning a wide range of ontogenetic stages from saplings (~1 cm in stem diameter) to trees >60 cm d.b.h. and nearing their maximum lifespan, in three temperate deciduous tree species in central Ontario, Canada. Traits associated with growth performance, including leaf photosynthetic capacity (expressed on either an area, mass or leaf N basis), stomatal conductance, leaf size and leaf N content, generally showed a unimodal ('hump-shaped') pattern, with peak values at an intermediate ontogenetic stage. In contrast, leaf mass per area (LMA) and related morphological parameters (leaf thickness, leaf tissue density, leaf C content) increased monotonically with tree size, as did water-use efficiency; these monotonic relationships were well described by simple allometric functions of the form Y = aXb. For traits showing unimodal patterns, tree size corresponding to the trait maximum differed markedly among traits: all three species showed a similar pattern in which the peak for leaf size occurred in trees ~2-6 cm d.b.h., followed by leaf chemical traits and photosynthetic capacity on a mass or leaf N basis and finally by photosynthetic capacity on a leaf area basis, which peaked approximately at the size of reproductive onset. It is argued that ontogenetic increases in photosynthetic capacity and related traits early in tree ontogeny are general among relatively shade-tolerant tree species that have a low capacity for leaf-level acclimation, as are declines in this set of traits late in tree ontogeny. © The Author 2010. Published by Oxford University Press. All rights reserved.


Adeyi O.A.,University of Toronto
Archives of Pathology and Laboratory Medicine | Year: 2011

Context. - Histopathology, like other branches of medicine in West Africa, has suffered largely from economic, political, social, and infrastructural problems, becoming a shadow of the top quality that had been obtained in the past. To address the prevailing problems, one needs to attempt defining them. Objective.-The existing structure of training and practice are discussed, highlighting the author's perception of the problems and suggesting practical ways to address these while identifying potential roles for North American pathology organizations. Design.-The author's past and ongoing association with pathology practice in Nigeria forms the basis for this review. Results.-Pathology practice is largely restricted to academic medical centers. The largest of academic centers each accession around 4000 or fewer surgical specimens per year to train 9 to 12 residents. Histopathology largely uses hematoxylin-eosin routine stains, sometimes with histochemistry but rarely immunohistochemistry. Pathologists depend largely on their skills in morphology (with its limitations) to classify and subclassify tumors on routine stains, including soft tissue and hematolymphoid malignancies. Immunofluorescence, intraoperative frozen section diagnosis, electronic laboratory system, and gross and microscopic imaging facilities are generally not available for clinical use. Conclusion.-The existing facilities and infrastructure can be augmented with provision of material and professional assistance from other pathology associations in more developed countries and should, among other things, focus on supplementing residency education. Virtual residency programs, short-visit observerships, development of simple but practical laboratory information systems, and closer ties with pathologists in these countries are some of the sueeested steps in achieving this goal.


A circular polarizer is used for the first time to image coccoliths without the extinction pattern of crossed polarized light at maximum interference colour. The combination of a circular polarizer with retardation measurements based on grey values derived from theoretical calculations allows for the first time accurate calculations of the weight of single coccoliths thinner than 1.37 I1/4m. The weight estimates of 364 Holocene coccoliths using this new method are in good agreement with published volumetric estimates. A robust calibration method based on the measurement of a calibration target of known retardation enables the comparison of data between different imaging systems. Therefore, the new method overcomes the shortcomings of the error prone empirical calibration procedure of a previously reported method based on birefringence of calcite. Furthermore, it greatly simplifies the identification of coccolithophore species on the light microscope as well as the calculation of the area and thus weight of a coccolith. © Author(s) 2014.


George I.J.,University of Leeds | Abbatt J.P.D.,University of Toronto
Nature Chemistry | Year: 2010

Atmospheric aerosol particles play pivotal roles in climate and air quality. Just as chemically reduced gases experience oxidation in the atmosphere, it is now apparent that solid and liquid atmospheric particulates are also subject to similar oxidative processes. The most reactive atmospheric gas-phase radicals, in particular the hydroxyl radical, readily promote such chemistry through surficial interactions. This Review looks at progress made in this field, discussing the radical-initiated heterogeneous oxidation of organic and inorganic constituents of atmospheric aerosols. We focus on the kinetics and reaction mechanisms of such processes as well as how they can affect the physicoĝ€"chemical properties of particles, such as their composition, size, density and hygroscopicity. Potential impacts on the atmosphere include the release of chemically reactive gases such as halogens, aldehydes and organic acids, reactive loss of particle-borne molecular tracer and toxic species, and enhanced hygroscopic properties of aerosols that may improve their ability to form cloud droplets. © 2010 Macmillan Publishers Limited. All rights reserved.


Fox S.H.,University of Toronto
Drugs | Year: 2013

The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl d-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR5) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT 2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M 4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms. © 2013 Springer International Publishing Switzerland.


Mclean H.,University of Toronto
Antipode | Year: 2014

This paper contributes a critical and intersectional feminist analysis and methodological approach to debates about creative city policies and practices. Through a narrative description of community-engaged arts interventions based on action research with the Toronto Free Gallery, an artist-run centre and activist space, I demonstrate how feminist arts activism uncovers the multiple exclusions that creative city policies and practices entrench. In some ways, community-engaged arts interventions can be complicit in exclusionary gentrification dynamics, particularly the production of spaces of white privilege and heteronormativity. But neoliberal imperatives are not always over determining. Feminist artists and activists are also finding ways to performatively and playfully push back at this highly regulated, gendered, and raced regime. © 2014 Antipode Foundation Ltd.


Li T.M.,University of Toronto
Transactions of the Institute of British Geographers | Year: 2014

The so-called global land rush has drawn new attention to land, its uses and value. But land is a strange object. Although it is often treated as a thing and sometimes as a commodity, it is not like a mat: you cannot roll it up and take it away. To turn it to productive use requires regimes of exclusion that distinguish legitimate from illegitimate uses and users, and the inscribing of boundaries through devices such as fences, title deeds, laws, zones, regulations, landmarks and story-lines. Its very 'resourceness' is not an intrinsic or natural quality. It is an assemblage of materialities, relations, technologies and discourses that have to be pulled together and made to align. To render it investible, more work is needed. This Transactions of the Institute of British Geographers Plenary Lecture uses an analytic of assemblage to examine the practices that make up land as a resource. It focuses especially on the 'statistical picturing' devices and other graphic forms that make large-scale investments in land thinkable, and the practices through which relevant actors (experts, investors, villagers, governments) are enrolled. It also considers some of the risks that follow when these large-scale investments land in particular places, as land they must. © 2014 Royal Geographical Society (with the Institute of British Geographers).


Kirton A.,University of Calgary | De Veber G.,University of Toronto
Stroke | Year: 2013

Life after perinatal stroke can certainly be good. The high level of functioning attained by many children despite large brain lesions is a remarkable testament to the potential power of developmental plasticity. However, it is clear that such early injury places many other children on an abnormal developmental trajectory with functional consequences. How the interplay of multiple disordered functions in individual children may combine to impact the eventual outcome is of great interest. A child with great developmental potential may be stymied by pathological electrographic brain activity during sleep. Another child highly capable of acquiring new motor skills may fail to gain practical function because proprioceptive deficits prevent him or her from knowing where his or her hand is in space. Another with normal intelligence but an attention disorder may not be able to engage in school, therapy, or sports that could each improve function. With improving recognition and measurement, an integrated understanding of how these multiple factors dictate outcomes in individual children will be a major challenge of perinatal stroke research going forward.


Charach A.,University of Toronto
Current psychiatry reports | Year: 2013

Safe and effective medication for attention deficit hyperactivity disorder (ADHD) is available and recommended as first-line treatment for the core symptoms of inattention, overactivity and impulsiveness. Despite impaired functioning during adolescence, many discontinue medication treatment. For children, healthcare decisions are usually made by the parent; older youth make their own decisions. Beliefs and attitudes may differ widely. Some families understand that ADHD is a neurobiological condition and accept that medication is indicated, for others, such treatment is unacceptable. Converging evidence describes negative perceptions of the burden associated with medication use as well as concerns about potential short and long term adverse effects. Indeed experiences of adverse effects are a frequent explanation for discontinuation among youth. Ways to improve shared decision making among practitioners, parents and youth, and to monitor effectiveness, safety and new onset of concurrent difficulties are likely to optimize outcomes.


Krings T.,University of Toronto
Clinical Neuroradiology | Year: 2010

Spinal vascular malformations are rare diseases with a wide variety of neurologic presentations. Their classification depends on the differentiation of shunting versus nonshunting lesions, the latter being the spinal cord cavernomas. In the shunting lesions, the next step in the proposed classification scheme is related to the feeding artery which can subdivide the dural vascular shunts from the pial vascular malformations: while those shunts that are fed by radiculomeningeal arteries (i.e., the counterparts of meningeal arteries in the brain) constitute the dural arteriovenous fistulas, the shunts that are fed by arteries that would normally supply the spinal cord (i.e., the radiculomedullary and radiculopial arteries) are the pial cord arteriovenous malformations (AVMs; whose cranial counterparts are the brain AVMs). Depending on the type of transition between artery and vein, the latter pial AVMs can be further subdivided into glomerular (plexiform or nidus-type) AVMs with a network of intervening vessels in between the artery and vein and the fistulous pial AVMs. The last step in the classification then describes whether the type of fistula has a high or a low shunting volume which will differentiate the "macro-" from the "micro"fistulas. The proposed classification is therefore based on a stepwise analysis of the shunt including its arterial anatomy, its nidus architecture and its flow-volume evaluation. The major advantage of this approach is that it leads to a subclassification with direct implications on the choice of treatment, thereby constituting a simple and practical approach to evaluate these rare diseases.


Recent studies have demonstrated that the COOH-terminal fragment of the incretin hormone glucagon-like peptide-1 (GLP-1), a nonapeptide GLP-1(28-36)amide, attenuates diabetes and hepatic steatosis in diet-induced obese mice. However, the effect of this nonapeptide in pancreatic β-cells remains largely unknown. Here, we show that in a streptozotocin-induced mouse diabetes model, GLP-1(28-36)amide improved glucose disposal and increased pancreatic β-cell mass and β-cell proliferation. An in vitro investigation revealed that GLP-1(28-36)amide stimulates β-catenin (β-cat) Ser(675) phosphorylation in both the clonal INS-1 cell line and rat primary pancreatic islet cells. In INS-1 cells, the stimulation was accompanied by increased nuclear β-cat content. GLP-1(28-36)amide was also shown to increase cellular cAMP levels, PKA enzymatic activity, and cAMP response element-binding protein (CREB) and cyclic AMP-dependent transcription factor-1 (ATF-1) phosphorylation. Furthermore, GLP-1(28-36)amide treatment enhanced islet insulin secretion and increased the growth of INS-1 cells, which was associated with increased cyclin D1 expression. Finally, PKA inhibition attenuated the effect of GLP-1(28-36)amide on β-cat Ser(675) phosphorylation and cyclin D1 expression in the INS-1 cell line. We have thus revealed the beneficial effect of GLP-1(28-36)amide in pancreatic β-cells in vitro and in vivo. Our observations suggest that GLP-1(28-36)amide may exert its effect through the PKA/β-catenin signaling pathway.


Holdom B.,University of Toronto
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

If fourth family condensates are responsible for electroweak symmetry breaking then they may also break approximate global symmetries. Among the resulting pseudo-Goldstone bosons are those that can have diquark quantum numbers. We describe the variety of diquarks and their decay modes, and we find aspects that are particular to the fourth family framework. Spectacular signatures at the LHC appear and are explored for color sextet diquarks with 600 GeV mass. We consider a simple search strategy which avoids diquark reconstruction. We also consider 350 GeV mass diquarks that are accessible at the Tevatron. © 2011 Elsevier B.V.


Klotz L.,University of Toronto
Journal of the National Cancer Institute - Monographs | Year: 2012

Active surveillance has evolved to become a standard of care for favorable-risk prostate cancer. This is a summary of the rationale, method, and results of active surveillance beginning in 1995 with the first prospective trial of this approach. This was a prospective, single-arm cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression (to 4+3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data. Since November 1995, 450 patients have been managed with active surveillance. The cohort included men under 70 with favorable-risk disease and men of age more than 70 with favorable- or intermediate-risk cancer (Gleason score 3+4 or PSA 10-15). Median follow-up is 6.8 years (range 1-16 years). Overall survival is 78.6%. Ten-year prostate cancer actuarial survival is 97.2%. Five of 450 patients (1.1%) have died of prostate cancer. Thirty percent of patients have been reclassified as higher-risk patients and offered definitive therapy. The commonest indication for treatment was a PSA doubling time less than 3 years (48%) or Gleason upgrading (26%). Of 117 patients treated radically, the PSA failure rate was 50%. This represents 13% of the total cohort. Most PSA failures occurred early; at 2 years, 44% of the treated patients had PSA failure. The hazard ratio for non-prostate cancer mortality to prostate cancer mortality was 18.6 at 10 years. In conclusion, we observed a very low rate of prostate cancer mortality in an intermediate time frame. Among the one-third of patients who were reclassified as higher risk and retreated, PSA failure was relatively common. However, other-cause mortality accounted for almost all of the deaths. Further studies are warranted to improve the identification of patients who harbor more aggressive disease in spite of favorable clinical parameters at diagnosis [reproduced from Klotz (1) with permission from Wolters Kluwer Health].


Clinical trials on low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the right dorsolateral prefrontal cortex have yielded conflicting evidence concerning its overall efficacy for treating major depression (MD). As this may have been the result of limited statistical power of individual trials, we have carried the present systematic review and meta-analysis to examine this issue. We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on LF-rTMS for treating MD from 1995 through July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses, and from October 2008 until July 2012 using MEDLINE. The main outcome measures were response and remission rates as well as overall dropout rates at study end. We used a random-effects model, odds ratios (ORs) and number needed to treat (NNT). Data were obtained from eight RCTs, totaling 263 subjects with MD. After an average of 12.6±3.9 rTMS sessions, 38.2% (50/131) and 15.1% (20/132) of subjects receiving active LF-rTMS and sham rTMS were classified as responders (OR=3.35; 95% CI=1.4-8.02; p=0.007). Also, 34.6% (35/101) and 9.7% (10/103) of subjects receiving active LF-rTMS and sham rTMS were classified as remitters (OR=4.76; 95% CI=2.13-10.64; p<0.0001). The associated NNT for both response and remission rates was 5. Sensitivity analyses have shown that protocols delivering >1200 magnetic pulses in total as well as those offering rTMS as a monotherapy for MD were associated with higher rates of response to treatment. No differences on mean baseline depression scores and dropout rates for active and sham rTMS groups were found. Finally, the risk of publication bias was low. In conclusion, LF-rTMS is a promising treatment for MD, as it provides clinically meaningful benefits that are comparable to those of standard antidepressants and high-frequency rTMS. Furthermore, LF-rTMS seems to be an acceptable intervention for depressed subjects. © 2013 American College of Neuropsychopharmacology. All rights reserved.


Klotz L.,University of Toronto
Current Opinion in Urology | Year: 2013

PURPOSE OF REVIEW: This is a summary of the current approach to patient selection for active surveillance, including eligibility criteria, current controversies and the role of imaging. RECENT FINDINGS: Active surveillance is based on the concept that Gleason 6 prostate cancer is, in most cases, an indolent condition that poses little or no threat to the patients life. Substantial recent data suggest that Gleason pattern 3 does not have the molecular characteristics of malignancy. A subset of patients harbour more aggressive disease that was missed on the initial diagnostic biopsies, and a smaller group will progress over time to higher grade disease. Active surveillance involves initial expectant management for patients with favourable risk disease, and serial biopsy and prostate-specific antigen (PSA). Most patients with Gleason 6 prostate cancer are candidates. Very low risk patients fulfil the Epstein criteria, with only one or two positive cores, no core with more than 50% involvement and a PSA density of less than 0.15. Low-risk patients have Gleason 6 disease and PSA 10 or less but do not satisfy the Epstein criteria. Higher volume of Gleason 6 disease on biopsy predicts for a higher likelihood of higher grade cancer, but in and of itself should not mandate treatment. Patients with Gleason 7 in whom the extent of Gleason 4 pattern is less than 10% may also be candidates. Patient age, comorbidity and personal preferences must also be considered. SUMMARY: Active surveillance is an effective and well tolerated method to reduce the overtreatment associated with screen-detected prostate cancer. About 50% of newly diagnosed patients are eligible for this approach. Multiple factors, including patient age, comorbidity, cancer risk category and patient preferences, must be considered. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Charron M.,University of Toronto
Quarterly Journal of Nuclear Medicine and Molecular Imaging | Year: 2013

The diagnostic value of Metaiodobenzylguanidine (MIBG) scintigraphy in the management of neuroblastoma is well established. The specificity of MIBG is virtually 100% and remains the most specific imaging modality. Numerous semi-quantitative scores and guidelines have emerged in the last decade that illustrate standardization of the procedure. Other pharmaceuticals such as norcholesterol derivatives, [111In]pentetreotide and [ 68Ga]somatostatin analogs, [18F]fluorodeoxyglucose, [ 18F]fluorodopa, [18F]fluorodopamine, [11C]meta hydroxyephedrine, and [11C]/[18F]/[123I] Metomidate (MTO) have been or are being evaluated currently (including development of new analogues labeled with positron emitting radionuclides such as [124I], [18F], and [76Br]. Radiopharmaceutical therapy of neuroblastoma, initiated over 30 years ago, demonstrates that a significant fraction of patients enter partial remission but complete remission is rare and relapse is frequent. With the combination of chemotherapy, radiosensitizers, and autologous stem cell support, some centers have seen overall response rates of up to 30% in refractory or recurrent diseases. Topoisomerase I inhibitor topotecan may improve upon existing [ 131I]MIBG therapy. Areas of future development may be in vitro cultures and animal models, proper instrumentation to acquire sub-centimeter resolution and human clinical trials to evaluate treatment at earlier times or stages of disease, evaluation with concomitant immunotherapy with monoclonal antibodies targeting the GD2 ganglioside or inhibitors of anaplastic lymphoma kinase. Because of the complexity of those trials, progress remains extremely slow as well designed multicenter studies are required. Nonetheless, the future has never been so hopeful.


Object. In this study the author documents the epidemiology of spine and spinal cord injuries (SCIs) over 2 decades at the largest Level I adult trauma center in Canada. He describes the current state of spine injuries (SIs), their changing patterns over the years, and the relative distribution of different demographic factors in a defined group of trauma patients. Methods. Data on all trauma patients admitted to Sunnybrook Health Sciences Centre between 1986 and 2006 were collected from the Sunnybrook Trauma Registry Database. Aggregate data on SIs and SCIs, including demographic information, etiology, severity of injuries (injury severity score [ISS]), and associated injuries, were recorded. The data were analyzed in a main category of spinal fracture and/or dislocation with or without SI and in two subgroups of patients with SIs, one encompassing all forms of SCIs and the other including only complete SCIs (CSCIs). Collected data were evaluated using univariate techniques to depict the trend of variables over the years. The number of deaths per year and the length of stay (LOS) were used as crude measures of outcome. Several multivariate analysis techniques, including Poisson regression, were used to model the frequency of death and LOS as functions of various trauma variables. Results. There were 12,192 trauma patients in the study period with 23.2% having SIs, 5.4% having SCIs, and 3% having CSCIs. The SCIs constituted 23.3% of all SIs. The respective characteristics of the SI, SCI, and CSCI groups were as follows: median age 36, 33, and 30 years; median LOS 18, 27, and 29 days; median ISS 29, 30, and 34; female sex ratio 34, 24, and 23%; and case fatality rate 16.7, 16.6, and 21%. Seventy-nine percent of patients had associated head injuries; conversely, 24% of patients with head injuries had SIs. The mean admission age of patients increased by ∼ 10 years over the study period, from the early 30s to the early 40s. The relative incidence of SIs remained stable at ∼ 23%, but the incidence of SCIs decreased ∼ 40% over time to 4.5%. Motor vehicle accidents remained the principal etiology of trauma, although falling and violence became more frequent contributors of SIs. The average annual ISS remained stable over time, but the LOS was reduced by 50% in both the SI and SCI groups. Age, ISS, and SCIs were associated with a longer LOS. The case fatality rate remained relatively unchanged over time. Poisson analysis suggested that the presence of an SCI does not change the case fatality rate. Conclusions. Data in this analysis will provide useful information to guide future studies on changing SI patterns, possible etiologies, and efficient resource allocation for the management of these diseases.


Eder L.,University of Toronto
Lupus | Year: 2013

With the improvement of survival of systemic lupus erythematosus (SLE) patients, prevention of organ damage has become a major goal in the management of these patients. The need for a reliable tool for assessment of cumulative damage over time led to the development of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI) that allowed a standardized measurement of damage and facilitated research in the field. Damage accumulates over the course of the disease; however, some patients do not accrue any damage even after many years. Damage accrues at a higher rate among patients with more active disease, highlighting the importance of prompt control of disease manifestations. However, medications administered to control disease activity, particularly corticosteroids, can also result in organ damage, emphasizing the need for adjustment of these agents as soon as disease is under control.


Sellwood J.A.,Rutgers University | Carlberg R.G.,University of Toronto
Astrophysical Journal | Year: 2014

We present evidence that recurrent spiral activity, long manifested in simulations of disk galaxies, results from the superposition of a few transient spiral modes. Each mode lasts between 5 and 10 rotations at its corotation radius where its amplitude is greatest. The scattering of stars as each wave decays takes place over narrow ranges of angular momentum, causing abrupt changes to the impedance of the disk to subsequent traveling waves. Partial reflections of waves at these newly created features allows new standing-wave instabilities to appear that saturate and decay in their turn, scattering particles at new locations, creating a recurring cycle. The spiral activity causes the general level of random motion to rise, gradually decreasing the ability of the disk to support further activity unless the disk contains a dissipative gas component from which stars form on near-circular orbits. We also show that this interpretation is consistent with the behavior reported in other recent simulations with low-mass disks. © 2014. The American Astronomical Society. All rights reserved..


Bogdan N.,Concordia University at Montreal | Vetrone F.,University of Quebec | Ozin G.A.,University of Toronto | Capobianco J.A.,Concordia University at Montreal
Nano Letters | Year: 2011

The synthesis using the thermal decomposition of metal trifluoroacetates is being widely used to prepare oleate-capped lanthanide-doped upconverting NaYF4:Er3+/Yb3+ nanoparticles (Ln-UCNPs). These nanoparticles have no inherent aqueous dispersibility and inconvenient postsynthesis treatments are required to render them water dispersible. Here, we have developed a novel and facile approach to obtain water-dispersible, ligand-free, brightly upconverting Ln-UCNPs. We show that the upconversion luminescence is affected by the local environment of the lanthanide ions at the surface of the Ln-UCNPs. We observe a dramatic difference of the integrated upconverted red:green emission ratio for Ln-UCNPs dispersed in toluene compared to Ln-UCNPs dispersed in water. We can enhance or deactivate the upconversion luminescence by pH and H/D isotope vibronic control over the competitive radiative and nonradiative relaxation pathways for the red and green excited states. Direct biofunctionalization of the ligand-free, water-dispersible Ln-UCNPs will enable myriad new opportunities in targeting and drug delivery applications. © 2011 American Chemical Society.


Toplak M.E.,York University | West R.F.,James Madison University | Stanovich K.E.,University of Toronto
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background: Both performance-based and rating measures are commonly used to index executive function in clinical and neuropsychological assessments. They are intended to index the same broad underlying mental construct of executive function. The association between these two types of measures was investigated in the current article. Method and Results: We examined the association between performance-based and rating measures of executive function in 20 studies. These studies included 13 child and 7 adult samples, which were derived from 7 clinical, 2 nonclinical, and 11 combined clinical and nonclinical samples. Only 68 (24%) of the 286 relevant correlations reported in these studies were statistically significant, and the overall median correlation was only.19. Conclusions: It was concluded that performance-based and rating measures of executive function assess different underlying mental constructs. We discuss how these two types of measures appear to capture different levels of cognition, namely, the efficiency of cognitive abilities and success in goal pursuit. Clinical implications of using performance-based and rating measures of executive function are discussed, including the use of these measures in assessing ADHD. © 2012 Association for Child and Adolescent Mental Health.


Barrett S.C.H.,University of Toronto
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Flowering plants display spectacular floral diversity and a bewildering array of reproductive adaptations that promote mating, particularly outbreeding. A striking feature of this diversity is that related species often differ in pollination and mating systems, and intraspecific variation in sexual traits is not unusual, especially among herbaceous plants. This variation provides opportunities for evolutionary biologists to link micro-evolutionary processes to the macro-evolutionary patterns that are evident within lineages. Here, I provide some personal reflections on recent progress in our understanding of the ecology and evolution of plant reproductive diversity. I begin with a brief historical sketch of the major developments in this field and then focus on three of the most significant evolutionary transitions in the reproductive biology of flowering plants: the pathway from outcrossing to predominant self-fertilization, the origin of separate sexes (females and males) from hermaphroditism and the shift from animal pollination to wind pollination. For each evolutionary transition, I consider what we have discovered and some of the problems that still remain unsolved. I conclude by discussing how new approaches might influence future research in plant reproductive biology. © 2010 The Royal Society.


Stephan D.W.,University of Toronto
Chemical Communications | Year: 2010

This feature article reviews advances in the metal-free activation of hydrogen and the utilization of these and related systems in catalytic hydrogenations. © 2010 The Royal Society of Chemistry.


Stanovich K.E.,University of Toronto
Behavioral and Brain Sciences | Year: 2011

Elqayam & Evans (E&E) drive a wedge between Bayesianism and instrumental rationality that most decision scientists will not recognize. Their analogy from linguistics to judgment and decision making is inapt. Normative models remain extremely useful in the progressive research programs of the judgment and decision making field. © 2011 Cambridge University Press.


Hoang T.,University of Toronto | Lazarian A.,University of Wisconsin - Madison
Monthly Notices of the Royal Astronomical Society | Year: 2014

Grain alignment by radiative torques (RATs) has been extensively studied for various environment conditions, including interstellar medium, dense molecular clouds and accretion discs, thanks to significant progress in observational, theoretical and numerical studies. In this paper, we explore the alignment by RATs and provide quantitative predictions of dust polarization for a set of astrophysical environments that can be tested observationally. We first consider the alignment of grains in the local interstellar medium and compare predictions for linear polarization by aligned grains with recent observational data for nearby stars. We then revisit the problem of grain alignment in accretions discs by taking into account the dependence of RAT alignment efficiency on the anisotropic direction of radiation fields relative to magnetic fields. Moreover, we study the grain alignment in interplanetary medium, including diffuse Zodiacal cloud and cometary comae, and calculate the degree of circular polarization (CP) of scattered light arising from single scattering by aligned grains. We also discuss a new type of grain alignment, namely the alignment with respect to the ambient electric field instead of the alignment with the magnetic field. We show that this type of alignment can allow us to reproduce the systematic features of CP observed across a cometary coma. Our findings suggest that polarized Zodiacal dust emission may be an important polarized foreground component, which should be treated carefully in cosmic microwave background experiments. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.


Klotz L.,University of Toronto
Current Urology Reports | Year: 2015

There is ample evidence that low risk and many cases of low-/intermediate-risk prostate cancer, are indolent, have little or no metastatic potential, and do not pose a threat to the patient in his lifetime. Major strides have been made in understanding who these patients are and in encouraging the use of conservative management in such individuals. A component of conservative management is the early identification of those ‘low-risk’ patients who harbour higher risk disease, and benefit from definitive therapy. This represents about 30 % of newly diagnosed low-risk patients. A further small proportion of patients with low-risk disease demonstrate biological progression to higher grade disease. Men with lower risk disease can defer treatment, in most cases for life. Men with higher risk disease that can be localized to a relatively small volume of the prostate can undergo selective therapy. The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are re-classified as higher risk overtime based on repeat biopsy, imaging or biomarker results have shown that this approach is safe in the intermediate to long term, with a 3 % cancer specific mortality at 10–15 years. Further refinement of the surveillance approach is ongoing, incorporating MRI, targeted biopsies and molecular biomarkers. © 2015, Springer Science+Business Media New York.


Yudin A.K.,University of Toronto
Chemical Science | Year: 2015

A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that "are up to the task" to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality. This journal is © The Royal Society of Chemistry.


Nano N.,University of Toronto
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Rvb1 and Rvb2 are highly conserved and essential eukaryotic AAA+ proteins linked to a wide range of cellular processes. AAA+ proteins are ATPases associated with diverse cellular activities and are characterized by the presence of one or more AAA+ domains. These domains have the canonical Walker A and Walker B nucleotide binding and hydrolysis motifs. Rvb1 and Rvb2 have been found to be part of critical cellular complexes: the histone acetyltransferase Tip60 complex, chromatin remodelling complexes Ino80 and SWR-C, and the telomerase complex. In addition, Rvb1 and Rvb2 are components of the R2TP complex that was identified by our group and was determined to be involved in the maturation of box C/D small nucleolar ribonucleoprotein (snoRNP) complexes. Furthermore, the Rvbs have been associated with mitotic spindle assembly, as well as phosphatidylinositol 3-kinase-related protein kinase (PIKK) signalling. This review sheds light on the potential role of the Rvbs as chaperones in the assembly and remodelling of these critical complexes.


