Constraint methods for determining pathways and free energy of activated processes

Activated processes from chemical reactions up to conformational transitions of large biomolecules are hampered by barriers which are overcome only by the input of some free energy of activation. Hence, the characteristic and rate-determining barrier regions are not sufficiently sampled by usual simulation techniques. Constraints on a reaction coordinate r have turned out to be a suitable means to explore difficult pathways without changing potential function, energy or temperature. For a dense sequence of values of r, the corresponding sequence of simulations provides a pathway for the process. As only one coordinate among thousands is fixed during each simulation, the pathway essentially reflects the system's internal dynamics. From mean forces the free energy profile can be calculated to obtain reaction rates and insight in the reaction mechanism. In the last decade, theoretical tools and computing capacity have been developed to a degree where simulations give impressive qualitative insight in the processes at quantitative agreement with experiments. Here, we give an introduction to reaction pathways and coordinates, and develop the theory of free energy as the potential of mean force. We clarify the connection between mean force and constraint force which is the central quantity evaluated, and discuss the mass metric tensor correction. Well-behaved coordinates without tensor correction are considered. We discuss the theoretical background and practical implementation on the example of the reaction coordinate of targeted molecular dynamics simulation. Finally, we compare applications of constraint methods and other techniques developed for the same purpose, and discuss the limits of the approach

Empowerment, stress vulnerability and burnout among portuguese nursing staff

The work environment in Portuguese hospitals, characterized by economic cutbacks, can lead to higher levels of burnout experienced by nursing staff. Furthermore, vulnerability to stress can negatively affect the perception of burnout in the workplace. However, structural empowerment is an organizational process that can prevent and decrease burnout among nurses. Consequently, the aim of the study was to examine to what extent structural empowerment and vulnerability to stress can play a predictive role in core burnout in a sample of Portuguese nurses. A convenience sample of 297 nursing staff members from Portuguese hospitals was used in this study. Core burnout was negatively and significantly related to all the dimensions of structural empowerment, and it was positively and significantly related to vulnerability to stress. Regression models showed that core burnout was significantly predicted by access to funds, access to opportunities and vulnerability to stress. Organizational administrations must make every effort in designing interventions focused on structural empowerment, as well as interventions focused on individual interventions that enhance skills for coping with stress.info:eu-repo/semantics/publishedVersio

Novel oral targeted therapies in inflammatory bowel disease

Background: There is a great unmet clinical need for efficacious, tolerable, economical and orally administrated drugs for the treatment of inflammatory bowel disease (IBD). New therapeutic avenues have become possible including the development of medications that target specific genetic pathways found to be relevant in other immune mediated diseases. Aims: To provide an overview of recent clinical trials for new generation oral targeted medications that may have a future role in IBD management. Methods: Pubmed and Medline searches were performed up to 01/03/18 using keywords: ‘IBD’, ‘UC’, ‘CD’, ‘inflammatory bowel disease’ ‘ulcerative colitis’, Crohn’s disease’ in combination with ‘phase’, ‘study’, ‘trial’, and ‘oral’. A manual search of the clinical trial register, article reference lists, abstracts from meetings of Digestive Disease Week, United European Gastroenterology Week and ECCO congress were also conducted. Results: In randomised controlled trials primary efficacy endpoints were met for tofacitinib (JAK 1/3 inhibitor-phase III), upadacitinib (JAK 1 inhibitor-phase II) and AJM-300 (α4-integrin antagonist-phase II) in ulcerative colitis. Ozanimod (S1P receptor agonist-phase II) also demonstrated clinical remission. For Crohn’s disease, filgotinib (JAK1 inhibitor-phase II) met primary endpoints and laquinimod (quinolone-3-carboxide small molecule-phase II) was also efficacious. Trials using mongersen (SMAD7 inhibitor) and vidofludimus (dihydroorotate dehydrogenase inhibitor) have been halted. Conclusions: This is potentially the start of an exciting new era in which multiple therapeutic options are at the disposal of physicians to treat IBD on an individualised basis. Head-to-head studies with existing treatments and longer term safety data are needed for this to be possible

MicroRNAs:New players in IBD

MicroRNAs (miRNAs) are small non-coding RNAs, 18–23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications

Lack of benefit for early escalation to advanced therapies in ulcerative colitis: critical appraisal of current evidence.

Although ulcerative colitis (UC) shares many common pathways and therapeutic options with Crohn's disease (CD), CD patients are four times more likely to undergo surgery 10 years into their disease in biologic era and are more likely to have extraintestinal manifestations than UC patients. Early treatment in CD has been demonstrated to modify natural history of disease and potentially delay surgery. Previous reviews on this topic borrowed their evidence from CD to make UC-specific recommendations. This review highlights the emergence of UC-specific data from larger cohort studies and a comprehensive individual patient data systemic review and meta-analysis to critically appraise the evidence on utility of early escalation to advanced therapies with respect to short-, medium-, and long-term outcomes. In UC, the utility of the early escalation concept for the purposes of changing the natural history, including reducing colectomy and hospitalisations, is not supported by the available data. Data on targeting clinical, biochemical, endoscopic, and histological outcomes are needed to demonstrate that they are meaningful with regards to achieving reductions in hospitalization and surgery, improving quality of life, and minimizing disability. The analyses of different populations of UC patients, such as those with "relapsing & remitting" disease or with severe or complicated disease course, are urgently needed. The costs and risk/benefit profile of some of the newer advanced therapies should be carefully considered. In this clinical landscape, it appears premature to advocate an indiscriminate 'one size fits all' approach to escalating to advanced therapies early during the course of UC