Monoacylglycerol lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The identification of reversible MAGL inhibitors, devoid of the side effects associated to prolonged MAGL inactivation, is a hot topic in medicinal chemistry. In this study, a novel phenyl(piperazin-1-yl)methanone inhibitor of MAGL was identified through a virtual screening protocol based on a fingerprint-driven consensus docking (CD) approach. Molecular modeling and preliminary structure-based hit optimization studies allowed the discovery of derivative 4, which showed an efficient reversible MAGL inhibition (IC50 = 6.1 µM) and a promising antiproliferative activity on breast and ovarian cancer cell lines (IC50 of 31-72 µM), thus representing a lead for the development of new and more potent reversible MAGL inhibitors. Moreover, the obtained results confirmed the reliability of the fingerprint-driven CD approach herein developed.

Growing awareness of Alzheimer's disease (AD) has prompted a demand for quick and effective ways to screen for memory loss and cognitive decline in large numbers of individuals in the community. Periodic Memory Screening Day events provide free, brief cognitive screening aimed at those 65 years and older, and can serve as an opportunity to gauge participants' attitudes towards AD research and recruit them into ongoing research projects.

Background The Canadian Institutes of Health Research funded a program, "patient-oriented research" (POR), to change the way health research is done. POR involves patients and their families/caregivers as equal partners on research teams with researchers, healthcare providers and decision-makers. The authors of this paper work through a unit in British Columbia, Canada that functions to help research teams learn how to do patient-oriented research. We felt that we could not train people if we didn't first understand what others had learned about what competencies (knowledge, skills and attitudes) were helpful for members of these research teams. Method We used a method called a scoping review to search literature on patient-involved research. Our search included papers in academic journals as well as information on websites, training manuals, conference proceedings, governmental documents and statements from health organizations. Findings Writers reported the usefulness of many competencies for researchers and patients, with fewer competencies for healthcare providers or decision-makers. The main competencies for researchers had to do with participation, communication and conflict management; for patients they had to do with research knowledge and skills, cultural competence and participation. It was helpful that all team members want to work as part of a group for the public good. Conclusions We worked with an advisory group of people representing patients and their families/caregivers, researchers, healthcare providers and decision-makers to review our findings. We concluded that our competency statements are helpful for people to determine what they need to know or learn as they join research teams.

The European population is rapidly ageing. In order to handle substantial future challenges in the healthcare system, we need to shift focus from treatment towards health promotion. The PreventIT project has adapted the Lifestyle-integrated Exercise (LiFE) programme and developed an intervention for healthy young older adults at risk of accelerated functional decline. The intervention targets balance, muscle strength and physical activity, and is delivered either via a smartphone application (enhanced LiFE, eLiFE) or by use of paper manuals (adapted LiFE, aLiFE).

Telemedicine gained strength in primary healthcare (PHC) during the COVID-19 pandemic. Thus, there is a need to know its scope, technologies used and impacts on people's health. This study will map telemedicine use in PHC around the world and its impacts on quality of care in the context of the COVID-19 pandemic.

Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status.

Culture, tradition, structural violence, and mental health-related stigma play a major role in global mental health for refugees. Our aim was to understand what factors determine the success or failure of community-based psychotherapy for trauma-affected refugees and discuss implications for primary health care programs. Using a systematic realist-informed approach, we searched five databases from 2000 to 2018. Two reviewers independently selected RCTs for inclusion, and we contacted authors to obtain therapy training manuals. Fifteen articles and 11 training manuals met our inclusion criteria. Factors that improved symptoms of depression, anxiety, and PTSD included providing culturally adapted care in a migrant-sensitive setting, giving a role to other clinical staff (task-shifting), and intervention intensity. Precarious asylum status, constraining program monitoring requirements, and diverse socio-cultural and gender needs within a setting may reduce the effectiveness of the program. Primary care programs may enable community based mental health care and may reduce mental health-related stigma for refugees and other migrants. More research is needed on the cultural constructs of distress, programs delivered in primary care, and the role of cultural and language interpretation services in mental health care.

