St. Joseph’s Healthcare Hamilton

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies. The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies. This contribution from The Cancer Genome Atlas (TCGA) project describes the molecular evaluation of 295 primary gastric adenocarcinomas. Based on the results, the authors propose a novel classification separating gastric cancers into four subtypes according to: Epstein–Barr virus positive status, microsatellite instability, chromosomal instability or genomic stability. Given the histologic and etiologic heterogeneity of gastric cancer identification of these subtypes, using a schema that can readily be applied to patient samples should help with patient stratification and trials of targeted therapies.

The factor structure, reliability, and validity of the Depression Anxiety Stress Scales (DASS; S. H. Lovibond & P. F. Lovibond, 1995) and the 21-item short form of these measures (DASS-21) were examined in nonclinical volunteers (n = 49) and patients with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) diagnoses of panic disorder (n = 67), obsessive-compulsive disorder (n = 54), social phobia (n = 74), specific phobia (n = 17), and major depressive disorder (n = 46). This study replicates previous findings indicating that the DASS distinguishes well between features of depression, physical arousal, and psychological tension and agitation and extends these observations to the DASS-21. In addition, the internal consistency and concurrent validity of the DASS and DASS-21 were in the acceptable to excellent ranges. Mean scores for the various groups were similar to those in previous research, and in the expected direction. The implications of these findings are discussed.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and is spread person-to-person through close contact. We aimed to investigate the effects of physical distance, face masks, and eye protection on virus transmission in health-care and non-health-care (eg, community) settings. METHODS: We did a systematic review and meta-analysis to investigate the optimum distance for avoiding person-to-person virus transmission and to assess the use of face masks and eye protection to prevent transmission of viruses. We obtained data for SARS-CoV-2 and the betacoronaviruses that cause severe acute respiratory syndrome, and Middle East respiratory syndrome from 21 standard WHO-specific and COVID-19-specific sources. We searched these data sources from database inception to May 3, 2020, with no restriction by language, for comparative studies and for contextual factors of acceptability, feasibility, resource use, and equity. We screened records, extracted data, and assessed risk of bias in duplicate. We did frequentist and Bayesian meta-analyses and random-effects meta-regressions. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. This study is registered with PROSPERO, CRD42020177047. FINDINGS: =0·090; posterior probability >95%, low certainty). Eye protection also was associated with less infection (n=3713; aOR 0·22, 95% CI 0·12 to 0·39, RD -10·6%, 95% CI -12·5 to -7·7; low certainty). Unadjusted studies and subgroup and sensitivity analyses showed similar findings. INTERPRETATION: The findings of this systematic review and meta-analysis support physical distancing of 1 m or more and provide quantitative estimates for models and contact tracing to inform policy. Optimum use of face masks, respirators, and eye protection in public and health-care settings should be informed by these findings and contextual factors. Robust randomised trials are needed to better inform the evidence for these interventions, but this systematic appraisal of currently best available evidence might inform interim guidance. FUNDING: World Health Organization.

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format.

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities. This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far. This study of 131 high-grade muscle-invasive urothelial bladder carcinomas, part of The Cancer Genome Atlas (TCGA) project, reports recurrent mutations in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date. Recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of viruses associated with gene inactivation are also identified. Importantly, potential therapeutic targets are identified in 69% of the tumours.

BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).

BACKGROUND: Risedronate increases bone mineral density in elderly women, but whether it prevents hip fracture is not known. METHODS: We studied 5445 women 70 to 79 years old who had osteoporosis (indicated by a T score for bone mineral density at the femoral neck that was more than 4 SD below the mean peak value in young adults [-4] or lower than -3 plus a nonskeletal risk factor for hip fracture, such as poor gait or a propensity to fall) and 3886 women at least 80 years old who had at least one nonskeletal risk factor for hip fracture or low bone mineral density at the femoral neck (T score, lower than -4 or lower than -3 plus a hip-axis length of 11.1 cm or greater). The women were randomly assigned to receive treatment with oral risedronate (2.5 or 5.0 mg daily) or placebo for three years. The primary end point was the occurrence of hip fracture. RESULTS: Overall, the incidence of hip fracture among all the women assigned to risedronate was 2.8 percent, as compared with 3.9 percent among those assigned to placebo (relative risk, 0.7; 95 percent confidence interval, 0.6 to 0.9; P=0.02). In the group of women with osteoporosis (those 70 to 79 years old), the incidence of hip fracture among those assigned to risedronate was 1.9 percent, as compared with 3.2 percent among those assigned to placebo (relative risk, 0.6; 95 percent confidence interval, 0.4 to 0.9; P=0.009). In the group of women selected primarily on the basis of nonskeletal risk factors (those at least 80 years of age), the incidence of hip fracture was 4.2 percent among those assigned to risedronate and 5.1 percent among those assigned to placebo (P=0.35). CONCLUSIONS: Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density.

