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Showing papers by "Sunnybrook Health Sciences Centre published in 2009"


Journal ArticleDOI
TL;DR: It is reported that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors.

1,733 citations


Journal ArticleDOI
04 Nov 2009-JAMA
TL;DR: Critical illness from 2009 influenza A(H1N1) in Mexico occurred in young individuals, was associated with severe acute respiratory distress syndrome and shock, and had a high case-fatality rate.
Abstract: Context In March 2009, novel 2009 influenza A(H1N1) was first reported in the southwestern United States and Mexico. The population and health care system in Mexico City experienced the first and greatest early burden of critical illness. Objective To describe baseline characteristics, treatment, and outcomes of consecutive critically ill patients in Mexico hospitals that treated the majority of such patients with confirmed, probable, or suspected 2009 influenza A(H1N1). Design, Setting, and Patients Observational study of 58 critically ill patients with 2009 influenza A(H1N1) at 6 hospitals between March 24 and June 1, 2009. Demographic data, symptoms, comorbid conditions, illness progression, treatments, and clinical outcomes were collected using a piloted case report form. Main Outcome Measures The primary outcome measure was mortality. Secondary outcomes included rate of 2009 influenza (A)H1N1−related critical illness and mechanical ventilation as well as intensive care unit (ICU) and hospital length of stay. Results Critical illness occurred in 58 of 899 patients (6.5%) admitted to the hospital with confirmed, probable, or suspected 2009 influenza (A)H1N1. Patients were young (median, 44.0 [range, 10-83] years); all presented with fever and all but 1 with respiratory symptoms. Few patients had comorbid respiratory disorders, but 21 (36%) were obese. Time from hospital to ICU admission was short (median, 1 day [interquartile range {IQR}, 0-3 days]), and all patients but 2 received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia (median day 1 ratio of PaO 2 to fraction of inspired oxygen, 83 [IQR, 59-145] mm Hg). By 60 days, 24 patients had died (41.4%; 95% confidence interval, 28.9%-55.0%). Patients who died had greater initial severity of illness, worse hypoxemia, higher creatine kinase levels, higher creatinine levels, and ongoing organ dysfunction. After adjusting for a reduced opportunity of patients dying early to receive neuraminidase inhibitors, neuraminidase inhibitor treatment (vs no treatment) was associated with improved survival (odds ratio, 8.5; 95% confidence interval, 1.2-62.8). Conclusion Critical illness from 2009 influenza A(H1N1) in Mexico occurred in young individuals, was associated with severe acute respiratory distress syndrome and shock, and had a high case-fatality rate.Published online October 12, 2009 (doi:10.1001/jama.2009.1536).

839 citations


Journal ArticleDOI
TL;DR: Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopIDogrel and an increased risk of reinfarction.
Abstract: Background: Most proton pump inhibitors inhibit the bioactivation of clopidogrel to its active metabolite. The clinical significance of this drug interaction is unknown. Methods: We conducted a population-based nested case–control study among patients aged 66 years or older who commenced clopidogrel between Apr. 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute myocardial infarction. The cases in our study were those readmitted with acute myocardial infarction within 90 days after discharge. We performed a secondary analysis considering events within 1 year. Event-free controls (at a ratio of 3:1) were matched to cases on age, percutaneous coronary intervention and a validated risk score. We categorized exposure to proton pump inhibitors before the index date as current (within 30 days), previous (31–90 days) or remote (91–180 days). Results: Among 13 636 patients prescribed clopidogrel following acute myocardial infarction, we identified 734 cases readmitted with myocardial infarction and 2057 controls. After extensive multivariable adjustment, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03–1.57). We found no association with more distant exposure to proton pump inhibitors or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70–1.47). Interpretation: Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopidogrel and an increased risk of reinfarction.