To study the effects of backbone composition and charge of biotin-functionalized metal-chelating polymers (Bi-MCPs) for (111)In complexed to streptavidin (SAv)-trastuzumab Fab fragments on tumor and normal tissue localization. Bi-MCPs were synthesized with a polyacrylamide [Bi-PAm(DTPA)(40)], polyaspartamide [Bi-PAsp(DTPA)(33)] or polyglutamide [Bi-PGlu(DTPA)(28)] backbone and harboured diethylenetriaminepentaacetic acid (DTPA) chelators for (111)In. Bi-PAm(DTPA)(40) had a net negative charge; Bi-PAsp(DTPA)(33) and Bi-PGlu(DTPA)(28) were zwitterionic with a net neutral charge. Binding to HER2+ SKOV-3 human ovarian carcinoma cells was determined. Tissue uptake was studied in Balb/c mice by MicroSPECT/CT imaging and biodistribution studies. Tumor and normal tissue uptake of (111)In-labeled Bi-PAsp(DTPA)(33) or Bi-PGlu(DTPA)(28) complexed to SAv-Fab was evaluated 48 h post-injection in athymic mice with subcutaneous SKOV-3 xenografts. SAv-Fab complexed to MCPs bound specifically to SKOV-3 cells; but specific binding was decreased 2-fold. Liver uptake was 5-13 fold higher for Bi-PAm(DTPA)(40) than Bi-PAsp(DTPA)(33) and Bi-PGlu(DTPA)(28) but was reduced by decreasing negative charges by saturation with indium. (111)In-Bi-PAsp(DTPA)(33) complexed to SAv-Fab accumulated in SKOV-3 tumors; low tumor uptake was found for (111)In-Bi-PGlu(DTPA)(28)-SAv-Fab. Zwitterionic MCPs composed of polyaspartamide with a net neutral charge are most desirable for constructing radioimmunoconjugates.


Bioactive molecules typically mediate their biological effects through direct physical association with one or more cellular proteins. The detection of drug-target interactions is therefore essential for the characterization of compound mechanism of action and off-target effects, but generic label-free approaches for detecting binding events in biological mixtures have remained elusive. Here, we report a method termed target identification by chromatographic co-elution (TICC) for routinely monitoring the interaction of drugs with cellular proteins under nearly physiological conditions in vitro based on simple liquid chromatographic separations of cell-free lysates. Correlative proteomic analysis of drug-bound protein fractions by shotgun sequencing is then performed to identify candidate target(s). The method is highly reproducible, does not require immobilization or derivatization of drug or protein, and is applicable to diverse natural products and synthetic compounds. The capability of TICC to detect known drug-protein target physical interactions (K(d) range: micromolar to nanomolar) is demonstrated both qualitatively and quantitatively. We subsequently used TICC to uncover the sterol biosynthetic enzyme Erg6p as a novel putative anti-fungal target. Furthermore, TICC identified Asc1 and Dak1, a core 40 S ribosomal protein that represses gene expression, and dihydroxyacetone kinase involved in stress adaptation, respectively, as novel yeast targets of a dopamine receptor agonist.


Agrawal A.F.,University of Toronto | Whitlock M.C.,University of British Columbia
Genetics | Year: 2011

Data from several thousand knockout mutations in yeast (Saccharomyces cerevisiae) were used to estimate the distribution of dominance coefficients. We propose a new unbiased likelihood approach to measuring dominance coefficients. On average, deleterious mutations are partially recessive, with a mean dominance coefficient ∼0.2. Alleles with large homozygous effects are more likely to be more recessive than are alleles of weaker effect. Our approach allows us to quantify, for the first time, the substantial variance and skew in the distribution of dominance coefficients. This heterogeneity is so great that many population genetic processes analyses based on the mean dominance coefficient alone will be in substantial error. These results are applied to the debate about various mechanisms for the evolution of dominance, and we conclude that they are most consistent with models that depend on indirect selection on homeostatic gene expression or on the ability to perform well under periods of high demand for a protein. Copyright © 2011 by the Genetics Society of America.


Holdom B.,University of Toronto
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

The infrared divergence of the self-energy of a color charge is due to an enhancement of the long wavelength modes of the color Coulomb potential field. There are also long wavelength contributions to the QCD vacuum energy that are similarly enhanced. Vacuum modes of Hubble scale wavelengths may be affected in a cosmological setting and this can lead to a residual positive energy density of the form HdδQCD4-d. Lattice studies constrain d. If the dark energy takes this form then the universe is driven towards de Sitter expansion, and we briefly study this cosmology when d is just slightly above unity. © 2011 Elsevier B.V.


Chiang E.,University of California at Berkeley | Youdin A.N.,University of Toronto
Annual Review of Earth and Planetary Sciences | Year: 2010

Planets are built from planetesimals: solids larger than a kilometer that grow by colliding in pairs. Planetesimals themselves are unlikely to form by two-body collisions alone; subkilometer objects have gravitational fields individually too weak, and electrostatic attraction is too feeble for growth beyond a few centimeters. We review the possibility that planetesimals form when self-gravity brings together vast ensembles of small particles. Even when self-gravity is weak, aerodynamic processes can accumulate solids relative to gas, paving the way for gravitational collapse. Particles pile up as they drift radially inward. Gas turbulence stirs particles but can also seed collapse by clumping them. Whereas the feedback of solids on gas triggers vertical-shear instabilities that obstruct self-gravity, this same feedback triggers streaming instabilities that strongly concentrate particles. Numerical simulations find that solids ∼10-100 cm in size gravitationally collapse in turbulent disks. We outline areas for progress, including the possibility that still smaller objects self-gravitate. Copyright © 2010 by Annual Reviews. All rights reserved.


Gupta V.,University of Toronto | Tallman M.S.,Sloan Kettering Cancer Center | Weisdorf D.J.,University of Minnesota
Blood | Year: 2011

Progress in the last decade has improved the understanding of leukemia biology. Molecular markers in combinations with cytogenetics have improved the risk stratification of acute myeloid leukemia (AML) and informed decision-making. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients. In this review, the positioning of HCT in the management of patients with AML is evaluated in view of changing risk/benefit ratios associated with both conventional treatments and transplantation, and some of the controversies are addressed in light of emerging data. Increasing data demonstrate outcomes of alternative donor transplantation approaching HLA-identical sibling donors in high-risk AML supporting the inclusion of alternative donors in trials of prospective studies evaluating post remission strategies for high-risk AML. The use of reduced-intensity conditioning has expanded the eligibility of HCT to older patients with AML, and outcome data are encouraging. Continued study of HCT versus alternative therapies is required to optimize patients' outcomes in AML. © 2011 by The American Society of Hematology.


This article reviews the design approaches and technologies that have been used to reduce the energy requirements of new buildings by a factor of 2 to 4 compared to the energy use of otherwise comparable recent new buildings or that have been used to achieve comparable savings in retrofits of existing buildings. This is followed by a critical discussion of documented studies of the energy performance of new and retrofitted buildings from around the world, along with cost ormation where-ever available. The additional costs of meeting the Passive Standard for heating loads in new buildings, which represents a factor of 5 to 10 reduction of heating load compared to current standard practice, have ranged from 0% to 16% of the construction costs of reference buildings. High-performance commercial buildings, with overall energy intensities of 25-50% that of recent conventional buildings, have been built at less cost, or only at a few percent more cost, than conventional buildings. © 2013 by Annual Reviews. All rights reserved.


Epithelial tissue formation and function requires the apical-basal polarization of individual epithelial cells. Apical polarity regulators (APRs) are an evolutionarily conserved group of key factors that govern polarity and several other aspects of epithelial differentiation. APRs compose a diverse set of molecules including a transmembrane protein (Crumbs), a serine/threonine kinase (aPKC), a lipid phosphatase (PTEN), a small GTPase (Cdc42), FERM domain proteins (Moesin, Yurt), and several adaptor or scaffolding proteins (Bazooka/Par3, Par6, Stardust, Patj). These proteins form a dynamic cooperative network that is engaged in negative-feedback regulation with basolateral polarity factors to set up the epithelial apical-basal axis. APRs port the formation of the apical junctional complex and the segregation of the junctional domain from the apical membrane. It is becoming increasingly clear that APRs interact with the cytoskeleton and vesicle trafficking machinery, regulate morphogenesis, and modulate epithelial cell growth and survival. Not surprisingly, APRs have multiple fundamental links to human diseases such as cancer and blindness. Copyright © 2012 by Annual Reviews. All rights reserved.


Richardson D.B.,University of Toronto
Renewable and Sustainable Energy Reviews | Year: 2013

Electric vehicles (EVs) and renewable energy sources offer the potential to substantially decrease carbon emissions from both the transportation and power generation sectors of the economy. Mass adoption of EVs will have a number of impacts and benefits, including the ability to assist in the integration of renewable energy into existing electric grids. This paper reviews the current literature on EVs, the electric grid, and renewable energy integration. Key methods and assumptions of the literature are discussed. The economic, environmental and grid impacts of EVs are reviewed. Numerous studies assessing the ability of EVs to integrate renewable energy sources are assessed; the literature indicates that EVs can significantly reduce the amount of excess renewable energy produced in an electric system. Studies on wind-EV interaction are much more detailed than those on solar photovoltaics (PV) and EVs. The paper concludes with recommendations for future research. © 2012 Elsevier Ltd.


Althoff D.M.,Syracuse University | Segraves K.A.,Syracuse University | Johnson M.T.J.,University of Toronto
Trends in Ecology and Evolution | Year: 2014

Coevolutionary diversification is cited as a major mechanism driving the evolution of diversity, particularly in plants and insects. However, tests of coevolutionary diversification have focused on elucidating macroevolutionary patterns rather than the processes giving rise to such patterns. Hence, there is weak evidence that coevolution promotes diversification. This is in part due to a lack of understanding about the mechanisms by which coevolution can cause speciation and the difficulty of integrating results across micro- and macroevolutionary scales. In this review, we highlight potential mechanisms of coevolutionary diversification, outline approaches to examine this process across temporal scales, and propose a set of minimal requirements for demonstrating coevolutionary diversification. Our aim is to stimulate research that tests more rigorously for coevolutionary diversification. © 2013 Elsevier Ltd.


Smith M.R.,University of Cambridge | Caron J.-B.,Royal Ontario Museum | Caron J.-B.,University of Toronto
Nature | Year: 2015

The molecularly defined clade Ecdysozoa comprises the panarthropods (Euarthropoda, Onychophora and Tardigrada) and the cycloneuralian worms (Nematoda, Nematomorpha, Priapulida, Loricifera and Kinorhyncha). These disparate phyla are united by their means of moulting, but otherwise share few morphological characters-none of which has a meaningful fossilization potential. As such, the early evolutionary history of the group as a whole is largely uncharted. Here we redescribe the 508-million-year-old stem-group onychophoran Hallucigenia sparsa from the mid-Cambrian Burgess Shale. We document an elongate head with a pair of simple eyes, a terminal buccal chamber containing a radial array of sclerotized elements, and a differentiated foregut that is lined with acicular teeth. The radial elements and pharyngeal teeth resemble the sclerotized circumoral elements and pharyngeal teeth expressed in tardigrades, stem-group euarthropods and cycloneuralian worms. Phylogenetic results indicate that equivalent structures characterized the ancestral panarthropod and, seemingly, the ancestral ecdysozoan, demonstrating the deep homology of panarthropod and cycloneuralian mouthparts, and providing an anatomical synapomorphy for the ecdysozoan supergroup. © 2015 Macmillan Publishers Limited. All rights reserved.


Weis A.E.,University of Toronto
Journal of Evolutionary Biology | Year: 2015

Gene flow is generally considered a random process, that is the loci under consideration have no effect on dispersal success. Edelaar and Bolnick (Trends Ecol Evol, 27, 2012 659) recently argued that nonrandom gene flow could exert a significant evolutionary force. It can, for instance, ameliorate the maladaptive effects of immigration into locally adapted populations. I examined the potential strength for nonrandom gene flow for flowering time genes, a trait frequently found to be locally adapted. The idea is that plants that successfully export pollen into a locally adapted resident population will be a genetically biased subset of their natal population - they will have resident-like flowering times. Reciprocally, recipients will be more migrant-like than the resident population average. I quantified the potential for biased pollen exchange among three populations along a flowering time cline in Brassica rapa from southern California. A two-generation line cross experiment demonstrated genetic variance in flowering time, both within and among populations. Calculations based on the variation in individual flowering schedules showed that resident plants with the most migrant-like flowering times could expect to have up to 10 times more of the their flowers pollinated by immigrant pollen than the least migrant-like. Further, the mean flowering time of the pollen exporters that have access to resident mates differs by up to 4 weeks from the mean in the exporters' natal population. The data from these three populations suggest that the bias in gene flow for flowering time cuts the impact on the resident population by as much as half. This implies that when selection is divergent between populations, migrants with the highest mating success tend to be resident-like in their flowering times, and so, fewer maladaptive alleles will be introduced into the locally adapting gene pool. © 2015 European Society For Evolutionary Biology.


Barrett S.C.H.,University of Toronto
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Flowering plants possess an unrivaled diversity of mechanisms for achieving sexual and asexual reproduction, often simultaneously. The commonest type of asexual reproduction is clonal growth (vegetative propagation) in which parental genotypes (genets) produce vegetative modules (ramets) that are capable of independent growth, reproduction, and often dispersal. Clonal growth leads to an expansion in the size of genets and increased fitness because large floral displays increase fertility and opportunities for outcrossing. Moreover, the clonal dispersal of vegetative propagules can assist "mate finding," particularly in aquatic plants. However, there are ecological circumstances in which functional antagonism between sexual and asexual reproductive modes can negatively affect the fitness of clonal plants. Populations of heterostylous and dioecious species have a small number of mating groups (two or three), which should occur at equal frequency in equilibrium populations. Extensive clonal growth and vegetative dispersal can disrupt the functioning of these sexual polymorphisms, resulting in biased morph ratios and populations with a single mating group, with consequences for fertility and mating. In populations in which clonal propagation predominates, mutations reducing fertility may lead to sexual dysfunction and even the loss of sex. Recent evidence suggests that somatic mutations can play a significant role in influencing fitness in clonal plants and may also help explain the occurrence of genetic diversity in sterile clonal populations. Highly polymorphic genetic markers offer outstanding opportunities for gaining novel insights into functional interactions between sexual and clonal reproduction in flowering plants. © 2015, National Academy of Sciences. All rights reserved.


Sage R.F.,University of Toronto
Plant Biology | Year: 2013

This paper reviews how terrestrial plants reduce photorespiration and thus compensate for its inhibitory effects. As shown in the equation φ{symbol} = (1/Sc/o)O/C, where φ{symbol} is the ratio of oxygenation to carboxylation, Sc/o is the relative specificity of Rubisco, O is stromal O2 level and C is the stromal CO2 concentration, plants can reduce photorespiration by increasing Sc/o or C, or by reducing O. By far the most effective means of reducing φ{symbol} is by concentrating CO2, as occurs in C4 and CAM plants, and to a lesser extent in plants using a glycine shuttle to concentrate CO2 into the bundle sheath. Trapping and refixation of photorespired CO2 by a sheath of chloroplasts around the mesophyll cell periphery in C3 plants also enhances C, particularly at low atmospheric CO2. O2 removal is not practical because high energy and protein investment is needed to have more than a negligible effect. Sc/o enhancement provides for modest reductions in φ{symbol}, but at the potential cost of limiting the kcat of Rubisco. An effective means of decreasing φ{symbol} and enhancing carbon gain is to lower leaf temperature by reducing absorbance of solar radiation, or where water is abundant, opening stomata. By using a combination of mechanisms, C3 plants can achieve substantial (>30%) reductions in φ{symbol}. This may have allowed many C3 species to withstand severe competition from C4 plants in low CO2 atmospheres of recent geological time, thereby preserving some of the Earth's floristic diversity that accumulated over millions of years. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.


Neuromuscular complications of critical illness are common, and can be severe and persistent, with substantial impairment in physical function and long-term quality of life. While the etiology of ICU-acquired weakness (ICUAW) is multifactorial, both direct (ie, critical illness neuromyopathy) and indirect (ie, immobility/disuse atrophy) complications of critical illness contribute to it. ICUAW is often difficult to diagnose clinically during the acute phase of critical illness, due to the frequent use of deep sedation, encephalopathy, and delirium, which impair physical examination for patient strength. Despite its limitations, physical examination is the starting point for identification of ICUAW in the cooperative patient. Given the relative cost, invasiveness, and need for expertise, electrophysiological testing and/or muscle biopsy may be reserved for weak patients with slower than expected improvement on serial clinical examination. Currently there are limited interventions to prevent or treat ICUAW, with tight glycemic control having the greatest supporting evidence. There is a paucity of clinical trials evaluating the specific role of early rehabilitation in the chronic critically ill. However, a number of studies support the benefit of intensive rehabilitation in patients receiving chronic mechanical ventilation. Furthermore, emerging data demonstrate the safety, feasibility, and potential benefit of early mobility in critically ill patients, with the need for multicenter randomized trials to evaluate potential short- and long-term benefits of early mobility, including the potential to prevent the need for prolonged mechanical ventilation and/or the development of chronic critical illness, and other novel treatments on patients' muscle strength, physical function, quality of life, and resource utilization. Finally, the barriers, feasibility, and efficacy of early mobility in both medical and other ICUs (eg, surgical, neurological, pediatric), as well as in the chronic critically ill, have not been formally evaluated and require exploration in future clinical trials. © 2012 Daedalus Enterprises.


Cutter A.D.,University of Toronto
Molecular Phylogenetics and Evolution | Year: 2013

Evolutionary theory is primed to synthesize microevolutionary processes with macroevolutionary divergence by taking advantage of multilocus multispecies genomic data in the molecular evolutionary analysis of biodiversity. While coalescent theory bridges across timescales to facilitate this integration, it is important to appreciate the assumptions, caveats, and recent theoretical advances so as to most effectively exploit genomic analysis. Here I outline the connections between population processes and phylogeny, with special attention to how genomic features play into underlying predictions. I discuss empirical and theoretical complications, and solutions, relating to recombination and multifurcating genealogical processes, predictions about how genome structure affects gene tree heterogeneity, and practical choices in genome sequencing and analysis. I illustrate the conceptual implications and practical benefits of how genomic features generate predictable patterns of discordance of gene trees and species trees along genomes, for example, as a consequence of how regions of low recombination and sex linkage interact with natural selection and with the accumulation of reproductive incompatibilities in speciation. Moreover, treating population genetic parameters as characters to be mapped onto phylogenies offers a new way to understand the evolutionary drivers of diversity within and differentiation between populations. Despite a number of challenges conferred by genomic information, the melding of phylogenetics, phylogeography and population genetics into integrative molecular evolution is poised to improve our understanding of biodiversity at all levels. © 2013 Elsevier Inc.


Tuohy C.H.,University of Toronto
Journal of Health Politics, Policy and Law | Year: 2012

This article examines the cases of three health care states-two of which (Britain and the Netherlands) have undergone major policy reform and one of which (Canada) has experienced only marginal adjustments. The British and Dutch reforms have variously altered the balance of power, the mix of instruments of control, and the organizing principles. As a result, mature systems representing the ideal-typical health care state categories of national health systems and social insurance (Britain and the Netherlands, respectively) were transformed into distinctive national hybrids. These processes have involved a politics of redesign that differs from the politics of earlier phases of establishment and retrenchment. In particular, the redesign phase is marked by the activity of institutional entrepreneurs who exploit specific opportunities afforded by public programs to combine public and private resources in innovative organizational arrangements. Canada stands as a counterpoint: no window of opportunity for major change occurred, and the bilateral monopoly created by its prototypical single-payer model provided few footholds for entrepreneurial activity. The increased significance of institutional entrepreneurs gives greater urgency to one of the central projects of health policy: the design of accountability frameworks to allow for an assessment of performance against objectives. © 2012 by Duke University Press.


Feld J.J.,University of Toronto
Best Practice and Research: Clinical Gastroenterology | Year: 2012

Great strides have been made in the treatment of hepatitis C virus (HCV) infection in the past decade. Although there is much focus on the development of new direct-acting antivirals (DAA), interferon and ribavirin remain the backbone of therapy for both acute and chronic HCV infections. While DAA therapy will likely eventually largely replace interferon, in much of the world and for genotype non-1 patients, peginterferon and ribavirin remain first-line therapy. Interferon-based therapy is highly effective in acute HCV with high response rates with short courses of therapy. Unfortunately once infection progresses to chronicity, treatment success rates drop off considerably. The indications, pre-treatment evaluation and efficacy of peginterferon and ribavirin therapy in the treatment of acute and chronic HCV infection are discussed with strategies to improve outcomes and manage adverse events. © 2012 Elsevier Ltd. All rights reserved.


Faulkner G.,University of Toronto
American Journal of Preventive Medicine | Year: 2013

Context Given its high prevalence and impact on quality of life, more research is needed in identifying factors that may prevent depression. This review examined whether physical activity (PA) is protective against the onset of depression. Evidence acquisition A comprehensive search was conducted up until December 2012 in the following databases: MEDLINE, Embase, PubMed, PsycINFO, SPORTDiscus, and Cochrane Database of Systematic Reviews. Data were analyzed between July 2012 and February 2013. Articles were chosen for the review if the study used a prospective-based, longitudinal design and examined relationships between PA and depression over at least two time intervals. A formal quality assessment for each study also was conducted independently by the two reviewers. Evidence synthesis The initial search yielded a total of 6363 citations. After a thorough selection process, 30 studies were included for analyses. Among these, 25 studies demonstrated that baseline PA was negatively associated with a risk of subsequent depression. The majority of these studies were of high methodologic quality, providing consistent evidence that PA may prevent future depression. There is promising evidence that any level of PA, including low levels (e.g., walking <150 minutes/weeks), can prevent future depression. Conclusions From a population health perspective, promoting PA may serve as a valuable mental health promotion strategy in reducing the risk of developing depression.


Scholes G.D.,University of Toronto
Journal of Physical Chemistry Letters | Year: 2010

Recent research suggests that electronic energy transfer in complex biological and chemical systems can involve quantum coherence, even at ambient temperature conditions. It is particularly notable that this phenomenon has been found in some photosynthetic proteins. The role of these proteins in photosynthesis is introduced. The meaning of quantum-coherent energy transfer is explained, and it is compared to Forster energy transfer. Broad, interdisciplinary questions for future work are noted. For example, how can chemists use quantum coherence in synthetic systems (perhaps in organic photovoltaics)? Why did certain photosynthetic organisms evolve to use quantum coherence in light harvesting? Are these electronic excitations entangled?. © 2010 American Chemical Society.


Jha P.,University of Toronto
BMC Medicine | Year: 2014

Background: Most of the 48 million annual deaths in low- and middle-income countries (LMICs) occur without medical attention at the time of death so that the causes of death (COD) are largely unknown. A review of low-cost methods of obtaining nationally representative COD data is timely.Discussion: Despite clear historic evidence of their usefulness, most LMICs lack reliable nationally representative COD data. Indirect methods to estimate COD for most countries are inadequate, mainly because they currently rely on an average ratio of 1 nationally representative COD to every 850 estimated deaths in order to measure the cause of 25 million deaths across 110 LMICs. Direct measurement of COD is far more reliable and relevant for country priorities. Five feasible methods to expand COD data are: sample registration systems (which form the basis for the ongoing Million Death Study in India; MDS); strengthening the INDEPTH network of 42 demographic surveillance sites; adding retrospective COD surveys to the demographic household and health surveys in 90 countries; post-census retrospective mortality surveys; and for smaller countries, systematic assembly of health records. Lessons learned from the MDS, especially on low-cost, high-quality methods of verbal autopsy, paired with emerging use of electronic data capture and other innovations, can make COD systems low-cost and relevant for a wide range of childhood and adult conditions.Summary: Low-cost systems to obtain and report CODs are possible. If implemented widely, COD systems could identify disease control priorities, help detect emerging epidemics, enable evaluation of disease control programs, advance indirect methods, and improve the accountability for expenditures of disease control programs. © 2014 Jha; licensee BioMed Central Ltd.


Rudzicz F.,University of Toronto
IEEE Transactions on Audio, Speech and Language Processing | Year: 2011

Disabled speech is not compatible with modern generative and acoustic-only models of speech recognition (ASR). This work considers the use of theoretical and empirical knowledge of the vocal tract for atypical speech in labeling segmented and unsegmented sequences. These combined models are compared against discriminative models such as neural networks, support vector machines, and conditional random fields. Results show significant improvements in accuracy over the baseline through the use of production knowledge. Furthermore, although the statistics of vocal tract movement do not appear to be transferable between regular and disabled speakers, transforming the space of the former given knowledge of the latter before retraining gives high accuracy. This work may be applied within components of assistive software for speakers with dysarthria. © 2010 IEEE.


Dirks P.B.,University of Toronto
Molecular Oncology | Year: 2010

Brain tumors, which are typically very heterogeneous at the cellular level, appear to have a stem cell foundation. Recently, investigations from multiple groups have found that human as well as experimental mouse brain tumors contain subpopulations of cells that functionally behave as tumor stem cells, driving tumor growth and generating tumor cell progeny that form the tumor bulk, but which then lose tumorigenic ability. In human glioblastomas, these tumor stem cells express neural precursor markers and are capable of differentiating into tumor cells that express more mature neural lineage markers. In addition, modeling brain tumors in mice suggests that neural precursor cells more readily give rise to full blown tumors, narrowing potential cells of origin to those rarer brain cells that have a proliferative potential. Applying stem cell concepts and methodologies is giving fresh insight into brain tumor biology, cell of origin and mechanisms of growth, and is offering new opportunities for development of more effective treatments. The field of brain tumor stem cells remains very young and there is much to be learned before these new insights are translated into new patient treatments. © 2010 Federation of European Biochemical Societies.


Dorian P.,University of Toronto
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2010

Dronedarone, a recently approved antiarrhythmic agent, is a chemical analog of amiodarone. It has an approximately 15% bioavailability, with plasma concentrations markedly increasing after a high-fat meal; it is recommended to be taken with food. The primary metabolic clearance pathway for dronedarone is via the hepatic enzyme system (primarily cytochrome P450 3A4 [CYP3A4]); the half-life of dronedarone is 27 to 31 hours. Strong CYP3A4 inhibitors, such as ketoconazole, are associated with a marked increase in dronedarone maximum concentration and are thus contraindicated; inducers of CYP3A4 will conversely decrease dronedarone exposure. Dronedarone is a substrate for P-glycoprotein (P-gp) and will lead to an increase in concentration of P-gp substrates such as digoxin. Dronedarone will cause a small increase in creatinine concentrations, without a change in glomerular filtration rate (GFR). Gender, renal dysfunction, weight, and age have little effect on the pharmacokinetics of dronedarone, and dose adjustment for these variables is not required. © The Author(s) 2010.


Murray N.,University of Toronto
Astrophysical Journal | Year: 2011

We use a sample of the 13 most luminous WMAP Galactic free-free sources, responsible for 33% of the free-free emission of the Milky Way, to investigate star formation. The sample contains 40 star-forming complexes; we combine this sample with giant molecular cloud (GMC) catalogs in the literature to identify the host GMCs of 32 of the complexes. We estimate the star formation efficiency εGMC and star formation rate per free-fall time εff. We find that εGMC ranges from 0.002 to 0.2, with an ionizing luminosity-weighted average 〈εGMC〉 Q = 0.08, compared to the Galactic average ≈0.005. Turning to the star formation rate per free-fall time, we find values that range up to . Weighting by ionizing luminosity, we find an average of 〈ε ff〉Q = 0.14-0.24 depending on the estimate of the age of the system. Once again, this is much larger than the Galaxy-wide average value εff = 0.006. We show that the lifetimes of GMCs at the mean mass found in our sample is 27±12 Myr, a bit less than three free-fall times. The GMCs hosting the most luminous clusters are being disrupted by those clusters. Accordingly, we interpret the range in εff as the result of a time-variable star formation rate; the rate of star formation increases with the age of the host molecular cloud, until the stars disrupt the cloud. These results are inconsistent with the notion that the star formation rate in Milky Way GMCs is determined by the properties of supersonic turbulence. © 2011. The American Astronomical Society. All rights reserved.


Allali-Hassani A.,University of Toronto
Journal of biomolecular screening | Year: 2012

The histone methyltransferase (HMT) family of proteins consists of enzymes that methylate lysine or arginine residues on histone tails as well as other proteins. Such modifications affect chromatin structure and play a significant regulatory role in gene expression. Many HMTs have been implicated in tumorigenesis and progression of multiple malignancies and play essential roles in embryonic development and stem cell renewal. Overexpression of some HMTs has been observed and is correlated positively with various types of cancer. Here the authors report development of a continuous fluorescence-based methyltransferase assay in a 384-well format and its application in determining kinetic parameters for EHMT1, G9a, PRMT3, SETD7, and SUV39H2 as well as for screening against libraries of small molecules to identify enzyme inhibitors. They also report the development of a peptide displacement assay using fluorescence polarization in a 384-well format to assay and screen protein peptide interactions such as those of WDR5 and EED, components of MLL and EZH2 methyltransferase complexes. Using these high-throughput screening methods, the authors have identified potent inhibitors and ligands for some of these proteins.


Inzlicht M.,University of Toronto
Journal of personality and social psychology | Year: 2010

Stereotype threat spillover is a situational predicament in which coping with the stress of stereotype confirmation leaves one in a depleted volitional state and thus less likely to engage in effortful self-control in a variety of domains. We examined this phenomenon in 4 studies in which we had participants cope with stereotype and social identity threat and then measured their performance in domains in which stereotypes were not "in the air." In Study 1 we examined whether taking a threatening math test could lead women to respond aggressively. In Study 2 we investigated whether coping with a threatening math test could lead women to indulge themselves with unhealthy food later on and examined the moderation of this effect by personal characteristics that contribute to identity-threat appraisals. In Study 3 we investigated whether vividly remembering an experience of social identity threat results in risky decision making. Finally, in Study 4 we asked whether coping with threat could directly influence attentional control and whether the effect was implemented by inefficient performance monitoring, as assessed by electroencephalography. Our results indicate that stereotype threat can spill over and impact self-control in a diverse array of nonstereotyped domains. These results reveal the potency of stereotype threat and that its negative consequences might extend further than was previously thought. (PsycINFO Database Record (c) 2010 APA, all rights reserved).


