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ObjectivesTo summarise logistical aspects of recently completed systematic reviews that were registered in the International Prospective Register of Systematic Reviews (PROSPERO) registry to quantify the time and resources required to complete such projects.DesignMeta-analysis.Data sources and study selectionAll of the 195 registered and completed reviews (status from the PROSPERO registry) with associated publications at the time of our search (1 July 2014).Data extractionAll authors extracted data using registry entries and publication information related to the data sources used, the number of initially retrieved citations, the final number of included studies, the time between registration date to publication date and number of authors involved for completion of each publication. Information related to funding and geographical location was also recorded when reported.ResultsThe mean estimated time to complete the project and publish the review was 67.3 weeks (IQR=42). The number of studies found in the literature searches ranged from 27 to 92 020; the mean yield rate of included studies was 2.94% (IQR=2.5); and the mean number of authors per review was 5, SD=3. Funded reviews took significantly longer to complete and publish (mean=42 vs 26 weeks) and involved more authors and team members (mean=6.8 vs 4.8 people) than those that did not report funding (both p<0.001).ConclusionsSystematic reviews presently take much time and require large amounts of human resources. In the light of the ever-increasing volume of published studies, application of existing computing and informatics technology should be applied to decrease this time and resource burden. We discuss recently published guidelines that provide a framework to make finding and accessing relevant literature less burdensome.

Many different nanostructures have been developed for biomedical applications to date. Among them, iron oxide nanoparticles have been very prominent in MRI in diagnostic radiology. Nowadays, nanoparticle-based therapeutic applications have gained increased interest, leading to the development of a great variety of different and, in parts, sophisticated nanoparticle formulations. Whereas nanotherapy has been confined to the preclinical phase, magnetic hyperthermia has entered into the clinical phase via controlled studies in patients. Owing to the versatility of nanoparticles, researchers envision the combination of multiple modalities (e.g., targeting, diagnostics and therapy) to one carrier. Nevertheless, such approaches have been challenging due to the necessity of the adaptation of at least partially counteracting parameters between the different modalities, which will be analyzed in this review.

Oxidative protein folding in the endoplasmic reticulum (ER) has emerged as a potentially significant source of cellular reactive oxygen species (ROS). Recent studies suggest that levels of ROS generated as a byproduct of oxidative folding rival those produced by mitochondrial respiration. Mechanisms that protect cells against oxidant accumulation within the ER have begun to be elucidated yet many questions still remain regarding how cells prevent oxidant-induced damage from ER folding events. Here we report a new role for a central well-characterized player in ER homeostasis as a direct sensor of ER redox imbalance. Specifically we show that a conserved cysteine in the lumenal chaperone BiP is susceptible to oxidation by peroxide, and we demonstrate that oxidation of this conserved cysteine disrupts BiP's ATPase cycle. We propose that alteration of BiP activity upon oxidation helps cells cope with disruption to oxidative folding within the ER during oxidative stress. The endoplasmic reticulum is the cellular compartment where approximately one third of the cell's proteins are made. Inside, chaperone molecules bind to newly made protein chains and help them to fold into the three-dimensional structure required for the protein to work correctly. A chaperone called Ero1 helps to facilitate this folding process by catalyzing a reaction that forms strong chemical bonds, which help stabilize the final protein structures. However, this help from Ero1 comes at a cost: forming a stabilizing bond this way also produces a peroxide molecule as a byproduct. Peroxide is a ‘reactive oxygen species’: a chemical that can oxidize and damage proteins and DNA, which can potentially kill the cell. Three other enzymes in the endoplasmic reticulum can convert peroxide into water, to protect the cells from reactive oxygen species build-up. However, not all cells that use Ero1 have these other enzymes, suggesting that other pathways must exist to manage reactive oxygen species. Wang et al. took advantage of yeast cells containing a hyperactive mutant version of the Ero1 enzyme to look for alternative detoxifying mechanisms that occur when the cell is stressed by an excess of reactive oxygen species. In these cells, Wang et al. observed that the high levels of reactive oxygen species caused part of a chaperone molecule called BiP to oxidize. This modification of BiP acts like a switch that the reactive oxygen species flip on. When activated by the reactive oxygen species, BiP enhances its activity as a folding molecular chaperone, keeping proteins apart. This is thought to allow BiP to minimize the protein misfolding that may otherwise occur in the wake of the damage caused by the building levels of peroxide. Wang et al. created a mutant BiP chaperone that mimics the oxidized form, and found that it also protects cells from the damage inflicted by the excess of reactive oxygen species. Wang et al. propose that the BiP chaperone may be an important sensor of reactive oxygen species that changes its activity when these harmful chemicals are present and helps to protect the cell from damage. The success in mimicking the protective effects of oxidized BiP with a mutant BiP suggest that in the future one may be able to design small molecule drugs that bind to BiP to produce the activity of the modified form.