740 citations


Journal ArticleDOI
TL;DR: The psychometric properties of the ASES, DASH, and SPADI have been shown to be acceptable for clinical use, and some properties ofThe SST still need be evaluated, particularly the absolute errors of measurement.
Abstract: Objective To conduct a systematic review of the quality and content of the psychometric evidence relating to 4 shoulder disability scales: the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, the Shoulder Pain and Disability Index (SPADI), the American Shoulder and Elbow Surgeons (ASES) score, and the Simple Shoulder Test (SST). Methods We conducted a structured search using 3 databases (Medline, CINAHL, EMBase). In total, 71 published primary studies were analyzed. A pair of raters conducted data extraction and critical appraisal using structured tools. A descriptive synthesis was performed. Results Quality ratings of 55% of the studies reviewed reached a level of ≥75%. Most studies suggest that all 4 questionnaires have excellent reliability (intraclass correlation coefficient ≥0.90). The 4 questionnaires are strongly correlated (r >0.70) with each other and with a number of similar indices, and the questionnaires were able to differentiate between different populations and disability levels. The minimal detectable change (MDC) is ∼9.4 for the ASES, 10.5 for the DASH, and 18 for the SPADI; the minimal clinically important difference (MCID) is ∼6.4 for the ASES and 10.2 for the DASH, and ranges between 8 and 13 for the SPADI. MDC and MCID have not been defined for the SST. Conclusion The psychometric properties of the ASES, DASH, and SPADI have been shown to be acceptable for clinical use. Conversely, some properties of the SST still need be evaluated, particularly the absolute errors of measurement. Overall, validation studies have focused on less clinically relevant properties (construct validity or group reliability) than estimates of MDC and MCID.

618 citations


Journal ArticleDOI
TL;DR: In this article, a novel clot burden score (CBS) and collateral score (CS) were proposed to predict clinical and radiologic outcomes in patients with anterior circulation infarct presenting within 3 hours of stroke onset.
Abstract: BACKGROUND AND PURPOSE: Clot extent, location, and collateral integrity are important determinants of outcome in acute stroke. We hypothesized that a novel clot burden score (CBS) and collateral score (CS) are important determinants of clinical and radiologic outcomes and serve as useful additional stroke outcome predictors. MATERIALS AND METHODS: One hundred twenty-one patients with anterior circulation infarct presenting within 3 hours of stroke onset were reviewed. The Spearman correlation was performed to assess the correlation between CBS and CS and clinical and radiologic outcome measures. Patients were dichotomized by using a 90-day modified Rankin scale (mRS) score. Uni- and multivariate logistic regression models were used to assess variables predicting favorable clinical and radiologic outcomes. Receiver operating characteristic and intraclass correlation coefficient (ICC) analyses were performed. Diagnostic performance of a CBS threshold of >6 was assessed. RESULTS: There were 85 patients (mean age, 70 ± 14.5 years). Patients with higher CBS and CS demonstrated smaller pretreatment perfusion defects and final infarct volume and better clinical outcome (all, P 6 predicted good clinical outcome with an area under the curve of 0.75 (95% confidence interval [CI], 0.65–0.84; P = .0001), sensitivity of 73.0 (95% CI, 55.9–86.2), and specificity of 64.6 (95% CI, 49.5–77.8). The recanalization rate with intravenous recombinant tissue plasminogen activator was higher in patients with CBS >6 (P = .04; odds ratio, 3.2; 95% CI, 1.1–9.4). The ICC was 0.97 (95% CI, 0.95–0.98) and 0.87 (95% CI, 0.80–0.91) for CBS and CS, respectively. CONCLUSIONS: CBS and CS are useful additional markers predicting clinical and radiologic outcomes.