Accurate aphasia diagnosis is important in stroke care. A wide range of language tests are available and include informal assessments, tests developed by healthcare institutions and commercially published tests available for purchase in pre-packaged kits. The psychometrics of these tests are often reported online or within the purchased test manuals, not the peer-reviewed literature, therefore the diagnostic capabilities of these measures have not been systematically evaluated. This review aimed to identify both commercial and non-commercial language tests and tests used in stroke care and to examine the diagnostic capabilities of all identified measures in diagnosing aphasia in stroke populations.

Dementia from Alzheimer's disease (AD) is characterized primarily by a significant decline in memory abilities; however, language abilities are also commonly affected and may precede the decline of other cognitive abilities. To study the progression of language, there is a need for open-access databases that can be used to build algorithms to produce translational models sensitive enough to detect early declines in language abilities. DementiaBank is an open-access repository of transcribed video/audio data from communicative interactions from people with dementia, mild cognitive impairment (MCI), and controls. The aims of this tutorial are to (a) describe the newly established standardized DementiaBank discourse protocol, (b) describe the Delaware corpus data, and (c) provide examples of automated linguistic analyses that can be conducted with the Delaware corpus data and describe additional DementiaBank resources.

Inadequately treated pain and distress elicited by medical procedures can put children at higher risk of acute and chronic biopsychosocial sequelae. Children can benefit from hypnotherapy, a psychologically tailored intervention, as an adjunct to pharmacological agents to address the multiple components of pain and distress. Despite providing evidence on the effectiveness and potential superiority of hypnotherapy to other psychological interventions, research on hypnotherapy for pediatric procedural pain and distress has been predominantly limited to oncology and needle procedures. Plus, there is a lack of reporting of intervention manuals, factors influencing hypnotic responding, pain unpleasantness outcomes, theoretical frameworks, adverse events, as well as barriers and facilitators to the feasibility of delivering the intervention and study procedures. The proposed review aims to map the range and nature of the evidence on hypnotherapy for procedural pain and distress in children to identify gaps in literature and areas requiring further investigation.

qRT-PCR is one of the most popular approaches to analyze specific gene expression level, and stably expressed reference genes are essential to obtain reliable results. However, many reference genes are only stable under certain circumstances and different reference genes might be required in different experiments. High temperature is a common stress that affects rice endosperm development and it has become a hot topic recently. Although study about reference genes at different developmental stages in rice has been reported, these genes may not be suitable to study high temperature mediated responses especially in endosperm. In our quest for proper reference genes to quantify gene expression in rice endosperm under high temperature, we studied 6 candidate genes selected from the transcriptome data and 11 housekeeping genes. All genes were analyzed with qRT-PCR and the expression stability was assessed with software geNorm and NormFinder. Fb15 and eIF-4a were identified as the two most stable genes in endosperm at different developmental stages, while high temperature treatment has a least effect on expression of Fb15 and UBQ5 in rice endosperm. Our results provide some good candidate reference genes for qRT-PCR normalization in rice endosperm under different temperatures.

