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ormulating recommendations. In this case, clinical guidelines may not be reliable decision-support tools for facilitating clinical decision making. © 2020 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.RATIONALE, AIMS, AND OBJECTIVES Clinical practice guidelines (CPGs) have become a common feature in the health and social care fields, as they promote evidence-based practice and aim to improve quality of care and patient outcome. However, the benefits of the recommendations reported in CPGs are only as good as the quality of the CPGs themselves. Indeed, rigorous development and strategies for reporting are significant precursors to successful implementation of the recommendations that are proposed. Unfortunately, research has demonstrated that there is much variability in their level of quality. Furthermore, the quality of many CPGs has yet to be examined. The aim of the present study was to assess the quality of seven CPGs from four Quebec professional regulatory bodies pertaining to clinical evaluations in the fields of medicine, psychoeducation, psychotherapy, and social work. METHODS The seven Quebec CPGs were assessed by four trained appraisers using the Appraisal of Guidelines for Research and Evaluation II guideline evaluation tool. RESULTS Results suggest that while some quality criteria were met, most were not, denoting that these CPGs are of sub-optimal quality. CONCLUSION Our findings highlight that there is still a lot to be done in order to improve the rigour and transparency with which scientific evidence is assessed and applied when developing CPGs. Impacts regarding the implementation of these CPGs are discussed in light of their use in clinical practice. © 2020 John Wiley & Sons, Ltd.Merkel cell carcinoma is rare and aggressive skin cancer, which occurrence is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus. In recent years, significant progress in understanding the mechanism of Merkel cell carcinoma pathogenesis has been observed. This neoplasm often expresses PD-L1, and MCPyV-specific T cells can express PD-1 thus PD-1/PD-L1 checkpoint therapies seem to be remarkably interesting treatment options. Many clinical trials are currently being conducted to confirm their effectiveness and safety for this group of patients. However, only about half of advanced Merkel cell carcinoma patients could achieve remission or disease stabilization through PD-1/PD-L1 checkpoint therapies thus innovative treatments are still needed. In this article, we have presented current and future directions in the development of Merkel cell carcinoma therapy. © 2020 Wiley Periodicals, Inc.The exciting discovery of the giant DNA Mimivirus in 2003 challenged the conventional description of viruses in a radical way, and since then, dozens of additional giant viruses have been identified. It has now been demonstrated that the Mimivirus genome encodes for the two enzymes required for the production of the unusual sugar 4-amino-4,6-dideoxy-d-glucose, namely a 4,6-dehydratase and an aminotransferase. In light of our long-standing interest in the bacterial 4,6-dehydratases and in unusual sugars in general, we conducted a combined structural and functional analysis of the Mimivirus 4,6-dehydratase referred to as R141. For this investigation, the three-dimensional X-ray structure of R141 was determined to 2.05 Å resolution and refined to an R-factor of 18.3%. The overall fold of R141 places it into the short-chain dehydrogenase/reductase (SDR) superfamily of proteins. Whereas its molecular architecture is similar to that observed for the bacterial 4,6-dehydratases, there are two key regions where the polypeptide chain adopts different conformations. In particular, the conserved tyrosine that has been implicated as a catalytic acid or base in SDR superfamily members is splayed away from the active site by nearly 12 Å, thereby suggesting that a major conformational change must occur upon substrate binding. In addition to the structural analysis, the kinetic parameters for R141 using either dTDP-d-glucose or UDP-d-glucose as substrates were determined. Contrary to a previous report, R141 demonstrates nearly identical catalytic efficiency with either nucleotide-linked sugar. The data presented herein represent the first three-dimensional model for a viral 4,6-dehydratase and thus expands our understanding of these fascinating enzymes. © 2020 The Protein Society.Cost-effectiveness is traditionally treated as a static estimate driven by clinical trial efficacy and drug price at launch. Prior studies suggest that cost-effectiveness varies over the drug’s lifetime. We examined the impact of “learning by doing,” one of the least studied drivers of changes in cost-effectiveness across the product life cycle. We combined time-series trends in effectiveness over time by cancer regimen using the Surveillance, Epidemiology, and End Results-Medicare database. We estimated the time-varying effects of treatments in colorectal and pancreatic cancer over their life cycle, including FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) and gemcitabine, on survival of patients. Selleck GLX351322 Mean prices over time by strength and dosage form were calculated using historical wholesale acquisition costs. We found consistent downward trends in the mortality hazard ratios, which suggest that effectiveness improves over time. In the case of first-line FOLFOX for colorectal cancer, the implied incremental cost-effectiveness ratio based on the observational data fell from $610,000 per life year gained in 2004 to $27,000 per life year gained in 2011. Cost-effectiveness estimated at launch is unlikely to be representative of cost-effectiveness over the drug’s lifetime. In the drugs studied, the impact of time-varying clinical effectiveness dominated the impact of changing prices overtime. © 2020 John Wiley & Sons, Ltd.Processing metal-organic-frameworks (MOFs) into hierarchical macroscopic materials can greatly extend their practical applications. However, current strategies suffer from severe aggregation of MOFs and limited tuning of the hierarchical porous network. Here, we report a controlled strategy that can simultaneously tune the MOF loading, composition, spatial distribution, and confinement within various bio-originated macroscopic supports, as well as control the accessibility, robustness, and formability of the support itself. Our methodology enables the good dispersion of individual MOF nanoparticles on a spiderweb-like network within each macrovoid even at high loadings (up to 86 wt%), ensuring the foam pores are highly accessible for excellent adsorption and catalytic capacity. Additionally, this approach allows the direct pre-incorporation of other functional components into the framework . Our strategy provides a general toolbox for precise control over the properties of both the hierarchical support and MOF, opening new possibilities to construct tunable multi-scale porous platforms with desired functionalities .