514 citations


Journal ArticleDOI
TL;DR: The excess risk of distant recurrence in triple-negative breast cancers, versus other forms of cancer, is attributable in large part to an excess of visceral metastases in the first five years following diagnosis.
Abstract: Purpose The prognosis of women with triple-negative breast cancers (defined as cancers that are estrogen receptor-negative, progesterone receptor-negative and HER2/neu negative) is poor, compared to women with other subtypes of breast cancer. It is proposed that the underlying difference in recurrence rates may be explained in part by different routes of metastatic spread. Experimental design We studied a cohort of 1608 patients diagnosed with breast cancer, diagnosed between January 1987 and December 1997 at Women’s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor-negative, progesterone receptor-negative and HER2/neu-negative. We compared the incidence rates of metastatic spread to bone and to other (non-bone) organs in women with triple-negative and other forms of breast cancer. Results Of the 1,608 patients, 180 (11.2%) had triple-negative breast cancer. The 1608 women were followed for a median of 9.0 years (range 0.1–19 years). Compared to other patients, those with triple-negative breast cancer had an increased likelihood of distant recurrence over the study period (adjusted hazard ratio (HR) 1.9; 95% CI: 1.5–2.5, P < 0.0001). The relatively poor prognosis was apparent in the five years after diagnosis (HR 2.9; 95% CI: 2.1–3.9; P = 0.0001) but not thereafter (HR 0.5; 95% CI: 0.2–1.1; P = 0.07). In particular, women with triple-negative breast cancer were four times more likely to experience a visceral metastasis within five years of diagnosis than those with other types of cancer (HR 4.0; 95% CI: 2.7–5.9; P < 0.0001). The rates of bone metastases were comparable for triple-negative and for other forms of cancer in this time period (HR 0.8; 95% CI: 0.4–1.6 P = 0.5). Conclusions The excess risk of distant recurrence in triple-negative breast cancers, versus other forms of cancer, is attributable in large part to an excess of visceral metastases in the first five years following diagnosis.

480 citations


Journal ArticleDOI
TL;DR: A minority of interventions showed larger effects, but no specific reminder or contextual features were significantly associated with effect magnitude, and further research must identify design features and contextual factors consistently associated with larger improvements in provider behaviour.
Abstract: Background The opportunity to improve care by delivering decision support to clinicians at the point of care represents one of the main incentives for implementing sophisticated clinical information systems. Previous reviews of computer reminder and decision support systems have reported mixed effects, possibly because they did not distinguish point of care computer reminders from e-mail alerts, computer-generated paper reminders, and other modes of delivering ‘computer reminders’. Objectives To evaluate the effects on processes and outcomes of care attributable to on-screen computer reminders delivered to clinicians at the point of care. Search methods We searched the Cochrane EPOC Group Trials register, MEDLINE, EMBASE and CINAHL and CENTRAL to July 2008, and scanned bibliographies from key articles. Selection criteria Studies of a reminder delivered via a computer system routinely used by clinicians, with a randomised or quasi-randomised design and reporting at least one outcome involving a clinical endpoint or adherence to a recommended process of care. Data collection and analysis Two authors independently screened studies for eligibility and abstracted data. For each study, we calculated the median improvement in adherence to target processes of care and also identified the outcome with the largest such improvement. We then calculated the median absolute improvement in process adherence across all studies using both the median outcome from each study and the best outcome. Main results Twenty-eight studies (reporting a total of thirty-two comparisons) were included. Computer reminders achieved a median improvement in process adherence of 4.2% (interquartile range (IQR): 0.8% to 18.8%) across all reported process outcomes, 3.3% (IQR: 0.5% to 10.6%) for medication ordering, 3.8% (IQR: 0.5% to 6.6%) for vaccinations, and 3.8% (IQR: 0.4% to 16.3%) for test ordering. In a sensitivity analysis using the best outcome from each study, the median improvement was 5.6% (IQR: 2.0% to 19.2%) across all process measures and 6.2% (IQR: 3.0% to 28.0%) across measures of medication ordering. In the eight comparisons that reported dichotomous clinical endpoints, intervention patients experienced a median absolute improvement of 2.5% (IQR: 1.3% to 4.2%). Blood pressure was the most commonly reported clinical endpoint, with intervention patients experiencing a median reduction in their systolic blood pressure of 1.0 mmHg (IQR: 2.3 mmHg reduction to 2.0 mmHg increase). Authors' conclusions Point of care computer reminders generally achieve small to modest improvements in provider behaviour. A minority of interventions showed larger effects, but no specific reminder or contextual features were significantly associated with effect magnitude. Further research must identify design features and contextual factors consistently associated with larger improvements in provider behaviour if computer reminders are to succeed on more than a trial and error basis.

