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Background: The transition from surgical residency to independent practice is a challenging period that has not been well studied. Methods: An email invitation to complete a 55-item survey and the Maslach Burnout Inventory–Human Services Survey (MBI-HSS) was sent to early career general surgeons across Canada. The chi-square test or Fisher’s exact test was used to compare demographic and survey characteristics with burnout. Multivariable logistic regression was performed. Results: Of the 586 surgeons contacted, 88 responded (15%); 51/88 surgeons (58.0%) were classified as burnt out according to the MBI-HSS. Most surgeons (68.2%) were not confident in their abilities to handle the business aspect of practice. The majority (60.2%) believed that a transition to independent practice program would be beneficial to recent surgical graduates. Conclusions: Our data showed high prevalence of burnout among recently graduated general surgeons across Canada. Further, respondents were not confident in their managerial and administrative skills required to run a successful independent practice.

Objective: To estimate the bias associated with specific nonrandomized study attributes among studies comparing transcatheter aortic valve implantation with surgical aortic valve replacement for the treatment of severe aortic stenosis.Data sources and study selection: We searched 7 databases from inception to June 2017: Medline, Medline In-Process/ePubs, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and Web of Science. We included all RCTs and nonrandomized studies that reported outcomes of interest.Data extraction and synthesis: We categorized studies according to study design, and evaluated 41 nonrandomized study attributes as potential sources of bias. We calculated odds ratios (OR) and other effect measures with 95% confidence intervals (CI) using random effects models.Main outcomes: One month postoperative mortality, and length of stay. Bias was defined as the difference in estimates of treatment effects between nonrandomized studies and high quality (low risk of bias) RCTs, which were considered to provide “gold standard” estimates.Results: We included 6 RCTs and 87 nonrandomized studies. Surgical risk scores were similar for comparison groups in RCTs, but were higher for patients having transcatheter aortic valve implantation in nonrandomized studies. Nonrandomized studies underestimated the benefit of transcatheter aortic valve implantation compared with RCTs. For example, nonrandomized studies without adjustment estimated a higher risk of postoperative mortality for transcatheter aortic valve implantation compared with surgical aortic valve replacement (OR 1.43 [95% CI, 1.26 to 1.62]) than high quality RCTs (OR 0.78 [95% CI, 0.54 to 1.11). Nonrandomized studies using propensity score matching (OR 1.13 [95% CI, 0.85 to 1.52]) and regression modelling (OR 0.68 [95% CI, 0.57 to 0.81]) to adjust results estimated treatment effects closer to high quality RCTs. Nonrandomized studies describing losses to follow-up estimated treatment effects that were significantly closer to high quality RCT than nonrandomized studies that did not.Conclusion: Studies with different attributes produce different estimates of treatment effects. Study design attributes related to the completeness of follow-up may explain biased treatment estimates in nonrandomized studies, as in the case of aortic valve replacement where high-risk patients were preferentially selected for the newer (transcatheter) procedure.

Achalasia is a chronic, progressive, and incurable esophageal motility disease. There is clinical uncertainty about which treatment should be recommended as first-line therapy. Our objective was to evaluate the effectiveness of pneumatic dilation compared with laparoscopic Heller myotomy with partial fundoplication in improving achalasia-specific quality of life.This was a prospective, multicenter, randomized trial at five academic hospitals in Canada. Fifty previously untreated adults with a clinical diagnosis of primary achalasia, confirmed by manometric testing, were enrolled between November 2005 and March 2010, and followed for 5 years after treatment. Randomization was stratified by site, in random blocks of size four and with balanced allocation. Patients were treated with pneumatic dilation or laparoscopic Heller myotomy with partial fundoplication. The primary outcome was the difference between the treatments in the mean improvement of the achalasia severity questionnaire (ASQ) score at 1 year from baseline. Prespecified secondary outcomes included general and gastrointestinal quality of life, symptoms, esophageal physiology measures (lower esophageal sphincter relaxation and pressure, esophageal emptying, abnormal esophageal acid exposure), complications, and incidence of retreatment. Functional and imaging studies were performed blinded and all outcome assessors were blinded.There were no significant differences between treatments in the improvement of ASQ score at 1 year from baseline (27.5 points in the Heller myotomy arm vs. 20.2 points in the pneumatic dilation arm; difference 7.3 points, 95% confidence interval -4.7 to 19.3; P=0.23). There were no differences between treatments in improvement of symptoms, general and gastrointestinal quality of life, or measures of esophageal physiology. Improvements in ASQ score diminished over time for both interventions. At 5 years, there were no differences between treatments in improvement of ASQ score, symptoms, and general or gastrointestinal quality of life. There were no serious adverse events. No patient who received Heller myotomy required retreatment, whereas five patients treated initially with pneumatic dilation required retreatment.Treatment with pneumatic dilation or laparoscopic Heller myotomy similarly improves achalasia-specific disease severity at 1 year. Either of the therapeutic approaches can be used as first-line therapy for previously untreated adults with achalasia.

BACKGROUND Extraordinary technological advances and decreases in the cost of DNA sequencing have made the possibility of whole genome sequencing (WGS) as a highly accessible clinical test for numerous indications feasible. There have been many recent, successful applications of WGS in establishing the etiology of complex diseases and guiding therapeutic decision-making in neoplastic and nonneoplastic diseases and in various aspects of reproductive health. However, there are major, but not insurmountable, obstacles to the increased clinical implementation of WGS, such as hidden costs, issues surrounding sequencing and analysis, quality assurance and standardization protocols, ethical dilemmas, and difficulties with interpretation of the results. CONTENT The widespread use of WGS in routine clinical practice remains a distant proposition. Prospective trials will be needed to establish if, and for whom, the benefits of WGS will outweigh the likely substantial costs associated with follow-up tests, the risks of overdiagnosis and overtreatment, and the associated emotional distress. SUMMARY WGS should be carefully implemented in the clinic to allow the realization of its potential to improve patient health in specific indications. To minimize harm the use of WGS for all other reasons must be carefully evaluated before clinical implementation.

