Showing papers by "Sunnybrook Health Sciences Centre published in 2017"
St George's Hospital1, New York University2, McMaster University3, Brown University4, Catholic University of the Sacred Heart5, Hebron University6, University of Manitoba7, Emory University Hospital8, Hebrew University of Jerusalem9, Sunnybrook Health Sciences Centre10, University of Pittsburgh11, Saint Thomas - West Hospital12, University College London13, Vanderbilt University Medical Center14, Keio University15, Memorial Hospital of South Bend16, Cooper University Hospital17, University of Mississippi Medical Center18, Rush University Medical Center19, University of Ulsan20, Federal University of São Paulo21, Regions Hospital22, St. Michael's Hospital23, Washington University in St. Louis24, Ottawa Hospital25, University of Sydney26, Mount Sinai Hospital27, University of New South Wales28, Fujita Health University29, Christiana Care Health System30, Stanford University31, King Abdullah University of Science and Technology32, University of Kansas33, Harvard University34, California Pacific Medical Center35, University of Amsterdam36, Houston Methodist Hospital37
TL;DR: Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
Abstract: To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
4,303 citations
TL;DR: After 5 years of adjuvant endocrine therapy, breast‐cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years, with risks ranging from 10 to 41%, depending on TN status and tumor grade.
Abstract: BackgroundThe administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)–positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. MethodsIn this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan–Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients’ outcomes during the period from 5 to 20 years. ResultsBreast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence w...
929 citations
Sheba Medical Center1, University of California, Los Angeles2, Royal North Shore Hospital3, Aix-Marseille University4, university of lille5, University of California, San Francisco6, University of Sydney7, Royal Prince Alfred Hospital8, Hebrew University of Jerusalem9, The Royal Marsden NHS Foundation Trust10, University of Manchester11, Netherlands Cancer Institute12, Sunnybrook Health Sciences Centre13, Merck & Co.14, University of Paris-Sud15
TL;DR: The final protocol-specified survival analysis as mentioned in this paper showed that pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between the two dosing schedules.
904 citations
TL;DR: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years and no significant overall survival difference was observed between the treatment arms.
Abstract: Purpose To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P =.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P P =.004) and biochemical failure (MVA HR 6.30; P P =.62). Conclusions Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.
577 citations
TL;DR: In this large population-based cohort study, living close to heavy traffic was associated with a higher incidence of dementia, but not with Parkinson's disease or multiple sclerosis.
568 citations
TL;DR: It is found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ- Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts, and cell apoptosis was induced by upregulation of the Foxo 3 downstream target PUMA.
Abstract: Circular RNAs are a class of non-coding RNAs that are receiving extensive attention. Despite reports showing circular RNAs acting as microRNA sponges, the biological functions of circular RNAs remain largely unknown. We show that in patient tumor samples and in a panel of cancer cells, circ-Foxo3 was minimally expressed. Interestingly, during cancer cell apoptosis, the expression of circ-Foxo3 was found to be significantly increased. We found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ-Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts. Also, expression of circ-Foxo3 increased Foxo3 protein levels but repressed p53 levels. By binding to both, circ-Foxo3 promoted MDM2-induced p53 ubiquitination and subsequent degradation, resulting in an overall decrease of p53. With low binding affinity to Foxo3 protein, circ-Foxo3 prevented MDM2 from inducing Foxo3 ubiquitination and degradation, resulting in increased levels of Foxo3 protein. As a result, cell apoptosis was induced by upregulation of the Foxo3 downstream target PUMA.
480 citations
University of Alberta1, Montreal Heart Institute2, University Health Network3, McGill University4, McMaster University5, University of Waterloo6, University of Calgary7, Université de Sherbrooke8, University of Western Ontario9, St. Michael's Hospital10, Halifax11, Royal Jubilee Hospital12, University of British Columbia13, St. Boniface General Hospital14, Sunnybrook Health Sciences Centre15, University of Saskatchewan16, Durham University17, Laval University18, University of Colorado Boulder19, Université de Montréal20, St. John's University21
TL;DR: The 2017 HF guidelines provide updated guidance on the diagnosis and management that should aid in day-to-day decisions for caring for patients with HF, with attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care.