466 citations


Journal ArticleDOI
16 Oct 2009-BMJ
TL;DR: A nurse led intensive care follow-up programme showed no evidence of being effective or cost effective in improving patients’ quality of life in the year after discharge from intensive care.
Abstract: Objectives To test the hypothesis that nurse led follow-up programmes are effective and cost effective in improving quality of life after discharge from intensive care. Design A pragmatic, non-blinded, multicentre, randomised controlled trial. Setting Three UK hospitals (two teaching hospitals and one district general hospital). Participants 286 patients aged ≥18 years were recruited after discharge from intensive care between September 2006 and October 2007. Intervention Nurse led intensive care follow-up programmes versus standard care. Main outcome measure(s) Health related quality of life (measured with the SF-36 questionnaire) at 12 months after randomisation. A cost effectiveness analysis was also performed. Results 286 patients were recruited and 192 completed one year follow-up. At 12 months, there was no evidence of a difference in the SF-36 physical component score (mean 42.0 (SD 10.6) v 40.8 (SD 11.9), effect size 1.1 (95% CI −1.9 to 4.2), P=0.46) or the SF-36 mental component score (effect size 0.4 (−3.0 to 3.7), P=0.83). There were no statistically significant differences in secondary outcomes or subgroup analyses. Follow-up programmes were significantly more costly than standard care and are unlikely to be considered cost effective. Conclusions A nurse led intensive care follow-up programme showed no evidence of being effective or cost effective in improving patients’ quality of life in the year after discharge from intensive care. Further work should focus on the roles of early physical rehabilitation, delirium, cognitive dysfunction, and relatives in recovery from critical illness. Intensive care units should review their follow-up programmes in light of these results. Trial registration ISRCTN 24294750

418 citations


Journal ArticleDOI
01 Jan 2009-Stroke
TL;DR: In high-risk patients with atrial fibrillation admitted with a stroke, and who were candidates for anticoagulation, most were either not taking warfarin or were subtherapeutic at the time of ischemic stroke.
Abstract: Background and Purpose— Warfarin is the most effective stroke prevention medication for high-risk individuals with atrial fibrillation, yet it is often underused. This study examined the magnitude of this problem in a large contemporary, prospective stroke registry. Methods— We analyzed data from the Registry of the Canadian Stroke Network, a prospective database of consecutive patients with stroke admitted to 12 designated stroke centers in Ontario (2003 to 2007). We included patients admitted with an acute ischemic stroke who (1) had a known history of atrial fibrillation; (2) were classified as high risk for systemic emboli according to published guidelines; and (3) had no known contraindications to anticoagulation. Primary end points were the use of prestroke antithrombotic medications and admission international normalized ratio. Results— Among patients admitted with a first ischemic stroke who had known atrial fibrillation (n=597), strokes were disabling in 60% and fatal in 20%. Preadmission medicat...

404 citations


Journal ArticleDOI
03 Jun 2009-Trials
TL;DR: If the authors want evidence from trials to be used in clinical practice and policy, trialists should make every effort to make their trial widely applicable, which means that more trials should be pragmatic in attitude.
Abstract: Randomised controlled trials are the best research design for decisions about the effect of different interventions but randomisation does not, of itself, promote the applicability of a trial's results to situations other than the precise one in which the trial was done. While methodologists and trialists have rightly paid great attention to internal validity, much less has been given to applicability. This narrative review is aimed at those planning to conduct trials, and those aiming to use the information in them. It is intended to help the former group make their trials more widely useful and to help the latter group make more informed decisions about the wider use of existing trials. We review the differences between the design of most randomised trials (which have an explanatory attitude) and the design of trials more able to inform decision making (which have a pragmatic attitude) and discuss approaches used to assert applicability of trial results. If we want evidence from trials to be used in clinical practice and policy, trialists should make every effort to make their trial widely applicable, which means that more trials should be pragmatic in attitude.