Bourgeois F.T.,Childrens Hospital Boston | Murthy S.,University of Toronto | Mandl K.D.,Harvard-MIT Division of Health Sciences and Technology
Annals of Internal Medicine | Year: 2010

Background: Clinical trial registries are in widespread use to promote transparency around trials and their results. Objective: To describe characteristics of drug trials listed in ClinicalTrials. gov and examine whether the funding source of these trials is associated with favorable published outcomes. Design: An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006. Setting: ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999. Measurements: Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations. Results: Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization-funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization-funded trials without industry contributions (P = 0.005 across groups). Limitations: The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting. Conclusion: In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources. Primary Funding Source: National Library of Medicine and National Institute of Child Health and Human Development, National Institutes of Health. © 2010 American College of Physicians.


Miyasaki J.M.,University of Toronto
Current Neurology and Neuroscience Reports | Year: 2013

Palliative care for Parkinson disease (PD) is a new concept in neurodegenerative care. Abundant evidence exists supporting PD as increasing risk of death, most commonly from aspiration pneumonia despite improvements in motor and non-motor symptom management. Palliative care emphasizes an interdisciplinary and holistic approach to symptom management. In the following, the timing for considering palliative care, the communication surrounding this stage of illness, and assessing patients and caregivers will be discussed. Evaluation using the Edmonton Symptom Assessment Scale-PD can help practitioners identify symptoms requiring intervention and track their response to interventions. Adopting palliative care principles will allow neurologists to fulfill the needs of PD patients in advanced stages to the end of life. © 2013 Springer Science+Business Media New York.


Siddiqi A.,University of Toronto
International Journal of Health Services | Year: 2013

This article draws on the vast evidence that suggests, on one hand, that socioeconomic inequalities in health are present in every society in which they have been measured and, on the other hand, that the size of inequalities varies substantially across societies. We conduct a comparative case study of the United States and Canada to explore the role of neoliberalism as a force that has created inequalities in socioeconomic resources (and thus in health) in both societies and the roles of other societal forces (political, economic, and social) that have provided a buffer, thereby lessening socioeconomic inequalities or their effects on health. Our findings suggest that, from 1980 to 2008, while both the United States and Canada underwent significant neoliberal reforms, Canada showed more resilience in terms of health inequalities as a result of differences in: (a) the degree of income inequality, itself resulting from differences in features of the labor market and tax and transfer policies, (b) equality in the provision of social goods such as health care and education, and (c) the extent of social cohesiveness across race/ethnic- and class-based groups. Our study suggests that further attention must be given to both causes and buffers of health inequalities. © 2013, Baywood Publishing Co., Inc.


Katz P.R.,University of Toronto
Journal of the American Medical Directors Association | Year: 2011

The world is facing an unprecedented growth of older adults, a sizable number of whom will require nursing home services. Although community-based care delivery systems strive to keep most of those in need at home, nursing homes are increasingly accommodating a more frail population that is straining available resources. This article focuses on common themes evident around the world regarding long-term care of the elderly. Issues related to service delivery, financing, and quality are highlighted. © 2011 American Medical Directors Association.


Tein I.,University of Toronto
Handbook of Clinical Neurology | Year: 2013

Recognition of fatty acid oxidation (FAO) disorders is important for the pediatric neurologist as they present with a spectrum of clinical disorders, including progressive lipid storage myopathy, recurrent myoglobinuria, neuropathy, progressive cardiomyopathy, recurrent hypoglycemic hypoketotic encephalopathy or Reye-like syndrome, seizures, and mental retardation. They constitute a critical group of diseases because they are potentially rapidly fatal and a source of major morbidity. There is frequently a family history of sudden infant death syndrome in siblings. Early recognition and prompt institution of therapy and appropriate preventive measures, and in certain cases specific therapy, may be life-saving and may significantly decrease long-term morbidity, particularly with respect to CNS sequelae. All currently known conditions are inherited as autosomal recessive traits. There are now at least 25 enzymes and specific transport proteins in the β-oxidation pathway and 18 have been associated with human disease. The most common defect is medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, which had an incidence of 1 in 8930 live births in one series. The identification of serum acylcarnitines by electrospray ionization-tandem mass spectrometry of dried blood spots on filter paper in newborn screening programs has significantly enhanced the early recognition of these disorders. © 2013 Elsevier B.V.


Pelletier L.,Samuel Lunenfeld Research Institute | Pelletier L.,University of Toronto | Yamashita Y.M.,University of Michigan
Current Opinion in Cell Biology | Year: 2012

The centrosome is a subcellular organelle that is responsible for the majority of microtubule organization. Through this ability, the centrosome is involved in cell division, migration, and polarization. Recent studies have revealed intriguing asymmetries between mother and daughter centrioles as well as between mother and daughter centrosomes, and the involvement of such asymmetries in multiple cellular and developmental processes. This review aims to summarize recent discoveries on such asymmetries in centrioles/centrosomes and the potential implication of their inheritance patterns during cell division and development. © 2012 Elsevier Ltd.


Ivarsson Y.,University of Toronto
FEBS Letters | Year: 2012

The PDZ domain is a protein-protein interacting module that plays an important role in the organization of signaling complexes. The recognition of short intrinsically disordered C-terminal peptide motifs is the archetypical PDZ function, but the functional repertoire of this versatile module also includes recognition of internal peptide sequences, dimerization and phospholipid binding. The PDZ function can be tuned by various means such as allosteric effects, changes of physiological buffer conditions and phosphorylation of PDZ domains and/or ligands, which poses PDZ domains as dynamic regulators of cell signaling. This review is focused on the plasticity of the PDZ interactions. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Lok C.E.,University of Toronto | Foley R.,U.S. Renal System
Clinical Journal of the American Society of Nephrology | Year: 2013

During the past decade, clear trends in the types of incident and prevalent hemodialysis vascular access can be observed. There has been a steady increase and recent stabilizaton of patients initiating hemodialysis with a central venous catheter, representing approximately 80% of all incident accesses. There has also been a steady increase in prevalent fistula use, currently greater than 50%within 4 months of hemodialysis initiation. Patient and vascular access related morbidity and mortality are reflected in the type of vascular access used at initiation and for long-term maintenance dialysis. There is a three- to fourfold increase in risk of infectious complications in patients initiating dialysis with a catheter compared with either a fistula or graft and a sevenfold higher risk when the catheter is used as a prevalent access. Procedure rates have increased two- to threefold for all types of access. There is a significant increased risk of mortality associated with catheter use, especially within the first year of dialysis initiation. © 2013 by the American Society of Nephrology.


O'Sullivan B.,University of Toronto
Medicina Oral, Patologia Oral y Cirugia Bucal | Year: 2013

The term oral cavity cancer (OSCC) constitutes cancers of the mucosal surfaces of the lips, floor of mouth, oral tongue, buccal mucosa, lower and upper gingiva, hard palate and retromolar trigone. Treatment approaches for OSCC include single management with surgery, radiotherapy [external beam radiotherapy (EBRT) and/or brachytherapy], as well as adjuvant systemic therapy (chemotherapy and/or target agents); various combinations of these modalities may also be used depending on the disease presentation and pathological findings. The selection of sole or combined modality is based on various considerations that include disease control probability, the anticipated functional and cosmetic outcomes, tumor resectability, patient general condition, and availability of resources and expertise. For resectable OSCC, the mainstay of treatment is surgery, though same practitioners may advocate for the use of radiotherapy alone in selected "early" disease presentations or combined with chemotherapy in more locally advanced stage disease. In general, the latter is more commonly reserved for cases where surgery may be problematic. Thus, primary radiotherapy ± chemotherapy is usually reserved for patients unable to tolerate or who are otherwise unsuited for surgery. On the other hand, brachytherapy may be considered as a sole modality for early small primary tumor. It also has a role as an adjuvant to surgery in the setting of inadequate pathologically assessed resection margins, as does postoperative external beam radiotherapy ± chemotherapy, which is usually reserved for those with unfavorable pathological features. Brachytherapy can also be especially useful in the reirradiation setting for persistent or recurrent disease or for a second primary arising within a previous radiation field. Biological agents targeting the epithelial growth factor receptor (EGFR) have emerged as a potential modality in combination with radiotherapy or chemoradiotherpy and are currently under evaluation in clinical trials. © Medicina Oral S. L. C.I.F. B.


Warr D.,University of Toronto
Current Opinion in Oncology | Year: 2012

Purpose of review: This review updates the clinical data on antiemetic therapy for chemotherapy classified as highly emetogenic. Recent findings: A meta-analysis demonstrated that palonosetron was superior to other 5-hydroxytryptamine3 (5-HT3) receptor antagonists at least in the absence of aprepitant. Two major guideline groups have reclassified all chemotherapy that contains cyclophosphamide and an anthracycline as 'highly emetogenic'. Although recommended prophylaxis for drugs in that category includes aprepitant, phase II studies with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and doxorubicin, bleomycin, vincristine and dacarbazine (ABVD) demonstrated that single agent palonosetron alone provided control of emesis over 85% of patients. A randomized phase III trial of olanzapine versus aprepitant found that the control of emesis was similar and nausea was significantly better controlled with olanzapine. Two studies showed that there is no impact of the moderate cytochrome P450 3A4 (CYP3A4) inhibitor aprepitant on the pharmacokinetics of cyclophosphamide. Surveys in the United States and Europe demonstrated that antiemetic prescribing practices often do not adhere to guidelines even for highly emetogenic chemotherapy. Summary: The major guideline groups recommend a combination of a 5-HT 3 receptor antagonist, dexamethasone and aprepitant ('triple therapy') for treatment categorized as highly emetogenic. Recent data suggest that, although classified as highly emetogenic, palonosetron may provide very good control of emesis for CHOP and ABVD. Guidelines have not made firm recommendations for highly emetogenic chemotherapy administered over several days or stem cell transplant preparative regimens due to the lack of published randomized trials. Although well tolerated and effective, many patients receive suboptimal antiemetic therapy that includes aprepitant. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Weirauch M.T.,Donnelly Center for Cellular and Biomolecular Research | Hughes T.R.,Donnelly Center for Cellular and Biomolecular Research | Hughes T.R.,University of Toronto
Trends in Genetics | Year: 2010

Regulatory regions with similar transcriptional output often have little overt sequence similarity, both within and between genomes. Although cis- and trans-regulatory changes can contribute to sequence divergence without dramatically altering gene expression outputs, heterologous DNA often functions similarly in organisms that share little regulatory sequence similarities (e.g. human DNA in fish), indicating that trans-regulatory mechanisms tend to diverge more slowly and can accommodate a variety of cis-regulatory configurations. This capacity to 'tinker' with regulatory DNA probably relates to the complexity, robustness and evolvability of regulatory systems, but cause-and-effect relationships among evolutionary processes and properties of regulatory systems remain a topic of debate. The challenge of understanding the concrete mechanisms underlying cis-regulatory evolution - including the conservation of function without the conservation of sequence - relates to the challenge of understanding the function of regulatory systems in general. Currently, we are largely unable to recognize functionally similar regulatory DNA. © 2009 Elsevier Ltd. All rights reserved.


Wells P.G.,University of Toronto
Handbook of Experimental Pharmacology | Year: 2010

Drugs and environmental chemicals can adversely alter the development of the fetus at critical periods during pregnancy, resulting in death, or in structural and functional birth defects in the surviving offspring. This process of teratogenesis may not be evident until a decade or more after birth. Postnatal functional abnormalities include deficits in brain function, a variety of metabolic diseases, and cancer. Due to the high degree of fetal cellular division and differentiation, and to differences from the adult in many biochemical pathways, the fetus is highly susceptible to teratogens, typically at low exposure levels that do not harm the mother. Insights into the mechanisms of teratogenesis come primarily from animal models and in vitro systems, and involve either receptor-mediated or reactive intermediate-mediated processes. Receptor-mediated mechanisms involving the reversible binding of xenobiotic substrates to a specific receptor are exemplified herein by the interaction of the environmental chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or "dioxin") with the cytosolic aryl hydrocarbon receptor (AHR), which translocates to the nucleus and, in association with other proteins, binds to AH-responsive elements (AHREs) in numerous genes, initiating changes in gene transcription that can perturb development. Alternatively, many xenobiotics are bioactivated by fetal enzymes like the cytochromes P450 (CYPs) and prostaglandin H synthases (PHSs) to highly unstable electrophilic or free radical reactive intermediates. Electrophilic reactive intermediates can covalently (irreversibly) bind to and alter the function of essential cellular macromolecules (proteins, DNA), causing developmental anomalies. Free radical reactive intermediates can enhance the formation of reactive oxygen species (ROS), resulting in oxidative damage to cellular macromolecules and/or altered signal transduction. The teratogenicity of reactive intermediates is determined to a large extent by the balance among embryonic and fetal pathways of xenobiotic bioactivation, detoxification of the xenobiotic reactive intermediate, detoxification of ROS, and repair of oxidative macromolecular damage. © 2010 Springer-Verlag Berlin Heidelberg.


Uetrecht J.P.,University of Toronto
Handbook of Experimental Pharmacology | Year: 2010

Treatment of HIV-1 infections with nevirapine is associated with skin and liver toxicity. These two organ toxicities range from mild to severe, in rare cases resulting in life-threatening liver failure or toxic epidermal necrolysis. The study of the mechanistic steps leading to nevirapine-induced skin rash has been facilitated by the discovery of an animal model in which nevirapine causes a skin rash in rats that closely mimics the rash reported in patients. The similarity in characteristics of the rash between humans and rats strongly suggests that the basic mechanism is the same in both. The rash is clearly immune-mediated in rats, and partial depletion of CD4+ T cells, but not CD8+ T cells, is protective. We have demonstrated that the rash is related to the 12-hydroxylation of nevirapine rather than to the parent drug. This is presumably because the 12-hydroxy metabolite can be converted to a reactive quinone methide in skin, but that remains to be demonstrated. Although the rash is clearly related to the 12-hydroxy metabolite rather than the parent drug, cells from rechallenged animals respond ex vivo to the parent drug by producing cytokines such as interferon-γ with little response to the 12-hydroxy metabolite, even when the rash was induced by treatment with the metabolite rather than the parent drug. This indicates that the response of T cells in vitro cannot be used to determine what caused an immune response. We are now studying the detailed steps by which the 12-hydroxy metabolite induces an immune response and skin rash. This animal model provides a unique tool to study the mechanistic details of an idiosyncratic drug reaction; however, it is likely that there are significant differences in the mechanisms of different idiosyncratic drug reactions, and therefore the results of these studies cannot safely be generalized to all idiosyncratic drug reactions. © 2010 Springer-Verlag Berlin Heidelberg.


Li J.,University of Toronto
Handbook of Experimental Pharmacology | Year: 2010

The danger hypothesis has had a profound effect on the way immunologists view the immune response. This hypothesis proposes that the major determinant of whether an immune response is mounted against some agent is determined by whether that agent causes some type of cell damage. Assuming that most idiosyncratic drug reactions (IDRs) are immune-mediated, this hypothesis also has the potential to explain many aspects of the mechanism of these adverse drug reactions. For example, most IDRs appear to be caused by chemical metabolites rather than the parent drug, but not all drugs that form reactive metabolites are associated with a significant incidence of IDRs. Therefore, using the danger hypothesis, one feature of a drug candidate that may predict whether it causes an IDR is whether the drug, or more likely its reactive metabolites, cause cell damage. Although the range of molecules that can act as danger signals is unknown, the most attractive candidates are high mobility group box 1 protein (HMGB1), heat shock proteins, and S100 proteins. These molecules act through the same receptors (toll-like receptors) as pathogen-associated molecules that stimulate the immune system. Therefore, other environmental factors such as infections or trauma might determine which patients would be at increased risk for IDRs. Although there are examples where this appears to be the case, in most cases there are no obvious environmental factors that determine IDR risk. In addition, in animal models of immune-mediated reactions, stimulation of toll-like receptors often does not increase the immune response, and depending on the timing, it can actually be protective. Therefore, there may be additional unknown control mechanisms that are involved. A better understanding of these fundamental immune mechanisms has the potential to have a significant impact on many areas of medicine. © 2010 Springer-Verlag Berlin Heidelberg.


Treanor B.,University of Toronto
Immunology | Year: 2012

B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). The early molecular events triggered by BCR binding of ligand have been well-characterized both biochemically and using optical microscopy techniques to visualize B-cell activation as it happens. However, we understand much less about the BCR before activation. For this reason, this review will address recent advances in our view of the structure, organization and dynamics of the resting, unstimulated BCR. These parameters have important implications for our understanding of the initiation of B-cell activation and will be discussed in the context of current models for BCR activation. These models include the conformation-induced oligomerization model, in which binding of antigen to monomeric BCR induces a pulling or twisting force causing conformational unmasking of a clustering interface in the Cμ4 domain. Conversely, the dissociation activation model proposes that BCRs exist in auto-inhibitory oligomers on the resting B-cell surface and binding of antigen promotes the dissociation of the BCR oligomer exposing phosphorylation residues within Igα/Igβ. Finally, the collision coupling model suggests that BCR are segregated from activating co-receptors or kinases and activation is associated with changes in BCR mobility on the cell surface, which allows for the functional interaction of these elements. © 2012 The Author. Immunology © 2012 Blackwell Publishing Ltd.


Bolt L.M.,University of Toronto
International Journal of Primatology | Year: 2013

Long calls are sex-specific vocalizations used for mate attraction or mate defense in many animal species. Ring-tailed lemurs (Lemur catta), female-dominant strepsirrhines, have a male-specific long call termed a howl, with proposed functions that have never been empirically tested. I aimed to investigate why ring-tailed lemur males howl and to test whether the mate defense and mate attraction hypotheses for long-calling were applicable to this species. From March to July 2010, I collected 600 h of focal data on 25 males aged ≥3 year at Beza Mahafaly Special Reserve, Madagascar. I observed each male continuously for 30 min at a time and noted all agonism using one-zero sampling at 2. 5-min intervals. I calculated male dominance rank from these data. I recorded days when female estrus occurred and noted howling and intergroup encounters using all-occurrences sampling. Howling rate was not significantly related to female estrus or male dominance rank, providing no support for the mate attraction hypothesis or the intragroup mate defense hypothesis. In contrast, the intergroup mate defense hypothesis was strongly supported. During intergroup encounters, male howling rate significantly increased compared to howling rate at times without other groups present, and a greater number of males participated in multimale howling choruses when compared to times without nongroup members present. My results suggest that male ring-tailed lemurs howl to advertise their presence and location to other groups, but not to male or female members of their own group. Howling could discourage male immigration by advertising the number of males already present in a group. Long calls are used for similar mate defense purposes during intergroup encounters by other primates, including Thomas langurs (Presbytis thomasi) and chacma baboons (Papio ursinus). © 2013 Springer Science+Business Media New York.


Boonstra R.,University of Toronto
Functional Ecology | Year: 2013

Chronic activation of the stress axis caused by long-term uncontrollable and unpredictable factors in the environment has been regarded as causing maladaptive and/or pathological effects, both by those studying animals in the laboratory and in nature. While pathology may apply to the former, I argue that it does not apply to the latter. Our thinking on the role of chronic stress in animals in nature has been heavily influenced by biomedical research, but much less so by the ecological and evolutionary context within which animals actually function. I argue that when such stressors occur (e.g. periods of high predation risk, food limitation, prolonged severe weather, social conflict, etc.), although the animal may be chronically stressed, its responses are adaptive and continue to promote fitness. Chronic stressors in nature can be subdivided into whether they are reactive (direct physiological challenges threatening homeostasis and not requiring cognitive processing - for example, food limitation) or anticipatory (perceived to be threatening and requiring cognitive processing - for example, high predation risk). For anticipatory stressors, their impact on the animal should not be based on their absolute duration (they may be acute), but rather by the duration of their physiological consequences. The anticipatory stressor of persistent high predation risk does not elicit chronic stress in all prey classes. Cyclic snowshoe hare and arctic ground squirrels exhibit evidence of chronic stress when predator numbers are high, but cyclic vole and noncyclic elk populations do not. I suggest that chronic stress has evolved to benefit the fitness of the former and not the later, with the key factors being lifespan and life history. I propose that chronic stress evolves in a species only if it is adaptive. © 2012 The Author. Functional Ecology © 2012 British Ecological Society.


Rogers R.S.,University of Toronto
Molecular & cellular proteomics : MCP | Year: 2012

We investigate the role of glial cell activation in the human optic nerve caused by raised intraocular pressure, and their potential role in the development of glaucomatous optic neuropathy. To do this we present a proteomics study of the response of cultured, optic nerve head astrocytes to biomechanical strain, the magnitude and mode of strain based on previously published quantitative models. In this case, astrocytes were subjected to 3 and 12% stretches for either 2 h or 24 h. Proteomic methods included nano-liquid chromatography, tandem mass spectrometry, and iTRAQ labeling. Using controls for both stretch and time, a six-plex iTRAQ liquid chromatography- tandem MS (LC/MS/MS) experiment yielded 573 proteins discovered at a 95% confidence limit. The pathways included transforming growth factor β1, tumor necrosis factor, caspase 3, and tumor protein p53, which have all been implicated in the activation of astrocytes and are believed to play a role in the development of glaucomatous optic neuropathy. Confirmation of the iTRAQ analysis was performed by Western blotting of various proteins of interest including ANXA 4, GOLGA2, and αB-Crystallin.


Katzberg H.D.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2011

Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss. To examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival;(2) nutritional status; (3) quality of life;(4) minor and major complications of percutaneous endoscopic gastrostomy. We searched the Cochrane Neuromuscular Disease Group Trials Register (24 November 2009), MEDLINE (from January 1966 to September 2009), and EMBASE (from January 1980 to September 2009) for all papers on enteral tube feeding in amyotrophic lateral sclerosis/motor neuron disease. The results were screened to identify randomised controlled trials and to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles and enlisted personal communications to identify any additional references.  A priori selection criteria included randomised and quasi-randomized controlled trials evaluating the efficacy of percutaneous endoscopic gastrostomy or other feeding tube placement. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review. We independently assessed study design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, (3) self-perceived quality of life and (4) safety of the procedure as indicated by minor and major complications of surgical or radiological guided PEG tube insertion.  We found no randomised controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective studies in the 'Discussion' section. There are no randomised controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for any of the outcome measures. The 'best' evidence to date suggests a survival advantage for some people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable.  Quality of life has been addressed in studies and needs more attention. Based on a number of recent non-randomized studies comparing surgical and radiographic approaches to feeding tube insertion these two procedures for PEG tube insertion appear to be equivalent.


Wong F.,University of Toronto
Clinics in Liver Disease | Year: 2011

Many liver diseases coexist with chronic renal disease, because many systemic conditions affect both the liver and the kidneys. Certain liver diseases are also common in patients with chronic renal disease, especially viral hepatitis, either because the renal disease occurs as a complication of viral hepatitis, or the viral hepatitis is acquired as a result of dialysis. Renal tubular dysfunction is also frequently observed with cholestasis. However, liver complications of renal diseases are extremely uncommon, notable examples include nephrogenic ascites and nephrogenic hepatic dysfunction. Nephrogenic ascites can mimic liver cirrhosis with ascites, and it improves with renal transplantation. Nephrogenic hepatic dysfunction is a manifestation of renal cell carcinoma, which settles with the removal of the renal cell carcinoma, but returns with the recurrence of the tumor. In general, the presence of liver disease in patients with chronic renal disease makes management of both conditions more challenging. Viral hepatitis should be treated, if possible, before renal transplant. If cirrhosis is present, renal transplant alone is contraindicated; combined liver and kidney transplantation is indicated in patients with end-stage renal disease and advanced cirrhosis. © 2011 Elsevier Inc.


Ramesh Prasad G.V.,University of Toronto
Clinical Transplantation | Year: 2012

Solid organ transplant recipients are at an increased risk for hypertension and cardiovascular disease. To assist in their management, 24-h ambulatory blood pressure monitoring (ABPM) has become increasingly used in both clinical research settings and practice. ABPM has been used to better define post-transplant hypertension incidence and prevalence in different solid organ transplantation populations. ABPM provides additional information on cardiovascular risk beyond that obtained by clinic-based readings, based on its ability to assess 24-h blood pressure (BP) load, detect nocturnal non-dipping, and predict target organ damage. It has provided some assurance about the safety of living kidney donation. Information from ABPM can be used to guide living kidney donor selection, and because ABPM-related data has been correlated with clinically important kidney and heart transplant recipient outcomes, it may be a valuable adjunct in their management. Despite these advantages, barriers to wider use of ABPM include expense, clinical inertia in hypertension management, lack of prospective clinical trial data, and clinical problems that compete with hypertension for attention such as acute or chronic allograft dysfunction. The increasing amount of research and clinical use for ABPM may allow for closer assessment and intervention to help address the increased cardiovascular risk faced by many solid organ transplant recipients. © 2011 John Wiley & Sons A/S.


Ching A.T.,University of Toronto
International Journal of Industrial Organization | Year: 2010

This paper introduces an empirical demand model with aggregate learning and consumer heterogeneity in price sensitivity. The model is applied to the prescription drug market after patent expiration during the 80s, when the diffusion of generic drugs is fairly slow and consumer price sensitivity is known to be heterogeneous. I also introduce a new estimation approach to take the price endogeneity problem into account for this class of models. My approach is to estimate the demand model jointly with a pseudo-pricing policy function, which is a reduced-form function of observed and unobserved state variables. My estimation and counterfactual exercises demonstrate the value of estimating such a structural demand model, e.g., it allows one to learn whether consumers have optimistic or pessimistic prior, how aggregate learning affects the product diffusion rates in different latent segments of the population, and quantify the role of learning in explaining new product diffusion. I also find evidence that the brand-name price elasticities of demand (evaluated at the observed prices) are often less than one and increase over time, suggesting that brand-name firms might set their prices lower than what they would do if they were myopic, in order to slow down the learning process for generic qualities. But such an incentive might diminish over time as the uncertainty slowly resolves. © 2010 Elsevier B.V.


Robinson G.E.,University of Toronto
Journal of Nervous and Mental Disease | Year: 2015

There is controversy about the use of antidepressant medication during pregnancy. Decisions about their use are affected by understanding the risks of these medications causing pregnancy loss, congenitalmalformations, neonatal adaptation syndrome, persistent pulmonary hypertension of the newborn, autism spectrum disorder, or long-term neurocognitive deficits. Although some research has raised concerns about antidepressants causing harm to the fetus and neonate, other studies have disputed these findings or noted that any risks found do not exceed the risk of congenital problems found in 1%to 3% of neonates in the general population. Untreated depression during pregnancy can also cause harm from poor diet, substance abuse, suicidal behavior, or prematurity. Decisions about the use of antidepressants during pregnancy must be based on a risk-benefit analysis based on the best evidence of the risks of treating or not treatingmaternal depression. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Huse J.T.,Sloan Kettering Cancer Center | Aldape K.D.,University of Toronto
Clinical Cancer Research | Year: 2014

While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management. © 2014 AACR.


Gareau M.G.,University of Toronto
Nature reviews. Gastroenterology & hepatology | Year: 2010

The use of probiotics is increasing in popularity for both the prevention and treatment of a variety of diseases. While a growing number of well-conducted, prospective, randomized, controlled, clinical trials are emerging and investigations of underlying mechanisms of action are being undertaken, questions remain with respect to the specific immune and physiological effects of probiotics in health and disease. This Review considers recent advances in clinical trials of probiotics for intestinal disorders in both adult and pediatric populations. An overview of recent in vitro and in vivo research related to potential mechanisms of action of various probiotic formulations is also considered.


Breslin F.C.,University of Toronto
Journal of occupational rehabilitation | Year: 2010

INTRODUCTION: This systematic review was conducted to identify effective occupational health and safety interventions for small businesses. METHODS: The review focused on peer-reviewed intervention studies conducted in small businesses with 100 or fewer employees, that were published in English and several other languages, and that were not limited by publication date. Multidisciplinary members of the review team identified relevant articles and assessed their quality. Studies assessed as medium or high quality had data extracted, which was then synthesized. RESULTS: Five studies were deemed of medium or high quality, and proceeded to data extraction and evidence synthesis. The types of interventions identified: a combination of training and safety audits; and a combination of engineering, training, safety audits, and a motivational component, showed a limited amount of evidence in improving safety outcomes. Overall, this evidence synthesis found a moderate level of evidence for intervention effectiveness, and found no evidence that any intervention had adverse effects. CONCLUSIONS: Even though there were few studies that adequately evaluated small business intervention, several studies demonstrate that well-designed evaluations are possible with small businesses. While stronger levels of evidence are required to make recommendations, these interventions noted above were associated with positive changes in safety-related attitudes and beliefs and workplace parties should be aware of them.