An easy and safe dose-response histamine-inhalation test is described, to measure the level of non-specific bronchial reactivity. The test was performed in 307 subject. Non-specific bronchial reactivity was increased in 3% of presumed normal subjects, in 100% of active asthmatics and in 69% of asymptomatic asthmatics with previous symptoms only at times of exposure to clinically relevant allergens. It was also increased in 47% of patients with cough and no other chest symptoms, in 40% of patients with rhinitis and vague chest symptoms not by themselves diagnostic of asthma, and in 22% of patients with rhinitis and no chest symptoms. The patients with asthma were studied when their asthma was well controlled and when their minimum drug requirements had been established. The mean level of bronchial reactivity increased with increasing minimum drug requirements. The level of bronchial reactivity also showed a strong negative correlation with the forced expiratory volume in 1 sec (FEV1). Atopic subjects, with or without asthma, showed a significant positive correlation between the level of bronchial reactivity and atopic status as indicated by the number of positive allergy skin tests.

BACKGROUND: The outcome of childhood asthma in adults has been described in high-risk cohorts, but few population-based studies have reported the risk factors for persistence and relapse. METHODS: We assessed children born from April 1972 through March 1973 in Dunedin, New Zealand, repeatedly from 9 to 26 years of age with questionnaires, pulmonary-function tests, bronchial-challenge testing, and allergy testing. RESULTS: By the age of 26 years, 51.4 percent of 613 study members with complete respiratory data had reported wheezing at more than one assessment. Eighty-nine study members (14.5 percent) had wheezing that persisted from childhood to 26 years of age, whereas 168 (27.4 percent) had remission, but 76 (12.4 percent) subsequently relapsed by the age of 26. Sensitization to house dust mites predicted the persistence of wheezing (odds ratio, 2.41; P=0.001) and relapse (odds ratio, 2.18; P=0.01), as did airway hyperresponsiveness (odds ratio for persistence, 3.00; P<0.001; odds ratio for relapse, 3.03; P<0.001). Female sex predicted the persistence of wheezing (odds ratio, 1.71; P=0.03), as did smoking at the age of 21 years (odds ratio, 1.84; P=0.01). The earlier the age at onset, the greater the risk of relapse (odds ratio, 0.89 per year of increase in the age at onset; P<0.001). Pulmonary function was consistently lower in those with persistent wheezing than in those without persistent wheezing. CONCLUSIONS: In an unselected birth cohort, more than one in four children had wheezing that persisted from childhood to adulthood or that relapsed after remission. The factors predicting persistence or relapse were sensitization to house dust mites, airway hyperresponsiveness, female sex, smoking, and early age at onset. These findings, together with persistently low lung function, suggest that outcomes in adult asthma may be determined primarily in early childhood.

BACKGROUND: There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS: We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. KEY RESULTS: Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. CONCLUSIONS & INFERENCES: We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.

BACKGROUND: Eosinophilic inflammation, which may be a consequence of interleukin-5 action, is a characteristic feature of some forms of asthma. However, in three previous clinical trials involving patients with asthma, blockade of this cytokine did not result in a significant improvement in outcomes. We studied the prednisone-sparing effect of mepolizumab, a monoclonal antibody against interleukin-5, in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone. Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood, symptoms, and airflow limitation. METHODS: In this randomized, double-blind, parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment, we assigned 9 patients to receive mepolizumab (administered in five monthly infusions of 750 mg each) and 11 patients to receive placebo. RESULTS: There were 12 asthma exacerbations in 10 patients who received placebo, 9 of whom had sputum eosinophilia at the time of exacerbation. In comparison, only one patient who received mepolizumab had an asthma exacerbation, and this episode was not associated with sputum eosinophilia (P=0.002). Patients who received mepolizumab were able to reduce their prednisone dose by a mean (+/-SD) of 83.8+/-33.4% of their maximum possible dose, as compared with 47.7+/-40.5% in the placebo group (P=0.04). The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils. Improvements in eosinophil numbers, asthma control, and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion. There were no serious adverse events. CONCLUSIONS: Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment. (ClinicalTrials.gov number, NCT00292877.)

The label 'chronic fatigue syndrome' (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term 'myalgic encephalomyelitis' (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization's International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.

BACKGROUND: Warfarin is a highly efficacious oral anticoagulant, but its use is limited by a well-founded fear of bleeding. Drug and food interactions are frequently cited as causes of adverse events with warfarin. We provide an updated systematic overview of the quality, clinical effect, and importance of these reported interactions. DATA SOURCES: MEDLINE, TOXLINE, IPA, and EMBASE databases from October 1993 to March 2004. Database searches combined the keyword warfarin with drug interactions, herbal medicines, Chinese herbal drugs, and food-drug interactions. STUDY SELECTION: Eligible articles contained original reports of warfarin drug or food interactions in human subjects. Non-English articles were included if sufficient information could be abstracted. DATA EXTRACTION: Reports were rated independently by 2 investigators for interaction direction, clinical severity, and quality of evidence. Quality of evidence was based on previously validated causation criteria and study design. DATA SYNTHESIS: Of 642 citations retrieved, 181 eligible articles contained original reports on 120 drugs or foods. Inter-rater agreement was excellent, with weighted kappa values of 0.84 to 1.00. Of all reports, 72% described a potentiation of warfarin's effect and 84% were of poor quality, 86% of which were single case reports. The 31 incidents of clinically significant bleeding were all single case reports. Newly reported interactions included celecoxib, rofecoxib, and herbal substances, such as green tea and danshen. CONCLUSIONS: The number of drugs reported to interact with warfarin continues to expand. While most reports are of poor quality and present potentially misleading conclusions, the consistency of reports of interactions with azole antibiotics, macrolides, quinolones, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, selective serotonin reuptake inhibitors, omeprazole, lipid-lowering agents, amiodarone, and fluorouracil, suggests that coadministration with warfarin should be avoided or closely monitored. More systematic study of warfarin drug interactions in patients is urgently needed.