465 citations
TL;DR: The Middle East respiratory syndrome is caused by a coronavirus that was first identified in Saudi Arabia in 2012 and continues to occur in the Middle East and elsewhere.
Abstract: Between September 2012 and January 20, 2017, the World Health Organization (WHO) received reports from 27 countries of 1879 laboratory-confirmed cases in humans of the Middle East respiratory syndrome (MERS) caused by infection with the MERS coronavirus (MERS-CoV) and at least 659 related deaths. Cases of MERS-CoV infection continue to occur, including sporadic zoonotic infections in humans across the Arabian Peninsula, occasional importations and associated clusters in other regions, and outbreaks of nonsustained human-to-human transmission in health care settings. Dromedary camels are considered to be the most likely source of animal-to-human transmission. MERS-CoV enters host cells after binding the dipeptidyl peptidase 4 (DPP-4) receptor and the carcinoembryonic antigen–related cell-adhesion molecule 5 (CEACAM5) cofactor ligand, and it replicates efficiently in the human respiratory epithelium. Illness begins after an incubation period of 2 to 14 days and frequently results in hypoxemic respiratory failure and the need for multiorgan support. However, asymptomatic and mild cases also occur. Real-time reverse-transcription–polymerase-chain-reaction (RT-PCR) testing of respiratory secretions is the mainstay for diagnosis, and samples from the lower respiratory tract have the greatest yield among seriously ill patients. There is no antiviral therapy of proven efficacy, and thus treatment remains largely supportive; potential vaccines are at an early developmental stage. There are multiple gaps in knowledge regarding the evolution and transmission of the virus, disease pathogenesis, treatment, and prospects for a vaccine. The ongoing occurrence of MERS in humans and the associated high mortality call for a continued collaborative approach toward gaining a better understanding of the infection both in humans and in animals.MERS-CoV was first identified in September 2012 in a patient from Saudi Arabia who had hypoxemic respiratory failure and multiorgan illness. Subsequent cases have included infections in humans across the Arabian Peninsula, occasional importations and associated clusters in other regions, and outbreaks of nonsustained human-to-human transmission in health care settings (Fig. 1).
441 citations
TL;DR: High NLR is associated with an adverse OS and DFS in patients with breast cancer with a greater effect on disease-specific outcome in ER and HER2-negative disease and its addition to established risk prediction models warrants further investigation.
Abstract: The presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in several malignancies. Here, we quantify the effect of NLR on survival in patients with breast cancer, and examine the effect of clinicopathologic factors on its prognostic value. A systematic search of electronic databases was conducted to identify publications exploring the association of blood NLR (measured pre treatment) and overall survival (OS) and disease-free survival (DFS) among patients with breast cancer. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance. Meta-regression was performed to evaluate the influence of clinicopathologic factors such as age, disease stage, tumor grade, nodal involvement, receptor status, and NLR cutoff on the HR for OS and DFS. All statistical tests were two-sided. Fifteen studies comprising a total of 8563 patients were included. The studies used different cutoff values to classify high NLR (range 1.9–5.0). The median cutoff value for high NLR used in these studies was 3.0 amongst 13 studies reporting a HR for OS, and 2.5 in 10 studies reporting DFS outcomes. NLR greater than the cutoff value was associated with worse OS (HR 2.56, 95% CI = 1.96–3.35; P < 0.001) and DFS (HR 1.74, 95% CI = 1.47–2.07; P < 0.001). This association was similar in studies including only early-stage disease and those comprising patients with both early-stage and metastatic disease. Estrogen receptor (ER) and HER-2 appeared to modify the effect of NLR on DFS, because NLR had greater prognostic value for DFS in ER-negative and HER2-negative breast cancer. No subgroup showed an influence on the association between NLR and OS. High NLR is associated with an adverse OS and DFS in patients with breast cancer with a greater effect on disease-specific outcome in ER and HER2-negative disease. NLR is an easily accessible prognostic marker, and its addition to established risk prediction models warrants further investigation.