Pearson C.E.,Program of Genetics and Genome Biology | Pearson C.E.,University of Toronto
PLoS Genetics | Year: 2011

Diseases associated with unstable repetitive elements in the DNA, RNA, and amino acids have consistently revealed scientific surprises. Most diseases are caused by expansions of trinucleotide repeats, which ultimately lead to diseases like Huntington's disease, myotonic dystrophy, fragile X syndrome, and a series of spinocerebellar ataxias. These repeat mutations are dynamic, changing through generations and within an individual, and the repeats can be bi-directionally transcribed. Unsuspected modes of pathogenesis involve aberrant loss of protein expression; aberrant over-expression of non-mutant proteins; toxic-gain-of-protein function through expanded polyglutamine tracts that are encoded by expanded CAG tracts; and RNA-toxic-gain-of-function caused by transcripts harboring expanded CUG, CAG, or CGG tracts. A recent advance reveals that RNA transcripts with expanded CAG repeats can be translated in the complete absence of a starting ATG, and this Repeat Associated Non-ATG translation (RAN-translation) occurs across expanded CAG repeats in all reading frames (CAG, AGC, and GCA) to produce homopolymeric proteins of long polyglutamine, polyserine, and polyalanine tracts. Expanded CTG tracts expressing CUG transcripts also show RAN-translation occurring in all three frames (CUG, UGC, and GCU), to produce polyleucine, polycysteine, and polyalanine. These RAN-translation products can be toxic. Thus, one unstable (CAG)•(CTG) DNA can produce two expanded repeat transcripts and homopolymeric proteins with reading frames (the AUG-directed polyGln and six RAN-translation proteins), yielding a total of potentially nine toxic entities. The occurrence of RAN-translation in patient tissues expands our horizons of modes of disease pathogenesis. Moreover, since RAN-translation counters the canonical requirements of translation initiation, many new questions are now posed that must be addressed. This review covers RAN-translation and some of the pertinent questions. © 2011 Christopher E. Pearson.


Morris R.H.,University of Toronto
Journal of the American Chemical Society | Year: 2014

A simple equation (pKa THF = ΣAL + Ccharge + Cnd + Cd6) can be used to obtain an estimate of the pKa of diamagnetic transition metal hydride and dihydrogen complexes in tetrahydrofuran, and, by use of conversion equations, in other solvents. It involves adding acidity constants AL for each of the ligands in the 5-, 6-, 7-, or 8-coordinate conjugate base complex of the hydride or dihydrogen complex along with a correction for the charge (C charge = -15, 0 or 30 for x = +1, 0 or -1 charge, respectively) and the periodic row of the transition metal (Cnd = 0 for 3d or 4d metal, 2 for 5d metal) as well as a correction for d6 octahedral acids (Cd6 = 6 for d6 metal ion in the acid, 0 for others) that are not dihydrogen complexes. Constants AL are provided for 13 commonly occurring ligand types; of these, nine neutral ligands are correlated with Lever's electrochemical ligand parameters EL. This method gives good estimates of the over 170 literature pKa values that range from less than zero to 50 with a standard deviation of 3 pKa units for complexes of the metals chromium to nickel, molybdenum, ruthenium to palladium, and tungsten to platinum in the periodic table. This approach allows a quick assessment of the acidity of hydride complexes found in nature (e.g., hydrogenases) and in industry (e.g., catalysis and hydrogen energy applications). The pKa values calculated for acids that have bulky or large bite angle chelating ligands deviate the most from this correlation. The method also provides an estimate of the base strength of the deprotonated form of the complex. © 2014 American Chemical Society.


This section of the cervical spondylotic myelopathy Spine focus issue collates the existing evidence related to natural history and nonoperative management. In the case of patients with symptomatic cervical spondylotic myelopathy treated nonoperatively, while 20% to 62% will deteriorate at 3 to 6 years of follow-up, no specific patient or disease characteristics have been shown to predict this change reliably. For patients without myelopathy with spondylotic cord compression, the rate of myelopathy development is approximately 8% at 1 year and approximately 23% at 4 years of follow-up. Clinical and/or electrophysiological evidence of cervical radiculopathy has been shown to predict such progression and should prompt strong consideration of surgical decompression. With respect to nonoperative care, in the case of mild myelopathy, there is low evidence that such treatment may have a role; for moderate and severe myelopathy, this treatment results in outcomes inferior to those of surgery and is not recommended. Given the unpredictably progressive nature of cervical myelopathy, the indications for nonoperative management are ostensibly limited. Finally, the preclinical rationale and clinical translation of a putative neuroprotective drug, which may one day serve to augment the effects of surgery in the treatment of cervical spondylotic myelopathy, is presented and discussed.


Billeter J.C.,University of Toronto
Proceedings. Biological sciences / The Royal Society | Year: 2012

In Drosophila melanogaster, biological rhythms, aggression and mating are modulated by group size and composition. However, the fitness significance of this group effect is unknown. By varying the composition of groups of males and females, we show that social context affects reproductive behaviour and offspring genetic diversity. Firstly, females mating with males from the same strain in the presence of males from a different strain are infecund, analogous to the Bruce effect in rodents, suggesting a social context-dependent inbreeding avoidance mechanism. Secondly, females mate more frequently in groups composed of males from more than one strain; this mitigates last male sperm precedence and increases offspring genetic diversity. However, smell-impaired Orco mutant females do not increase mating frequency according to group composition; this indicates that social context-dependent changes in reproductive behaviour depend on female olfaction, rather than direct male-male interactions. Further, variation in mating frequency in wild-type strains depends on females and not males. The data show that group composition can affect variance in the reproductive success of its members, and that females play a central role in this process. Social environment can thus influence the evolutionary process.


Weatheritt R.J.,University of Toronto | Gibson T.J.,Structural and Computational Biology Unit | Babu M.M.,University of Cambridge
Nature Structural and Molecular Biology | Year: 2014

Although many proteins are localized after translation, asymmetric protein distribution is also achieved by translation after mRNA localization. Why are certain mRNA transported to a distal location and translated on-site? Here we undertake a systematic, genome-scale study of asymmetrically distributed protein and mRNA in mammalian cells. Our findings suggest that asymmetric protein distribution by mRNA localization enhances interaction fidelity and signaling sensitivity. Proteins synthesized at distal locations frequently contain intrinsically disordered segments. These regions are generally rich in assembly-promoting modules and are often regulated by post-translational modifications. Such proteins are tightly regulated but display distinct temporal dynamics upon stimulation with growth factors. Thus, proteins synthesized on-site may rapidly alter proteome composition and act as dynamically regulated scaffolds to promote the formation of reversible cellular assemblies. Our observations are consistent across multiple mammalian species, cell types and developmental stages, suggesting that localized translation is a recurring feature of cell signaling and regulation.


Cox R.A.,University of Toronto
International Journal of Molecular Sciences | Year: 2011

If a species does not have a finite lifetime in the reaction medium, it cannot be a mechanistic intermediate. This principle was first enunciated by Jencks, as the concept of an enforced mechanism. For instance, neither primary nor secondary carbocations have long enough lifetimes to exist in an aqueous medium, so S N1 reactions involving these substrates are not possible, and an S N2 mechanism is enforced. Only tertiary carbocations and those stabilized by resonance (benzyl cations, acylium ions) are stable enough to be reaction intermediates. More importantly, it is now known that neither H 3O + nor HO - exist as such in dilute aqueous solution. Several recent high-level calculations on large proton clusters are unable to localize the positive charge; it is found to be simply "on the cluster" as a whole. The lifetime of any ionized water species is exceedingly short, a few molecular vibrations at most; the best experimental study, using modern IR instrumentation, has the most probable hydrated proton structure as H 13O 6+, but only an estimated quarter of the protons are present even in this form at any given instant. Thanks to the Grotthuss mechanism of chain transfer along hydrogen bonds, in reality a proton or a hydroxide ion is simply instantly available anywhere it is needed for reaction. Important mechanistic consequences result. Any charged oxygen species (e.g., a tetrahedral intermediate) is also not going to exist long enough to be a reaction intermediate, unless the charge is stabilized in some way, usually by resonance. General acid catalysis is the rule in reactions in concentrated aqueous acids. The Grotthuss mechanism also means that reactions involving neutral water are favored; the solvent is already highly structured, so the entropy involved in bringing several solvent molecules to the reaction center is unimportant. Examples are given. © 2011 by the authors; licensee MDPI, Basel, Switzerland.


Devlin B.,University of Pittsburgh | Scherer S.W.,University of Toronto
Current Opinion in Genetics and Development | Year: 2012

Autism spectrum disorder (ASD) is characterized by impairments in reciprocal social interaction and communication, and by restricted and repetitive behaviors. Family studies indicate a significant genetic basis for ASD susceptibility, and genomic scanning is beginning to elucidate the underlying genetic architecture. Some 5-15% of individuals with ASD have an identifiable genetic etiology corresponding to known chromosomal rearrangements or single gene disorders. Rare (<1% frequency) de novo or inherited copy number variations (CNVs) (especially those that affect genes with synaptic function) are observed in 5-10% of idiopathic ASD cases. These findings, coupled with genome sequencing data suggest the existence of hundreds of ASD risk genes. Common variants, yet unidentified, exert only small effects on risk. Identification of ASD risk genes with high penetrance will broaden the targets amenable to genetic testing; while the biological pathways revealed by the deeper list of ASD genes should narrow the targets for therapeutic intervention. © 2012 Elsevier Ltd.


Schachter H.,University of Toronto
Seminars in Cell and Developmental Biology | Year: 2010

UDP-GlcNAc:α3-d-mannoside β1,2-N-acetylglucosaminyltransferase I (GnTI, encoded by Mgat1) first appeared in evolution at about the same time as metazoa suggesting that GnTI-dependent glycans are essential for the development of multicellular organisms. This review describes the effects of mutations in the Mgat1 gene on the development of Caenorhabditis elegans, Drosophila melanogaster and mice. © 2010 Elsevier Ltd.


Blencowe B.J.,University of Toronto
Biochemistry and Cell Biology | Year: 2012

During the past ten years, remarkable progress has been made in our understanding of the complexity and regulation of alternative splicing. The generation of large datasets of quantitative alternative splicing profiling information has revealed that transcripts from at least 95% of multi-exon human genes undergo alternative splicing, and that thousands of exons in mammalian transcriptomes are subject to striking regulatory patterns. Together with advanced computational methods, these datasets have enabled the inference of a predictive code for tissue-dependent alternative splicing. This code has further provided new insight into splicing regulatory mechanisms. Collectively, these approaches are revealing the existence of discrete networks of exons that are coordinately regulated in diverse biologically normal and disease contexts. A major challenge ahead is to systematically determine the functions of exons comprising these exon networks as well as the factors and mechanisms responsible for their regulation. This perspective provides an account of progress in these areas and also discusses future avenues of exon-centric exploration. © 2012 Published by NRC Research Press.


Malti T.,University of Toronto
Developmental Review | Year: 2016

An integrated clinical-developmental model is proposed for understanding the development of guilt feelings from early childhood to adolescence. The central goal is to posit a new theoretical framework that expands existing social-cognitive models, social-domain models, and clinical approaches to the study of guilt (i.e., the Affect-Event Model [Arsenio, Gold, & Adams, 2006] and the Affect-Cognition Model [Malti & Keller, 2010]). Because guilt feelings are multifaceted and depend on both contextual variation (e.g., moral transgressions versus conventional issues) and dispositional guilt proneness, they can be associated with both adaptive and maladaptive outcomes for children and adolescents. The proposed model therefore suggests several clinical effects on adaptive, other-oriented behaviors and maladaptive, externalizing and internalizing symptoms across childhood and adolescence. The available evidence for each of these hypotheses is presented. The developmental model of guilt lays the groundwork for a more complete understanding of adaptive and maladaptive behaviors across development and provides new means for developing interventions that will reduce mental health problems and promote adaptive behaviors in children and adolescents. The model assumes that intervention efforts will be effective at producing behavioral change when (a) they are developmentally sensitive, rather than one-size-fits-all, and (b) they acknowledge that both extensively low and extensively high/inappropriate levels of guilt may be pathogenic and need to be targeted. © 2016 Elsevier Inc.


Sinha S.S.,University of Toronto
Sleep Medicine Reviews | Year: 2016

Traumatic events have been increasingly recognized as important precipitants of clinically significant insomnia. Trauma is an extreme form of stressful life event that generates a sustained neurobiological response triggering the onset and maintenance of insomnia. Trauma may disrupt the normal sleep-wake regulatory mechanism by sensitizing the central nervous system's arousal centers, leading to pronounced central and physiological hyperarousal. The central concept of hyperarousal has been linked to both the pathogenesis of insomnia and to the neurobiological changes in the aftermath of traumatic events, and may be a neurobiological commonality underlying trauma and insomnia. This paper presents evidence for trauma-induced insomnia and advances a model of it as an important nosological and neurobiological entity. Trauma-induced insomnia may occur in the absence of full-blown posttraumatic stress disorder (PTSD), and may also be a precursor of subsequent PTSD development. Converging lines of evidence from the neuroscience of insomnia with the neurobiology and psychophysiology of stress, fear, trauma and PTSD will be integrated to advance understanding of the condition. Preclinical and clinical stress and fear paradigms have informed the neurobiological pathways mediating the production of insomnia by trauma. Elucidating the underlying neurobiological substrates can establish novel biological markers to identify persons at risk for the condition, and help optimize treatment of the trauma-insomnia interface. Early identification and treatment of trauma-induced insomnia may prevent the development of PTSD, as well as other important sequelae such as depression, substance dependence, and other medical conditions. © 2015 Elsevier Ltd.


Walks A.,University of Toronto
Urban Studies | Year: 2013

Much attention has been given to increasing dominance of the post-war suburbs, and the concomitant rise of 'suburbanism' in ways of life in the 'post-metropolis'. However, the meaning of suburbanism is rarely specified and there have been insufficient attempts to theorise its relationship to the urban. Drawing on the dialectical analyses of Henri Lefebvre, this article presents a theory of suburbanism as a subset of urbanism, with which it is in constant productive tension. Six distinct dimensions of the urbanism-suburbanism dialectic are identified, derived from extrapolating Lefebvre's urban theory into second- and third-order analyses. These aspects of suburbanism are conceptualised not as static characteristics but as qualities that dynamically flow through, rather than define, particular places. Suburbanism is thus conceptualised separately from those places often termed suburbs, opening up the potential for interaction between these dimensions and the lived realities of everyday urban life and politics. © 2012 Urban Studies Journal Limited.


Sarris C.D.,University of Toronto
IEEE Microwave and Wireless Components Letters | Year: 2011

It is shown that the well-known Courant stability limit of the finite-difference time-domain (FDTD) method can be controlled and extended by filtering out unstable spatial harmonics that develop when the time-step is chosen to exceed this limit. The formulation of a spatially filtered FDTD algorithm is accompanied by a numerical benchmarking study that includes cavity resonator and backward wave media simulations. © 2011 IEEE.


Chalikian T.V.,University of Toronto
Biophysical Chemistry | Year: 2011

Interactions of proteins and protein groups with water-soluble cosolvents have been studied for the last 50 years with a variety of theoretical and experimental methods. The contribution of volumetric techniques to these studies is relatively modest, although volumetric properties of solutes are sensitive to the entire spectrum of solute-solvent and solute-cosolvent interactions. This deficiency is partly related to formidable experimental difficulties related to conducting volumetric measurements at high cosolvent concentrations and partly to the lack of the theoretical framework within which volumetric results can be rationalized in terms of solute-solvent and solute-cosolvent interactions. However, recent years have witnessed a revival of interest in application of the volumetric approach to characterization of solute-solvent interactions in protein solutions in binary mixtures. This review presents an overview of recent advances in the field, focusing on both the theoretical and the experimental developments. While presenting the current state of the art, it also outlines the strategy for future volumetric studies that will result in new insights into the old problem of interactions of proteins with protecting and denaturing osmolytes. © 2010 Elsevier B.V. All rights reserved.


Bradbury A.R.M.,Los Alamos National Laboratory | Sidhu S.,University of Toronto | Dubel S.,TU Braunschweig | McCafferty J.,University of Cambridge
Nature Biotechnology | Year: 2011

In vitro display technologies, best exemplified by phage and yeast display, were first described for the selection of antibodies some 20 years ago. Since then, many antibodies have been selected and improved upon using these methods. Although it is not widely recognized, many of the antibodies derived using in vitro display methods have properties that would be extremely difficult, if not impossible, to obtain by immunizing animals. The first antibodies derived using in vitro display methods are now in the clinic, with many more waiting in the wings. Unlike immunization, in vitro display permits the use of defined selection conditions and provides immediate availability of the sequence encoding the antibody. The amenability of in vitro display to high-throughput applications broadens the prospects for their wider use in basic and applied research. © 2011 Nature America, Inc. All rights reserved.


Lanner F.,Hospital for Sick Children Research Institute | Rossant J.,Hospital for Sick Children Research Institute | Rossant J.,University of Toronto
Development | Year: 2010

Fibroblast growth factor (FGF) signaling controls fundamental processes such as proliferation, differentiation and migration throughout mammalian development. Here we discuss recent discoveries that implicate FGF/Erk signaling in the control of pluripotency and lineage specification in several different stem cell states, including the separation of pluripotent epiblast and primitive endoderm in the blastocyst, the lineage priming of embryonic stem (ES) cells, and in the stabilization of the metastable state of mouse epiblast and human ES cells. Understanding how extrinsic signals such as FGF regulate different stem cell states will be crucial to harvest the clinical promise of induced pluripotent and embryo-derived stem cells.


Fisher J.A.,University of Toronto
Journal of Cerebral Blood Flow and Metabolism | Year: 2016

Cerebrovascular reactivity (CVR) studies have elucidated the physiology and pathophysiology of cerebral blood flow regulation. A non-invasive, high spatial resolution approach uses carbon dioxide (CO2) as the vasoactive stimulus and magnetic resonance techniques to estimate the cerebral blood flow response. CVR is assessed as the ratio response change to stimulus change. Precise control of the stimulus is sought to minimize CVR variability between tests, and show functional differences. Computerized methods targeting end-tidal CO2 partial pressures are precise, but expensive. Simpler, improvised methods that fix the inspired CO2 concentrations have been recommended as less expensive, and so more widely accessible. However, these methods have drawbacks that have not been previously presented by those that advocate their use, or those that employ them in their studies. As one of the developers of a computerized method, I provide my perspective on the trade-offs between these two methods. The main concern is that declaring the precision of fixed inspired concentration of CO2 is misleading: it does not, as implied, translate to precise control of the actual vasoactive stimulus-the arterial partial pressure of CO2. The inherent test-to-test, and therefore subject-to-subject variability, precludes clinical application of findings. Moreover, improvised methods imply widespread duplication of development, assembly time and costs, yet lack uniformity and quality control. A tabular comparison between approaches is provided. © 2015 The Author(s).


Bruix J.,University of Barcelona | Reig M.,University of Barcelona | Sherman M.,University of Toronto
Gastroenterology | Year: 2016

Evidence-based management of patients with hepatocellular carcinoma (HCC) is key to their optimal care. For individuals at risk for HCC, surveillance usually involves ultrasonography (there is controversy over use of biomarkers). A diagnosis of HCC is made based on findings from biopsy or imaging analyses. Molecular markers are not used in diagnosis or determination of prognosis and treatment for patients. The Barcelona Clinic Liver Cancer algorithm is the most widely used staging system. Patients with single liver tumors or as many as 3 nodules ≤3 cm are classified as having very early or early-stage cancer and benefit from resection, transplantation, or ablation. Those with a greater tumor burden, confined to the liver, and who are free of symptoms are considered to have intermediate-stage cancer and can benefit from chemoembolization if they still have preserved liver function. Those with symptoms of HCC and/or vascular invasion and/or extrahepatic cancer are considered to have advanced-stage cancer and could benefit from treatment with the kinase inhibitor sorafenib. Patients with end-stage HCC have advanced liver disease that is not suitable for transplantation and/or have intense symptoms. Studies now aim to identify molecular markers and imaging techniques that can detect patients with HCC at earlier stages and better predict their survival time and response to treatment. © 2016 AGA Institute.


Juurlink D.N.,University of Toronto
British Journal of Clinical Pharmacology | Year: 2016

Sometimes mistakenly characterized as a 'universal antidote,' activated charcoal (AC) is the most frequently employed method of gastrointestinal decontamination in the developed world. Typically administered as a single dose (SDAC), its tremendous surface area permits the binding of many drugs and toxins in the gastrointestinal lumen, reducing their systemic absorption. Like other decontamination procedures, the utility of SDAC attenuates with time, and, although generally safe, it is not free of risk. A large body of evidence demonstrates that SDAC can reduce the absorption of drugs and xenobiotics but most such studies involve volunteers and have little generalizability to clinical practice. Few rigorous clinical trials of SDAC have been conducted, and none validate or refute its utility in those patients who are intuitively most likely to benefit. Over the past decade, a growing body of observational data have demonstrated that SDAC can elicit substantial reductions in drug absorption in acutely poisoned patients. The challenge for clinicians rests in differentiating those patients most likely to benefit from SDAC from those in whom meaningful improvement is doubtful. This is often a difficult determination not well suited to an algorithmic approach. The present narrative review summarizes the data supporting the benefits and harms of SDAC, and offers pragmatic suggestions for clinical practice. © 2015 The British Pharmacological Society.


Atesok K.I.,University of Toronto
The Journal of the American Academy of Orthopaedic Surgeons | Year: 2011

Osteoid osteoma and osteoblastoma are commonly seen benign osteogenic bone neoplasms. Both tumors are typically seen in the second decade of life, with a notable predilection in males. Histologically, these tumors resemble each other, with characteristically increased osteoid tissue formation surrounded by vascular fibrous stroma and perilesional sclerosis. However, osteoblastomas are larger than osteoid osteomas, and they exhibit greater osteoid production and vascularity. Clinically, osteoid osteoma most commonly occurs in the long bones (eg, femur, tibia). The lesions cause night pain that is relieved with nonsteroidal anti-inflammatory drugs (NSAIDs). Osteoblastoma is most frequently located in the axial skeleton, and the pain is usually not worse at night and is less likely to be relieved with NSAIDs. Osteoblastoma can be locally aggressive; osteoid osteoma lacks growth potential. Osteoid osteoma may be managed nonsurgically with NSAIDs. When surgery is required, minimally invasive methods (eg, CT-guided excision, radiofrequency ablation) are preferred. Osteoblastoma has a higher rate of recurrence than does osteoid osteoma, and patients must be treated surgically with intralesional curettage or en bloc resection.


Adams-Cioaba M.A.,University of Toronto
Nature communications | Year: 2011

Proteolysis of eukaryotic histone tails has emerged as an important factor in the modulation of cell-cycle progression and cellular differentiation. The recruitment of lysosomal cathepsin L to the nucleus where it mediates proteolysis of the mouse histone H3 tail has been described recently. Here, we report the three-dimensional crystal structures of a mature, inactive mutant of human cathepsin L alone and in complex with a peptide derived from histone H3. Canonical substrate-cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide. Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides. This is the first report of cathepsin L-histone H3 interaction and the first structural description of cathepsin L in complex with a substrate.


MacEachen E.,University of Toronto
Journal of occupational rehabilitation | Year: 2010

INTRODUCTION: Small businesses (SBs) play an important role in global economies, employ half of all workers, and pose distinct workplace health problems. This systematic review of qualitative peer-reviewed literature was carried out to identify and synthesize research findings about how SB workplace parties understand and enact processes related to occupational health and safety (OHS). METHODS: The review was conducted as part of a larger mixed-method review and in consultation with stakeholders. A comprehensive literature search identified 5067 studies. After screening for relevance, 20 qualitative articles were identified. Quality assessment led to 14 articles of sufficient quality to be included in the meta-ethnographic findings synthesis. RESULTS: This review finds that SBs have distinctive social relations of work, apprehensions of workplace risk, and legislative requirements. Eight themes were identified that consolidate knowledge on how SB workplace parties understand OHS hazards, how they manage risk and health problems, and how broader structures, policies and systems shape the practice of workplace health in SBs. The themes contribute to 'layers of evidence' that address SB work and health phenomena at the micro (e.g. employer or worker behavior), meso (e.g. organizational dynamics) and macro (e.g. state policy) levels. CONCLUSIONS: This synthesis details the unique qualities and conditions of SBs that merit particular attention from planners and occupational health policy makers. In particular, the informal workplace social relations can limit workers' and employers' apprehension of risk, and policy and complex contractual conditions in which SBs are often engaged (such as chains of subcontracting) can complicate occupational health responsibilities. This review questions the utility of SB exemptions from OHS regulations and suggests a legislative focus on the particular needs of SBs. It considers ways that workers might activate their own workplace health concerns, and suggests that more qualitative research on OHS solutions is needed. It suggests that answers to the SB OHS problems identified in this review might lie in third party interventions and improved worker representation.


Chin K.J.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Several approaches exist to produce local anaesthetic blockade of the brachial plexus. It is not clear which is the technique of choice for providing surgical anaesthesia of the lower arm, although infraclavicular blockade (ICB) has several purported advantages. We therefore performed a systematic review of ICB compared to the other brachial plexus blocks (BPBs). This review was originally published in 2010 and was updated in 2013. The objective of this review was to evaluate the efficacy and safety of infraclavicular block (ICB) compared to other approaches to the brachial plexus in providing regional anaesthesia for surgery on the lower arm. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5); MEDLINE (1966 to June 2013) via OvidSP; and EMBASE (1980 to June 2013) via OvidSP. We also searched conference proceedings (from 2004 to 2012) and the www.clinicaltrials.gov trials registry. The searches for the original review were performed in September 2008. We included any randomized controlled trials (RCTs) that compared ICB with other BPBs as the sole anaesthetic technique for surgery on the lower arm. The primary outcome was adequate surgical anaesthesia within 30 minutes of block completion. Secondary outcomes included sensory block of individual nerves, tourniquet pain, onset time of sensory blockade, block performance time, block-associated pain and complications related to the block. In our original review we included 15 studies with 1020 participants and excluded two. In this updated review we included seven new studies and excluded six, bringing the total number of included studies to 22 and involving 1732 participants. The control group intervention was the axillary block in 14 studies, supraclavicular block in six studies, mid-humeral block in two studies, and parascalene block in one study. One study compared ICB to both axillary and supraclavicular blocks. Nine studies employed ultrasound-guided ICB. The risk of failed surgical anaesthesia 30 minutes after block completion was similar for ICB and all other BPBs (11.4% versus 12.9%, risk ratio (RR) 0.88, 95% CI 0.51 to 1.52, P = 0.64), but tourniquet pain was less likely with ICB (11.9% versus 18.0%; RR of experiencing tourniquet pain 0.66, 95% CI 0.47 to 0.92, P = 0.02). Subgroup analysis by method of nerve localization, and by control group intervention, did not show any statistically significant differences in the risk of failed surgical anaesthesia. However when compared to a single-injection axillary block, ICB was better at providing complete sensory block of the musculocutaneous nerve (RR for failure 0.46, 95% CI 0.27 to 0.60, P < 0.0001). ICB had a slightly longer sensory block onset time (mean difference (MD) 1.9 min, 95% CI 0.2 to 3.6, P = 0.03) but was faster to perform than multiple-injection axillary (MD -2.7 min, 95% CI -3.4 to -2.0, P < 0.00001) or mid-humeral (MD -4.8 min, 95% CI -6.0 to -3.6, P < 0.00001) blocks. ICB is as safe and effective as any other BPBs, regardless of whether ultrasound or neurostimulation guidance is used. The advantages of ICB include a lower likelihood of tourniquet pain during surgery, more reliable blockade of the musculocutaneous nerve when compared to a single-injection axillary block, and a significantly shorter block performance time compared to multi-injection axillary and mid-humeral blocks.


Schafer M.H.,University of Toronto
Journals of Gerontology - Series B Psychological Sciences and Social Sciences | Year: 2011

Background.The overlap between social networks and health represents a key area of research in social gerontology. Set in a continuing care retirement community, this research focuses on how health is related to outgoing and incoming reports of social interaction among residents. Method.Study participants (n = 123) were given the RAND 36-item Health Survey and asked about their social interaction with other people living at the retirement community. Negative binomial and linear regression analysis was used to assess associations between measures of network centrality and health. Results.Retirement community residents in better health received more nominations from their peers about general socializing, net of how many ties they themselves reported. The ties received by healthier people, moreover, tended to come from others who were central in the network. Conversely, those in better health reported fewer close ties with their coresidents, net of the alter reports. Discussion.Results are interpreted in light of status processes, which emerge in bounded social settings. © The Author 2011.


Rose L.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Automated closed loop systems may improve adaptation of the mechanical support to a patient's ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. To compare the duration of weaning from mechanical ventilation for critically ill ventilated adults and children when managed with automated closed loop systems versus non-automated strategies. Secondary objectives were to determine differences in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1948 to August 2011); EMBASE (OvidSP) (1980 to August 2011); CINAHL (EBSCOhost) (1982 to August 2011); and the Latin American and Caribbean Health Sciences Literature (LILACS). In addition we received and reviewed auto-alerts for our search strategy in MEDLINE, EMBASE, and CINAHL up to August 2012. Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles. We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning strategies including non-protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an intensive care unit (ICU). Two authors independently extracted study data and assessed risk of bias. We combined data into forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria. Pooled data from 15 eligible trials (14 adult, one paediatric) totalling 1173 participants (1143 adults, 30 children) indicated that automated closed loop systems reduced the geometric mean duration of weaning by 32% (95% CI 19% to 46%, P = 0.002), however heterogeneity was substantial (I(2) = 89%, P < 0.00001). Reduced weaning duration was found with mixed or medical ICU populations (43%, 95% CI 8% to 65%, P = 0.02) and Smartcare/PS™ (31%, 95% CI 7% to 49%, P = 0.02) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (17%, 95% CI 8% to 26%) and ICU length of stay (LOS) (11%, 95% CI 0% to 21%). There was no difference in mortality rates or hospital LOS. Overall the quality of evidence was high with the majority of trials rated as low risk. Automated closed loop systems may result in reduced duration of weaning, ventilation, and ICU stay. Reductions are more likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.


