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Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses—termed the Burden of Proof studies—designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk–outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk–outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk–outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study.

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Background: Minimally invasive surgical techniques pose alternatives to conventional surgery for the treatment of aortic stenosis (AS). We present a Bayesian network analysis comparing Valve Academic Research Consortium-2 clinical outcomes between transcatheter aortic valve implantation (TAVI), sutureless (SL-AVR) and conventional aortic valve replacement (CAVR). Methods: Electronic searches of databases were conducted and seven two-arm randomized-controlled trials and 25 propensity-score-matched studies comparing clinical outcomes of TAVI, SL-AVR and CAVR for treatment of AS were identified. Bayesian Markov chain Monte Carlo modelling was used to analyze clinical outcomes. Results: The analysis included 16,432 patients who underwent TAVI [7,056], SL-AVR [1,238] or CAVR [8,138]. Compared to CAVR, TAVI and SL-AVR were associated with reduced postoperative major bleeding of 59% (OR 0.41, 95% CI: 0.28-0.59) and 44% (OR 0.56, 95% CI: 0.30-0.99) respectively. TAVI had a 41% reduction in postoperative myocardial infarction (OR 0.59, 95% CI: 0.40-0.86) and SL-AVR had a 40% reduction in postoperative acute kidney injury (AKI) (OR 0.62, 95% CI: 0.42-0.86). Compared to TAVI, CAVR and SL-AVR had a reduction in moderate/severe paravalvular regurgitation of 89% (OR 0.11, 95% CI: 0.07-0.16) and 92% (OR 0.08, 95% CI: 0.03-0.17). CAVR had a 67% decreased postoperative permanent pacemaker (PPM) implantation compared to TAVI (OR 0.33, 95% CI: 0.24-0.45) and a 63% reduction compared to SL-AVR (OR 0.37, 95% CI: 0.22-0.61). There were no differences in 30-day mortality or postoperative stroke between the groups. Conclusions: In selected patients, minimally invasive surgical interventions including TAVI and SL-AVR for severe AS are viable alternatives to conventional surgery. However, TAVI is associated with increased paravalvular regurgitation, whereas TAVI and SL-AVR are associated with increased conduction disturbances compared to CAVR.

Despite advancements in medical therapy of Crohn’s disease (CD), majority of patients with CD will eventually require surgical intervention, with at least a third of patients requiring multiple surgeries. It is important to understand the role and timing of surgery, with the goals of therapy to reduce the need for surgery without increasing the odds of emergency surgery and its associated morbidity, as well as to limit surgical recurrence and avoid intestinal failure. The profile of CD patients requiring surgical intervention has changed over the decades with improvements in medical therapy with immunomodulators and biological agents. The most common indication for surgery is obstruction from stricturing disease, followed by abscesses and fistulae. The risk of gastrointestinal bleeding in CD is high but the likelihood of needing surgery for bleeding is low. Most major gastrointestinal bleeding episodes resolve spontaneously, albeit the risk of re-bleeding is high. The risk of colorectal cancer associated with CD is low. While current surgical guidelines recommend a total proctocolectomy for colorectal cancer associated with CD, subtotal colectomy or segmental colectomy with endoscopic surveillance may be a reasonable option. Approximately 20%-40% of CD patients will need perianal surgery during their lifetime. This review assesses the practice parameters and guidelines in the surgical management of CD, with a focus on the indications for surgery in CD (and when not to operate), and a critical evaluation of the timing and surgical options available to improve outcomes and reduce recurrence rates.