421 citations
TL;DR: Increased wait time was associated with a greater risk of 30-day mortality and other complications and a wait time of 24 hours may represent a threshold defining higher risk.
Abstract: Importance Although wait times for hip fracture surgery have been linked to mortality and are being used as quality-of-care indicators worldwide, controversy exists about the duration of the wait that leads to complications. Objective To use population-based wait-time data to identify the optimal time window in which to conduct hip fracture surgery before the risk of complications increases. Design, Setting, and Participants Population-based, retrospective cohort study of adults undergoing hip fracture surgery between April 1, 2009, and March 31, 2014, at 72 hospitals in Ontario, Canada. Risk-adjusted restricted cubic splines modeled the probability of each complication according to wait time. The inflection point (in hours) when complications began to increase was used to define early and delayed surgery. To evaluate the robustness of this definition, outcomes among propensity-score matched early and delayed surgical patients were compared using percent absolute risk differences (RDs, with 95% CIs). Exposure Time elapsed from hospital arrival to surgery (in hours). Main Outcomes and Measures Mortality within 30 days. Secondary outcomes included a composite of mortality or other medical complications (myocardial infarction, deep vein thrombosis, pulmonary embolism, and pneumonia). Results Among 42 230 patients with hip fracture (mean [SD] age, 80.1 years [10.7], 70.5% women) who met study entry criteria, overall mortality at 30 days was 7.0%. The risk of complications increased when wait times were greater than 24 hours, irrespective of the complication considered. Compared with 13 731 propensity-score matched patients who received surgery earlier, 13 731 patients who received surgery after 24 hours had a significantly higher risk of 30-day mortality (898 [6.5%] vs 790 [5.8%]; % absolute RD, 0.79; 95% CI, 0.23-1.35) and the composite outcome (1680 [12.2%]) vs 1383 [10.1%]; % absolute RD, 2.16; 95% CI, 1.43-2.89). Conclusions and Relevance Among adults undergoing hip fracture surgery, increased wait time was associated with a greater risk of 30-day mortality and other complications. A wait time of 24 hours may represent a threshold defining higher risk.
414 citations
Lunenfeld-Tanenbaum Research Institute1, University of Toronto2, University of Calgary3, King's College London4, University of Cambridge5, Sunnybrook Research Institute6, Rabin Medical Center7, University of Southern California8, University of California, Santa Barbara9, University of Ottawa10, University of Western Ontario11, McMaster University12, Cambridge University Hospitals NHS Foundation Trust13, Nemours Foundation14, University Health Network15, University of East Anglia16, Mount Sinai Hospital, Toronto17, Hospital de Sant Pau18, Ottawa Hospital19, Norfolk and Norwich University Hospital20, Sunnybrook Health Sciences Centre21, Glasgow Royal Infirmary22, Université du Québec23, Queen's University24, Royal Victoria Infirmary25, Leeds Teaching Hospitals NHS Trust26, Edinburgh Royal Infirmary27, University of Southampton28, University College Hospital29, University of Manchester30, South Tees Hospitals NHS Trust31, Russells Hall Hospital32, Kingston General Hospital33, Royal University Hospital34, JDRF35
TL;DR: In this paper, the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes was examined in women with Type 1 diabetes and planning pregnancy.
TL;DR: It is hypothesized that circRNAs may bind, store, sort, and sequester proteins to particular subcellular locations, and act as dynamic scaffolding molecules that modulate protein-protein interactions.