Intensified relations between biodiversity conservation organizations and private-sector actors are analyzed through a historical perspective that positions biodiversity conservation as an organized political project. Within this view the organizational dimensions of conservation exist as coordinated agreement and action among a variety of actors that take shape within radically asymmetrical power relations. This paper traces the privileged position of " business" in aligning concepts of sustainable development and ecological modernization within the emerging institutional context of the Convention on Biological Diversity and the Global Environment Facility in ways that help to secure continued access to "nature as capital", and create the institutional conditions to shape the work of conservation organizations. The contemporary emergence of business as a major actor in shaping contemporary biodiversity conservation is explained in part by the organizational characteristics of modernist conservation that subordinates it to larger societal and political projects such as neoliberal capitalism. © 2010 The Author Journal compilation © 2010 Editorial Board of Antipode.


Panier S.,Sinai University | Panier S.,Cancer Research UK Research Institute | Durocher D.,Sinai University | Durocher D.,University of Toronto
Nature Reviews Molecular Cell Biology | Year: 2013

Single DNA lesions such as DNA double-strand breaks (DSBs) can cause cell death or trigger genome rearrangements that have oncogenic potential, and so the pathways that mend and signal DNA damage must be highly sensitive but, at the same time, selective and reversible. When initiated, boundaries must be set to restrict the DSB response to the site of the lesion. The integration of positive and, crucially, negative control points involving post-translational modifications such as phosphorylation, ubiquitylation and acetylation is key for building fast, effective responses to DNA damage and for mitigating the impact of DNA lesions on genome integrity. © 2013 Macmillan Publishers Limited. All rights reserved.


Van Assche G.,University of Toronto
American Journal of Gastroenterology | Year: 2013

Abstract: Intravenous (IV) iron therapy has been a major asset in the management of refractory iron-deficiency anemia in inflammatory bowel disease (IBD) and other diseases. However, the cost-effectiveness of parenteral substitution as the first-line treatment of this condition in IBD has been questioned. A study published by Reinisch et al. in this issue of the journal fails to show non-inferiority of iron isomaltose 1,000, a novel high-dose IV preparation, compared to oral iron sulfate. © 2013 by the American College of Gastroenterology.


Matthen M.,University of Toronto
Ear and Hearing | Year: 2016

Listening effort helps explain why people who are hard of hearing are prone to fatigue and social withdrawal. However, a one-factor model that cites only effort due to hardness of hearing is insufficient as there are many who lead happy lives despite their disability. This article explores other contributory factors, in particular motivational arousal and pleasure. The theory of rational motivational arousal predicts that some people forego listening comprehension because they believe it to be impossible and hence worth no effort at all. This is problematic. Why should the listening task be rated this way, given the availability of aids that reduce its difficulty? Two additional factors narrow the explanatory gap. First, we separate the listening task from the benefit derived as a consequence. The latter is temporally more distant, and is discounted as a result. The second factor is displeasure attributed to the listening task, which increases listening cost. Many who are hard of hearing enjoy social interaction. In such cases, the actual activity of listening is a benefit, not a cost. These people also reap the benefits of listening, but do not have to balance these against the displeasure of the task. It is suggested that if motivational harmony can be induced by training in somebody who is hard of hearing, then the obstacle to motivational arousal would be removed. This suggests a modified goal for health care professionals. Do not just teach those who are hard of hearing how to use hearing assistance devices. Teach them how to do so with pleasure and enjoyment.


McLeod D.S.A.,Royal Brisbane and Womens Hospital | McLeod D.S.A.,Queensland Institute of Medical Research | Sawka A.M.,University of Toronto | Cooper D.S.,Johns Hopkins University
The Lancet | Year: 2013

In many parts of the world, incidence of papillary thyroid cancer is increasing faster than any other malignancy. Most papillary thyroid cancers that are diagnosed are small and are generally regarded as being low risk, with little or no effect on mortality. Papillary thyroid cancer is a clinical challenge because it is difficult to prove benefit from the traditional therapeutic triad for this disorder (ie, total thyroidectomy with or without prophylactic central neck dissection, radioiodine remnant ablation, and suppression of serum thyroid-stimulating hormone with levothyroxine). However, risk of disease recurrence might be reduced by these therapies in a subset of patients with more aggressive disease. In the past decade, professional societies and other groups have established evidence-based clinical practice guidelines for management of papillary thyroid cancer, but these efforts have been made difficult by a paucity of randomised controlled trials. In this review, we summarise epidemiological data for disease incidence, discuss some controversies in disease management, and outline a therapeutic framework founded in the best available medical evidence and existing recommendations from clinical practice guidelines.


Lapinsky S.E.,University of Toronto
Critical Care | Year: 2015

Endotracheal intubation in the ICU is a high-risk procedure, resulting in significant morbidity and mortality. Up to 40% of cases are associated with marked hypoxemia or hypotension. The ICU patient is physiologically very different from the usual patient who undergoes intubation in the operating room, and different intubation techniques should be considered. The common operating room practice of sedation and neuromuscular blockade to facilitate intubation may carry significant risk in the ICU patient with a marked oxygenation abnormality, particularly when performed by the non-expert. Preoxygenation is largely ineffective in these patients and oxygen desaturation occurs rapidly on induction of anesthesia, limiting the time available to secure the airway. The ICU environment is less favorable for complex airway management than the operating room, given the frequent lack of availability of additional equipment or additional expert staff. ICU intubations are frequently carried out by trainees, with a lesser degree of airway experience. Even in the presence of a non-concerning airway assessment, these patients are optimally managed as a difficult airway, utilizing an awake approach. Endotracheal intubation may be achieved by awake direct laryngoscopy in the sick ICU patient whose level of consciousness may be reduced by sepsis, hypercapnia or hypoxemia. As the patient's spontaneous respiratory efforts are not depressed by the administration of drugs, additional time is available to obtain equipment and expertise in the event of failure to secure the airway. ICU intubation complications should be tracked as part of the ICU quality improvement process. © 2015 Lapinsky.


Weir J.T.,University of Toronto | Price T.D.,University of Chicago
American Naturalist | Year: 2011

Range expansions are critical to renewed bouts of allopatric or parapatric speciation. Limits on range expansions-and, by implication, speciation-include dispersal ability and permeability of geographical barriers. In addition, recently diverged taxa may interfere with each other, preventing mutual expansion of each other's range into sympatry, because reproductive isolation is incomplete and/or ecological competition particularly strong. On the basis of geographical distributions and mitochondrial DNA phylogenetic information for 418 recently diverged species of New World birds, we estimate that secondary sympatry takes on the order of millions of years following population splitting and hence could impose an important limit on the rate of range expansion, thereby limiting further rounds of species formation. Average rates of achievement of sympatry have been faster in the temperate region (we estimate 1.7 million years to sympatry at 60°) than in the tropics (3.2 million years to sympatry at the equator). Evidence from the ages of species with hybrid zones implies that one factor associated with the slowed sympatry in the tropics is the rate of accumulation of reproductive isolation. © 2011 by The University of Chicago.


Uetrecht J.,University of Toronto | Naisbitt D.J.,University of Liverpool
Pharmacological Reviews | Year: 2013

Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Mah C.L.,University of Toronto
Public Health Ethics | Year: 2015

Menu labelling is a public health policy intervention that applies principles of nutrition labelling to the eating out environment. While menu labelling has received a good deal of attention with regard to its effectiveness in shaping food choices for obesity prevention, its premises have not yet been fully explored in terms of its broader applications to social equity and population health. In the following case, we focus on the example of menu labelling within the context of food policy at the local level, a fruitful substantive area of consideration for public health ethics. © 2014 The Author.


Chitambar E.,University of Toronto
Physical Review Letters | Year: 2011

In this Letter, we investigate the number of measurement and communication rounds needed to implement certain tasks by local quantum operations and classical communication (LOCC), a relatively unexplored topic. To demonstrate the possible strong dependence on the round number, we consider the problem of converting three-qubit entanglement into two-qubit form, specifically in the random distillation setting of. We find that the number of LOCC rounds needed for a transformation can depend on the amount of entanglement distilled. In fact, for a wide range of transformations, the required number of rounds is infinite (unbounded). This represents the first concrete example of a task needing an infinite number of rounds to implement. © 2011 American Physical Society.


Anber M.M.,University of Toronto
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

Recently, it has been conjectured that deconfining phase transition in SU(Nc) pure Yang-Mills theories is continuously connected to a quantum phase transition in softly broken N=1 super Yang-Mills on R1 ,2×S1. We exploit this conjecture to study the strength of the transition and deconfining temperature as a function of the vacuum angle θ in pure Yang-Mills. We find that the transition temperature is a decreasing function of θâ̂̂[0,π), in an excellent agreement with recent lattice simulations. We also predict that the transition becomes stronger for the same range of θ, and comment on the θ dependence in the large Nc limit. More lattice studies are required to test our predictions. © 2013 American Physical Society.


Rubenfeld G.D.,University of Toronto
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Acute respiratory distress syndrome (ARDS) is a common, lethal, and morbid respiratory complication primarily seen in the setting of major trauma and infection. Despite advances in mechanical ventilation for ARDS, many interventions have not been successful in reducing mortality. Recent grant announcements and ongoing clinical trials indicate an interest in preventing ARDS. This Perspective challenges some of the basic assumptions of ARDS prevention and preventive care in the intensive care unit. ARDS is an organ function surrogate outcome. Studies of surrogate outcomes in medicine have repeatedly failed to show an association with patient-centered outcomes that might include mortality, quality of life, patient satisfaction, and cost. Organ failure surrogate outcomes in critical care, including oxygenation, cardiac output, and blood pressure, have similarly failed to show a consistent association with patient-centered benefit. Trials designed to demonstrate an effect on surrogate outcomes will rarely be able to demonstrate small, but important, harms so that the net benefit of prevention can be calculated. This will leave clinicians with insufficient information to balance the unknown benefits of ARDS prevention with imprecisely estimated costs or risks of prevention. Because ARDS diagnosis relies on oxygenation and the chest radiograph that might be directly influenced by the prophylactic intervention, studies must be designed to insure that the prevention is not merely cosmetic. Strategies that prevent ARDS need to be tested in trials sufficiently powered to demonstrate their patient-centered costs, benefits and harms before widespread adoption. Copyright © 2015 by the American Thoracic Society.


Marshall J.C.,Keenan Research Center for Biomedical Science | Marshall J.C.,University of Toronto
Trends in Molecular Medicine | Year: 2014

The systemic inflammatory response is biologically complex, redundant, and activated by both infectious and noninfectious triggers. Its manipulation can cause both benefit and harm. More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments. The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate large studies of clinical and biochemical epidemiology to understand the course of illness, better integration of basic and clinical science, and the creation of stratification systems to target treatment towards those who are most likely to benefit. © 2014 Elsevier Ltd.


Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D3 antagonist SB-277011-A (0.01-1 μg/0.5 μl/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 μg/0.5 μl/side) into the basolateral amygdala or lateral habenula had no effect on food self-administration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [125I]7-OH-PIPAT to D3 receptors in the lateral habenula and in the basolateral amygdala is consistent with an important role of D3 receptors in these areas in nicotine seeking. It was also found that systemic administration of the selective D2 antagonist L741626 decreased cue-induced reinstatement, consistent with a role of D2 and D3 receptors in modulating this behavior. The current study supports an important role for D3 receptors in the basolateral amygdala and lateral habenula in cue-induced reinstatement.Neuropsychopharmacology advance online publication, 6 August 2014; doi:10.1038/npp.2014.158.


Chan A.W.,University of Toronto
BMJ (Clinical research ed.) | Year: 2013

High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.


Mroziewicz M.,University of Toronto
Addiction science & clinical practice | Year: 2010

Pharmacogenetics research looks at variations in the human genome and ways in which genetic factors might influence how individuals respond to drugs. The authors review basic principles of pharmacogenetics and cite findings from several gene-phenotype studies to illustrate possible associations between genetic variants, drug-related behaviors, and risk for drug dependence. Some gene variants affect responses to one drug; others, to various drugs. Pharmacogenetics can inform medication development and personalized treatment strategies; challenges lie along the pathway to its general use in clinical practice.


This life cycle assessment (LCA) examines the claim that lightweight and refillable packaging alternatives to conventional single use glass bottles for wines and spirits reduce environmental impacts. Using LCA input data from laboratory and field research, as well as questionnaires to industry, the potential life cycle impacts of five types of 1 l wine packages and four types of 750 ml spirit packages are compared. In addition, detailed wine and spirit volume sales data are used to undertake an LCA comparison of packaging consumption at a municipal scale. Impacts associated with the wine and spirit packaging supplied in the City of Toronto, Canada in 2008 are compared with a plausible alternative comprising only lightweight and refillable containers which reduces the mass of waste by approximately half. Four alternative means of packaging, including the container, closures, capsules and labels, are evaluated: lightweight single use glass bottles; refillable glass bottles; polyethylene terephthalate bottles; and aseptic cartons. LCA results estimated using the ReCiPe impact assessment method address both the relative impact differences between the packaging systems, as well as the cumulative impacts from the consumption of packages of multiple sizes and types within a municipality. Out of the five types of packages evaluated, the refillable glass bottle and aseptic carton prove to have the lowest net endpoint level environmental impacts, with impact reductions, relative to the conventional single use glass container, reaching as high as 87%. At the municipal scale, the alternative packaging scenario is responsible for endpoint level impact reductions of between 40% and 42%. © 2013 Elsevier Ltd. All rights reserved.


Van Der Kwast T.H.,University of Toronto
Virchows Archiv | Year: 2014

In prostate biopsies and in prostatectomy specimens, the Gleason score remains the strongest prognosticator of prostate cancer progression, in addition to serum PSA level and DRE findings, in spite of numerous potential biomarkers discovered during the last few decades. Inter- and intratumoural heterogeneity may have limited the employment of tissue biomarkers on prostate biopsies. Nevertheless, the monoclonality of morphologically heterogeneous (Gleason score 7) tumour foci would suggest that genetic biomarkers, arising early in prostate carcinogenesis, may overcome issues related to intratumoural heterogeneity. In spite of the above limitations, a few biomarkers including the proliferation marker Ki-67 and genetic markers such as c-MYC and PTEN have consistently shown their independent prognostic impact both for biochemical recurrence and for clinical outcome parameters such as metastatic disease or prostate-specific mortality. The routine application of biomarkers requiring immunostaining (e.g. Ki-67) has particularly been hindered by the lack of standardized protocols for processing and scoring, while the application of fluorescence in situ hybridization (FISH) technology is considered more labour intensive but better standardized. Future steps to enhance the uptake of prostate tissue biomarkers should be focused on prospective studies, particularly on prostate biopsy specimens, using protocols that are highly standardized for the processing and scoring of the biomarkers. A few recently developed RNA-based test signatures may provide an alternative to FISH or immunohistochemistry-based tests. © 2014 Springer-Verlag.


Vincent J.-L.,Free University of Colombia | Rubenfeld G.D.,University of Toronto
Critical Care | Year: 2015

ICUs are an essential but expensive part of all modern hospitals. With increasingly limited healthcare funding, methods to reduce expenditure without negatively influencing patient outcomes are, therefore, of interest. One possible solution has been the development of 'intermediate care units' , which provide more intensive monitoring and patient management with higher nurse:patient ratios than the general ward but less than is offered in the ICU. However, although such units have been introduced in many hospitals, there is relatively little published, especially prospective, evidence to support the benefits of this approach on costs or patient outcomes. We review the available data and suggest that, where possible, a larger unit with combined intermediate care and intensive care beds in one location may be preferable in terms of greater flexibility and efficiency. © Vincent and Rubenfeld.


Gaisano H.Y.,University of Toronto
Trends in Endocrinology and Metabolism | Year: 2014

Exocytosis in pancreatic β-cells employs Munc18/soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes that mediate the priming and docking onto the plasma membrane (PM) of insulin granules, called predocked granules, that sit on the PM until Ca2+ influx evokes fusion. This accounts for most of the initial peak secretory response. However, the subsequent sustained phase of glucose-stimulated insulin secretion arises from newcomer granules that have a minimal residence time at the PM before fusion. In this Opinion I discuss recent work that has begun to decipher the components of the exocytotic machinery of newcomer granules, including a Munc18/SNARE complex that is different from that mediating the fusion of predocked granules and which can potentially rescue defective insulin secretion in diabetes. These insights are applicable to other neuroendocrine cells that exhibit sustained secretion. © 2014 Elsevier Ltd.


Gong S.-G.,University of Toronto
Journal of Cellular Physiology | Year: 2014

The breadth and scope of Fibroblast Growth Factor signaling is immense, with documentation of its role in almost every organism and system studied so far. FGF ligands signal through a family of four distinct tyrosine kinase receptors, the FGF receptors (FGFRs). One contribution to the diversity of function and signaling of FGFs and their receptors arises from the numerous alternative splicing variants that have been documented in the FGFR literature. The present review discusses the types and roles of alternatively spliced variants of the FGFR family members and the significant impact of alternative splicing on the physiological functions of five broad classes of FGFR isoforms. Some characterized known regulatory mechanisms of alternative splicing and future directions in studies of FGFR alternative splicing are also discussed. Presence, absence, and/or the combination of specific exons within each FGFR protein impart upon each individual isoform its unique function and expression pattern during normal function and in diseased states (e.g., in cancers and birth defects). A better understanding of the diversity of FGF signaling in different developmental contexts and diseased states can be achieved through increased knowledge of the presence of specific FGFR isoforms and their impact on downstream signaling and functions. Modern high-throughput techniques afford an opportunity to explore the distribution and function of isoforms of FGFR during development and in diseases. © 2014 Wiley Periodicals, Inc.


Zadeh G.,University of Toronto | Aldape K.,University of Texas M. D. Anderson Cancer Center
Nature Genetics | Year: 2014

Pediatric diffuse gliomas are rare but aggressive brain tumors for which effective therapies are unavailable. New studies identify recurrent mutations of the ACVR1 gene in these tumors, identify molecular subtypes and highlight differences between gliomas affecting children and adults. © 2014 Nature America, Inc. All rights reserved.


Guttman D.S.,University of Toronto | McHardy A.C.,Heinrich Heine University Dusseldorf | Schulze-Lefert P.,Cluster of Excellence on Plant science CEPLAS | Schulze-Lefert P.,Max Planck Institute for Plant Breeding Research
Nature Reviews Genetics | Year: 2014

Advances in genome-based studies on plant-associated microorganisms have transformed our understanding of many plant pathogens and are beginning to greatly widen our knowledge of plant interactions with mutualistic and commensal microorganisms. Pathogenomics has revealed how pathogenic microorganisms adapt to particular hosts, subvert innate immune responses and change host range, as well as how new pathogen species emerge. Similarly, culture-independent community profiling methods, coupled with metagenomic and metatranscriptomic studies, have provided the first insights into the emerging field of research on plant-associated microbial communities. Together, these approaches have the potential to bridge the gap between plant microbial ecology and plant pathology, which have traditionally been two distinct research fields.


Deber R.B.,University of Toronto
Healthcare Policy | Year: 2014

Accountability is a key component of healthcare reforms, in Canada and internationally, but there is increasing recognition that one size does not fit all. A more nuanced understanding begins with clarifying what is meant by accountability, including specifying for what, by whom, to whom and how. These papers arise from a Partnership for Health System Improvement (PHSI), funded by the Canadian Institutes of Health Research (CIHR), on approaches to accountability that examined accountability across multiple healthcare subsectors in Ontario. The partnership features collaboration among an interdisciplinary team, working with senior policy makers, to clarify what is known about best practices to achieve accountability under various circumstances. This paper presents our conceptual framework. It examines potential approaches (policy instruments) and postulates that their outcomes may vary by subsector depending upon (a) the policy goals being pursued, (b) governance/ownership structures and relationships and (c) the types of goods and services being delivered, and their production characteristics (e.g., contestability, measurability and complexity).


Isakson S.R.,University of Toronto
Journal of Agrarian Change | Year: 2015

While agricultural production has always been a risky endeavour, it has become even more so in the current context of climatic change and increasing market uncertainty. Meanwhile, the rollback of state protections has rendered small-scale farmers, especially marginalized peasant producers in the Global South, particularly vulnerable to these contemporary stressors. This essay critically evaluates the contemporary roll-out of financial derivatives that purportedly aim to mitigate smallholder vulnerability. It gives particular attention to a novel type of derivative known as index-based agricultural insurance (IBAI) that plays an increasingly prominent role in initiatives to 'climate proof' agriculture. The creation of IBAI markets has required significant work, including (1) technical interventions to debundle environmental risk from agricultural production and rebundle it in novel ways that support private financial capital and agricultural input suppliers, (2) extensive state support in the creation of risk markets, and (3) the construction of an accommodating 'insurance culture' among small-scale producers. In addition to mitigating weather-based risk, a primary objective of IBAI is to spur agricultural modernization. In promoting this agenda, IBAI initiatives may have the paradoxical effect of exposing smallholders to new risks while expanding their overall vulnerability to environmental and economic stressors. © 2015 John Wiley & Sons Ltd.


Eysenbach G.,University of Toronto
Journal of Medical Internet Research | Year: 2014

In 2012, the Internet Corporation for Assigned Names and Numbers (ICANN) opened a new round of applications for generic top-level domain (gTLD) names, receiving 1930 applications, of which at least 18 were related to health (eg, ".doctor", ".health", ".med"). The entry of new, commercial players applying to create health-related names reopens the debate on the role of international organizations, governments, non-governmental organizations, and other stakeholders regarding the safeguards and policies needed to protect consumers. © Holly O Witteman.


Murphy S.K.,University of California Irvine | Murphy S.K.,University of Toronto | Park J.-W.,University of California Irvine | Cruz F.A.,University of California Irvine | Dong V.M.,University of California Irvine
Science | Year: 2015

The dehydroformylation of aldehydes to generate olefins occurs during the biosynthesis of various sterols, including cholesterol in humans. Here, we implement a synthetic version that features the transfer of a formyl group and hydride from an aldehyde substrate to a strained olefin acceptor. A Rhodium(Xantphos)(benzoate) catalyst activates aldehyde carbon-hydrogen (C-H) bonds with high chemoselectivity to trigger carbon-carbon (C-C) bond cleavage and generate olefins at low loadings (0.3 to 2 mole percent) and temperatures (22° to 80°C). This mild protocol can be applied to various natural products and was used to achieve a three-step synthesis of (+)-yohimbenone. A study of the mechanism reveals that the benzoate counterion acts as a proton shuttle to enable transfer hydroformylation.


Whitehead C.,University of Toronto
Medical Education | Year: 2013

Context: The dominance of biomedical science in medical education has been contested throughout the past century, with recurring calls for more social science and humanities content. The centrality of biomedicine is frequently traced back to Abraham Flexner's 1910 report, 'Medical Education in the United States and Canada'. However, Flexner advocated for a scientist-doctor, rather than a curriculum filled with science content. Examination of the discourses of science since Flexner allows us to explore the place of various knowledge forms in medical education. Methods: A Foucauldian critical discourse analysis was performed, examining the discourses of scientific medicine in Flexner's works and North American medical education articles in subsequent decades. Foucault's methodological principles were used to identify statements, keywords and metaphors that emerged in the development of the discourses of scientific medicine, with particular attention to recurring arguments and shifts in the meaning and use of terms. Results: Flexner's scientist-doctor was an incisive thinker who drew upon multiple forms of knowledge. In the post-Flexner medical education reforms, the perception of science as a discursive object embedded in the curriculum became predominant over that of the scientist as the discursive subject who uses science. Science was then considered core curricular content and was discursively framed as impossibly vast. A parallel discourse, one of the insufficiency of biomedical science for the proper training of doctors, has existed over the past century, even as the humanities and social sciences have remained on the margins in medical school curricula. Conclusions: That discourses of scientific medicine have reinforced the centrality of biomedicine in medical education helps to explain the persistent marginalisation of other important knowledge domains. Medical educators need to be aware of the effects of these discourses on understandings of medical knowledge, particularly when contemplating curricular reform. © 2013 Blackwell Publishing Ltd.


Partitioning of Se and Te has been measured between coexisting sulfide liquid, monosulfide solid solution (MSS) and silicate melt at 0.9-1.5 GPa, 1200-1300 °C, fO2 controlled near the fayalite-magnetite-quartz buffer (FMQ-1.2 to -1.6) and 3-22 wt% FeO in the silicate melt. Both elements are highly compatible in the sulfide phase relative to silicate liquid (Dsulfide phase/silicate liquid > 600), with the identity of the sulfide dictating the sense of Se-Te fractionation. Whereas the measured DTe/DSe is ~5-9 for sulfide liquid/silicate liquid partitioning, MSS/silicate melt partitioning fractionates Te from Se in the opposite sense, with DTe/DSe of ~0.5-0.8. At fixed fO2, DSulLiq/SilLiq values for both Se and Te decrease ~8-fold over the range in silicate melt FeO content investigated. The relative values of DSulLiq/SilLiq for Cu to Se increase with increasing FeO in the silicate melt, such that DCu exceeds DSe only for melts with >11 wt% FeO. Hence the standard belief that DCu>DSe as indicative of sulfide removal should be carefully assessed in the context of the FeO content of the magmas involved.Assuming a chondritic mantle Se/Te, predicted MSS and sulfide liquid compositions are generally in accord with natural mantle sulfides, in terms of their designation as MSS or sulfide liquid, based on independent criteria. However, additional variability is likely due to Te redistribution in accessory platinum group minerals (PGM), or that some sulfides are metasomatic. Calculations show that the Se/Te ratio of silicate melt derived from a sulfide liquid-saturated mantle is significantly higher, and more variable, than for silicate melt in equilibrium with residual MSS; modest sulfide liquid removal at low pressure, however, likely obscures the Se/Te fractionation imposed by the source sulfide phase. Models indicate that the composition of MORB is consistent with melts produced from sulfide-bearing sources with chondritic Se/Te, and source sulfur contents higher than estimates for depleted mantle. The calculated composition of sulfide-saturated melting residues show relatively little deviation in Se/Te if MSS is residual, but a sharp drop in this ratio for sulfide liquid control. Although the data are scattered, a portion of the peridotite array near the primitive mantle composition is consistent with model trends, and suggests control by residual MSS. © 2015 Elsevier B.V.


Lo H.-K.,University of Toronto | Curty M.,University of Vigo | Tamaki K.,Nippon Telegraph and Telephone
Nature Photonics | Year: 2014

Secure communication is crucial in the Internet Age, and quantum mechanics stands poised to revolutionize cryptography as we know it today. In this Review, we introduce the motivation and the current state of the art of research in quantum cryptography. In particular, we discuss the present security model together with its assumptions, strengths and weaknesses. After briefly introducing recent experimental progress and challenges, we survey the latest developments in quantum hacking and countermeasures against it. © 2014 Macmillan Publishers Limited. All rights reserved.


Stephan D.W.,University of Toronto | Erker G.,University of Munster
Chemical Science | Year: 2014

Frustrated Lewis pairs have been used to activate a variety of small molecules. In this review we focus on the recent chemistry of FLPs with CO 2, CO, N2O, NO and SO2. While FLP capture of these small molecule is achieved in all of these cases, subsequent applications of the products include stoichiometric and catalytic reductions of CO 2, C-O bond scission of CO and use of FLP-NO radicals in polymerization. © 2014 the Partner Organisations.


Sigmond M.,University of Toronto | Scinocca J.F.,Canadian Center for Climate Modelling and Analysis
Journal of Climate | Year: 2010

Employing a comprehensive atmospheric general circulation model, the authors have shown in a previous study that the time-mean Northern Hemisphere (NH) winter circulation response to a CO2 doubling perturbation depends significantly on parameterized orographic gravity wave drag (OGWD) parameter settings, which are essentially related to the strength of OGWD. A possible implication is that aspects of the greenhouse gas-induced circulation response could depend directly on the formulation and internal parameters settings of the OGWD scheme. Such a result would further heighten the importance of OGWD parameterizations for climate studies and have far-reaching implications for modeled projections of future climate change. In this study the causal relationship between OGWD and changes in time-mean NH wintertime circulation response to CO2 doubling is investigated. This is accomplished by introducing a methodology that allows one to hold the OGWD forcing fixed to its 1 × CO2 value when CO2 is doubled. Employing this methodology for perturbation experiments with different strengths of OGWD, the authors find that the changes in OGWD forcing due to CO2 doubling have essentially no impact on the time-mean zonal-mean zonal wind response. The primary conclusion is that the OGWD influence is limited to its impact on the 1 × CO2 basic-state climatology, which defines the propagation characteristics of resolved waves. Different strengths of OGWD result in control basic states with different refractive properties for the resolved waves. It is shown that the action of resolved waves, as well as their sensitivity to such differences in the control climatology, explains essentially all of the NH wintertime circulation sensitivity identified here and in a previous study. Implications for climate change projections and climate-model development are discussed. © 2010 American Meteorological Society.


Moore G.W.K.,University of Toronto
Geophysical Research Letters | Year: 2012

The Beaufort Sea High (BSH), an anti-cyclone over the Beaufort Sea, is an important feature of the summer atmospheric circulation over the Arctic Ocean. For example, years characterized by low Arctic sea ice extent are typically associated with the presence of a stronger BSH; with the opposite occurring during years with high sea ice extent. In this paper, we show that there exists variability on the decadal time scale in the intensity and location of the summer BSH. We also show that there has been a trend towards a stronger summer BSH that began in the late 1990s. This trend is shown to be coincident with a tendency towards a reduction in cyclogenesis during the summer over the Beaufort Sea. We argue that that these trends are the result of a warming of the troposphere in the western Arctic and the concomitant reduction in baroclincity. © Copyright 2012 by the American Geophysical Union.