BACKGROUND: It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding. METHODS: We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding. RESULTS: In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority). CONCLUSIONS: In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).

In Brief Purpose: Oncologic concerns from high wound recurrence rates prompted a multi-institutional randomized trial to test the hypothesis that disease-free and overall survival are equivalent, regardless of whether patients receive laparoscopic-assisted or open colectomy. Methods: Eight hundred seventy-two patients with curable colon cancer were randomly assigned to undergo laparoscopic-assisted or open colectomy at 1 of 48 institutions by 1 of 66 credentialed surgeons. Patients were followed for 8 years, with 5-year data on 90% of patients. The primary end point was time to recurrence, tested using a noninferiority trial design. Secondary endpoints included overall survival and disease-free survival. (Kaplan–Meier) Results: As of March 1, 2007, 170 patients have recurred and 252 have died. Patients have been followed a median of 7 years (range 5–10 years). Disease-free 5-year survival (Open 68.4%, Laparoscopic 69.2%, P = 0.94) and overall 5-year survival (Open 74.6%, Laparoscopic 76.4%, P = 0.93) are similar for the 2 groups. Overall recurrence rates were similar for the 2 groups (Open 21.8%, Laparoscopic 19.4%, P = 0.25). These recurrences were distributed similarly between the 2 treatment groups. Sites of first recurrence were distributed similarly between the treatment arms (Open: wound 0.5%, liver 5.8%, lung 4.6%, other 8.4%; Laparoscopic: wound 0.9%, liver 5.5%, lung 4.6%, other 6.1%). Conclusion: Laparoscopic colectomy for curable colon cancer is not inferior to open surgery based on long-term oncologic endpoints from a prospective randomized trial. A multicenter prospective trial of 872 patients randomly assigned to undergo laparoscopic or open colectomy for curable cancer was performed. Laparoscopic colectomy for curable colon cancer is not inferior to open surgery based on 5-year overall survival, disease-free survival, and overall and site-specific rates of recurrence.

To formulate a parsimonious tool to assess empathy, we used factor analysis on a combination of self-report measures to examine consensus and developed a brief self-report measure of this common factor. The Toronto Empathy Questionnaire (TEQ) represents empathy as a primarily emotional process. In 3 studies, the TEQ demonstrated strong convergent validity, correlating positively with behavioral measures of social decoding, self-report measures of empathy, and negatively with a measure of Autism symptomatology. Moreover, it exhibited good internal consistency and high test-retest reliability. The TEQ is a brief, reliable, and valid instrument for the assessment of empathy.

BACKGROUND: Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. METHODS: In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed. RESULTS: ), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group. CONCLUSIONS: . (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).

OBJECTIVES: To evaluate and summarize the evidence of muscle weakness as a risk factor for falls in older adults. DESIGN: Random-effects meta-analysis. SETTING: English-language studies indexed in MEDLINE and CINAHL (1985-2002) under the key words aged and accidental falls and risk factors; bibliographies of retrieved papers. PARTICIPANTS: Fifty percent or more subjects in a study were aged 65 and older. Studies of institutionalized and community-dwelling subjects were included. MEASUREMENTS: Prospective cohort studies that included measurement of muscle strength at inception (in isolation or with other factors) with follow-up for occurrence of falls. METHODS: Sample size, population, setting, measure of muscle strength, and length of follow-up, raw data if no risk estimate, odds ratios (ORs), rate ratios, or incidence density ratios. Each study was assessed using the validity criteria: adjustment for confounders, objective definition of fall outcome, reliable method of measuring muscle strength, and blinded outcome measurement. RESULTS: Thirty studies met the selection criteria; data were available from 13. For lower extremity weakness, the combined OR was 1.76 (95% confidence interval (CI)=1.31-2.37) for any fall and 3.06 (95% CI=1.86-5.04) for recurrent falls. For upper extremity weakness the combined OR was 1.53 (95% CI=1.01-2.32) for any fall and 1.41 (95% CI=1.25-1.59) for recurrent falls. CONCLUSION: Muscle strength (especially lower extremity) should be one of the factors that is assessed and treated in older adults at risk for falls. More clinical trials are needed to isolate whether muscle-strengthening exercises are effective in preventing falls.

BACKGROUND: Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations--such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers--on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials. DISCUSSION: In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials. SUMMARY: When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.