Objectives: The purpose of evaluative instruments is to measure the magnitude of change in a construct of interest over time. The measurement properties of these instruments, as they relate to the instrument's ability to fulfill its purpose, determine the degree of certainty with which the results yielded can be viewed. This work systematically reviews all instruments that have been used to evaluate cognitive functioning in persons with traumatic brain injury (TBI), and critically assesses their evaluative measurement properties: construct validity, test-retest reliability, and responsiveness. Data Sources: MEDLINE, Central, EMBASE, Scopus, PsycINFO were searched from inception to December 2016 to identify longitudinal studies focused on cognitive evaluation of persons with TBI, from which instruments used for measuring cognitive functioning were abstracted. MEDLINE, instrument manuals, and citations of articles identified in the primary search were then screened for studies on measurement properties of instruments utilized at least twice within the longitudinal studies. Study Selection: All English-language, peer-reviewed studies of longitudinal design that measured cognition in adults with a TBI diagnosis over any period of time, identified in the primary search, were used to identify instruments. A secondary search was carried out to identify all studies that assessed the evaluative measurement properties of the instruments abstracted in the primary search. Data Extraction: Data on psychometric properties, cognitive domains covered and clinical utility were extracted for all instruments. Results: In total, 38 longitudinal studies from the primary search, utilizing 15 instruments, met inclusion and quality criteria. Following review of studies identified in the secondary search, it was determined that none of the instruments utilized had been assessed for all the relevant measurement properties in the TBI population. The most frequently assessed property was construct validity. Conclusions: There is insufficient evidence for the validity and reliability of instruments measuring cognitive functioning, longitudinally, in persons with TBI. Several instruments with well-defined construct validity in TBI samples warrant further assessment for test-retest reliability and responsiveness. Registration Number: www.crd.york.ac.uk/PROSPERO/, identifier CRD42017055309.

To examine all aspects affecting the functioning of the system and the most important factors in its assessment through a systematic review during 1990 to 2017.

Dementia impairs spatial orientation and route planning, thus often affecting the patient's ability to move outdoors and maintain social activities. Situation-aware deliberative assistive technology devices (ATD) can substitute impaired cognitive function in order to maintain one's level of social activity. To build such a system, one needs domain knowledge about the patient's situation and needs. We call this collection of knowledge situation model.

The mechanisms of how ligands enter and leave the binding cavity of fatty acid binding proteins (FABPs) have been a puzzling question over decades. Liver fatty acid binding protein (LFABP) is a unique family member which accommodates two molecules of fatty acids in its cavity and exhibits the capability of interacting with a variety of ligands with different chemical structures and properties. Investigating the ligand dissociation processes of LFABP is thus a quite interesting topic, which however is rather difficult for both experimental approaches and ordinary simulation strategies. In the current study, random expulsion molecular dynamics simulation, which accelerates ligand motions for rapid dissociation, was used to explore the potential egress routes of ligands from LFABP. The results showed that the previously hypothesized "portal region" could be readily used for the dissociation of ligands at both the low affinity site and the high affinity site. Besides, one alternative portal was shown to be highly favorable for ligand egress from the high affinity site and be related to the unique structural feature of LFABP. This result lends strong support to the hypothesis from the previous NMR exchange studies, which in turn indicates an important role for this alternative portal. Another less favored potential portal located near the N-terminal end was also identified. Identification of the dissociation pathways will allow further mechanistic understanding of fatty acid uptake and release by computational and/or experimental techniques.

The computational prediction of unbinding rate constants is presently an emerging topic in drug design. However, the importance of predicting kinetic rates is not restricted to pharmaceutical applications. Many biotechnologically relevant enzymes have their efficiency limited by the binding of the substrates or the release of products. While aiming at improving the ability of our model enzyme haloalkane dehalogenase DhaA to degrade the persistent anthropogenic pollutant 1,2,3-trichloropropane (TCP), the DhaA31 mutant was discovered. This variant had a 32-fold improvement of the catalytic rate toward TCP, but the catalysis became rate-limited by the release of the 2,3-dichloropropan-1-ol (DCP) product from its buried active site. Here we present a computational study to estimate the unbinding rates of the products from DhaA and DhaA31. The metadynamics and adaptive sampling methods were used to predict the relative order of kinetic rates in the different systems, while the absolute values depended significantly on the conditions used (method, force field, and water model). Free energy calculations provided the energetic landscape of the unbinding process. A detailed analysis of the structural and energetic bottlenecks allowed the identification of the residues playing a key role during the release of DCP from DhaA31 via the main access tunnel. Some of these hot-spots could also be identified by the fast CaverDock tool for predicting the transport of ligands through tunnels. Targeting those hot-spots by mutagenesis should improve the unbinding rates of the DCP product and the overall catalytic efficiency with TCP.