Liscidini M.,University of Pavia | Sipe J.E.,University of Toronto
Physical Review Letters | Year: 2013

We identify a relation between the number of photon pairs generated by parametric fluorescence, through either spontaneous parametric down-conversion (SPDC) or spontaneous four-wave mixing, and the number generated by the corresponding stimulated process, respectively, either difference-frequency generation or stimulated four-wave mixing. On the basis of this very general result, we show that the characterization of SPDC sources of two-photon states in a given system can be performed solely by studying stimulated emission. We call this technique stimulated emission tomography (SET). We show that the number of photons detected in SET can be 9 orders of magnitude larger than the average number of coincidence counts in two-photon quantum state tomography. These results open the way to the study of sources of quantum-correlated photon pairs with unprecedented precision and unparalleled resolution. © 2013 American Physical Society.


Diamond M.,University of Toronto | Schuster P.,Perimeter Institute for Theoretical Physics
Physical Review Letters | Year: 2013

New sub-GeV gauge forces ("dark photons") that kinetically mix with the photon provide a promising scenario for MeV-GeV dark matter and are the subject of a program of searches at fixed-target and collider facilities around the world. In such models, dark photons produced in collisions may decay invisibly into dark-matter states, thereby evading current searches. We reexamine results of the SLAC mQ electron beam dump experiment designed to search for millicharged particles and find that it was strongly sensitive to any secondary beam of dark matter produced by electron-nucleus collisions in the target. The constraints are competitive for dark photon masses in the ∼1-30 MeV range, covering part of the parameter space that can reconcile the apparent (g-2)μ anomaly. Simple adjustments to the original SLAC search for millicharges may extend sensitivity to cover a sizable portion of the remaining (g-2)μ anomaly-motivated region. The mQ sensitivity is therefore complementary to ongoing searches for visible decays of dark photons. Compared to existing direct-detection searches, mQ sensitivity to electron-dark-matter scattering cross sections is more than an order of magnitude better for a significant range of masses and couplings in simple models. © 2013 American Physical Society.


Holthausen M.H.,University of Toronto | Weigand J.J.,TU Dresden
Chemical Society Reviews | Year: 2014

The aim of this review is to provide a comprehensive view of the chemistry of cationic polyphosphorus cages. The synthetic protocols established for their preparation, which are all based on the functionalization of P4, and their intriguing follow-up chemistry are highlighted. In addition, this review intends to foster the interest of the inorganic, organic, catalytic and material oriented chemical communities in the versatile field of polyphosphorus cage compounds. In the long term, this is envisioned to contribute to the development of new synthetic procedures for the functionalization of P4 and its transformation into (organo-)phosphorus compounds and materials of added value. © 2014 the Partner Organisations.


Cowen D.,University of Toronto
Annals of the Association of American Geographers | Year: 2010

In recent years, U.S. military and civilian agencies have been rethinking security in the context of globalized production and trade. No longer lodged in a conflict between territorial borders and global flows, national security is increasingly a project of securing supranational systems. The maritime border has been a critical site for experimentation, and a spate of new policy is blurring "inside" and "outside" national space, reconfiguring border security, and reorganizing citizenship and labor rights. These programs seek to govern integrated economic space while they resurrect borders and sanction new forms of containment. Forces that disrupt commodity flows are cast as security threats with labor actions a key target of policy. Direct connections result between market rule created to secure logistic space and the broader project of neoliberalism. Even as neoliberalism is credited with expanding capitalist markets and market logics, it is logistics that have put the cold calculation of cost at the center of the production of space. Since World War II, logistics experts have conceptualized economy anew by spatializing cost-benefit analysis and applying systems analysis to distribution networks. The "revolution in logistics" has changed how space is conceived and represented, and transformed the practical management of supply chains. Historically a military technology of war and colonialism abroad, today logistics lead rather than support the strategies of firms and the security of nations across transnational space. These shifts have implications for the geopolitics of borders and security but also for social and political forms premised on the territory and ontology of national space. © 2010 by Association of American Geographers.


Rucinski S.M.,University of Toronto
Astronomical Journal | Year: 2015

High-resolution spectroscopic observations of AW UMa, obtained on three consecutive nights with a median time resolution of 2.1 minutes, have been analyzed using the broadening function method in the spectral window of 22.75 nm around the 518 nm Mg I triplet region. Doppler images of the system reveal the presence of vigorous mass motions within the binary system; their presence puts into question the solid-body rotation assumption of the contact binary model. AW UMa appears to be a very tight, semi-detached binary; the mass transfer takes place from the more massive to the less massive component. The primary, a fast-rotating star with V sin i = 181.4 ± 2.5 km s-1, is covered with inhomogeneities: very slowly drifting spots and a dense network of ripples more closely participating in its rotation. The spectral lines of the primary show an additional broadening component (called the " pedestal") that originates either in the equatorial regions, which rotate faster than the rest of the star by about 50 km s-1, or in an external disk-like structure. The secondary component appears to be smaller than predicted by the contact model. The radial velocity field around the secondary is dominated by accretion of matter transferred from (and possibly partly returned to) the primary component. The parameters of the binary are A sin i = 2.73 ± 0.11 R⊙ and M1 sin3 e i = 1.29 ± 0.15 M⊙, M2 sin3 i = 0.128 ± 0.016 M⊙. The mass ratio, qsp = M2/M1 = 0.099 ± 0.003, while still the most uncertain among the spectroscopic elements, is substantially different from the previous numerous and mutually consistent photometric investigations which were based on the contact model. It should be studied why photometry and spectroscopy give such discrepant results and whether AW UMa is an unusual object or if only very high-quality spectroscopy can reveal the true nature of W UMa-type binaries. © 2015. The American Astronomical Society. All rights reserved.


Stelfox H.T.,University of Calgary | Straus S.E.,University of Toronto
Journal of Clinical Epidemiology | Year: 2013

Objective In this article, we describe one approach for developing and evaluating quality indicators. Study Design and Setting We focus on describing different conceptual approaches to quality indicator development, review one approach for developing quality indicators, outline how to evaluate quality indicators once developed, and discuss quality indicator maintenance. Results The key steps for developing quality indicators include specifying a clear goal for the indicators; using methodologies to incorporate evidence, expertise, and patient perspectives; and considering contextual factors and logistics of implementation. The Strategic Framework Board and the National Quality Measure Clearinghouse have developed criteria for evaluating quality indicators that complement traditional psychometric evaluations. Optimal strategies for quality indicator maintenance and dissemination have not been determined, but experiences with clinical guideline maintenance may be informative. Conclusion For quality indicators to effectively guide quality improvement efforts, they must be developed, evaluated, maintained, and implemented using rigorous evidence-informed practices. © 2013 Elsevier Inc. All rights reserved.


Solomon P.H.,University of Toronto
Theoretical Criminology | Year: 2015

This article investigates the extent to which post-Soviet states have successfully reformed the system of criminal justice that they inherited from the USSR, and in particular reduced accusatorial bias and achieved procedural fairness. I argue that with the notable exception of Estonia, these countries have not eliminated the defining features of the Soviet criminal justice, what I call ‘distorted neo-inquisitorialism’—namely the excessive power of investigators and weakness of judges. The article examines in detail the reform of criminal justice in Russia, Estonia and Ukraine from 1992 to the present. © The Author(s) 2015


Ohlsson A.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Nosocomial infections continue to be a significant cause of morbidity and mortality among preterm and/or low birth weight (LBW) infants. Preterm infants are deficient in immunoglobulin G (IgG); therefore, administration of intravenous immunoglobulin (IVIG) may have the potential of preventing or altering the course of nosocomial infections. To use systematic review/meta-analytical techniques to determine whether IVIG administration (compared with placebo or no intervention) to preterm (< 37 weeks' postmenstrual age (PMA) at birth) or LBW (< 2500 g birth weight) infants or both is effective/safe in preventing nosocomial infection. For this update, MEDLINE, EMBASE, CINAHL, The Cochrane Library, Controlled Trials, ClinicalTrials.gov and PAS Abstracts2view were searched in May 2013. We selected randomised controlled trials (RCTs) in which a group of participants to whom IVIG was given was compared with a control group that received a placebo or no intervention for preterm (< 37 weeks' gestational age) and/or LBW (< 2500 g) infants. Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded, as were studies in which the follow-up period was one week or less. Data collection and analysis was performed in accordance with the methods of the Cochrane Neonatal Review Group. Nineteen studies enrolling approximately 5000 preterm and/or LBW infants met inclusion criteria. No new trials were identified in May 2013.When all studies were combined, a significant reduction in sepsis was noted (typical risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74 to 0.98; typical risk difference (RD) -0.03, 95% CI 0.00 to -0.05; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 20 to infinity), and moderate between-study heterogeneity was reported (I(2) 54% for RR, 55% for RD). A significant reduction of one or more episodes was found for any serious infection when all studies were combined (typical RR 0.82, 95% CI 0.74 to 0.92; typical RD -0.04, 95% CI -0.02 to -0.06; NNTB 25, 95% CI 17 to 50), and moderate between-study heterogeneity was observed (I(2) 50% for RR, 62% for RD). No statistically significant differences in mortality from all causes were noted (typical RR 0.89, 95% CI 0.75 to 1.05; typical RD -0.01, 95% CI -0.03 to 0.01), and no heterogeneity for RR (I(2) = 21%) or low heterogeneity for RD was documented (I(2) = 28%). No statistically significant difference was seen in mortality from infection; in incidence of necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) or intraventricular haemorrhage (IVH) or in length of hospital stay. No major adverse effects of IVIG were reported in any of these studies. IVIG administration results in a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection but is not associated with reductions in other clinically important outcomes, including mortality. Prophylactic use of IVIG is not associated with any short-term serious side effects.The decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes. There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infections in preterm and/or LBW infants.


Hirschfield G.M.,University of Toronto | Invernizzi P.,Center for Autoimmune Liver Diseases
Seminars in Liver Disease | Year: 2011

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that has a prevalence of 1 in 1000 women over the age of 40. Treatment is presently limited to ursodeoxycholic acid, a hydrophilic bile acid that has nonspecific, choleretic, effects in cholestatic liver disease. PBC has strong autoimmune features, including highly specific loss of tolerance to a ubiquitous mitochondrial antigen. Both environmental and genetic factors are considered important in the pathogenesis of disease. Prior to the advent of genome-wide association studies, only class II human leucocyte antigen (HLA) loci (HLA-DRB1*08,*11, and*13) had been reproducibly shown to associate with disease. Non-HLA loci were suggested for several genes (e.g., CTLA-4, MDR3), but often inconclusively replicated. With the application of genome-wide technology, HLA was confirmed as the strongest association and many other risk loci have been identified, with equivalent effect size to HLA, including IL12A, IL12RB2, STAT4, IRF5-TNPO3, 17q12.21, MMEL1, SPIB, and CTLA-4. These collectively support an important role for innate and adaptive immunity in development of disease. Further insights are predicted as studies with larger cohorts are assembled, and different approaches are taken to further discover common and uncommon gene variants associated with disease. Disease subphenotypes such as response to therapy, clinical progression, and symptoms remain additional areas for further dedicated studies, and in which different genetic risk factors may be relevant. Identification of risk loci associated with disease has the potential to aid development of rational, disease-specific, therapies in the future. © 2011 by Thieme Medical Publishers, Inc.


Ohlsson A.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Neonates are at higher risk of infection due to immuno-incompetence. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks' gestation, and endogenous synthesis begins several months after birth. Administration of intravenous immunoglobulin (IVIG) provides immunoglobulin G (IgG) that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody-dependent cytotoxicity and improve neutrophilic chemo-luminescence. Theoretically, infectious morbidity and mortality could be reduced by the administration of IVIG. To assess the effects of IVIG on mortality/morbidity caused by suspected or proven infection at study entry in neonates. To assess in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. For this update, MEDLINE, EMBASE, The Cochrane Library, CINAHL, trial registries, Web of Science, reference lists of identified studies, meta-analyses and personal files were searched in 2013. No language restrictions were applied. Randomised or quasi-randomised controlled trials; newborn infants (< 28 days old); IVIG for treatment of suspected or proven bacterial/fungal infection compared with placebo or no intervention; one of the following outcomes was reported: mortality, length of hospital stay or psychomotor development at follow-up. Statistical analyses included typical risk ratio (RR), risk difference (RD), weighted mean difference (WMD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) (all with 95% confidence intervals (CIs) and the I-squared (I(2)) statistic to examine for statistical heterogeneity). The updated search identified one published study and one ongoing study. A total of eight studies evaluating 3871 infants are included in this review.Mortality during hospital stay in infants with clinically suspected infection at trial entry was not significantly different after IVIG treatment (8 studies (n = 2425); typical RR 0.94, 95% CI 0.80 to 1.12; typical RD -0.01, 95% CI - 0.04 to 0.02 I(2) = 28% for RR and 32% for RD). Death or major disability at 2 years corrected age was not significantly different in infants with suspected infection after IVIG treatment (one study (n = 1985); RR 0.98, 95% CI 0.88 to 1.09 RD -0.01, 95% CI -0.05 to 0.03). Mortality during hospital stay was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 0.95, 95% CI 0.74 to 1.21 RD -0.01, 95% CI -0.04 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 1.03, 95% CI 0.91 to 1.18; RD 0.01, 95% CI -0.04 to 0.06). Mortality during hospital stay in infants with clinically suspected or proven infection at trial entry was not significantly different after IVIG treatment (1 study (n = 3493); RR 1.00, 95% CI 0.86 to 1.16; RD 0.00, 95% CI - 0.02 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with suspected or proven infection at trial entry (1 study (n = 3493); RR 1.00, 95% CI 0.92 to 1.09; RD -0.00, 95% CI -0.03 to 0.03). Length of hospital stay was not reduced for infants with suspected/proven infection at trial entry (1 study (n = 3493); mean difference (MD) 0.00 days, 95% CI -0.61 to 0.61). No significant difference in mortality during hospital stay after IgM-enriched IVIG treatment for suspected infection was reported at trial entry (3 studies (n = 164); typical RR 0.57, 95% CI 0.31 to 1.04; RD -0.12, 95% CI -0.24 to 0.00 ; P = 0.06); I(2) = 2% for RR and 0% for RD). In previous reviews, we encouraged researchers to undertake well-designed trials to confirm or refute the effectiveness of IVIG in reducing adverse outcomes in neonates with suspected infection. Such a trial has been undertaken. Results of the INIS trial, which enrolled 3493 infants, carry a heavy weight in the current update of this review, and the undisputed results show no reduction in death or major disability at 2 years of age. Routine administration of IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended.


Dennis C.L.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

A meta-analysis of 21 studies suggests the mean prevalence rate for depression across the antenatal period is 10.7%, ranging from 7.4% in the first trimester to a high of 12.8% in the second trimester. Due to maternal treatment preferences and potential concerns about fetal and infant health outcomes, diverse non-pharmacological treatment options are needed. To assess the effect of interventions other than pharmacological, psychosocial, or psychological interventions compared with usual antepartum care in the treatment of antenatal depression. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013), scanned secondary references and contacted experts in the field to identify other published or unpublished trials. All published and unpublished randomised controlled trials of acceptable quality evaluating non-pharmacological/psychosocial/psychological interventions to treat antenatal depression. Both review authors participated in the evaluation of methodological quality and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Six trials were included involving 402 women from the United States, Switzerland, and Taiwan. For most comparisons a single trial contributed data and there were few statistically significant differences between control and intervention groups.In a trial with 38 women maternal massage compared with non-specific acupuncture (control group) did not significantly decrease the number of women with clinical depression or depressive symptomatology immediately post-treatment (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.25 to 2.53; mean difference (MD) -2.30, 95% CI -6.51 to 1.91 respectively). In another trial with 88 women there was no difference in treatment response or depression remission rates in women receiving maternal massage compared with those receiving non-specific acupuncture (RR 1.33, 95% CI 0.82 to 2.18; RR 1.14, 95% CI 0.59 to 2.19 respectively).In a trial with 35 women acupuncture specifically treating symptoms of depression, compared with non-specific acupuncture, did not significantly decrease the number of women with clinical depression or depressive symptomatology immediately post-treatment (RR 0.47, 95% CI 0.11 to 2.13; MD -3.00, 95% CI -8.10 to 2.10). However, women who received depression-specific acupuncture were more likely to respond to treatment compared with those receiving non-specific acupuncture (RR 1.68, 95% CI 1.06 to 2.66).In a trial with 149 women, maternal massage by a woman's significant other, compared with standard care, significantly decreased the number of women with depressive symptomatology immediately post-treatment (MD -6.70, 95% CI -9.77 to -3.63). Further, women receiving bright light therapy had a significantly greater change in their mean depression scores over the five weeks of treatment than those receiving a dim light placebo (one trial, n = 27; MD -4.80, 95% CI -8.39 to -1.21). However, they were not more likely to have a treatment response or experience a higher remission rate (RR 1.79, 95% CI 0.90 to 3.56; RR 1.89, 95% CI 0.81 to 4.42).Lastly, two trials examined the treatment effect of omega-3 oils. Women receiving omega-3 had a significantly lower mean depression score following eight weeks of treatment than those receiving a placebo (one trial, n = 33; MD -4.70, 95% CI -7.82 to -1.58). Conversely, in a smaller trial (21 women) there was no significant difference in the change in mean depression scores for women receiving omega-3 and those receiving a placebo (MD 0.36, 95% CI -0.17 to 0.89), and women who received omega-3 were no more likely to respond to treatment (RR 2.26, 95% CI 0.78 to 6.49) or have higher remission rates (RR 2.12, 95% CI 0.51 to 8.84). Women in the placebo group were just as likely to report a side effect as those in the omega-3 group (RR 1.12, 95% CI 0.56 to 2.27). The evidence is inconclusive to allow us to make any recommendations for depression-specific acupuncture, maternal massage, bright light therapy, and omega-3 fatty acids for the treatment of antenatal depression. The included trials were too small with non-generalisable samples, to make any recommendations.


Field R.D.,University of Toronto
Journal of Geophysical Research: Atmospheres | Year: 2010

Stable isotopes of oxygen and hydrogen are important paleoclimate indicators and can be obtained from many different natural archives in Europe such as tree rings and speleothems. In this study, a comparison was made of controls on European precipitation δ18 O between observations from the Global Network of Isotopes in Precipitation and from the NASA Goddard Institute for Space Studies ModelE general circulation model. In both observations and the general circulation model, the local temperature effect was identified and extended outside of Europe. This temperature control, in turn, was related to a North Atlantic Oscillation-like dipóle but with centers of action different than standard NAO definitions. An examination of midtropospheric circulation controls showed that European δ18O in fact reflects the hemisphere-wide teleconnections associated with the Northern Annular Mode. Seasonal differences were found in the strength of all controls on δ18O, with the annual controls being the combination of strong winter and weak summer controls. The weaker temperature effect in summer is well-known and has been universally attributed to the effects of continental moisture recycling, but the results of this study show that an additional factor is the reduced variability in summertime atmospheric circulation. The strong agreement between observed and modeled controls can help to improve interpretations of paleoclimatic archives of δ18O, particularly in terms of shifts in atmospheric circulation. Copyright 2010 by the American Geophysical Union.


Shephard R.J.,University of Toronto
Journal of Physical Activity and Health | Year: 2015

Background: Traditional approaches to exercise prescription have included a preliminary medical screening followed by exercise tests of varying sophistication. To maximize population involvement, qualified fitness and exercise professionals (QFEPs) have used a self-administered screening questionnaire (the Physical Activity Readiness Questionnaire, PAR-Q) and a simple measure of aerobic performance (the Canadian Aerobic Fitness Test, CAFT). However, problems have arisen in applying the original protocol to those with chronic disease. Recent developments have addressed these issues. Methods: Evolution of the PAR-Q and CAFT protocol is reviewed from their origins in 1974 to the current electronic decision tree model of exercise screening and prescription. Results: About a fifth of apparently healthy adults responded positively to the original PAR-Q instrument, thus requiring an often unwarranted referral to a physician. Minor changes of wording did not overcome this problem. However, a consensus process has now developed an electronic decision tree for stratification of exercise risk not only for healthy individuals, but also for those with various types of chronic disease. Conclusions: The new approach to clearance greatly reduces physician referrals and extends the role of QFEPs. The availability of effective screening and simple fitness testing should contribute to the goal of maximizing physical activity in the entire population. © 2015 Human Kinetics, Inc.


Previous studies have demonstrated that lower local anaesthetic (LA) volumes can be used for ultrasound (US)-guided interscalene brachial plexus block (ISB). However, no study has examined whether US can reduce the volume required when compared with nerve stimulation (NS) for ISB. Our aim was to do this by comparing the minimum effective analgesic volumes (MEAVs). After ethics approval and informed consent, patients undergoing shoulder surgery were recruited to this randomized, double-blind, up-down sequential allocation study. The volume used for both US and NS was dependent upon the success or failure of the previous block. Success was defined as a verbal rating score of 0/10, 30 min after surgery. Ten needle passes were allowed before defaulting to the opposite group. Patients received general anaesthesia. Pain scores and analgesic consumption were assessed by a blinded observer. Statistical comparisons of continuous variables were performed using Student's t-test and Mann-Whitney U-test as appropriate. Categorical variables were analysed using χ 2 test. MEAV values were estimated using log-transformed up-down independent pairs analysis and probit regression. Significance was assumed at P<0.05 (two-sided). The MEAV required to provide effective analgesia was significantly (P=0.034) reduced to 0.9 ml [95% confidence interval (CI) 0.3-2.8] in the US group from 5.4 ml (95% CI 3.4-8.6) in the NS group. Fewer needle passes were needed to identify the brachial plexus with US (1 vs 3; P<0.0001) and patients had less pain at 30 min after surgery (P=0.03). US reduces the number of attempts, LA volume, and postoperative pain when compared with NS for ISB.


Narod S.A.,University of Toronto
Preventive Medicine | Year: 2011

A woman may be at high risk of breast cancer because of a strong family history of breast cancer or because she carries a mutation in the BRCA1 or BRCA2 gene. The annual risk for women in this category is between 1% and 2% and the lifetime risk of breast cancer among gene carriers may approach 80%. Several recent trials have reported that the sensitivity of MRI for imaging breast cancer greatly exceeds that of conventional mammography, but no study has yet determined that annual MRI reduces breast cancer-specific mortality. Women with breast cancer and a BRCA1 mutation typically develop aggressive breast cancers and the prognosis is relatively poor for women with small node-negative breast cancers (compared to non-carriers) in particular, if chemotherapy is not given. It is hoped that annual MRI screening combined with appropriate treatment will result in decreased mortality for this and other groups of high-risk women. MRI-based screening for women at moderate risk is a topic of great interest-MRI has not yet been endorsed in moderate risk women because of the high cost of screening and because the specificity of the screening test is not yet determined in this subgroup. © 2011 Elsevier Inc.


Stanley S.,University of Toronto
Geophysical Research Letters | Year: 2010

Magnetic field measurements demonstrate that Saturn's internally generated magnetic field has an extremely small dipole tilt. The nearly-perfect axisymmetry of Saturn's dipole is troubling because of Cowling's theorem which states that an axisymmetric magnetic field cannot be maintained by a dynamo. A possible mechanism to axisymmetrize the observed field involves differential rotation in a stably-stratified electrically conducting layer surrounding the dynamo. Here we use numerical dynamo models to study the axisymmetrizing effects of stably stratified layers surrounding the dynamo. We find that a thin stably-stratified layer which undergoes differential rotation due to thermal winds as a result of pole to equator temperature differences can produce a more axisymmetrized field. Surprisingly, we find that the direction of the zonal flows and their equatorial symmetry is a crucial factor for magnetic field axisymmetry since some zonal flows act to destabilize the dynamo producing non-axisymmetric fields. Copyright © 2010 by the American Geophysical Union.


Grusec J.E.,University of Toronto | Davidov M.,Hebrew University of Jerusalem
Child Development | Year: 2010

There are several different theoretical and research approaches to the study of socialization, characterized by frequently competing basic tenets and apparently contradictory evidence. As a way of integrating approaches and understanding discrepancies, it is proposed that socialization processes be viewed from a domain perspective, with each domain characterized by a particular form of social interaction between the object and agent of socialization and by specific socialization mechanisms and outcomes. It is argued that this approach requires researchers to identify the domain of social interaction they are investigating, to understand that phenotypically similar behaviors may belong to different domains, and to acknowledge that caregivers who are effective in one type of interaction may not be effective in another. © 2010, Copyright the Author(s). Journal Compilation © 2010, Society for Research in Child Development, Inc.


Mcnaughton N.,University of Toronto
Medical Education | Year: 2013

Context Emotion in medical education rests between the idealised and the invisible, sitting uneasily at the intersection between objective fact and subjective values. Examining the different ways in which emotion is theorised within medical education is important for a number of reasons. Most significant is the possibility that ideas about emotion can inform a broader understanding of issues related to competency and professionalism. Objectives The current paper provides an overview of three prevailing discourses of emotion in medical education and the ways in which they activate particular professional expectations about emotion in practice. Methods A Foucauldian critical discourse analysis of the medical education literature was carried out. Keywords, phrases and metaphors related to emotion were examined for their effects in shaping medical socialisation processes. Discussion Despite the increasing recognition over the last two decades of emotion as 'socially constructed', the view of emotion as individualised is deeply embedded in our language and conceptual frameworks. The discourses that inform our emotion talk and practice as teachers and health care professionals are important to consider for the effects they have on competence and professional identity, as well as on practitioner and patient well-being. Expanded knowledge of how emotion is 'put to work' within medical education can make visible the invisible and unexamined emotion schemas that serve to reproduce problematic professional behaviours. For this discussion, three main discourses of emotion will be identified: a physiological discourse in which emotion is described as located inside the individual as bodily states which are universally experienced; emotion as a form of competence related to skills and abilities, and a socio-cultural discourse which calls on conceptions from the humanities and social sciences and directs our attention to emotion's function in social exchanges and its role as a social, political and cultural mediator. © 2013 Blackwell Publishing Ltd.


O'Brien K.,University of Toronto
AIDS and behavior | Year: 2010

The purpose of this project was to identify key research priorities related to HIV and rehabilitation. We conducted a scoping study which included a literature review of published and grey literature, followed by focus group and interview consultations with 28 participants including people living with HIV, researchers, educators, clinicians, and policy makers with expertise in HIV and rehabilitation. Qualitative content analysis was used to identify emergent themes related to research priorities in HIV and rehabilitation. The resulting Framework of HIV and Rehabilitation Research provided an outline for approaching research in the field. The framework included three overlapping research priorities: (a) living with HIV across the lifespan, (b) disability, and (c) rehabilitation that should be viewed through environmental and/or personal contextual lenses, using different methodological approaches. Six key research priorities from this framework were identified through additional consultation with new and returning participants including: (1) disability and episodic disability, (2) concurrent health conditions aging with HIV, (3) HIV and the brain, (4) labour force and income support, (5) access to and effectiveness of rehabilitation, and (6) development and evaluation of outcome measurement tools. These priorities inform a future plan for HIV and rehabilitation research that will increase our knowledge to enhance practice, programming and policy for people living with HIV.


Lapinsky S.E.,University of Toronto
Current Opinion in Infectious Diseases | Year: 2010

Purpose of Review: Two recent viral epidemics producing pneumonitis (severe acute respiratory syndrome and pandemic influenza A H1N1) have highlighted the potential for viral infections to cause respiratory failure with a significant risk of mortality. This review describes these epidemics and other causes of epidemic viral pneumonia. Recent Findings: The recent literature highlights the rapidity with which these emerging viral infections can be characterized and how management strategies, including supportive care, antiviral therapy and infection control precautions, can be rapidly shared and implemented. Summary: The severe acute respiratory syndrome outbreak was too short to allow management protocols to be tested in a research environment. The current 2009 influenza A (H1N1) pandemic is fortunately not associated with as high a mortality rate as the avian influenza A (H5N1), another potential pandemic candidate virus. Prior pandemic planning as well as research planning has allowed a rapid response to this outbreak, with a significant amount of literature generated in a few months. Other common seasonal viruses, such as respiratory syncytial virus and parainfluenza, as well as previously poorly recognized viruses such as hantavirus, have the ability to cause significant respiratory morbidity and mortality. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Sessle B.J.,University of Toronto
International Review of Neurobiology | Year: 2011

Many orofacial pain conditions involve inflammation of orofacial tissues and they range from acute pulpitis (toothache) and mucositis to chronic arthritic conditions affecting the temporomandibular joint (TMJ). This article reviews the peripheral and central neural mechanisms involved in orofacial inflammatory pain states, including the integral role that peripheral and central sensitization play in the pain features that characterize these states. It also outlines the recent evidence for the contribution of non-neural processes, especially those involving glial cells. © 2011 Elsevier Inc.


Murphy M.,University of Toronto
Social Studies of Science | Year: 2015

Responding to the call by Maria Puig de la Bellacasa for Science and Technology Studies to take up ‘matters of care’, this article cautions against equating care with positive feelings and, in contrast, argues for the importance of grappling with the non-innocent histories in which the politics of care already circulates, particularly in transnational couplings of feminism and health. The article highlights these histories by tracing multiple versions of the politics of care in a select set of feminist engagements with the pap smear and cervical cancer. Drawing on postcolonial and indigenous feminist commitments, as well as amplifying Donna Haraway’s call to ‘stay with the trouble’, the article seeks to disturb hegemonic histories and arrangements of race, colonialism, and political economy, while simultaneously valuing divergent multi-local itineraries as relevant to technoscientific matters of care. This call for a politics of ‘unsettling’ care strives to stir up and put into motion what is sedimented, while embracing the generativity of discomfort, critique, and non-innocence. © 2015, © The Author(s) 2015.