Abstract: Circular RNAs have been identified as naturally occurring RNAs that are highly represented in the eukaryotic transcriptome. Although a large number of circRNAs have been reported, circRNA functions remain largely unknown. CircRNAs can function as miRNA sponges, thereby reducing their ability to target mRNAs. We hypothesize that circRNAs may bind, store, sort, and sequester proteins to particular subcellular locations, and act as dynamic scaffolding molecules that modulate protein-protein interactions. Here, we review the biological implication and function of circRNA-protein interaction, and reveal a dynamic model of the interaction in various tissues, development stages and physiological conditions. Improved techniques to identify and characterize the dynamic RNA-protein interactions may elucidate the molecular mechanisms associated with the expression and functional diversity of circRNAs.
TL;DR: Prone positioning is likely to reduce mortality among patients with severe ARDS when applied for at least 12 hours daily, and was associated with higher rates of endotracheal tube obstruction and pressure sores.
Abstract: Rationale: The application of prone positioning for acute respiratory distress syndrome (ARDS) has evolved, with recent trials focusing on patients with more severe ARDS, and applying prone ventilation for more prolonged periods.Objectives: This review evaluates the effect of prone positioning on 28-day mortality (primary outcome) compared with conventional mechanical ventilation in the supine position for adults with ARDS.Methods: We updated the literature search from a systematic review published in 2010, searching MEDLINE, EMBASE, and CENTRAL (through to August 2016). We included randomized, controlled trials (RCTs) comparing prone to supine positioning in mechanically ventilated adults with ARDS, and conducted sensitivity analyses to explore the effects of duration of prone ventilation, concurrent lung-protective ventilation and ARDS severity. Secondary outcomes included PaO2/FiO2 ratio on Day 4 and an evaluation of adverse events. Meta-analyses used random effects models. Methodologic quality of the ...
TL;DR: After accounting for patient, surgeon, and hospital characteristics, patients treated by female surgeons had a small but statistically significant decrease in 30 day mortality and similar surgical outcomes (length of stay, complications, and readmission), compared with those treated by male surgeons.
Abstract: Objective To examine the effect of surgeon sex on postoperative outcomes of patients undergoing common surgical procedures. Design Population based, retrospective, matched cohort study from 2007 to 2015. Setting Population based cohort of all patients treated in Ontario, Canada. Participants Patients undergoing one of 25 surgical procedures performed by a female surgeon were matched by patient age, patient sex, comorbidity, surgeon volume, surgeon age, and hospital to patients undergoing the same operation by a male surgeon. Interventions Sex of treating surgeon. Main outcome measure The primary outcome was a composite of death, readmission, and complications. We compared outcomes between groups using generalised estimating equations. Results 104 630 patients were treated by 3314 surgeons, 774 female and 2540 male. Before matching, patients treated by female doctors were more likely to be female and younger but had similar comorbidity, income, rurality, and year of surgery. After matching, the groups were comparable. Fewer patients treated by female surgeons died, were readmitted to hospital, or had complications within 30 days (5810 of 52 315, 11.1%, 95% confidence interval 10.9% to 11.4%) than those treated by male surgeons (6046 of 52 315, 11.6%, 11.3% to 11.8%; adjusted odds ratio 0.96, 0.92 to 0.99, P=0.02). Patients treated by female surgeons were less likely to die within 30 days (adjusted odds ratio 0.88; 0.79 to 0.99, P=0.04), but there was no significant difference in readmissions or complications. Stratified analyses by patient, physician, and hospital characteristics did not significant modify the effect of surgeon sex on outcome. A retrospective analysis showed no difference in outcomes by surgeon sex in patients who had emergency surgery, where patients do not usually choose their surgeon. Conclusions After accounting for patient, surgeon, and hospital characteristics, patients treated by female surgeons had a small but statistically significant decrease in 30 day mortality and similar surgical outcomes (length of stay, complications, and readmission), compared with those treated by male surgeons. These findings support the need for further examination of the surgical outcomes and mechanisms related to physicians and the underlying processes and patterns of care to improve mortality, complications, and readmissions for all patients.