BACKGROUND By using proteomics and bioinformatics, we have previously identified a group of highly pancreas-specific proteins as candidate pancreatic ductal adenocarcinoma (PDAC) biomarkers. With the use of commercially available ELISAs, the performance of some of these candidates was initially evaluated in a relatively small serum cohort (n = 100 samples). This phase revealed that CUB and zona pellucida-like domains protein 1 (CUZD1) may represent a new, promising PDAC biomarker. METHODS We performed detailed experiments to investigate the specificity of the commercial CUZD1 ELISA assay. CUZD1 was expressed in house in both bacteria and yeast expression systems. Recombinant CUZD1 and biological samples containing CUZD1, as well as commercial CUZD1 ELISA standards, were analyzed by Western blot, size exclusion HPLC, and mass spectrometry (LC-MS Orbitrap). RESULTS We confirmed that instead of CUZD1, the commercial assay is recognizing a nonhomologous, known cancer antigen [cancer antigen 125 (CA125)]. CONCLUSIONS We conclude that poor characterization of commercial ELISA assays is a factor that could lead to false biomarker discovery. To our knowledge, this is the first report documenting that a commercial ELISA marketed for one analyte (CUZD1) may, in fact, recognize a different, nonhomologous antigen (CA125).

In pancreatic cancer, the incidence and mortality curves coincide. One major reason for this high mortality rate in pancreatic ductal adenocarcinoma (PDAC) patients is the dearth of effective diagnostic, prognostic, and disease-monitoring biomarkers. Unfortunately, existing tumor markers, as well as current imaging modalities, are not sufficiently sensitive and/or specific for early-stage diagnosis. There is, therefore, an urgent need for improved serum markers of the disease. Herein, we performed Orbitrap® mass spectrometry proteomic analysis of four PDAC tissues and their adjacent benign tissues and identified a total of 2190 nonredundant proteins. Sixteen promising candidates were selected for further scrutiny using a systematic scoring algorithm. Our preliminary serum verification of the top four candidates (DSP, LAMC2, GP73, and DSG2) in 20 patients diagnosed with pancreatic cancer and 20 with benign pancreatic cysts, showed a significant (p < 0.05) elevation of LAMC2 in pancreatic cancer serum. Extensive validation of LAMC2 in healthy, benign, and PDAC sera from geographically diverse cohorts (n = 425) (Japan, Europe, and USA) demonstrated a significant increase in levels in early-stage PDAC compared with benign diseases. The sensitivity of LAMC2 was comparable to CA19.9 in all data sets, with an AUC value greater than 0.85 in discriminating healthy patients from early-stage PDAC patients. LAMC2 exhibited diagnostic complementarity with CA19.9 by showing significant (p < 0.001 in two out of three cohorts) elevation in PDAC patients with clinically low CA19.9 levels.

Pancreatic cancer is a significant cause of cancer mortality. The high mortality rate of this disease is associated with the complete lack of early clinical symptoms. Moreover, existing tumor markers (e.g., CA19-9) are not sufficiently sensitive and/or specific to early differentiate benign from cancer patients, therefore there is an urgent need for improved serum markers that can improve both early diagnosis and therapeutic monitoring. In pursuit of novel candidate markers, several genomic, transcriptomic, and proteomic studies have been recently reported, however no specific tumor marker has been as yet identified that can outperform CA19-9. In an effort to capture the complex pathophysiology of this disease we employed an integrated biomarker discovery approach which combines: 1) in vitro cell line secretome analyses, 2) ex vivo proteomic analysis of pancreatic ascites and pancreatic juice; 3) quantitative pancreatic tissue proteomics; 4) in silico mining of tissue expression databases and 5) extensive microarray data mining. A systemic grading system was applied to our lists of identified markers and the top-ranked candidates were selected for further validation in larger cohorts. Herein, we present our first-step validation of the two most promising candidates, CUB and zona pellucida-like domain-containing protein 1 (CUZD1) and laminin subunit gamma-2 (LAMC2), using commercially available enzyme-linked immunosorbent assays (ELISAs) in 150 serum samples including: 50 pancreatic ductal adenocarcinoma patients (PDAC), 50 patients with benign diseases and 50 healthy individuals. Statistical analysis indicated that CUZD1 and LAMC2 were significantly elevated in PDAC versus healthy controls and also significantly increased in PDAC versus benign diseases (p

Background There is an important need for the identification of novel serological biomarkers for the early detection of cancer. Current biomarkers suffer from a lack of tissue specificity, rendering them vulnerable to non-disease-specific increases. The present study details a strategy to rapidly identify tissue-specific proteins using bioinformatics. Methods Previous studies have focused on either gene or protein expression databases for the identification of candidates. We developed a strategy that mines six publicly available gene and protein databases for tissue-specific proteins, selects proteins likely to enter the circulation, and integrates proteomic datasets enriched for the cancer secretome to prioritize candidates for further verification and validation studies. Results Using colon, lung, pancreatic and prostate cancer as case examples, we identified 48 candidate tissue-specific biomarkers, of which 14 have been previously studied as biomarkers of cancer or benign disease. Twenty-six candidate biomarkers for these four cancer types are proposed. Conclusions We present a novel strategy using bioinformatics to identify tissue-specific proteins that are potential cancer serum biomarkers. Investigation of the 26 candidates in disease states of the organs is warranted.