Background-Luminal esophageal temperature (LET) monitoring is one strategy to minimize esophageal injury during atrial fibrillation ablation procedures. However, esophageal ulceration and fistulas have been reported despite adequate LET monitoring. The objective of this study was to assess a novel approach to LET monitoring with a deflectable LET probe on the rate of esophageal injury in patients undergoing atrial fibrillation ablation. Methods and Results-Forty-five consecutive patients undergoing an atrial fibrillation ablation procedure followed by esophageal endoscopy were included in this prospective observational pilot study. LET monitoring was performed with a 7F deflectable ablation catheter that was positioned as close as possible to the site of left atrial ablation using the deflectable component of the catheter guided by visualization of its position on intracardiac echocardiography. Ablation in the posterior left atrial was limited to 25 W and terminated when the LET increased 2°C from baseline. Endoscopy was performed 1 to 2 days after the procedure. All patients had at least 1 LET elevation >2°C necessitating cessation of ablation. Deflection of the LET probe was needed to accurately measure LET in 5% of patients when ablating near the left pulmonary veins, whereas deflection of the LET probe was necessary in 88% of patients when ablating near the right pulmonary veins. The average maximum increase in LET was 2.5±1.5°C. No patients had esophageal thermal injury on follow-up endoscopy. Conclusions-A strategy of optimal LET probe placement using a deflectable LET probe and intracardiac echocardiography guidance, combined with cessation of radiofrequency ablation with a 2°C rise in LET, may reduce esophageal thermal injury during left atrial ablation procedures. © 2011 American Heart Association, Inc.


Ohlsson A.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer side effects. To determine the efficacy and safety of ibuprofen for closing a PDA in preterm and/or low birth weight infants. Seperate comparisons are presented for 1. ibuprofen (iv) compared with placebo; 2. ibuprofen (oral) compared with placebo; 3. ibuprofen (oral or iv) compared with other cyclo-oxygenase inhibitors (given iv or orally); 4. ibuprofen (oral) versus indomethacin (given iv or orally); 5. ibuprofen (oral) versus iv ibuprofen; 6. high dose versus standard dose of iv ibuprofen; 7. early versus expectant administration of iv ibuprofen. We searched The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, www.abstracts2view.com/pas, and personal files in July 2012. Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in newborn infants. Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. Twenty-seven studies are included in this review. One study (n = 136) compared iv ibuprofen versus placebo. Ibuprofen reduced the composite outcome of infant deaths, infants who dropped out or required rescue treatment; risk ratio (RR) 0.58 (95% confidence interval (CI) 0.38 to 0.89); risk difference (RD) -0.22 (95% CI -0.38 to -06); number needed to benefit (NNTB) 5 (95% CI 3 to 17). One study (n = 64) compared oral ibuprofen with placebo. There was a significant reduction in the failure rate to close a PDA; RR 0.26 (95% CI 0.11 to 0.62); RD -0.44 (95% CI -0.65 to -0.23); NNTB 2 (95% CI 2 to 4). Failure rates for PDA closure with ibuprofen (oral or iv) compared with indomethacin (oral or iv) was reported in 20 studies (n = 1019 infants). There was no significant difference between the groups; typical RR 0.98 (95% CI 0.80 to 1.20) I(2) = 0%; typical RD -0.01 (95% CI -0.06 to 0.05); I(2) = 0%. The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (15 studies (n = 865); typical RR 0.68 (95% CI 0.47 to 0.99); typical RD -0.04 (95% CI -0.08 to -0.00; (P = 0.04); NNTB 25 (95% CI 13, infinity); I(2) = 0%). The duration of ventilatory support was reduced with ibuprofen (oral or iv) compared with iv or oral indomethacin (six studies, n = 471) mean difference (MD) -2.35 days (95% CI -3.71 to -0.99); I(2) = 19%. Failure rates for PDA closure with oral ibuprofen compared with indomethacin (oral or iv) were reported in seven studies (n = 189 infants). There was no significant difference between the groups; typical RR 0.82 (95% CI 0.52 to 1.29); typical RD -0.06 (95% CI -0.18 to 0.06). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (oral or iv) six studies (n = 166); typical RR 0.44 (95% CI 0.23 to 0.82); RD -0.15 (95% CI -0.25 to -0.04); NNTB 7 (95% CI 4 to 25). There was no heterogeneity for this outcome. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with iv ibuprofen, three studies (n = 236) typical RR 0.37 (95% CI 0.23 to 0.61); typical RD -0.24 (95% CI -0.35 to -0.13); NNTB 4 (95% CI 3 to 8). There was less evidence of transient renal insufficiency in infants who received ibuprofen compared with indomethacin. High dose versus standard dose of iv ibuprofen and early versus expectant administration of iv ibuprofen have only been studied in two trials. Ibuprofen is as effective as indomethacin in closing a PDA and reduces the risk of NEC and transient renal insufficiency. Given the reduction in NEC ibuprofen currently appears to be the drug of choice. Oro-gastric administration of ibuprofen appears at least as effective as iv administration. Too few patients have been enrolled in studies assessing the effectiveness of a high dose of ibuprofen versus the standard dose and early versus expectant administration of ibuprofen to make recommendations. Studies are needed to evaluate the effect of ibuprofen compared with indomethacin treatment on longer-term outcomes in infants with PDA.


Review of methods. To provide a detailed description of the methods undertaken in the articles in this focus issue pertaining to cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL) and to describe the process used to develop summary statements and clinical recommendations regarding factors associated with the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. We present methods used in conducting the systematic, evidence-based reviews and development of expert panel summary statements and clinical recommendations of the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. Our intent is that clinicians will combine the information from these systematic reviews, narrative reviews, and primary research studies with an understanding of their own capacities and experience to better manage patients with CSM or OPLL and consider future research for the diagnosis and treatment of these diseases. For the systematic reviews, which make up the bulk of the studies in this focus issue, a systematic search and critical review of the English language literature was undertaken for articles published on the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. Articles were screened for relevance using a priori criteria and relevant articles were critically reviewed. Whether an article was included for review depended on whether the study question was descriptive, one of therapy, or one of prognosis. The strength of evidence for the overall body of literature in each topic area was determined by 2 independent reviewers considering risk of bias, consistency, directness, and precision of results using a modification of the Grading of Recommendation Assessment, Development and Evaluation criteria. Disagreements were resolved by consensus. Findings from articles meeting inclusion criteria were summarized. From these summaries, summary statements or clinical recommendations were formulated among subject experts through a modified Delphi process using the Grading of Recommendation Assessment, Development and Evaluation approach. Methods for the 2 primary research studies and the narrative reviews are also reviewed. Because of the nature of questions that needed to be addressed, not all studies in this focus issue were amenable to systematic review. As a result, this focus issue consists of several different article types, including 1 research protocol, 2 primary research studies, 2 narrative literature reviews, 7 systematic reviews, and 3 articles that combine a systematic review component with either a narrative section (n = 2) or a provider survey (n = 1). In general, the strength of evidence ratings ranged from insufficient to moderate. Summary statements or clinical recommendations were made according to available evidence and study type: 16 summary statements were made across 8 articles, and 17 clinical recommendations were made across 9 articles. Three articles had both summary statements and clinical recommendations, 5 had summary statements only, 6 had clinical recommendations only, and 1 (the research protocol) was not amenable to either. Systematic reviews, narrative reviews, and primary research studies were undertaken to understand the mechanisms, diagnosis, progression, and treatment of CSM and OPLL and to provide summary statements and clinical recommendations. This article reports the methods used in the studies in this focus issue. SUMMARY STATEMENTS: The objectives of this focus issue were met using a variety of article and study designs, each of which has some unique methodological aspects associated with it. The reader should refer to the full article in this issue for additional details specific to that topic. The methods for systematic review follow accepted standards for rigor and, together with the application of Grading of Recommendation Assessment, Development and Evaluation, are intended to allow for transparency in the process for creating the clinical recommendation.


Lee W.L.,St. Michaels Hospital | Liles W.C.,University of Toronto
Current Opinion in Hematology | Year: 2011

Purpose of Review: Over the last few years, there have been major advances in our understanding of the role of the microvascular endothelium in the pathogenesis of severe, systemic infections. Recent Findings: Endothelial activation and dysfunction contribute directly to the morbidity and mortality of sepsis and other, severe systemic infections. The end-result of diffuse endothelial activation and dysfunction may be the loss of microvascular barrier integrity, leading to tissue edema, shock and multiple organ failure. Endothelial activation also leads to an increase in angiopoietin-2, which is known to destabilize barrier function and promote inflammation. Summary: The ratio of the secreted endothelial growth factors, angiopoietin-2 and angiopoietin-1 appears to be a useful prognostic tool during severe infections. Finally, agents that enhance endothelial barrier integrity may prove useful as therapies for sepsis. © 2011 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Ohlsson A.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2013

Maternal colonization with group B streptococcus (GBS) during pregnancy increases the risk of neonatal infection by vertical transmission. Administration of intrapartum antibiotic prophylaxis (IAP) during labor has been associated with a reduction in early onset GBS disease (EOGBSD). However, treating all colonized women during labor exposes a large number of women and infants to possible adverse effects without benefit. To assess the effect of IAP for maternal GBS colonization on neonatal: 1) all cause mortality and 2) morbidity from proven and probable EOGBSD, late onset GBS disease (LOD), maternal infectious outcomes and allergic reactions to antibiotics. We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 10 November 2012. Randomized trials assessing the impact of maternal IAP on neonatal GBS infections were included. We independently assessed eligibility and quality of the studies. We did not identify any new trials from the updated search so the results remain unchanged as follows.Three trials (involving 852 women) evaluating the effects of IAP versus no treatment were included. The risk of bias was high. The use of IAP did not significantly reduce the incidence of all cause mortality, mortality from GBS infection or from infections caused by bacteria other than GBS. The incidence of early GBS infection was reduced with IAP compared to no treatment (risk ratio 0.17, 95% confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk difference -0.04, 95% CI -0.07 to -0.01; number needed to treat to benefit 25, 95% CI 14 to 100, I(2) 0%). The incidence of LOD or sepsis from organisms other than GBS and puerperal infection was not significantly different between groups.One trial (involving 352 women) compared intrapartum ampicillin versus penicillin and reported no significant difference in neonatal or maternal outcomes. Intrapartum antibiotic prophylaxis appeared to reduce EOGBSD, but this result may well be a result of bias as we found a high risk of bias for one or more key domains in the study methodology and execution. There is lack of evidence from well designed and conducted trials to recommend IAP to reduce neonatal EOGBSD.Ideally the effectiveness of IAP to reduce neonatal GBS infections should be studied in adequately sized double-blind controlled trials. The opportunity to conduct such trials has likely been lost, as practice guidelines (albeit without good evidence) have been introduced in many jurisdictions.


Dennis C.L.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2013

Epidemiological studies and meta-analyses of predictive studies have consistently demonstrated the importance of psychosocial and psychological variables as postpartum depression risk factors. While interventions based on these variables may be effective treatment strategies, theoretically they may also be used in pregnancy and the early postpartum period to prevent postpartum depression. Primary: to assess the effect of diverse psychosocial and psychological interventions compared with usual antepartum, intrapartum, or postpartum care to reduce the risk of developing postpartum depression. Secondary: to examine (1) the effectiveness of specific types of psychosocial and psychological interventions, (2) the effectiveness of professionally-based versus lay-based interventions, (3) the effectiveness of individually-based versus group-based interventions, (4) the effects of intervention onset and duration, and (5) whether interventions are more effective in women selected with specific risk factors. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2011), scanned secondary references and contacted experts in the field. We updated the search on 31 December 2012 and added the results to the awaiting classification section of the review for assessment at the next update. All published and unpublished randomised controlled trials of acceptable quality comparing a psychosocial or psychological intervention with usual antenatal, intrapartum, or postpartum care. Review authors and a research co-ordinator with Cochrane review experience participated in the evaluation of methodological quality and data extraction. Additional information was sought from several trial researchers. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Twenty-eight trials, involving almost 17,000 women, contributed data to the review. Overall, women who received a psychosocial or psychological intervention were significantly less likely to develop postpartum depression compared with those receiving standard care (average RR 0.78, 95% confidence interval (CI) 0.66 to 0.93; 20 trials, 14,727 women). Several promising interventions include: (1) the provision of intensive, individualised postpartum home visits provided by public health nurses or midwives (RR 0.56, 95% CI 0.43 to 0.73; two trials, 1262 women); (2) lay (peer)-based telephone support (RR 0.54, 95% CI 0.38 to 0.77; one trial, 612 women); and (3) interpersonal psychotherapy (standardised mean difference -0.27, 95% CI -0.52 to -0.01; five trials, 366 women). Professional- and lay-based interventions were both effective in reducing the risk to develop depressive symptomatology. Individually-based interventions reduced depressive symptomatology at final assessment (RR 0.75, 95% CI 0.61 to 0.92; 14 trials, 12,914 women) as did multiple-contact interventions (RR 0.78, 95% CI 0.66 to 0.93; 16 trials, 11,850 women). Interventions that were initiated in the postpartum period also significantly reduced the risk to develop depressive symptomatology (RR 0.73, 95% CI 0.59 to 0.90; 12 trials, 12,786 women). Identifying mothers 'at-risk' assisted the prevention of postpartum depression (RR 0.66, 95% CI 0.50 to 0.88; eight trials, 1853 women). Overall, psychosocial and psychological interventions significantly reduce the number of women who develop postpartum depression. Promising interventions include the provision of intensive, professionally-based postpartum home visits, telephone-based peer support, and interpersonal psychotherapy.


Sud S.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2013

High frequency oscillation is an alternative to conventional mechanical ventilation that is sometimes used to treat patients with acute respiratory distress syndrome, but effects on oxygenation, mortality and adverse clinical outcomes are uncertain. This review was originally published in 2004 and was updated in 2011. To determine clinical and physiological effects of high frequency oscillation (HFO) in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) compared to conventional ventilation. We electronically searched CENTRAL (Ovid), MEDLINE (Ovid), EMBASE (Ovid), and ISI (from inception to March 2011). The original search was performed in 2002. We manually searched reference lists from included studies and review articles; searched conference proceedings of the American Thoracic Society (1994 to 2010), Society of Critical Care Medicine (1994 to 2010), European Society of Intensive Care Medicine (1994 to 2010), and American College of Chest Physicians (1994 to 2010); contacted clinical experts in the field; and searched for unpublished and ongoing trials in clinicaltrials.gov and controlled-trials.com. Randomized controlled clinical trials comparing treatment using HFO with conventional mechanical ventilation for children and adults diagnosed with ALI or ARDS. Three authors independently extracted data on clinical, physiological, and safety outcomes according to a predefined protocol. We contacted investigators of all included studies to clarify methods and obtain additional data. We used random-effects models in the analyses. Eight RCTs (n = 419) were included; almost all patients had ARDS. The risk of bias was low in six studies and unclear in two studies. The quality of evidence for hospital and six-month mortality was moderate and low, respectively. The ratio of partial pressure of oxygen to inspired fraction of oxygen at 24, 48, and 72 hours was 16% to 24% higher in patients receiving HFO. There were no significant differences in oxygenation index because mean airway pressure rose by 22% to 33% in patients receiving HFO (P < 0.01).  In patients randomized to HFO, mortality was significantly reduced (RR 0.77, 95% CI 0.61 to 0.98; P = 0.03; 6 trials, 365 patients, 160 deaths) and treatment failure (refractory hypoxaemia, hypercapnoea, hypotension, or barotrauma) was less likely (RR 0.67, 95% CI 0.46 to 0.99; P = 0.04; 5 trials, 337 patients, 73 events). Other risks, including adverse events, were similar. We found substantial between-trial statistical heterogeneity for physiological (I = 21% to 95%) but not clinical (I = 0%) outcomes.  Pooled results were based on few events for most clinical outcomes. The findings of this systematic review suggest that HFO was a promising treatment for ALI and ARDS prior to the uptake of current lung protective ventilation strategies. These findings may not be applicable with current conventional care, pending the results of large multi-centre trials currently underway.


Wright J.G.,University of Toronto
Clinical Orthopaedics and Related Research | Year: 2011

Background: Although many children with spina bifida and associated scoliosis or dislocated hips undergo spine or hip surgery, the benefits are uncertain. Questions/purposes: The purpose was to perform an evidence-based review on the benefits and risks of surgery for dislocated hips and scoliosis in spina bifida. Methods: I performed a Medline® and Embase® search from 1950 to 2009 for Level I to Level III studies investigating the benefits and risks of surgery for scoliosis and hip dislocation in patients with spina bifida. When available, I extracted types of surgery, complication rates, functional outcomes of seating, walking, and overall physical function. All treatment recommendations received a Grade of Recommendation: Grade A (consistent Level I studies); Grade B (consistent Level II and III studies); Grade C (consistent level IV and V studies); or Grade I (insufficient or contradictory studies). Results: Combined anterior and posterior surgery had lower rates of nonunion for scoliosis. Although there may be some benefit in seating, overall physical function measured in a different and nonstandardized fashion was not much changed and major complication rates, including nonunion and infections for scoliosis surgery, exceed 50% in several studies. For dislocated hips, the impact on walking ability appears related to contracture (not dislocation). Surgery for hip dislocation did not improve walking ability. The literature provides no guidance on the best treatment for unilateral dislocation. Conclusions: The benefits of scoliosis surgery are uncertain (Grade I). Spine surgery, if performed, should be anterior and posterior (Grade B). An all-pedicle approach for scoliosis surgery may be effective (Level I). Hip reduction surgery did not improve walking (Grade B) but may be appropriate in low-level unilateral dislocation (Level I). © 2011 The Association of Bone and Joint Surgeons®.


Jackson S.P.,University of Cambridge | Durocher D.,Samuel Lunenfeld Research Institute | Durocher D.,University of Toronto
Molecular Cell | Year: 2013

Ubiquitylation and sumoylation, the covalent attachment of the polypeptides ubiquitin and SUMO, respectively, to target proteins, are pervasive mechanisms for controlling cellular functions. Here, we summarize the key steps and enzymes involved in ubiquitin and SUMO conjugation and provide an overview of how they are crucial for maintaining genome stability. Specifically, we review research that has revealed how ubiquitylation and sumoylation regulate and coordinate various pathways of DNA damage recognition, signaling, and repair at the biochemical, cellular, and whole-organism levels. In addition to providing key insights into the control and importance of DNA repair and associated processes, such work has established paradigms for regulatory control that are likely to extend to other cellular processes and that may provide opportunities for better understanding and treatment of human disease. © 2013 Elsevier Inc.


Yeomans J.S.,University of Toronto
Handbook of Experimental Pharmacology | Year: 2012

All five muscarinic receptor subtypes and mRNAs are found widely in the brain stem, with M 2 muscarinic receptors most concentrated in the hindbrain. Three cholinergic cell groups, Ch5: pedunculopontine (PPT); Ch6: laterodorsal tegmental (LDT); Ch8: parabigeminal (PBG), are found in the tegmentum. Ch5,6 neurons are activated by arousing and reward-activating stimuli, and inhibited via M 2-like autoreceptors. Ch5,6 ascending projections activate many forebrain regions, including thalamus, basal forebrain, and orexin/hypocretin neurons (via M 3 receptors) for waking arousal and attention. Ch5,6 activation of dopamine neurons of the ventral tegmental area and substantia nigra (via M 5 receptors) increases reward-seeking and energizes motor functions. M 5 receptors on dopamine neurons facilitate brain-stimulation reward, opiate rewards and locomotion, and male ultrasonic vocalizations during mating in rodents. Ch5 cholinergic activation of superior colliculus intermediate layers facilitates fast saccades and approach turns, accompanied by nicotinic and muscarinic inhibition of the startle reflex in pons. Ch8 PBG neurons project to the outer layers of the superior colliculus only, where M 2 receptors are associated with retinotectal terminals. Ch5,6 descending projections to dorsal pontine reticular formation contribute to M 2-dependent REM sleep. © 2012 Springer-Verlag Berlin Heidelberg.


Kipps E.,Institute of Cancer Research | Tan D.S.P.,University of Toronto | Kaye S.B.,Drug Development Unit
Nature Reviews Cancer | Year: 2013

Malignant ascites presents a considerable clinical challenge to the management of ovarian cancer, but also provides a wealth of opportunities for translational research. The accessibility of ascitic fluid and its cellular components make it an excellent source of tumour tissue for the investigation of prognostic and predictive biomarkers, pharmacodynamic markers and for molecular profiling analysis. In this Opinion article, we discuss recent advances in our understanding of its pathophysiology, the development of new methods to characterize its molecular features and how these findings can be used to improve the treatment of malignant ascites, particularly in the context of ovarian cancer. © 2013 Macmillan Publishers Limited. All rights reserved.


In spite of the fact that the diagnosis of haemophilia is essentially clinical and laboratory-based, imaging has become an important tool for the evaluation of complications, diagnostic confirmation and/or complementation and therapeutic follow-up in haemophilic arthropathy. Radiography remains the workforce horse in the diagnosis and follow-up of haemophilic arthropathy. The radiographical findings in arthropathy follow an expected sequence of events and are overall similar in different joints. Magnetic resonance imaging (MRI) has advantages over radiography based on its capability of visualizing soft tissue and cartilage changes in haemophilic joints. The recent development and standardization of MRI scoring systems for measuring soft tissue and cartilage abnormalities may enable the comparison of pathological joint findings in clinical trials conducted at different institutions across the world. The implementation of high-frequency transducers and colour/power Doppler capabilities has provided new insights for clinical applications of ultrasonography (US) in haemophilic arthropathy. In spite of the imaging modality's technical challenges such as operator-dependency, US has advantages over MRI. One of these advantages is its ability of differentiating synovium hypertrophy and hemosiderin deposition, which is not possible with MRI given the presence of susceptibility artefacts from extracellular hemosiderin on gradient-echo MR images. In addition to the aforementioned conventional imaging modalities, novel imaging techniques (blood oxygen level dependent, ultrasmall superparamagnetic iron-oxide contrast-enhanced, and T1 and T2 mapping MRI, ultrasound biomicroscopy, microbubble contrast-enhanced US and positron emission tomography, among others) hold promise for early assessment of haemophilic arthropathy in the future upon completion of their clinical validation. © 2010 The Author. Journal compilation © 2010 Blackwell Publishing Ltd.


Swillam M.A.,University of Toronto
Optics express | Year: 2010

Plasmonic modes in rectangular metallic waveguides are analyzed in depth and are demonstrated to possess attractive properties for different applications. Their dispersion characteristics allow for wide range of applications including slow and fast light, metamaterial, low loss energy transmission, and opportunities for sensing devices. The sensitivity of this waveguide configuration is higher than its counterparts and can reach four times the sensitivity of the MIM structures. The characteristics of the TM(10) mode are demonstrated. Its applications for sensing, low propagation loss with relaxed practical dimension are also highlighted. A high effective index of more than 30 is also obtainable for the TE(01) mode for slow light operation. A non resonant negative index material with isotropic polarization in the visible region is also proposed using this waveguide structure.


Kluger R.,University of Toronto
Current Opinion in Chemical Biology | Year: 2010

Red cells are the oxygen-carrying components of blood. In modern medical practice, transfusions are given as suspensions of type-matched red cells in saline to replace lost blood, preventing organ damage and allowing for recovery. Since red cells cannot be stored for more than about 40 days and because they can transmit infections, alternative materials for transfusions were developed to replace the oxygenation function of the red cells. One approach involves chemically stabilizing hemoglobin, the oxygen-carrying protein of the red cell, while also adjusting its oxygenation properties to replicate that of the red cell. Evaluation of clinical trials of all products led to the conclusion that none that were tested would be suitable for clinical use [Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM: Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. J Am Med Assoc 2008, 299:2304-2312]. Most notably, the materials increased blood pressure and some were associated with increased risk of heart attacks. More recently, it was found that materials from covalent addition of polyethylene glycol polymers (PEG) to hemoglobin do not elicit the undesired effects on blood pressure [Vandegriff K, Bellelli A, Samaja M, Malavalli A, Brunori M, Winslow RM: Rates of NO binding to MP4, a non-hypertensive polyethylene glycol-conjugated hemoglobin. FASEB J 2003, 17:A183; Vandegriff KD, Malavalli A, Wooldridge J, Lohman J, Winslow RM: MP4: a new nonvasoactive PEG-Hb conjugate. Transfusion 2003, 43:509-516]. Also, materials with higher oxygen affinity than red cells are able to provide oxygenation at the sites in capillaries that have the most critical need for oxygen [Villela NR, Cabrales P, Tsai AG, Intaglietta M: Microcirculatory effects of changing blood hemoglobin oxygen affinity during hemorrhagic shock resuscitation in an experimental model. Shock 2009, 31:645-652]. It had been considered that the origin of the negative effects of the tested hemoglobin derivatives was because of their scavenging of endogenous nitric oxide (NO), the signal for vasodilation. It has been observed that an increase in the concentration of nitrite in circulation leads to an increase in NO concentration. This is consistent with the well-known reaction of hemoglobin with nitrite that produces NO and oxidized hemoglobin [Cannon RO 3rd, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT: Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest 2001, 108:279-287; Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, et al.: Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003, 9:1498-1505]. The PEG-hemoglobin and nitrite results are especially interesting as the hemoglobin to which PEG has been conjugated produces NO from nitrite at an enhanced rate [Lui FE, Dong P, Kluger R: Polyethylene glycol conjugation enhances the nitrite reductase activity of native and cross-linked hemoglobin. Biochemistry 2008, 47:10773-10780; Lui FE, Kluger R: Enhancing nitrite reductase activity of modified hemoglobin: bis-tetramers and their PEGylated derivatives. Biochemistry 2009, 48:11912-11919]. © 2010 Elsevier Ltd.


Gregoire V.,Catholic University of Louvain | Jeraj R.,University of Wisconsin - Madison | Lee J.A.,Catholic University of Louvain | O'Sullivan B.,University of Toronto
The Lancet Oncology | Year: 2012

Intensity-modulated radiation therapy (IMRT) is a conformal irradiation technique that enables steep dose gradients. In head and neck tumours this approach spares parotid-gland function without compromise to treatment efficacy. Anatomical and molecular imaging modalities may be used to tailor treatment by enabling proper selection and delineation of target volumes and organs at risk, which in turn lead to dose prescriptions that take into account the underlying tumour biology (eg, human papillomavirus status). Therefore, adaptations can be made throughout the course of radiotherapy, as required. Planned dose increases to parts of the target volumes may also be used to match the radiosensitivity of tumours (so-called dose-painting), assessed by molecular imaging. For swift implementation of tailored and adaptive IMRT, tools and procedures, such as accurate image acquisition and reconstruction, automatic segmentation of target volumes and organs at risk, non-rigid image and dose registration, and dose summation methods, need to be developed and properly validated. © 2012 Elsevier Ltd.


McKee M.D.,University of Toronto
Orthopedic Clinics of North America | Year: 2010

Clavicle fractures are common, and they comprise close to 3% of all fractures seen in fracture clinics. Midshaft fractures account for approximately 80% of all clavicle fractures and are the focus of this article. In carefully selected cases primary plate fixation of displaced midshaft clavicle fractures improves outcome, results in earlier return to function, and reduces the nonunion and symptomatic malunion rate significantly compared with nonoperative treatment. © 2010 Elsevier Inc.


Eder L.,University of Toronto
Arthritis care & research | Year: 2011

Epidemiologic studies about the incidence of psoriatic arthritis (PsA) are limited to a few population-based studies. There are limited data regarding the incidence of PsA in patients with psoriasis. We aimed to determine the incidence of PsA among a prospective cohort of psoriasis patients. The setting is a prospective longitudinal cohort study of psoriasis patients without arthritis. The patients are assessed annually by a rheumatologist in order to detect the onset of arthritis. We summarize the results of 4 years of followup and report the cumulative incidence of PsA from the time of entry to the study that was estimated using an event per person-years analysis and a nonparametric analysis. Three hundred thirteen psoriasis patients that had at least 1 year of followup were included in the analysis. The annual incidence rate was found to be 1.87 (95% confidence interval 0.71-3.03) PsA cases per 100 psoriasis patients. The incidence rate of PsA in patients with psoriasis may be higher than previously reported, particularly among patients with moderate to severe psoriasis. Copyright © 2011 by the American College of Rheumatology.