St. Michael's Hospital1, Queen's University2, Sunnybrook Health Sciences Centre3, Guy's and St Thomas' NHS Foundation Trust4, California Pacific Medical Center5, Johns Hopkins University School of Medicine6, Katholieke Universiteit Leuven7, University of Genoa8, Université libre de Bruxelles9, Houston Methodist Hospital10
TL;DR: A scoping review of the peer‐reviewed and gray literature was undertaken to assemble existing models for ICU stratification and present a proposed definition and classification of ICUs.
TL;DR: In this review, the key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence that support the rationale for the use of S GLT2 inhibitor in patients with HF who have T2D are summarized and a detailed overview and summary of ongoing cardiovascular outcome trials with SGLt2 inhibitors are provided.
Abstract: Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of patients with HF. The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes mellitus (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor. The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) subsequently reported a reduction in 3-point major adverse cardiovascular events and HF hospitalization risk. Although SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, and decreases in blood pressure, arterial stiffness, and afterload as well, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients who have HF with and without T2D. Accordingly, in this review, we summarize the key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence that support the rationale for the use of SGLT2 inhibitors in patients with HF who have T2D. Because these favorable effects presumably occur independent of blood glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.
The George Institute for Global Health1, Peking University2, Sunnybrook Health Sciences Centre3, University of Oxford4, University of British Columbia5, University Health Network6, University of California, Los Angeles7, University College London8, Johns Hopkins University9, University of Hong Kong10, University of Queensland11, Charles Darwin University12, University of Leicester13, RWTH Aachen University14, Mario Negri Institute for Pharmacological Research15, Indiana University16
TL;DR: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study as discussed by the authors was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1).
Abstract: Importance Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. Objective To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. Design, Setting, and Participants The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m 2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. Interventions Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. Main Outcomes and Measures The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. Results After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m 2 ; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group ( P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P P = .02). Conclusions and Relevance Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. Trial Registration clinicaltrials.gov Identifier:NCT01560052
TL;DR: It is suggested that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment and inversely correlated with mean MMSE scores.
Abstract: Objectives Increasing evidence suggests that inflammation is involved in Alzheimer’s disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC). Methods Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type. Results A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1β, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores. Conclusions These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers.
TL;DR: It is concluded that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT.
Abstract: As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio-protective role in cardiovascular disease. Here we describe a circular RNA, circ-Amotl1 that is highly expressed in neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to AKT1 phosphorylation and nuclear translocation. In primary cardiomyocytes, epithelial cells, and endothelial cells, we found that forced circ-Amotl1 expression increased the nuclear fraction of pAKT. We further detected increased nuclear pAKT in circ-Amotl1-treated hearts. In vivo, circ-Amotl1 expression was also found to be protective against Doxorubicin (Dox)-induced cardiomyopathy. Putative PDK1- and AKT1-binding sites were then identified in silico. Blocking oligonucleotides could reverse the effects of exogenous circ-Amotl1. We conclude that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT.
TL;DR: The main limitations to promoting exercise through the patient-clinician interaction are the inadequate quality and scope of existing evidence, incomplete understanding of the mechanisms underlying the beneficial effects of exercise in people with multiple sclerosis, and the absence of a conceptual framework and toolkit for translating the evidence into practice.
Abstract: Summary Exercise can be a beneficial rehabilitation strategy for people with multiple sclerosis to manage symptoms, restore function, optimise quality of life, promote wellness, and boost participation in activities of daily living. However, this population typically engages in low levels of health-promoting physical activity compared with adults from the general population, a fact which has not changed in the past 25 years despite growing evidence of the benefits of exercise. To overcome this challenge, the main limitations to promoting exercise through the patient–clinician interaction must be addressed. These limitations are the inadequate quality and scope of existing evidence, incomplete understanding of the mechanisms underlying the beneficial effects of exercise in people with multiple sclerosis, and the absence of a conceptual framework and toolkit for translating the evidence into practice. Future research to address those limitations will be essential to inform decisions about the inclusion of exercise in the clinical care of people with multiple sclerosis.