The human pathogens N. gonorrhoeae and N. meningitidis display robust intra-and interstrain glycan diversity associated with their O-linked protein glycosylation (pgl) systems. In an effort to better understand the evolution and function of protein glycosylation operating there, we aimed to determine if other human-restricted, Neisseria species similarly glycosylate proteins and if so, to assess the levels of glycoform diversity. Comparative genomics revealed the conservation of a subset of genes minimally required for O-linked protein glycosylation glycan and established those pgl genes as core genome constituents of the genus. In conjunction with mass spectrometric-based glycan phenotyping, we found that extant glycoform repertoires in N. gonorrhoeae, N. meningitidis and the closely related species N. polysaccharea and N. lactamica reflect the functional replacement of a progenitor glycan biosynthetic pathway. This replacement involved loss of pgl gene components of the primordial pathway coincident with the acquisition of two exogenous glycosyltransferase genes. Critical to this discovery was the identification of a ubiquitous but previously unrecognized glycosyltransferase gene (pglP) that has uniquely undergone parallel but independent pseudogenization in N. gonorrhoeae and N. meningitidis. We suggest that the pseudogenization events are driven by processes of compositional epistasis leading to gene decay. Additionally, we documented instances where interspecies recombination influences pgl gene status and creates discordant genetic interactions due ostensibly to the multi-locus nature of pgl gene networks. In summary, these findings provide a novel perspective on the evolution of protein glycosylation systems and identify phylogenetically informative, genetic differences associated with Neisseria species.Bacteria express a remarkable diversity of sugars and oligosaccharides in conjunction with protein glycosylation systems. Currently however, little is known about the evolutionary processes and selective forces shaping glycan biosynthetic pathways. The closely related bacterial pathogens Neisseria gonorrhoeae and Neisseria meningitidis remain serious sources of human disease and these species express antigenically variable oligosaccharides as components of their broad-spectrum, O-linked protein glycosylation (pgl) systems. With the exception of isolates of Neisseria elongata subspecies glycolytica, the status of such post-translational modifications in related commensal species colonizing humans remains largely undefined. Here, we exploit new data from further studies of protein glycosylation in Neisseria elongata subspecies glycolytica to address these concerns. Employing comparative genomics and glycan phenotyping, we show that related pgl systems are indeed expressed by all human-restricted Neisseria species but identify unique gene gain and loss events as well as loss-of-function polymorphisms that accommodate a dramatic shift in glycoform structure occurring across the genus. These findings constitute ...

ObjectivesThe present Bayesian network meta-analysis aimed to compare the various strategies for acute ischemic stroke: direct endovascular thrombectomy within the thrombolysis window in patients with no contraindications to thrombolysis (DEVT); (2) direct endovascular thrombectomy secondary to contraindications to thrombolysis (DEVTc); (3) endovascular thrombectomy in addition to thrombolysis (IVEVT); and (4) thrombolysis without thrombectomy (IVT).MethodsSix electronic databases were searched from their dates of inception to May 2017 to identify randomized controlled trials (RCTs) comparing IVT versus IVEVT, and prospective registry studies comparing IVEVT versus DEVT or IVEVT versus DEVTc. Network meta-analyses were performed using ORs and 95% CIs as the summary statistic.ResultsWe identified 12 studies (5 RCTs, 7 prospective cohort) with a total of 3161 patients for analysis. There was no significant difference in good functional outcome at 90 days (modified Rankin Scale score ≤2) between DEVT and IVEVT. There was no significant difference in mortality between all treatment groups. DEVT was associated with a 49% reduction in intracranial hemorrhage (ICH) compared with IVEVT (OR 0.51; 95% CI 0.33 to 0.79), due to reduction in rates of asymptomatic ICH (OR 0.47; 95% CI 0.29 to 0.76). Patients treated with DEVT had higher rates of reperfusion compared with IVEVT (OR 1.73; 95% CI 1.04 to 2.94).ConclusionsTo our knowledge, this is the first network meta-analysis to be performed in the era of contemporary mechanical thrombectomy comparing DEVT and DEVTc. Our analysis suggests the addition of thrombolysis prior to thrombectomy for large vessel occlusions may not be associated with improved outcomes.

Study Design:Retrospective cohort study.Objective:Preoperative anemia has been associated with an increased need for blood transfusions and postoperative complications. The effects of anemia on the outcomes of anterior cervical discectomy and fusion (ACDF) have not been explored. The present study aimed to evaluate the association between preoperative anemia and 30-day complications following ACDF surgery.Methods:Data from the American College of Surgeons National Surgical Quality Improvement Program (2005-2012) was used. Preoperative anemia was defined as hematocrit <39% for males and <36% for females. A bivariate analysis was performed on demographic and perioperative variables. Multivariable logistic regression models were employed, adjusting for patient variables, to identify independent risk factors for complications.Results:A total of 3500 patients were included of which 444 (12.7%) were anemic patients. Multivariate analysis was used to quantify the predictive power of anemia on key postoperative outcomes, while controlling for the other statistically significant. Preoperative anemia was found to be a statistically significant predictor of any complication (odds ratio [OR] = 1.853; 95% confidence interval [CI] = 1.17-2.934; P = .0086), pulmonary complications (OR = 3.269; 95% CI = 1.745-6.126; P = .0002), intraoperative blood transfusion (OR = 4.364; 95% CI = 1.48-12.866; P = 0.0076), return to operating theatre (OR = 2.655; 95% CI = 1.539-4.582; P = .0005), and length of hospital stay more than 5 days (OR = 2.151; 95% CI = 1.499-3.085; P < .0001).Conclusion:Preoperative anemia appears to be a significant predictor of perioperative complications, reoperation, and extended length of hospital stay in patients undergoing elective ACDF. Future studies should explore outcomes of treatment of preoperative anemia prior to surgery to determine the optimal management strategy.