399 citations


Journal ArticleDOI
TL;DR: It is suggested that the first clinical applications of ETS fusions are likely to be in noninvasive detection of prostate cancer and in aiding with difficult diagnostic cases and tissue and functional studies suggest a specific role for Ets fusions in the transition to carcinoma.

Journal ArticleDOI
01 Mar 2009-Stroke
TL;DR: MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema.
Abstract: Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic white matter disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular disease, which is epidemic in our aging population.

Journal ArticleDOI
TL;DR: Results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.
Abstract: Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.

Journal ArticleDOI
TL;DR: These findings suggest that white-matter fibers in ventral occipito-temporal cortex support the integrated function of a distributed cortical network that subserves normal face processing.
Abstract: Prosopagnosics have impaired face recognition, but make relatively normal responses to face stimuli in core brain regions for face recognition. The authors now report that it is the connectivity among these regions that is being disrupted in the disorder. Using diffusion tensor imaging and tractography, we found that a disruption in structural connectivity in ventral occipito-temporal cortex may be the neurobiological basis for the lifelong impairment in face recognition that is experienced by individuals who suffer from congenital prosopagnosia. Our findings suggest that white-matter fibers in ventral occipito-temporal cortex support the integrated function of a distributed cortical network that subserves normal face processing.

Journal ArticleDOI
TL;DR: The study confirms the usefulness of the HADS as a marker of major depression and generalized anxiety disorder, but not other anxiety disorders, in multiple sclerosis patients.
Abstract: Detecting clinically significant symptoms of depression and anxiety in medically ill patients using self-report rating scales presents a challenge because of somatic confounders. The Hospital Anxiety and Depression Scale (HADS) was developed with this in mind, but has never been validated for a multiple sclerosis population. Our objective was to validate the HADS for multiple sclerosis patients. Multiple sclerosis patients were interviewed for the presence of major depression (n = 180) and anxiety disorders (n = 140) with the Structured Clinical Interview for DSM-IV disorders. A receiver operating characteristic (ROC) analysis was undertaken to assess which HADS cut-off scores give the best yield with respect to diagnoses of major depression and all anxiety disorders defined by the Structured Clinical Interview for DSM-IV. A threshold score of 8 or greater on the HADS depression subscale provides a sensitivity of 90% and specificity of 87.3% (ROC area under the curve 0.938). The same cut-off score gives a...

Journal ArticleDOI
TL;DR: The results indicate that ultrasound exposure parameters can be optimized for therapeutic sonoporation and that bubble disruption is a necessary but insufficient indicator of ultrasound-induced permeabilization.
Abstract: This work investigates the effect of ultrasound exposure parameters on the sonoporation of KHT-C cells in suspension by perflutren microbubbles. Variations in insonating acoustic pressure (0.05 to 3.5 MPa), pulse frequency (0.5 to 5.0 MHz), pulse repetition frequency (10 to 3000 Hz), pulse duration (4 to 32 micros) and insonation time (0.1 to 900 s) were studied. The number of cells permeabilised to a fluorescent tracer molecule (70 kDa FITC-dextran) and the number of viable cells were measured using flow cytometry. The effect of exposure on the microbubble population was measured using a Coulter counter. Cell viability and membrane permeability were found to depend strongly on the acoustic exposure conditions. Cell permeability increased and viability decreased with increasing peak negative pressure, pulse repetition frequency, pulse duration and insonation time and with decreasing pulse centre frequency. The highest therapeutic ratio (defined as the ratio of permeabilised to nonviable cells) achieved was 8.8 with 32 +/- 4% permeabilization and 96 +/- 1% viability at 570 kPa peak negative pressure, 8 micros pulse duration, 3 kHz pulse repetition frequency, 500 kHz centre frequency and 12 s insonation time with microbubbles at 3.3% volume concentration. These settings correspond to an acoustic energy density (E(SPPA)) of 3.12 J/cm(2). Cell permeability and viability did not correlate with bubble disruption. The results indicate that ultrasound exposure parameters can be optimized for therapeutic sonoporation and that bubble disruption is a necessary but insufficient indicator of ultrasound-induced permeabilization.