TL;DR: In this large cohort, exposure to air pollution, even at the relative low levels, was associated with higher dementia incidence, and associations were robust to all sensitivity analyses examined.
TL;DR: The surprise question performs poorly to modestly as a predictive tool for death, with worse performance in noncancer illness, and further studies are needed to develop accurate tools for patients with palliative care needs.
Abstract: BACKGROUND: The surprise question — “Would I be surprised if this patient died in the next 12 months?” — has been used to identify patients at high risk of death who might benefit from palliative care services. Our objective was to systematically review the performance characteristics of the surprise question in predicting death. METHODS: We searched multiple electronic databases from inception to 2016 to identify studies that prospectively screened patients with the surprise question and reported on death at 6 to 18 months. We constructed models of hierarchical summary receiver operating characteristics (sROCs) to determine prognostic performance. RESULTS: Sixteen studies (17 cohorts, 11 621 patients) met the selection criteria. For the outcome of death at 6 to 18 months, the pooled prognostic characteristics were sensitivity 67.0% (95% confidence interval [CI] 55.7%–76.7%), specificity 80.2% (73.3%–85.6%), positive likelihood ratio 3.4 (95% CI 2.8–4.1), negative likelihood ratio 0.41 (95% CI 0.32–0.54), positive predictive value 37.1% (95% CI 30.2%–44.6%) and negative predictive value 93.1% (95% CI 91.0%–94.8%). The surprise question had worse discrimination in patients with noncancer illness (area under sROC curve 0.77 [95% CI 0.73–0.81]) than in patients with cancer (area under sROC curve 0.83 [95% CI 0.79–0.87; p = 0.02 for difference]). Most studies had a moderate to high risk of bias, often because they had a low or unknown participation rate or had missing data. INTERPRETATION: The surprise question performs poorly to modestly as a predictive tool for death, with worse performance in noncancer illness. Further studies are needed to develop accurate tools to identify patients with palliative care needs and to assess the surprise question for this purpose.
TL;DR: A novel function of circRNAs in tumorigenesis is revealed, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.
Abstract: Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1-transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142-fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm3 in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.
TL;DR: The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity, and no differences in the frequency of erectile dysfunction were observed.
Abstract: Purpose To report the genitourinary (GU) and gastrointestinal (GI) morbidity and erectile dysfunction in a randomized trial comparing 2 methods of dose escalation for high- and intermediate-risk prostate cancer. Methods and Materials ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) enrolled 398 men, median age 68 years, who were then randomized to either a standard arm that included 12 months of androgen deprivation therapy and pelvic irradiation to 46 Gy followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. At clinic visits, investigators recorded GU and GI morbidity and information on urinary continence, catheter use, and erectile function. Exclusion of 15 who received nonprotocol treatment and correction of 14 crossover events left 195 men who actually received a DE-EBRT boost and 188, an LDR-PB boost. Median follow-up was 6.5 years. Results The LDR-PB boost increased the risk of needing temporary catheterization and/or requiring incontinence pads. At 5 years the cumulative incidence of grade 3 GU events was 18.4% for LDR-PB, versus 5.2% for DE-EBRT ( P P =.058). The 5-year cumulative incidence of grade 3 GI events was 8.1% for LDR-PB, versus 3.2% for DE-EBRT ( P =.124). The 5-year prevalence of grade 3 GI toxicity was lower than the cumulative incidence for both arms (1.0% vs 2.2%, respectively). Among men reporting adequate baseline erections, 45% of LDR-PB patients reported similar erectile function at 5 years, versus 37% after DE-EBRT ( P =.30). Conclusions The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity. No differences in the frequency of erectile dysfunction were observed.