Brock K.K.,University of Toronto
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: To assess the accuracy, reproducibility, and computational performance of deformable image registration algorithms under development at multiple institutions on common datasets. Methods and Materials: Datasets from a lung patient (four-dimensional computed tomography [4D-CT]), a liver patient (4D-CT and magnetic resonance imaging [MRI] at exhale), and a prostate patient (repeat MRI) were obtained. Radiation oncologists localized anatomic structures for accuracy assessment. Algorithm accuracy was determined by comparing the computer-predicted displacement at each bifurcation point with the displacement computed from the oncologists' annotations. Thirty-seven academic institutions and medical device manufacturers with published evidence of active deformable image registration capabilities were invited to participate. Results: Twenty-seven groups agreed to participate; 6 did not return results. Sixteen completed the liver 4D-CT, 12 the lung 4D-CT, 3 the prostate MRI, and 3 the liver MRI-CT. The range of average absolute error for the lung 4D-CT was 0.6-1.2 mm (left-right [LR]), 0.5-1.8 mm (anterior-posterior [AP]), and 0.7-2.0 mm (superior-inferior [SI]); the liver 4D-CT was 0.8-1.5 mm (LR), 1.0-5.2 mm (AP), and 1.0-5.9 mm (SI); the liver MRI-CT was 1.1-2.6 mm (LR), 2.0-5.0 mm (AP), and 2.2-2.6 mm (SI); and the repeat prostate MRI prostate datasets was 0.5-6.2 mm (LR), 3.1-3.7 mm (AP), and 0.4-2.0 mm (SI). Conclusions: An infrastructure was developed to assess multi-institution deformable registration accuracy. The results indicate large discrepancies in reported shifts, although the majority of deformable registration algorithms performed at an accuracy equivalent to the voxel size, promising to improve treatment planning, delivery, and assessment. © 2010 Elsevier Inc. All rights reserved.


Carlen P.L.,University of Toronto
Brain Research | Year: 2012

Glia play an under-recognized role in epilepsy. This review examines the involvement of glial connexins (Cxs) and pannexins (Panxs), proteins which form gap junctions and membrane hemichannels (connexins) and hemichannels (pannexins), in epilepsy. These proteins, particularly glial Cx43, have been shown to be upregulated in epileptic brain tissue. In a cobalt model of in vitro seizures, seizures increased Panxs1 and 2 and Cx43 expression, and remarkably reorganized the interrelationships between their mRNA levels (transcriptome) which then became statistically significant. Gap junctions are highly implicated in synchronous seizure activity. Blocking gap junctional communication (GJC) is often anticonvulsant, and assumed to be due to blocking gap junctionally-medicated electrotonic coupling between neurons. However, in organotypic hippocampal slice cultures, connexin43 specific peptides, which attenuate GJC possibly by blocking connexon docking, diminished spontaneous seizures. Glia have many functions including extracellular potassium redistribution, in part via gap junctions, which if blocked, can be seizuregenic. Glial gap junctions are critical for the delivery of nutrients to neurons, which if interrupted, can depress seizure activity. Other functions of glia possibly related to epileptogenesis are mentioned including anatomic reorganization in chronic seizure models greatly increasing the overlapping domains of glial processes, changes in neurotransmitter re-uptake, and possible glial generation of currents and fields during seizure activity. Finally there is recent evidence for Cx43 hemichannels and Panx1 channels in glial membranes which could play a role in brain damage and seizure activity. Although glial Cxs and Panxs are increasingly recognized as contributing to fundamental mechanisms of epilepsy, the data are often contradictory and controversial, requiring much more research. This article is part of a Special Issue entitled Electrical Synapses. © 2012 Elsevier B.V.


Adeli K.,University of Toronto
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

Regulated cell metabolism involves acute and chronic regulation of gene expression by various nutritional and endocrine stimuli. To respond effectively to endogenous and exogenous signals, cells require rapid response mechanisms to modulate transcript expression and protein synthesis and cannot, in most cases, rely on control of transcriptional initiation that requires hours to take effect. Thus, co-and posttranslational mechanisms have been increasingly recognized as key modulators of metabolic function. This review highlights the critical role of mRNA translational control in modulation of global protein synthesis as well as specific protein factors that regulate metabolic function. First, the complex lifecycle of eukaryotic mRNAs will be reviewed, including our current understanding of translational control mechanisms, regulation by RNA binding proteins and microRNAs, and the role of RNA granules, including processing bodies and stress granules. Second, the current evidence linking regulation of mRNA translation with normal physiological and metabolic pathways and the associated disease states are reviewed. A growing body of evidence supports a key role of translational control in metabolic regulation and implicates translational mechanisms in the pathogenesis of metabolic disorders such as type 2 diabetes. The review also highlights translational control of apolipoprotein B (apoB) mRNA by insulin as a clear example of endocrine modulation of mRNA translation to bring about changes in specific metabolic pathways. Recent findings made on the role of 5′-untranslated regions (5′-UTR), 3′-UTR, RNA binding proteins, and RNA granules in mediating insulin regulation of apoB mRNA translation, apoB protein synthesis, and hepatic lipoprotein production are discussed. © 2011 the American Physiological Society.


Pace-Asciak C.R.,University of Toronto
Cancer and Metastasis Reviews | Year: 2011

Cancer is often accompanied with inflammatory, thrombotic, and diabetic complications. Alternatively, chronic inflammation is believed to be a causative factor in several cancers. This review article brings together reported biological actions in these areas of the unstable naturally derived hepoxilins (HX), metabolites of arachidonic acid formed through the 12-LO pathway, and those of their synthetically derived stable HX antagonists (PBT; proprietary bioactive therapeutics). Although the HX pathway has been known for some three decades since its discovery by the author with much data originating from the author's laboratory, studies by others over the past few years have confirmed early findings of the actions of HX as potent pro-inflammatory chemoattractant mediators and further showed HX to be involved in bacterial infection (Salmonella-induced intestinal inflammation and in bone inflammation caused by infection with the Lyme bacterium). The HX pathway appears to be an important early signal leading to inflammation. This provides important therapeutic potential for the PBTs as the only available selective antagonists of this pathway. The PBTs have shown benefit and efficacy in animal models of cancer and inflammation, which together with their known actions as anti-thrombotic (thromboxane (TPα) receptor antagonists) and hypoglycemic agents in vivo appears to make the PBTs suitable as therapeutics to control these disorders. The PBT structure is both stable in vivo and is essentially devoid of side effects in the animal models tested. The PBT structure serves as an important platform for selective HX and TX antagonists. © 2011 Springer Science+Business Media, LLC.


Boone C.,University of Toronto
Genetics | Year: 2014

THE Genetics Society of America’s Edward Novitski Prize recognizes an extraordinary level of creativity and intellectual ingenuity in the solution of significant problems in genetics research. The 2014 recipient, Charles Boone, has risen to the top of the emergent discipline of postgenome systems biology by focusing on the global mapping of genetic interaction networks. Boone invented the synthetic genetic array (SGA) technology, which provides an automated method to cross thousands of strains carrying precise mutations and map large-scale yeast genetic interactions. These network maps offer researchers a functional wiring diagram of the cell, which clusters genes into specific pathways and reveals functional connections. © 2014 by the Genetics Society of America.


Tator C.H.,University of Toronto
Journal of neurosurgery. Spine | Year: 2012

There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium. The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria. In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.


Anagnostou E.,Bloorview Research Institute | Taylor M.J.,University of Toronto
Molecular Autism | Year: 2011

Autism spectrum disorder (ASD) refers to a syndrome of social communication deficits and repetitive behaviors or restrictive interests. It remains a behaviorally defined syndrome with no reliable biological markers. The goal of this review is to summarize the available neuroimaging data and examine their implication for our understanding of the neurobiology of ASD. Although there is variability in the literature on structural magnetic resonance literature (MRI), there is evidence of volume abnormalities in both grey and white matter, with a suggestion of some region-specific differences. Early brain overgrowth is probably the most replicated finding in a subgroup of people with ASD, and new techniques, such as cortical-thickness measurements and surface morphometry have begun to elucidate in more detail the patterns of abnormalities as they evolve with age, and are implicating specific neuroanatomical or neurodevelopmental processes. Functional MRI and diffusion tensor imaging techniques suggest that such volume abnormalities are associated with atypical functional and structural connectivity in the brain, and researchers have begun to use magnetic resonance spectroscopy (MRS) techniques to explore the neurochemical substrate of such abnormalities. The data from multiple imaging methods suggests that ASD is associated with an atypically connected brain. We now need to further clarify such atypicalities, and start interpreting them in the context of what we already know about typical neurodevelopmental processes including migration and organization of the cortex. Such an approach will allow us to relate imaging findings not only to behavior, but also to genes and their expression, which may be related to such processes, and to further our understanding of the nature of neurobiologic abnormalities in ASD. © 2011 Anagnostou and Taylor; licensee BioMed Central Ltd.


Carlberg R.G.,University of Toronto
Astrophysical Journal | Year: 2015

A sufficiently extended satellite in the tidal field of a host galaxy loses mass to create nearly symmetric leading and trailing tidal streams. We study the case in which tidal heating drives mass loss from a low mass satellite. The stream effectively has two dynamical components, a common angular momentum core superposed with episodic pulses with a broader angular momentum distribution. The pulses appear as spurs on the stream, oscillating above and below the stream centerline, stretching and blurring in configuration space as they move away from the cluster. Low orbital eccentricity streams are smoother and have less differential motion than high eccentricity streams. The tail of a high eccentricity stream can develop a fan of particles that wraps around at apocenter in a shell feature. We show that scaling the essentially stationary action-angle variables with the cube root of the satellite mass allows a low mass satellite stream to accurately predict the features in the stream from a satellite a thousand times more massive. As a practical astrophysical application, we demonstrate that narrow gaps in a moderate eccentricity stream, such as GD-1, blur out to 50% contrast over approximately six radial periods. A high eccentricity stream, such as Pal 5, will blur small gaps in only two radial orbits as can be understood from the much larger dispersion of angular momentum in the stream. © 2015. The American Astronomical Society. All rights reserved.


Feld J.J.,University of Toronto | Feld J.J.,Toronto Center for Liver Disease
Antiviral Research | Year: 2014

Interferon has been the backbone of therapy for hepatitis C virus (HCV) infection for over 20 years. Initial response rates were poor, however they have slowly but steadily improved, such that with the addition of the nucleotide analogue ribavirin and the pegylation of interferon, over 50% of infected individuals could be cured with a course of therapy. However, interferon therapy is not ideal, requiring up to a year of weekly injections and associated with numerous systemic side effects. Advances in understanding of the HCV lifecycle have led to the development of numerous highly effective, well-tolerated oral direct acting antivirals (DAAs). Although the first DAAs were combined with peginterferon and ribavirin, with the rapid progress in the field, it is likely that interferon-free therapy will be available for most patients in the relatively near future. In the short term, peginterferon will be required with either the protease inhibitor simeprevir, or the nucleotide analogue polymerase inhibitor, sofosbuvir, for the treatment of genotype 1 infection. Peginterferon also appears to be a useful adjunct to sofosbuvir and ribavirin for patients with genotype 3 infection, particularly those with cirrhosis. In the future, once combination DAA therapies are available, peginterferon will serve a smaller and smaller role. Peginterferon may be useful as part of QUAD therapy with 2 DAAs and ribavirin in prior null responders or in patients who fail DAA regimens with multi-drug resistant HCV. Peginterferon may also have a role in resource-limited regions to reduce the number and/or duration of DAAs required. Ultimately, although peginterferon will remain a salvage therapy, its days as a mainstay of therapy are definitely numbered. © 2014 Elsevier B.V. All rights reserved.


Liu L.W.C.,University of Toronto
Canadian Journal of Gastroenterology | Year: 2011

Chronic constipation is a common functional gastrointestinal disorder that affects patients of all ages. In 2007, a consensus group of 10 Canadian gastroenterologists developed a set of recommendations pertaining to the management of chronic constipation and constipation-dominant irritable bowel syndrome. Since then, tegaserod has been withdrawn from the Canadian market. A new, highly selective serotonin receptor subtype 4 agonist, prucalopride, has been examined in several large, randomized, placebo-controlled trials demonstrating its efficacy and safety in the management of patients with chronic constipation. Additional studies evaluating the use of stimulant laxatives, polyethylene glycol and probiotics in the management of chronic constipation have also been published. The present review summarizes the previous recommendations and new evidence supporting different treatment modalities - namely, diet and lifestyle, bulking agents, stool softeners, osmotic and stimulant laxatives, prucalopride and probiotics in the management of chronic constipation. A brief summary of lubiprostone and linaclotide is also presented. The quality of evidence is presented by adopting the Grading of Recommendations, Assessment, Development and Evaluation system. Finally, a management pyramid for patients with chronic constipation is proposed based on the quality of evidence, impact of each modality on constipation and on general health, and their availabilities in Canada. ©2011 Pulsus Group Inc. All rights reserved.


Oishi S.,University of Virginia | Schimmack U.,University of Toronto
Journal of Personality and Social Psychology | Year: 2010

We tested the relation between residential mobility and well-being in a sample of 7,108 American adults who were followed for 10 years. The more residential moves participants had experienced as children, the lower the levels of well-being as adults. As predicted, however, the negative association between the number of residential moves and well-being was observed among introverts but not among extraverts. We further demonstrated that the negative association between residential mobility and well-being among introverts was explained by the relative lack of close social relationships. Finally, we found that introverts who had moved frequently as children were more likely to have died during the 10-year follow-up. Among extraverts, childhood residential mobility was unrelated to their mortality risk as adults. These findings indicate that residential moves can be a risk factor for introverts and that extraversion can be an interpersonal resource for social relationships and well-being in mobile societies. © 2010 American Psychological Association.


Antonini F.,University of Toronto | Merritt D.,Rochester Institute of Technology
Astrophysical Journal Letters | Year: 2013

We consider the orbital evolution of the S-stars, the young main-sequence stars near the supermassive black hole (SBH) at the Galactic center, and put constraints on competing models for their origin. Our analysis includes for the first time the joint effects of Newtonian and relativistic perturbations to the motion, including the dragging of inertial frames by a spinning SBH as well as torques due to finite-N asymmetries in the field-star distribution (resonant relaxation, RR). The evolution of the S-star orbits is strongly influenced by the Schwarzschild barrier (SB), the locus in the (E, L) plane where RR is ineffective at driving orbits to higher eccentricities. Formation models that invoke tidal disruption of binary stars by the SBH tend to place stars below (i.e., at higher eccentricities than) the SB; some stars remain below the barrier, but most stars are able to penetrate it, after which they are subject to RR and achieve a nearly thermal distribution of eccentricities. This process requires roughly 50 Myr in nuclear models with relaxed stellar cusps, or ≳ 10 Myr, regardless of the initial distribution of eccentricities, in nuclear models that include a dense cluster of 10 M⊙ black holes. We find a probability of ≲ 1% for any S-star to be tidally disrupted by the SBH over its lifetime. © 2013. The American Astronomical Society. All rights reserved.


Kumar V.,University of Toronto
Immunology Letters | Year: 2014

Immune system is well characterized by immunologists into two major arms called innate immunity and adaptive immunity. However, recent advances in the field of immunology has led to the identification of specific immune cells, which lack signature signs of mature lymphocytes (i.e. antigen receptors), yet produce major cytokines (i.e. IFN-γ, IL-4, IL-5, IL-13, IL-9, etc.) of helper T (Th) cell mediated immune response. Therefore, these cells can be represented as the innate counterpart of helper T cells of adaptive immunity and are known as innate lymphoid cells (ILCs). These ILCs comprise of three different groups having different kinds of cells, i.e. group 1 (NK cells and ILC1 cells), group 2 and group 3 ILCs. However, they are also emerging as novel regulators of both chronic as well as acute inflammation induced by infection or caused by sterile inflammation. Therefore, an attempt has been made to highlight the regulatory role of ILCs during inflammation and modulation of these cells as novel tissue protective mechanism. © 2013 Elsevier B.V.


Chen C.I.,University of Toronto
Current Hematologic Malignancy Reports | Year: 2013

Lenalidomide is a member of the immunomodulatory agents (IMiDs), and is currently approved for use in myelodysplastic syndromes and multiple myeloma. In chronic lymphocytic leukemia (CLL), lenalidomide has anti-tumor activity which appears distinct, both mechanistically and clinically, from that observed in the approved indications. Furthermore, lenalidomide leads to toxicities, such as tumor flare reaction and tumor lysis, even at low dosing, that is not anticipated with lenalidomide therapy in other disorders. This review will discuss the current understanding of the mechanisms of action of lenalidomide in CLL, lessons of administration learned from clinical trials in CLL to date, and the potential role of lenalidomide in CLL for the future. © 2012 Springer Science+Business Media New York.


Cowen L.E.,University of Toronto
Current Opinion in Microbiology | Year: 2013

There is a pressing need for new therapeutic strategies for life-threatening fungal infections. Targeting the molecular chaperone Hsp90 has emerged as a promising approach to cripple fungal pathogens, thereby enhancing antifungal efficacy, impairing the evolution of drug resistance, and rendering resistant pathogens responsive to treatment. Hsp90 inhibitors in clinical development for cancer may be repurposed for some therapeutic applications, though others require fungal selective Hsp90 inhibitors or alternative strategies to inhibit the chaperone machinery. Novel targets include upstream regulators of Hsp90 function and downstream effectors, such as co-chaperones, lysine deacetylases, kinases, and phosphatases. As a hub of cellular circuitry governing stress responses, drug resistance, morphogenesis, and virulence, Hsp90 serves as a fungal Achilles' heel, with broad therapeutic potential. © 2013 Elsevier Ltd.


Koren G.,University of Toronto
Therapeutic Drug Monitoring | Year: 2014

While perceived safe in pregnancy, several recent studies raise concerns about both fetal and maternal safety of ondansetron. Until more data are available, it should not be a first-line medication for morning sickness. © 2013 by Lippincott Williams and Wilkins.


Wennberg R.,University of Toronto
Clinical Neurophysiology | Year: 2010

Objective: The K-complex was first identified in human sleep EEG more than 70. years ago, but the localization of its intracranial generators is an unresolved issue. In this study, K-complexes recorded using simultaneous scalp and intracranial EEG were analyzed to discover the intracranial distribution of the human K-complex. Methods: Stereoelectroencephalographic recordings were performed in six patients with medically-refractory epilepsy. Full 10-20 scalp montages were used and intracranial macroelectrodes sampled medial, lateral and basal frontal and temporal cortices, medial and lateral parietal and occipital cortices, as well as the hippocampus and thalamus. Spontaneous K-complexes were visually identified in stage II sleep and averaged off-line. Results: The intracranial K-complex field was maximal over the anterior and superior aspects of the medial and lateral frontal lobe cortices, consistent with the frontal midline scalp EEG maximum. The frontal maximum surface-negative field was volume conducted as an inverted, positive field posteriorly and inferiorly, the polarity reversing laterally above the inferior temporal region and medially above the cingulate cortex. Conclusions: As suggested by the scalp EEG topography, the intracranial distribution of the human K-complex is maximal over the anterior and superior frontal cortices. K-complex generation appears limited to cortical regions above the inferior temporal sulcus laterally, the cingulate sulcus medially and the parietooccipital junction posteriorly. Significance: The human K-complex is produced by synchronous cortical activity that appears maximal intracranially over the superior medial and lateral aspects of the frontal lobes. The cingulate cortex and functionally related mesial temporal structures appear uninvolved in human K-complex generation. © 2010 International Federation of Clinical Neurophysiology.


Gertler M.S.,University of Toronto
Regional Studies | Year: 2010

Gertler M. S. Rules of the game: the place of institutions in regional economic change, Regional Studies. Institutions exert a pervasive influence on the evolution and character of regional economies. Yet, this role is poorly understood within recent debates on neoliberalism, varieties of capitalism, and other approaches to the study of economic change. A reconstituted institutional economic geography must accommodate individual agency, institutional evolution, interscalar relations, and comparative methodologies. Examining recent work on universities in local economies, as well as on creativity-based strategies and social inclusion/polarization, it is shown how locally distinctive institutional architectures shape evolutionary trajectories, leading to differentiated social and economic outcomes. The paper then enunciates some important principles of methodology and theory-building in institutional analysis. © 2010 Regional Studies Association.


Ratto M.,University of Toronto
Information Society | Year: 2011

This article provides an overview of a series of experiments in what the author calls critical making, a mode of materially productive engagement that is intended to bridge the gap between creative physical and conceptual exploration. Although they share much in common with forms of design and art practice, the goal of these events is primarily focused on using material production-making things-as part of an explicit practice of concept elaboration within the social study of technology. © Taylor & Francis Group, LLC.


Corts K.S.,University of Toronto
Journal of Environmental Economics and Management | Year: 2010

One significant obstacle to meeting aggressive federal and state alternative fuel consumption targets is the relative scarcity of retail fueling stations that carry alternative fuels. Policies that encourage or mandate use of alternative fuel vehicles in government fleets, thereby increasing demand for such fuels, are one popular approach to stimulating further development of the alternative fuel retail infrastructure. I focus specifically on flex-fuel vehicles (FFVs) that burn E85, a combination of 85% ethanol and 15% gasoline, to study the impact of government fleet composition on retail alternative fuel infrastructure. Using data from six states in the Midwest that account for over 60% of US E85 stations, I show that government fleet adoption of FFVs leads to an increase in retail E85 stations. This finding persists when using instrumental variables techniques to address the endogeneity of government fleet FFV purchases. © 2010 Elsevier Inc. All rights reserved.


This article tests the hypothesis that health influences older adults' position within a defined social structure. Building on a recent synthesis of social gerontology and network analysis, good health was expected to be associated with more network constraint and less network integration-two indicators of autonomy and access to social resources and information within a network. The study was conducted within a continuing care retirement community, a unique site offering several advantages for a novel test of the health-begets-position hypothesis. Consistent with this hypothesis, residents with the best health had positional advantage in the network. Results also highlight the particular importance of good health during the initial period of community tenancy. © The Author(s) 2012.


Kraev A.,University of Toronto
Biology Direct | Year: 2014

Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as " Black Six" , stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign " essential" and " redundant" qualifiers to numerous genes, thus creating an internally consistent " parallel universe" of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of " strain-unawareness" will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of " parallel universes" should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor's strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified.Reviewers: This article was reviewed by Dr. Neil Smalheiser and Dr. Miguel Andrade-Navarro. © 2014 Kraev; licensee BioMed Central Ltd.


Shepherd F.A.,University of Toronto
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC). KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.


Girz L.,University of Toronto
International journal of obesity (2005) | Year: 2012

To examine the effects of calorie labeling on food selection and intake in dieters and non-dieters, and to explore whether expectations about food healthfulness moderate these effects. Participants were presented with a menu containing two items, a salad and a pasta dish. The menu had (a) no calorie information, (b) information that the salad was low in calories and the pasta was high in calories, (c) information that the salad was high in calories and the pasta was low in calories or (d) information that both were high in calories (study 2 only). Calorie labels influenced food selection for dieters, but not for non-dieters. Dieters were more likely to order salad when the salad was labeled as low in calories and more likely to order pasta, even high-calorie pasta, when the salad was labeled as high in calories. Participants who chose high-calorie foods over low-calorie foods did not eat less in response to calorie information, although non-dieters reduced their intake somewhat when calorie labels were put in the context of recommended daily calories. The results suggest that the rush to provide calorie information may not prove to be the best approach to fighting the obesity epidemic.


Xie J.-W.,Nanjing University | Xie J.-W.,University of Toronto
Astrophysical Journal, Supplement Series | Year: 2014

Following on from Paper I in this series, I report the confirmation of a further 30 planets in 15 multiple-planet systems via transit timing variations (TTVs), using the publicly available Kepler light curves (Q0-Q16). All 15 pairs are near first-order mean motion resonances, showing sinusoidal TTVs consistent with theoretically predicted periods, which demonstrate they are orbiting and interacting in the same systems. Although individual masses cannot be accurately extracted based only on TTVs (because of the well known degeneracy between mass and eccentricity), the measured TTV phases and amplitudes can still place relatively tight constraints on their mass ratios and upper limits on their masses, which confirm their planetary nature. Some of these systems (KOI-274, KOI-285, KOI-370, and KOI-2672) are relatively bright and thus suitable for further follow-up observations. © 2014. The American Astronomical Society. All rights reserved..


Valverde M.,University of Toronto
Theoretical Criminology | Year: 2011

Scholars have noted that we are increasingly being governed in the name of security, in literature that usually treats security as an entity in need of a theory. This article begins by noting that 'security' does not need theories, but rather questions that can generate concrete analyses. Three sets of questions are elaborated here. The first concerns the logics of security projects. The second set raises questions of scale and jurisdiction. Finally, governance projects are distinguished by the techniques used. This set of questions about security-which, this article argues, always need to be posed in relation to specific security projects-is a theoretically significant revision of the governmentality literature's distinction between rationalities and technologies of governance. © The Author(s) 2010.


Primary outcome measures for the upper limb in trials concerning human spinal cord injury (SCI) need to distinguish between functional and neurological changes and require satisfying psychometric properties for clinical application. The Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) was developed by the International GRASSP Research and Design Team as a clinical outcome measure specific to the upper limbs for individuals with complete and incomplete tetraplegia (that is, paralysis or paresis). It can be administered across the continuum of recovery after acute cervical SCI. An international multicenter study (involving centers in North America and Europe) was conducted to apply the measure internationally and examine its applicability. The GRASSP is a multimodal test comprising 5 subtests for each upper limb: dorsal sensation, palmar sensation (tested with Semmes-Weinstein monofilaments), strength (tested with motor grading of 10 muscles), and prehension (distinguishes scores for qualitative and quantitative grasping). Thus, administration of the GRASSP results in 5 numerical scores that provide a comprehensive profile of upper-limb function. The established interrater and test-retest reliability for all subtests within the GRASSP range from 0.84 to 0.96 and from 0.86 to 0.98, respectively. The GRASSP is approximately 50% more sensitive (construct validity) than the International Standards of Neurological Classification of SCI (ISNCSCI) in defining sensory and motor integrity of the upper limb. The subtests show concurrence with the Spinal Cord Independence Measure (SCIM), SCIM self-care subscales, and Capabilities of Upper Extremity Questionnaire (CUE) (the strongest concurrence to impairment is with self-perception of function [CUE], 0.57-0.83, p < 0.0001). The GRASSP was found to demonstrate reliability, construct validity, and concurrent validity for use as a standardized upper-limb impairment measure for individuals with complete or incomplete tetraplegia. Responsiveness (follow-up from onset to 1 year postinjury) is currently being tested in international studies (in North America and Europe). The GRASSP can be administered early after injury, thus making it a tool that can be administered in acute care (in the ICU), rehabilitation, and outpatient clinics.


Cameron F.J.,University of Melbourne | Wherrett D.K.,University of Toronto
The Lancet | Year: 2015

Diabetes is one of the most common chronic medical disorders in children. The management of diabetes remains a substantial burden on children with diabetes and their families, despite improvements in treatment and rates of morbidity and mortality. Although most children with diabetes have type 1 diabetes, the increasing recognition of type 2 diabetes and genetic forms of diabetes in the paediatric population has important treatment implications. Diabetes therapy focuses strongly on targets for good metabolic control to reduce the risk of long-term complications. A parallel goal is to minimise short-term complications of hypoglycaemia and diabetic ketoacidosis. Technology offers opportunity for improvement in care, but has not yet fully lived up to its potential. New insights into the pathogenesis of diabetes and the development of new therapies have led to clinical trials aimed at the prevention of diabetes. © 2015 Elsevier Ltd.


Klotz L.,University of Toronto
Nature Reviews Urology | Year: 2015

Testosterone is a potent hormone with a variety of physiological effects. The diagnosis of androgen deficiency has increased dramatically over the past decade, along with the widespread use of testosterone supplementation therapy (TST). The long-term effects of TST are uncertain, and the risk of overdiagnosis and overtreatment of men who have a normal age-related decline in testosterone is substantial. The biology of the androgen receptor (AR) pathway is complex, and the saturation model does not take the heterogeneity of human prostate cancer into account. Large-scale trials to confirm the safety of testosterone with respect to the risks of prostate cancer and cardiovascular disease with reasonable confidence limits have not been done, and existing data are insufficient to exclude these adverse events. Instead, evidence suggests that prostate cancer could, in fact, be stimulated by TST, and that the risk of cardiovascular events is increased. Overall, TST seems to impose significant risks, and should be used with caution. © 2015 Macmillan Publishers Limited. All rights reserved.


Agren J.A.,University of Toronto
Trends in Ecology and Evolution | Year: 2014

The history of life has been characterised by evolutionary transitions in individuality, the grouping together of independently replicating units into new larger wholes: genes to chromosomes, chromosomes in genomes, up to three genomes in cells, and cells in multicellular organisms that form groups and societies. Central to understanding these transitions is to determine what prevents selfish behaviour at lower levels from disrupting the functionality of higher levels. Here, I review work on transposable elements, a common source of disruption at the genome level, in light of the evolutionary transitions framework, and argue that the rapid influx of data on transposons from whole-genome sequencing has created a rich data source to incorporate into the study of evolutionary transitions in individuality. © 2013 Elsevier Ltd.


The dopamine D2 receptor continues to be the major target for the treatment of schizophrenia and is one of many genes genetically associated with this disease. Recent data show that fewer short forms of the D2 receptor protein are synthesized if there is a genetic variant in the D2 receptor (with a T in rs 1076560 in intron 6). At the same time, at least six publications report that the binding of radioactive benzamides is reduced in the schizophrenia thalamus. A review of the benzamide pharmacology of the short and long forms of the D2 receptor shows that benzamides have a 2.4-fold higher affinity for the D2Short receptor relative to the D2Long form. Hence, the reduced amount of benzamide binding to the D2 receptors in the schizophrenia thalamus suggests that there is a reduced amount of D2Short receptors in this diseased region, and may possibly also mean fewer presynaptic terminals because that is where D2Short receptors mostly reside. If so, fewer presynaptic dopamine terminals in various brain regions may be the basis of the known behavioural dopamine supersensitivity in schizophrenia. © 2013 Elsevier Ireland Ltd.


Truan J.S.,University of Toronto
Molecular nutrition & food research | Year: 2010

Flaxseed (FS) has been shown to attenuate mammary tumorigenesis, possibly due to its high α-linolenic acid (ALA)-rich oil (FSO) content. This study determined the effect of FSO on the growth of