Journal ArticleDOI
TL;DR: Key challenges facing the preclinical and clinical development of antiangiogenic agents are discussed, including potential differences in drug efficacies when treating primary tumors or various stages of metastatic disease.
Abstract: Despite early benefits seen in cancer patients treated with antivascular endothelial growth factor (VEGF) pathway-targeted drugs, the clinical benefits obtained in terms of progression-free or overall survival have been more modest than expected. This outcome is, at least in part, due to antiangiogenic drug resistance mechanisms that involve pathways mediated largely by the tumor, whether intrinsic or acquired in response to therapy, or by the host, which is either responding directly to therapy or indirectly to tumoral cues. The focus of this review is to distinguish, where possible, between such host and tumor-mediated pathways of resistance and discuss key challenges facing the preclinical and clinical development of antiangiogenic agents, including potential differences in drug efficacies when treating primary tumors or various stages of metastatic disease.

Journal ArticleDOI
TL;DR: The observed water relaxation and diffusion changes help better define the validity and limitations of using chemically‐fixed nervous tissue for MRI investigations.
Abstract: Chemically-fixed nervous tissues are well-suited for high-resolution, time-intensive MRI acquisitions without motion artifacts, such as those required for brain atlas projects, but the aldehyde fixatives used may significantly alter tissue MRI properties. To test this hypothesis, this study characterized the impact of common aldehyde fixatives on the MRI properties of a rat brain slice model. Rat cortical slices immersion-fixed in 4% formaldehyde demonstrated 21% and 81% reductions in tissue T(1) and T(2), respectively (P < 0.001). The T(2) reduction was reversed by washing slices with phosphate-buffered saline (PBS) for 12 h to remove free formaldehyde solution. Diffusion MRI of cortical slices analyzed with a two-compartment analytical model of water diffusion demonstrated 88% and 30% increases in extracellular apparent diffusion coefficient (ADC(EX)) and apparent restriction size, respectively, when slices were chemically-fixed with 4% formaldehyde (P

Journal ArticleDOI
TL;DR: The incidence and attributable mortality of Clostridium difficile infection in Canada is remarkably similar to those found in a previous study, although there are wide variations in HA CDI among the participating hospitals.
Abstract: Background. Clostridium difficile infection (CDI) is the most frequent cause of health care-associated infectious diarrhea in industrialized countries. The only previous report describing the incidence of health care-associated CDI (HA CDI) in Canada was conducted in 1997 by the Canadian Nosocomial Infection Surveillance Program. We re-examined the incidence of HA CDI with an emphasis on patient outcomes. Methods. A prospective surveillance was conducted from 1 November 2004 through 30 April 2005. Basic demographic data were collected, including age, sex, type of patient ward where the patient was hospitalized on the day HA CDI was identified, and patient comorbidities. Data regarding severe outcome were collected 30 days after the diagnosis of HA CDI; severe outcome was defined as an admission to the intensive care unit because of complications of CDI, colectomy due to CDI, and/or death attributable to CDI. Results. A total of 1430 adults with HA CDI were identified in 29 hospitals during the 6-month surveillance period. The overall incidence rate of HA CDI for adult patients admitted to these hospitals was 4.6 cases per 1000 patient admissions and 65 per 100,000 patient-days. At 30 days after onset of HA CDI, 233 patients (16.3%) had died from all causes; 31 deaths (2.2%) were a direct result of CDI, and 51 deaths (3.6%) were indirectly related to CDI, for a total attributable mortality rate of 5.7%. Conclusions. The rates are remarkably similar to those found in our previous study; although we found wide variations in HA CDI among the participating hospitals. However, the attributable mortality increased almost 4-fold (5.7% vs. 1.5%; P<.001).