Assessing cognitive decline and everyday functioning (EvF) in older age is valuable in detecting age-related neurological disorders. In Greece, there is a lack of sensitive instruments that capture fluctuations in EvF among older persons who are cognitively healthy or have subtle cognitive impairments. The EPT 28-items test, a widely used paper-and-pencil EvF measure, was translated in Greek and adapted to the Greek culture in this study. A multi-step methodology using a sample of 139 older Greek persons was employed. The results indicate that the Greek version of the EPT 28-items (i.e., the EPT-G) was well adapted, representing everyday tasks in Greece within a good range of task difficulty. The psychometric properties of the EPT-G replicate those of the original instrument, capturing EvF fluctuations among older persons with mild cognitive impairments. It was concluded that the EPT-G is a useful measure of EvF among Greek older persons.

Functional RNA molecules depend on three-dimensional (3D) structures to carry out their tasks within the cell. Understanding how these molecules interact to carry out their biological roles requires a detailed knowledge of RNA 3D structure and dynamics as well as thermodynamics, which strongly governs the folding of RNA and RNA-RNA interactions as well as a host of other interactions within the cellular environment. Experimental determination of these properties is difficult, and various computational methods have been developed to model the folding of RNA 3D structures and their interactions with other molecules. However, computational methods also have their limitations, especially when the biological effects demand computation of the dynamics beyond a few hundred nanoseconds. For the researcher confronted with such challenges, a more amenable approach is to resort to coarse-grained modeling to reduce the number of data points and computational demand to a more tractable size, while sacrificing as little critical information as possible. This review presents an introduction to the topic of coarse-grained modeling of RNA 3D structures and dynamics, covering both high- and low-resolution strategies. We discuss how physics-based approaches compare with knowledge based methods that rely on databases of information. In the course of this review, we discuss important aspects in the reasoning process behind building different models and the goals and pitfalls that can result.

Recently Nutrition and Food Chemistry researches have been focused on plants and their products or their secondary metabolites having anti-alzheimer, anti-cancer, anti-aging, and antioxidant properties. Among these plants Salvia L. (Lamiaceae) species come into prominence with their booster effects due to high antioxidant contents, which have over 900 species in the world and 98 in Turkey. Some Salvia species are already in use as herbal treatment of vessel stiffness, Dementia like problems and cancer. Recently some species of Salvia are of extensive research topic. In this study, inhibitory potentials of secondary metabolites, rosmarinic acid, salvigenin, salvianolic acid A and B, tanshinone I and IIA, cyrtotanshinone, dihydrotanshinone I, carnosic acid, carnosol, and danshensu sodium salt were investigated against acetylcholinesterase, butyrylcholinesterase, urease and tyrosinase enzymes both in-vitro and in slico in detail. Elevated inhibitory effects on acetyl- and butyryl-cholinesterase of dihydrotanshinone I (IC50: 1.50 ± 0.02 and 0.50 ± 0.01 µg/mL, respectively), carnasol (IC50: 11.15 ± 0.05 ve 3.92 ± 0.03 µg/mL) and carnosic acid (IC50: 31.83 ± 0.65 ve 4.12±0.04 µg/mL) were observed. Furthermore, all other secondary metabolites were active against butyrylcholinesterase. Anti-urease (42.41 ± 0.85%) and anti-tyrosinase (39.82 ± 1.16%) activities of tanshinone I were also observed. Potential inhibitory effects of these molecules on target proteins were investigated using DOCK and molecular dynamics calculations. Dock score analysis and Lipinski parameters were demonstrated that these ligands are potential inhibitors against relevant enzymes. Our findings suggest that Salvia species can be utilized as a ptential source of anti-alzheimer active compounds for designing novel products.

The World Organization recommends to implement National Quality Policies and Strategies in health systems, but few instruments have been proposed to assess and monitor these quality interventions at the system level. This study will map and compare instruments for the assessment of quality policies and strategies in health systems around the world.