Although West Nile virus (WNV) has been a prominent mosquito-transmitted infection in North America for twenty years, no human vaccine has been licensed. With a cumulative number of 24,714 neurological disease cases and 2314 deaths in the U.S. since 1999, plus a large outbreak in Europe in 2018 involving over 2000 human cases in 15 countries, a vaccine is essential to prevent continued morbidity, mortality, and economic burden. Currently, four veterinary vaccines are licensed, and six vaccines have progressed into clinical trials in humans. All four veterinary vaccines require multiple primary doses and annual boosters, but for a human vaccine to be protective and cost effective in the most vulnerable older age population, it is ideal that the vaccine be strongly immunogenic with only a single dose and without subsequent annual boosters. Of six human vaccine candidates, the two live, attenuated vaccines were the only ones that elicited strong immunity after a single dose. As none of these candidates have yet progressed beyond phase II clinical trials, development of new candidate vaccines and improvement of vaccination strategies remains an important area of research.

The recent successes of adoptive T-cell immunotherapy for the treatment of hematologic malignancies have highlighted the need for manufacturing processes that are robust and scalable for product commercialization. Here we review some of the more outstanding issues surrounding commercial scale manufacturing of personalized-adoptive T-cell medicinal products. These include closed system operations, improving process robustness and simplifying work flows, reducing labor intensity by implementing process automation, scalability and cost, as well as appropriate testing and tracking of products, all while maintaining strict adherence to Current Good Manufacturing Practices and regulatory guidelines. A decentralized manufacturing model is proposed, where in the future patients’ cells could be processed at the point-of-care in the hospital.

The incidence, prediction and mortality outcomes of intraoperative and postoperative cardiac arrest requiring cardiopulmonary resuscitation (CPR) in surgical patients are under investigated and have not been studied concurrently in a single study. A retrospective cohort study was conducted using the American College of Surgeons National Surgical Quality Improvement Program data between 2008 and 2012. Firth's penalized logistic regression was used to study the incidence and identify risk factors for intra- and postoperative CPR and 30-day mortality. simplified prediction model was constructed and internally validated to predict the studied outcomes. Among about 1.86 million non-cardiac operations, the incidence rate of intraoperative CPR was 0.03%, and for postoperative CPR was 0.33%. The 30-day mortality incidence rate was 1.25%. The incidence rate of events decreased overtime between 2008-2012. Of the 29 potential predictors, 14 were significant for intraoperative CPR, 23 for postoperative CPR, and 25 for 30-day mortality. The five strongest predictors (highest odd ratios) of intraoperative CPR were the American Society of Anesthesiologists (ASA) physical status, Systemic Inflammatory Response Syndrome (SIRS)/sepsis, surgery type, urgent/emergency case and anesthesia technique. Intraoperative CPR, ASA, age, functional status and end stage renal disease were the most significant predictors for postoperative CPR. The most significant predictors of 30-day mortality were ASA, age, functional status, SIRS/sepsis, and disseminated cancer. The predictions with the simplified five-factor model performed well and was comparable to the full prediction model. Postoperative cardiac arrest requiring CPR, compared to intraoperative, was associated with much higher mortality. The incidence of cardiac arrest requiring CPR in surgical patients decreased overtime. Risk factors for intraoperative CPR, postoperative CPR and perioperative mortality are overlapped. We proposed a simplified approach compromised of five-factor model to identify patients at high risk. Postoperative, compare to intraoperative, cardiac arrest requiring CPR was associated with much higher mortality.

