Showing papers by "Sunnybrook Health Sciences Centre published in 2014"

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial

Abstract: Summary Background Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. Methods In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. Findings Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8–28·8) in the cilengitide group and 26·3 months (23·9–34·7) in the control group (hazard ratio 1·02, 95% CI 0·81–1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). Interpretation The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. Funding Merck KGaA, Darmstadt, Germany.

Rates and risk factors for prolonged opioid use after major surgery: population based cohort study

Abstract: Objective To describe rates and risk factors for prolonged postoperative use of opioids in patients who had not previously used opioids and undergoing major elective surgery. Design Population based retrospective cohort study. Setting Acute care hospitals in Ontario, Canada, between 1 April 2003 and 31 March 2010. Participants 39 140 opioid naive patients aged 66 years or older who had major elective surgery, including cardiac, intrathoracic, intra-abdominal, and pelvic procedures. Main outcome measure Prolonged opioid use after discharge, as defined by ongoing outpatient prescriptions for opioids for more than 90 days after surgery. Results Of the 39 140 patients in the entire cohort, 49.2% (n=19 256) were discharged from hospital with an opioid prescription, and 3.1% (n=1229) continued to receive opioids for more than 90 days after surgery. Following risk adjustment with multivariable logistic regression modelling, patient related factors associated with significantly higher risks of prolonged opioid use included younger age, lower household income, specific comorbidities (diabetes, heart failure, pulmonary disease), and use of specific drugs preoperatively (benzodiazepines, selective serotonin reuptake inhibitors, angiotensin converting enzyme inhibitors). The type of surgical procedure was also highly associated with prolonged opioid use. Compared with open radical prostatectomies, both open and minimally invasive thoracic procedures were associated with significantly higher risks (odds ratio 2.58, 95% confidence interval 2.03 to 3.28 and 1.95 1.36 to 2.78, respectively). Conversely, open and minimally invasive major gynaecological procedures were associated with significantly lower risks (0.73, 0.55 to 0.98 and 0.45, 0.33 to 0.62, respectively). Conclusions Approximately 3% of previously opioid naive patients continued to use opioids for more than 90 days after major elective surgery. Specific patient and surgical characteristics were associated with the development of prolonged postoperative use of opioids. Our findings can help better inform understanding about the long term risks of opioid treatment for acute postoperative pain and define patient subgroups that warrant interventions to prevent progression to prolonged postoperative opioid use.

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

Abstract: MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

The link between multiple sclerosis and depression

Abstract: Depression--be it a formal diagnosis based on consensus clinical criteria, or a collection of symptoms revealed by a self-report rating scale--is common in patients with multiple sclerosis (MS) and adds substantially to the morbidity and mortality associated with this disease. This Review discusses the prevalence and epidemiology of depression in patients with MS, before covering aetiological factors, including genetics, brain pathology, immunological changes, dysregulation of the hypothalamic-pituitary-adrenal axis, and psychosocial influences. Treatment options such as antidepressant drugs, cognitive-behavioural therapy, mindfulness-based therapy, exercise and electroconvulsive therapy are also reviewed in the context of MS-related depression. Frequent comorbid conditions, namely pain, fatigue, anxiety, cognitive dysfunction and alcohol use, are also summarized. The article then explores three key challenges facing researchers and clinicians: what is the optimal way to define depression in the context of diseases such as MS, in which the psychiatric and neurological symptoms overlap; how can current knowledge about the biological and psychological underpinnings of MS-related depression be used to boost the validity of this construct; and can intervention be made more effective through use of combination therapies with additive or synergistic effects, which might exceed the modest benefits derived from their individual components?

Randomized Comparison of Gemcitabine, Dexamethasone, and Cisplatin Versus Dexamethasone, Cytarabine, and Cisplatin Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed and Refractory Aggressive Lymphomas: NCIC-CTG LY.12

Abstract: Purpose For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. Patients and methods We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. Results For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P Conclusion For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.

Obstructive Sleep Apnea and Risk of Cardiovascular Events and All-Cause Mortality: A Decade-Long Historical Cohort Study

Abstract: Background: Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events. Methods and Findings: A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael’s Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation ,90% (9 minutes versus 0; HR=1.50, 95% CI 1.25–1.79), sleep time (4.9 versus 6.4 hours; HR=1.20, 95% CI 1.12–1.27), awakenings (35 versus 18; HR=1.06, 95% CI 1.02–1.10), periodic leg movements (13 versus 0/ hour; HR=1.05, 95% CI 1.03–1.07), heart rate (70 versus 56 beats per minute [bpm]; HR=1.28, 95% CI 1.19–1.37), and daytime sleepiness (HR=1.13, 95% CI 1.01–1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence. Conclusion: OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice. Please see later in the article for the Editors’ Summary.