Journal ArticleDOI
TL;DR: Regional suppression of TRPM7 is feasible, well tolerated and inhibits delayed neuronal death in vivo and prevented ischemia-induced deficits in LTP and preserved performance in fear-associated and spatial-navigational memory tasks.
Abstract: In a model of stroke, the authors show that suppressing the expression of TRPM7 in hippocampal CA1 neurons conferred resistance to ischemic death, preserving function and morphology. Also, TRPM7 suppression prevented ischemia-induced deficits in LTP and fear-associated and spatial navigational memory tasks.

Journal ArticleDOI
TL;DR: In this paper, the authors conducted a comprehensive literature search for relevant studies on bisphosphonates associated osteonecrosis of the jaw (ONJ) in oncology and osteoporosis patients published before February 2008.
Abstract: In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%-12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.

Journal ArticleDOI
29 Apr 2009-PLOS ONE
TL;DR: In this article, the authors presented the results of the Canadian Institutes of Health Research (CIHR) Training Grant and the US Lymphoma Foundation Training Grant (USLGF).
Abstract: Canadian Institutes of Health Research (16512, Cancer Consortium Training Grant Award, CancerConsortium Training Grant Award); US Lymphoma Foundation Award; National Institute of Health (RO1 GM073855); National Crime Information Center (017099); Cole Foundation Award

Journal ArticleDOI
TL;DR: There was no difference between the VEGF-treated and the placebo groups in the primary end point of change in myocardial perfusion from baseline to 3 or 6 months, assessed by single photon emission tomography (SPECT) imaging, although a significant reduction in the ischemic area was seen in both groups.

Journal ArticleDOI
TL;DR: Based on the results obtained from the four groups of women in this study, the "50-50" breast is not a representative model of the breast composition.
Abstract: Purpose: For dosimetry and for work in optimization of x-ray imaging of the breast, it is commonly assumed that the breast is composed of 50% fibroglandular tissue and 50% fat. The purpose of this study was to assess whether this assumption was realistic. Methods: First, data obtained from an experimental breast CT scanner were used to validate an algorithm that measures breast density from digitized film mammograms. Density results obtained from a total of 2831 women, including 191 women receiving CT and from mammograms of 2640 women from three other groups, were then used to estimate breast compositions. Results: Mean compositions, expressed as percent fibroglandular tissue (including the skin), varied from 13.7% to 25.6% among the groups with an overall mean of 19.3%. The mean compressed breast thickness for the mammograms was 5.9 cm ({sigma}=1.6 cm). 80% of the women in our study had volumetric breast density less than 27% and 95% were below 45%. Conclusions: Based on the results obtained from the four groups of women in our study, the ''50-50'' breast is not a representative model of the breast composition.

Journal ArticleDOI
TL;DR: The development of PE is 1 of the earliest clinically identifiable markers of a woman's heightened risk of cardiovascular disease, and mathematical modeling of cardiovascular event risk suggests that PE increases the risk by 2- to 3-fold.

Journal ArticleDOI
TL;DR: In this cohort with asymptomatic moderate carotid stenosis, MR-depicted IPH was associated with future ipsilateral cerebrovascular events, and the absence of IPH at MR imaging may be a reassuring marker of plaque stability and of a lower risk of thromboembolism.
Abstract: In men with asymptomatic moderate carotid stenosis, future ipsilatcral cerebrovascular events are associated with carotid intraplaque hemorrhage detected by using a rapid three-dimensional Tl-weighted fat-suppressed spoiled gradientecho MR sequence.