Roy J. and Lucille A. Carver College of Medicine1, Emory University2, University of Pennsylvania3, Memorial Sloan Kettering Cancer Center4, LSU Health Sciences Center New Orleans5, Sunnybrook Health Sciences Centre6, Icahn School of Medicine at Mount Sinai7, University of South Florida8, University of California, San Francisco9, Oregon Health & Science University10
TL;DR: A consensus conference was held assembling experts in the field to review and discuss the available literature and patterns of practice pertaining to specific management issues regarding the management of small bowel neuroendocrine tumors.
Abstract: Small bowel neuroendocrine tumors (SBNETs) have been increasing in frequency over the past decades, and are now the most common type of small bowel tumor. Consequently, general surgeons and surgical oncologists are seeing more patients with SBNETs in their practices than ever before. The management of these patients is often complex, owing to their secretion of hormones, frequent presentation with advanced disease, and difficulties with making the diagnosis of SBNETs. Despite these issues, even patients with advanced disease can have long-term survival. There are a number of scenarios which commonly arise in SBNET patients where it is difficult to determine the optimal management from the published data. To address these challenges for clinicians, a consensus conference was held assembling experts in the field to review and discuss the available literature and patterns of practice pertaining to specific management issues. This paper summarizes the important elements from these studies and the recommendations of the group for these questions regarding the management of SBNET patients.
University of New Mexico1, Washington University in St. Louis2, University of Aberdeen3, University of the District of Columbia4, George Washington University5, Oswaldo Cruz Foundation6, Silver Spring Networks7, Medical University of South Carolina8, Brunel University London9, Centre national de la recherche scientifique10, Oregon State University11, University of Wisconsin-Madison12, Carleton University13, Iowa State University14, Harvard University15, Sunnybrook Health Sciences Centre16, University of Utah17, New Mexico State University18, Aberystwyth University19, European Bioinformatics Institute20, IFREMER21, University of the Sunshine Coast22, Peter MacCallum Cancer Centre23, Walter and Eliza Hall Institute of Medical Research24, University of Notre Dame25, University of Copenhagen Faculty of Science26, National Institutes of Health27, Bowling Green State University28, University of Alberta29, Lawrence University30, University of Göttingen31, Pennsylvania State University32, VU University Amsterdam33, Whitney Laboratory for Marine Bioscience34, Kingston University35, QIMR Berghofer Medical Research Institute36, Kenya Medical Research Institute37, University of Pennsylvania38, Lawrence Berkeley National Laboratory39, University of California, Santa Cruz40, American Museum of Natural History41, University of Westminster42, Rutherford Appleton Laboratory43, London Centre for Nanotechnology44
TL;DR: Parts of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata are described and several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis are identified.
Abstract: Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B glabrata in the field and may define this species as a suitable snail host for S mansoni We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis
TL;DR: Cardiovascular death is an important competing risk for older women with early-stage breast cancer and mandates adequate attention to cardiovascular preventive therapy after diagnosis of breast cancer.