Animal models in burn research

Abstract: Burn injury is a severe form of trauma affecting more than 2 million people in North America each year Burn trauma is not a single pathophysiological event but a devastating injury that causes structural and functional deficits in numerous organ systems Due to its complexity and the involvement of multiple organs, in vitro experiments cannot capture this complexity nor address the pathophysiology In the past two decades, a number of burn animal models have been developed to replicate the various aspects of burn injury, to elucidate the pathophysiology, and to explore potential treatment interventions Understanding the advantages and limitations of these animal models is essential for the design and development of treatments that are clinically relevant to humans This review aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications While many animal models of burn exist, we limit our discussion to the skin healing of mouse, rat, and pig Additionally, we briefly explain hypermetabolic characteristics of burn injury and the animal model utilized to study this phenomena Finally, we discuss the economic costs associated with each of these models in order to guide decisions of choosing the appropriate animal model for burn research

Warfarin Use and the Risk for Stroke and Bleeding in Patients With Atrial Fibrillation Undergoing Dialysis

Abstract: Background—Current observational studies on warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation (AF) undergoing dialysis found conflicting results. Methods and Results—We conducted a population-based retrospective cohort study of patients aged ≥65 years admitted to a hospital with a primary or secondary diagnosis of AF, in Quebec and Ontario, Canada from 1998 to 2007. The AF cohort was grouped into dialysis (hemodialysis and peritoneal dialysis) and nondialysis patients and into warfarin and no-warfarin users according to the first prescription filled for warfarin within 30 days after AF hospital discharge. We determined the association between warfarin use and the risk for stroke and bleeding in dialysis and nondialysis patients. The cohort comprised 1626 dialysis patients and 204 210 nondialysis patients. Among dialysis patients, 46% (756/1626) patients were prescribed warfarin. Among dialysis patients, warfarin users had more congestive heart failure and diabetes mell...

Flail chest injuries: a review of outcomes and treatment practices from the National Trauma Data Bank

Abstract: BACKGROUNDFlail chest injuries are associated with severe pulmonary restriction, a requirement for intubation and mechanical ventilation, and high rates of morbidity and mortality. Our goals were to investigate the prevalence, current treatment practices, and outcomes of flail chest injuries in poly

Trends in Incidence of Diabetes in Pregnancy and Serious Perinatal Outcomes: A Large, Population-Based Study in Ontario, Canada, 1996–2010

Abstract: OBJECTIVE Women with diabetes in pregnancy have high rates of pregnancy complications. Our aims were to explore trends in the incidence of diabetes in pregnancy and examine whether the risk of serious perinatal outcomes has changed. RESEARCH DESIGN AND METHODS We performed a population-based cohort study of 1,109,605 women who delivered in Ontario, Canada, between 1 April 1996 and 31 March 2010. We categorized women as gestational diabetes (GDM) ( n = 45,384), pregestational diabetes (pre-GDM) ( n = 13,278), or no diabetes ( n = 1,050,943). The annual age-adjusted rates of diabetes in pregnancy were calculated, and rates of serious perinatal outcomes were compared between groups and by year using Poisson regression. RESULTS The age-adjusted rate of both GDM (2.7–5.6%, P P CONCLUSIONS The incidence of both GDM and pre-GDM in pregnancy has doubled over the last 14 years, and the overall burden of diabetes in pregnancy on society is growing. Although congenital anomaly rates have declined in women with diabetes, perinatal mortality rates remain unchanged, and the risk of both remains significantly elevated compared with nondiabetic women. Increased efforts are needed to reduce these adverse outcomes.

Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials

Abstract: Background Brachial plexus nerve blocks (BPBs) have analgesic and opioid sparing benefits for upper extremity surgery. Single-injection techniques are limited by the pharmacological duration and therapeutic index of local anaesthetics (LAs). Continuous catheter techniques, while effective can present management challenges. Off-label use of perineural dexamethasone as an LA adjuvant has been utilized to prolong single-injection techniques. The objectives of this systematic review and meta-analysis are to assess the contemporary literature and quantify the effects of dexamethasone on BPB. Methods The authors searched for randomized, placebo-controlled trials that compared BPB performed with LA alone with that performed with LA and perineural dexamethasone. Meta-analysis was performed using a random effects model with subgroup analysis stratified by LA (long vs intermediate). The primary outcome was duration of sensory block or analgesia; the secondary outcomes were motor block duration, opioid consumption, and BPB complications. Results Nine trials (801 patients) were included with 393 patients receiving dexamethasone (4–10 mg). Dexamethasone prolonged the analgesic duration for long-acting LA from 730 to 1306 min [mean difference 576 min, 95% confidence interval (CI) 522–631] and for intermediate from 168 to 343 min (mean 175, 95% CI 73–277). Motor block was prolonged from 664 to 1102 min (mean 438, 95% CI 89–787). The most recent trial demonstrated equivalent prolongation with perineural or systemic administration of dexamethasone compared with placebo. Conclusions Perineural administration of dexamethasone with LA prolongs BPB effects with no observed adverse events. The effects of systemic administration of dexamethasone on BPB must be investigated.

Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review

Abstract: The understanding of coagulopathies in trauma has increased interest in thromboelastography (TEG®) and thromboelastometry (ROTEM®), which promptly evaluate the entire clotting process and may guide blood product therapy. Our objective was to review the evidence for their role in diagnosing early coagulopathies, guiding blood transfusion, and reducing mortality in injured patients. We considered observational studies and randomized controlled trials (MEDLINE, EMBASE, and Cochrane databases) to February 2014 that examined TEG®/ROTEM® in adult trauma patients. We extracted data on demographics, diagnosis of early coagulopathies, blood transfusion, and mortality. We assessed methodologic quality by using the Newcastle-Ottawa scale (NOS) for observational studies and QUADAS-2 tool for diagnostic accuracy studies. Fifty-five studies (12,489 patients) met inclusion criteria, including 38 prospective cohort studies, 15 retrospective cohort studies, two before-after studies, and no randomized trials. Methodologic quality was moderate (mean NOS score, 6.07; standard deviation, 0.49). With QUADAS-2, only three of 47 studies (6.4%) had a low risk of bias in all domains (patient selection, index test, reference standard and flow and timing); 37 of 47 studies (78.8%) had low concerns regarding applicability. Studies investigated TEG®/ROTEM® for diagnosis of early coagulopathies (n = 40) or for associations with blood-product transfusion (n = 25) or mortality (n = 24). Most (n = 52) were single-center studies. Techniques examined included rapid TEG® (n =12), ROTEM® (n = 18), TEG® (n = 23), or both TEG® and rapid TEG® (n = 2). Many TEG®/ROTEM® measurements were associated with early coagulopathies, including some (hypercoagulability, hyperfibrinolysis, platelet dysfunction) not assessed by routine screening coagulation tests. Standard measures of diagnostic accuracy were inconsistently reported. Many abnormalities predicted the need for massive transfusion and death, but predictive performance was not consistently superior to routine tests. One observational study suggested that a ROTEM® -based transfusion algorithm reduced blood-product transfusion, but TEG®/ROTEM®-based resuscitation was not associated with lower mortality in most studies. Limited evidence from observational data suggest that TEG®/ROTEM® tests diagnose early trauma coagulopathy and may predict blood-product transfusion and mortality in trauma. Effects on blood-product transfusion, mortality, and other patient-important outcomes remain unproven in randomized trials.

Point-of-care ultrasonography for the diagnosis of acute cardiogenic pulmonary edema in patients presenting with acute dyspnea: a systematic review and meta-analysis.

Abstract: Objectives:Acute dyspnea is a common presenting complaint to the emergency department (ED), and point-of-care (POC) lung ultrasound (US) has shown promise as a diagnostic tool in this setting. The primary objective of this systematic review was to determine the sensitivity and specificity of

Intensive Hemodialysis Associates with Improved Pregnancy Outcomes: A Canadian and United States Cohort Comparison