Journal ArticleDOI
TL;DR: This paper synthesizes the findings from three studies into a framework of ten separate but interconnected elements germane to successful priority setting: stakeholder understanding, shifted priorities/reallocation of resources, decision making quality, stakeholder acceptance and satisfaction, positive externalities, stakeholders engagement, and revision or appeals mechanism.
Abstract: The sustainability of healthcare systems worldwide is threatened by a growing demand for services and expensive innovative technologies Decision makers struggle in this environment to set priorities appropriately, particularly because they lack consensus about which values should guide their decisions One way to approach this problem is to determine what all relevant stakeholders understand successful priority setting to mean The goal of this research was to develop a conceptual framework for successful priority setting Three separate empirical studies were completed using qualitative data collection methods (one-on-one interviews with healthcare decision makers from across Canada; focus groups with representation of patients, caregivers and policy makers; and Delphi study including scholars and decision makers from five countries) This paper synthesizes the findings from three studies into a framework of ten separate but interconnected elements germane to successful priority setting: stakeholder understanding, shifted priorities/reallocation of resources, decision making quality, stakeholder acceptance and satisfaction, positive externalities, stakeholder engagement, use of explicit process, information management, consideration of values and context, and revision or appeals mechanism The ten elements specify both quantitative and qualitative dimensions of priority setting and relate to both process and outcome components To our knowledge, this is the first framework that describes successful priority setting The ten elements identified in this research provide guidance for decision makers and a common language to discuss priority setting success and work toward improving priority setting efforts

Journal ArticleDOI
TL;DR: The first population-based estimate of pediatric acute lung injury incidence in the United States is presented, finding that population incidence and mortality rates are lower than those for adult acute lungs injury.
Abstract: OBJECTIVE: This population-based, prospective, cohort study was designed to determine the population incidence and outcomes of pediatric acute lung injury. METHODS: Between 1999 and 2000, 1 year of screening was performed at all hospitals admitting critically ill children in King County, Washington. County residents 0.5 to 15 years of age who required invasive (through endotracheal tube or tracheostomy) or noninvasive (through full face mask) mechanical ventilation, regardless of the duration of mechanical ventilation, were screened. From this population, children meeting North American-European Consensus Conference acute lung injury criteria were eligible for enrollment. Postoperative patients who received mechanical ventilation for RESULTS: Thirty-nine children met the criteria for acute lung injury, resulting in a calculated incidence of 12.8 cases per 100000 person-years. Severe sepsis (with pneumonia as the infection focus) was the most common risk factor. The median 24-hour Pediatric Risk of Mortality III score was 9.0, and the mean ± SD was 11.7 ± 7.5. The hospital mortality rate was 18%, lower than that reported previously for pediatric acute lung injury. There were no statistically significant associations between age, gender, or risk factors and outcomes. CONCLUSIONS: We present the first population-based estimate of pediatric acute lung injury incidence in the United States. Population incidence and mortality rates are lower than those for adult acute lung injury. Low mortality rates in pediatric acute lung injury may necessitate clinical trial outcome measures other than death.

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TL;DR: It is shown that overexpression of miR-17 results in decreased cell adhesion, migration and proliferation, and the single miRNA expression assay may be evolved to allow the manipulation of individual miRNA functions in vitro and in vivo.
Abstract: MicroRNAs (miRNAs) are single-stranded regulatory RNAs, frequently expressed as clusters. Previous studies have demonstrated that the six-miRNA cluster miR-17~92 has important roles in tissue development and cancers. However, the precise role of each miRNA in the cluster is unknown. Here we show that overexpression of miR-17 results in decreased cell adhesion, migration and proliferation. Transgenic mice overexpressing miR-17 showed overall growth retardation, smaller organs and greatly reduced haematopoietic cell lineages. We found that fibronectin and the fibronectin type-III domain containing 3A (FNDC3A) are two targets that have their expression repressed by miR-17, both in vitro and in transgenic mice. Several lines of evidence support the notion that miR-17 causes cellular defects through its repression of fibronectin expression. Our single miRNA expression assay may be evolved to allow the manipulation of individual miRNA functions in vitro and in vivo. We anticipate that this could serve as a model for studying gene regulation by miRNAs in the development of gene therapy.

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TL;DR: As with baseline 25( OH)D, T436K genotype predicts 25(OH)D changes after long-term vitamin D supplementation.