Abstract: Importance There is increasing interest in the effect of cardiovascular disease on cancer survivors. However, there are limited contemporary population-based data on the risk of cardiovascular death after early-stage breast cancer. Objective To describe the incidence of cardiovascular death in a contemporary population of women with early-stage breast cancer while accounting for competing risks. Design, Setting, and Participants A population-based cohort study was conducted among 98 999 women diagnosed with early-stage breast cancer between April 1, 1998, and March 31, 2012. Patients were followed up until death or were censored on December 31, 2013. Baseline characteristics were determined from administrative databases and the Ontario Cancer registry. Vital statistics data were used to determine the cause of death. Cumulative incidence functions were used to estimate the incidence of cause-specific mortality. We studied the association between baseline characteristics and rates of cardiovascular death using cause-specific hazard functions. The analyses accounted for competing risks of noncardiovascular death. Statistical analysis was performed from July 16, 2015, to August 4, 2016. Exposures Early-stage breast cancer, age, cardiovascular disease, hypertension, and diabetes. Main Outcomes and Measures Cause of death, which was classified as breast cancer, cardiovascular disease, other cancers, or other noncancer causes. Results Of the 98 999 women (median age, 60 years [interquartile range, 50-71 years]) in the study, 21 123 (21.3%) died during follow-up. The median time to death was 4.2 years (IQR, 2.2-7.1 years). Breast cancer was the most common cause of death (10 550 deaths [49.9%]); 3444 deaths [16.3%] were from cardiovascular causes. Cardiovascular death was infrequent in women younger than 66 years without prior cardiovascular disease, diabetes, or hypertension. Among women 66 years or older, the risks of breast cancer death and cardiovascular death at 10 years were 11.9% (95% CI, 11.6%-12.3%) and 7.6% (95% CI, 7.3%-7.9%), respectively. Among patients with prior cardiovascular disease, the risk of death from breast cancer and cardiovascular disease were equivalent for the first 5 years, after which death from cardiovascular causes was more frequent (10-year cumulative incidence, 14.6% [95% CI, 13.7%-15.4%] for breast cancer vs 16.9% [95% CI, 16.0%-17.8%] for cardiovascular disease). For women 66 years or older who survived 5 years or more after diagnosis of breast cancer, cardiovascular disease exceeded breast cancer as the leading cause of death at 10 years after diagnosis, when the cumulative incidence of each was 5%. Conclusions and Relevance Cardiovascular death is an important competing risk for older women with early-stage breast cancer. This finding mandates adequate attention to cardiovascular preventive therapy after diagnosis of breast cancer.
TL;DR: A new nanoparticle-enabled method for CTC characterization, called magnetic ranking cytometry, is reported, which profiles CTCs on the basis of their surface expression phenotype, using a microfluidic chip that successfully processes whole blood samples.
Abstract: Profiling the heterogeneous phenotypes of rare circulating tumour cells (CTCs) in whole blood is critical to unravelling the complex and dynamic properties of these potential clinical markers. This task is challenging because these cells are present at parts per billion levels among normal blood cells. Here we report a new nanoparticle-enabled method for CTC characterization, called magnetic ranking cytometry, which profiles CTCs on the basis of their surface expression phenotype. We achieve this using a microfluidic chip that successfully processes whole blood samples. The approach classifies CTCs with single-cell resolution in accordance with their expression of phenotypic surface markers, which is read out using magnetic nanoparticles. We deploy this new technique to reveal the dynamic phenotypes of CTCs in unprocessed blood from mice as a function of tumour growth and aggressiveness. We also test magnetic ranking cytometry using blood samples collected from cancer patients.
Cedars-Sinai Medical Center1, University of Hamburg2, Ruhr University Bochum3, Vita-Salute San Raffaele University4, Technische Universität München5, University of Zurich6, Brighton and Sussex University Hospitals NHS Trust7, University of Texas Health Science Center at Houston8, University of Catania9, Leiden University Medical Center10, Valve Corporation11, Hospital General Universitario Gregorio Marañón12, Sunnybrook Health Sciences Centre13, St Thomas' Hospital14, university of lille15, Hospital Clínico San Carlos16, Martin Luther University of Halle-Wittenberg17, Erasmus University Rotterdam18, Scott & White Hospital19
TL;DR: TAVR using the new-generation devices was associated with improved procedural outcomes in treating patients with pure native AR, and significant post-procedural AR was independently associated with increased mortality.
TL;DR: This study assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy and the proportion of patients achieving haematocrit control at week 28.
Abstract: Summary Background In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. Methods RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients. Findings Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43–15·45]; p vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3–4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3–4 anaemia and three patients (4%) reported grade 3–4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3–4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. Interpretation RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population. Funding Novartis.