Given the increasing evidence that supports the ability of humans to taste non-esterified fatty acids (NEFA), recent studies have sought to determine if relationships exist between oral sensitivity to NEFA (measured as thresholds), food intake and obesity. Published findings suggest there is either no association or an inverse association. A systematic review and meta-analysis was conducted to determine if differences in fatty acid taste sensitivity or intensity ratings exist between individuals who are lean or obese. A total of 7 studies that reported measurement of taste sensations to non-esterified fatty acids by psychophysical methods (e.g.,studies using model systems rather than foods, detection thresholds as measured by a 3-alternative forced choice ascending methodology were included in the meta-analysis. Two other studies that measured intensity ratings to graded suprathreshold NEFA concentrations were evaluated qualitatively. No significant differences in fatty acid taste thresholds or intensity were observed. Thus, differences in fatty acid taste sensitivity do not appear to precede or result from obesity.

Background: Public health and clinical interventions for obesity in free-living adults may be diminished by individual compensation for the intervention. Approaches to predict weight outcomes do not account for all mechanisms of compensation, so they are not well suited to predict outcomes in free-living adults. Our objective was to quantify the range of compensation in energy intake or expenditure observed in human randomized controlled trials (RCTs). Methods: We searched multiple databases (PubMed, CINAHL, SCOPUS, Cochrane, ProQuest, PsycInfo) up to 1 August 2012 for RCTs evaluating the effect of dietary and/or physical activity interventions on body weight/composition. Inclusion criteria: subjects per treatment arm ⩾5; ⩾1 week intervention; a reported outcome of body weight/body composition; the intervention was either a prescribed amount of over- or underfeeding and/or supervised or monitored physical activity was prescribed; ⩾80% compliance; and an objective method was used to verify compliance with the intervention (for example, observation and electronic monitoring). Data were independently extracted and analyzed by multiple reviewers with consensus reached by discussion. We compared observed weight change with predicted weight change using two models that predict weight change accounting only for metabolic compensation. Findings: Twenty-eight studies met inclusion criteria. Overfeeding studies indicate 96% less weight gain than expected if no compensation occurred. Dietary restriction and exercise studies may result in up to 12–44% and 55–64% less weight loss than expected, respectively, under an assumption of no behavioral compensation. Interpretation: Compensation is substantial even in high-compliance conditions, resulting in far less weight change than would be expected. The simple algorithm we report allows for more realistic predictions of intervention effects in free-living populations by accounting for the significant compensation that occurs.

Active stakeholder involvement not only fosters the acceptance of chosen district solutions but also enhances the effectiveness of the measures. In this context, our research aims to support the integration of stakeholder preferences into heating planning through the use of interactive visualizations, making the decision-making process more transparent and comprehensible. Our research specifically focuses on how stakeholder weightings and the resulting assessments, gathered within the framework of a Decision Theatre, can be optimally visualized to facilitate the decision-making process using an interactive dialogue tool. The objective is to develop a methodology and a tool that allow stakeholder weightings and the associated assessments to be clearly and understandably presented while enabling interactive adjustments, thereby making the decision-making process intuitive and transparent. This approach considers technical, ecological, economic, and social sustainability criteria.

Many bacteria can rapidly traverse surfaces from which they are extracting nutrient for growth. They generate flat, spreading colonies, called swarms because they resemble swarms of insects. We seek to understand how members of any dense swarm spread efficiently while being able to perceive and interfere minimally with the motion of others. To this end, we investigate swarms of the myxobacterium, Myxococcus xanthus. Individual M. xanthus cells are elongated; they always move in the direction of their long axis; and they are in constant motion, repeatedly touching each other. Remarkably, they regularly reverse their gliding directions. We have constructed a detailed cell- and behavior-based computational model of M. xanthus swarming that allows the organization of cells to be computed. By using the model, we are able to show that reversals of gliding direction are essential for swarming and that reversals increase the outflow of cells across the edge of the swarm. Cells at the swarm edge gain maximum exposure to nutrient and oxygen. We also find that the reversal period predicted to maximize the outflow of cells is the same (within the errors of measurement) as the period observed in experiments with normal M. xanthus cells. This coincidence suggests that the circuit regulating reversals evolved to its current sensitivity under selection for growth achieved by swarming. Finally, we observe that, with time, reversals increase the cell alignment, and generate clusters of parallel cells.