Abstract: Pregnancy is rare in women with ESRD and when it occurs, it is often accompanied by significant maternal and fetal morbidity and even mortality. Preliminary data from the Toronto Nocturnal Hemodialysis Program suggested that increased clearance of uremic toxins by intensified hemodialysis improves pregnancy outcomes, but small numbers and the absence of a comparator group limited widespread applicability of these findings. We compared pregnancy outcomes from 22 pregnancies in the Toronto Pregnancy and Kidney Disease Clinic and Registry (2000–2013) with outcomes from 70 pregnancies in the American Registry for Pregnancy in Dialysis Patients (1990–2011). The primary outcome was the live birth rateandsecondaryoutcomesincludedgestationalageandbirthweight.ThelivebirthrateintheCanadian cohort (86.4%) was significantly higher than the rate in the American cohort (61.4%; P=0.03). Among patients with established ESRD, the median duration of pregnancy in the more intensively dialyzed Toronto cohort was 36 weeks (interquartile range, 32–37) compared with 27 weeks (interquartile range, 21–35) in the American cohort (P=0.002). Furthermore, a dose response between dialysis intensity and pregnancy outcomes emerged, with live birth rates of 48% in women dialyzed #20 hours per week and 85%inwomendialyzed.36hoursperweek(P=0.02),withalongergestationalageandgreaterinfantbirth weight for women dialyzed more intensively. Pregnancy complications were few and manageable. We conclude that pregnancy may be safe and feasible in women with ESRD receiving intensive hemodialysis.

Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review.

Abstract: Objective There has been rapid growth in research regarding inflammation in neuropsychiatric disorders as it relates to youth. We therefore set out to systematically review the literature on inflammation and neuropsychiatric disorders in children and adolescents. Method A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were included if proinflammatory markers (PIMs) in children and/or adolescents with neuropsychiatric disorders were measured. Results Sixty-seven studies were included, involving 3,952 youth. Evidence for a proinflammatory state is strongest for autism spectrum disorders (ASD). PIMs are elevated in children and adolescents with major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), Tourette's disorder (TD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SZ). However, the data are inconsistent. Evidence for specific PIMs is equivocal at this stage, although the findings in youth with MDD, BD, and PTSD converge with the extant adult literature in these areas. Definitive conclusions are limited by methodologic factors including cross-sectional and retrospective study design, between-study differences in specific markers and methods of analysis, small sample size, and other sources of heterogeneity. Conclusion The literature regarding inflammation among children and adolescents with neuropsychiatric disorders represents nearly 4,000 youth. There is preliminary evidence for elevated markers of inflammation in this population. Larger, prospective studies are needed to realize the goal of inflammatory markers informing clinical practice. In the interim, present findings suggest that further examination of this topic is warranted.

The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy

Abstract: Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline

Abstract: Purpose To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC).

Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis

Abstract: Background: Mechanical ventilation in the prone position is used to improve oxygenation and to mitigate the harmful effects of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). We sought to determine the effect of prone positioning on mortality among patients with ARDS receiving protective lung ventilation. Methods: We searched electronic databases and conference proceedings to identify relevant randomized controlled trials (RCTs) published through August 2013. We included RCTs that compared prone and supine positioning during mechanical ventilation in patients with ARDS. We assessed risk of bias and obtained data on all-cause mortality (determined at hospital discharge or, if unavailable, after longest follow-up period). We used random-effects models for the pooled analyses. Results: We identified 11 RCTs ( n = 2341) that met our inclusion criteria. In the 6 trials ( n = 1016) that used a protective ventilation strategy with reduced tidal volumes, prone positioning significantly reduced mortality (risk ratio 0.74, 95% confidence interval 0.59–0.95; I 2 = 29%) compared with supine positioning. The mortality benefit remained in several sensitivity analyses. The overall quality of evidence was high. The risk of bias was low in all of the trials except one, which was small. Statistical heterogeneity was low ( I 2 Interpretation: Our analysis of high-quality evidence showed that use of the prone position during mechanical ventilation improved survival among patients with ARDS who received protective lung ventilation.

Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study

Abstract: Summary Background Studies of complications resulting from surgery or radiotherapy for prostate cancer have mainly focused on incontinence and erectile dysfunction. We aimed to assess other important complications associated with these treatments for prostate cancer. Methods We did a population-based retrospective cohort study, in which we used administrative hospital data, physician billing codes, and cancer registry data for men who underwent either surgery or radiotherapy alone for prostate cancer between 2002 and 2009 in Ontario, Canada. We measured the 5-year cumulative incidence of five treatment-related complication endpoints: hospital admissions; urological, rectal, or anal procedures; open surgical procedures; and secondary malignancies. Findings In the 32 465 patients included in the study, the 5-year cumulative incidence of admission to hospital for a treatment-related complication was 22·2% (95% CI 21·7–22·7), but was 2·4% (2·2–2·6) for patients whose length of stay was longer than 1 day. The 5-year cumulative incidence of needing a urological procedure was 32·0% (95% CI 31·4–32·5), that of a rectal or anal procedure was 13·7% (13·3–14·1), and that of an open surgical procedure was 0·9% (0·8–1·1). The 5-year cumulative incidence of a second primary malignancy was 3·0% (2·6–3·5). These risks were significantly higher than were those of 32 465 matched controls with no history of prostate cancer. Older age and comorbidity at the time of index treatment were important predictors for a complication in all outcome categories, but the type of treatment received was the strongest predictor for complications. Patients who were given radiotherapy had higher incidence of complications for hospital admissions, rectal or anal procedures, open surgical procedures, and secondary malignancies at 5 years than did those who underwent surgery (adjusted hazard ratios 2·08–10·8, p Interpretation Complications after prostate cancer treatment are frequent and dependent on age, comorbidity, and the type of treatment. Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy. Funding Ajmera Family Chair in Urologic Oncology.

Risk of total knee arthroplasty after operatively treated tibial plateau fracture: a matched-population-based cohort study.

Abstract: Background: The aims of operative treatment of displaced tibial plateau fractures are to stabilize the injured knee to restore optimal function and to minimize the risk of posttraumatic arthritis and the eventual need for total knee arthroplasty. The purpose of our study was to define the rate of subsequent total knee arthroplasty after tibial plateau fractures in a large cohort and to compare that rate with the rate in the general population. Methods: All patients sixteen years of age or older who had undergone surgical treatment of a tibial plateau fracture from 1996 to 2009 in the province of Ontario, Canada, were identified from administrative health databases with use of surgeon fee codes. Each member of the tibial plateau fracture cohort was matched to four individuals from the general population according to age, sex, income, and urban/rural residence. The rates of total knee arthroplasty at two, five, and ten years were compared by using time-to-event analysis. A separate Cox proportional hazards model was used to explore the influence of patient, provider, and surgical factors on the time to total knee arthroplasty. Results: We identified 8426 patients (48.5% female; median age, 48.9 years) who had undergone fixation of a tibial plateau fracture and matched them to 33,698 controls. The two, five, and ten-year rates of total knee arthroplasty in the plateau fracture and control cohorts were 0.32% versus 0.29%, 5.3% versus 0.82%, and 7.3% versus 1.8%, respectively (p < 0.0001). After adjustment for comorbidity, plateau fracture surgery was found to significantly increase the likelihood of total knee arthroplasty (hazard ratio [HR], 5.29 [95% confidence interval, 4.58, 6.11]; p < 0.0001). Higher rates of total knee arthroplasty were also associated with increasing age (HR, 1.03 [1.03, 1.04] per year over the age of forty-eight; p < 0.0001), bicondylar fracture (HR, 1.53 [1.26, 1.84]; p < 0.0001), and greater comorbidity (HR, 2.17 [1.70, 2.77]; p < 0.001). Conclusions: Ten years after tibial plateau fracture surgery, 7.3% of the patients had had a total knee arthroplasty. This corresponds to a 5.3 times increase in likelihood compared with a matched group from the general population. Older patients and those with more severe fractures are also more likely to need total knee arthroplasty after repair of a tibial plateau fracture. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. Peer Review This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.

Epidemiology of primary anterior shoulder dislocation requiring closed reduction in Ontario, Canada.

Abstract: Background:There is a lack of high-quality population-based literature describing the epidemiology of primary anterior shoulder dislocation.Purpose:To (1) calculate the incidence density rate (IDR) of primary anterior shoulder dislocation requiring closed reduction (CR; “index event”) in the general population and demographic subgroups, and (2) determine the rate of and risk factors for repeat shoulder CR.Study Design:Cohort study (prognosis); Level of evidence, 2.Methods:All patients who underwent shoulder CR by a physician in Ontario between April 2002 and September 2010 were identified with administrative databases. Exclusion criteria included age 70 years, posterior dislocation, and prior shoulder dislocation or surgery. Index event IDR was calculated for all populations/subgroups, and IDR comparisons were made. Repeat shoulder CR was sought until September 2012. Risk factors for repeat shoulder CR were identified with a Prentice, Williams, and Peterson proportional hazards model.Results:Ther...

Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.

Abstract: OBJECTIVE To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? METHODS A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. RESULTS Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. SIGNIFICANCE This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B*15:02 and HLA-A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.