The devil is in the domain: understanding protein recognition of multiple RNA targets

RNA regulation provides a finely tuned and highly co-ordinated control of gene expression. Regulation is mediated by hundreds to thousands of multi-functional RNA-binding proteins which often interact with large sets of RNAs. In this brief review, we focus on a recent work that highlights how the proteins use multiple RNA-binding domains to interact selectively with the different RNA targets. Deconvoluting the molecular complexity of the RNA regulatory network is essential to understanding cell differentiation and function, and requires accurate models for protein–RNA recognition and protein target selectivity. We discuss that the structural and molecular understanding of the key determinant of recognition, together with the availability of methods to examine protein–RNA interactions at the transcriptome level, may provide an avenue to establish these models

Systematic review of the effects of exercise and physical activity on the gut microbiome of older adults

Recent evidence suggests that exercise/physical activity (PA) can beneficially alter the gut microbiome composition of young people, but little is known about its effects in older adults. The aim of this systematic review was to summarize results of human studies that have assessed the effects/associations of PA/exercise on the gut microbiome of older adults and to better understand whether this can help promote healthy ageing. Seven studies were included in the review and overall, exercise and increased amounts of PA were associated with decreases in the abundance of several well-known harmful taxa and increases in the abundance of health-promoting taxa. Altogether, the findings from the included studies suggest that exercise/PA have a beneficial impact on the gut health of older adults by improving the gut microbiome composition. However, due to methodological and sampling disparities, it was not possible to reach a consensus on which taxa were most affected by exercise or PA

Characterization of stochastic orders by L-functionals

Random variables may be compared with respect to their location by comparing certain functionals ad hoc, such as the mean or median, or by means of stochastic ordering based directly on the properties of the corresponding distribution functions. These alternative approaches are brought together in this paper. We focus on the class of L-functionals discussed by Bickel and Lehmann (1975) and characterize the comparison of random variables in terms of these measures by means of several stochastic orders based on iterated integrals, including the increasing convex orde

Description and evaluation of an EBM curriculum using a block rotation

BACKGROUND: While previous authors have emphasized the importance of integrating and reinforcing evidence-based medicine (EBM) skills in residency, there are few published examples of such curricula. We designed an EBM curriculum to train family practice interns in essential EBM skills for information mastery using clinical questions generated by the family practice inpatient service. We sought to evaluate the impact of this curriculum on interns, residents, and faculty. METHODS: Interns (n = 13) were asked to self-assess their level of confidence in basic EBM skills before and after their 2-week EBM rotation. Residents (n = 21) and faculty (n = 12) were asked to assess how often the answers provided by the EBM intern to the inpatient service changed medical care. In addition, residents were asked to report how often they used their EBM skills and how often EBM concepts and tools were used in teaching by senior residents and faculty. Faculty were asked if the EBM curriculum had increased their use of EBM in practice and in teaching. RESULTS: Interns significantly increased their confidence over the course of the rotation. Residents and faculty felt that the answers provided by the EBM intern provided useful information and led to changes in patient care. Faculty reported incorporating EBM into their teaching (92%) and practice (75%). Residents reported applying the EBM skills they learned to patient care (86%) and that these skills were reinforced in the teaching they received outside of the rotation (81%). All residents and 11 of 12 faculty felt that the EBM curriculum had improved patient care. CONCLUSIONS: To our knowledge, this is the first published EBM curriculum using an individual block rotation format. As such, it may provide an alternative model for teaching and incorporating EBM into a residency program

Predicting mental imagery based BCI performance from personality, cognitive profile and neurophysiological patterns

Mental-Imagery based Brain-Computer Interfaces (MI-BCIs) allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy— EEG), which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI-BCI control ability. However, these predictors were only explored for motor-imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants’ BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities) were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants’ performance with a mean error of less than 3 points. This study determined how users’ profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user

Cognitive-behaviour therapy for patients with Abridged Somatization Disorder (SSI 4,6) in primary care: a randomized, controlled study

Abstract Background Somatoform disorders are characterized by the presence of multiple somatic symptoms without an organic cause that completely explains their symptoms. These patients generate a high cost in health services. We aim to evaluate the effectiveness and feasibility of a cognitive-behaviour therapy (CBT) programme, administered in group and individual formats in primary care for patients who are diagnosed with abridged somatization disorder. Method/design Design: Multicentre, randomized, controlled trial involving 3 groups, one of which is the control group consisting of standardized recommended treatment for somatization disorder in primary care (Smith's norms) and the 2 others, the intervention groups, consisting of cognitive-behavioural therapy (10 sessions) administered in individual format (intervention group 1) or in group format (intervention group 2). Setting: 29 primary care health centres in the province of Zaragoza and 3 primary care health centres in the province of Mallorca, Spain. Sample: N = 204 patients, (68 in each of the three groups), aged 18–65 years, able to understand and read Spanish, who fulfil Escobar's criteria of Abridgged Somatization Disorder (SSI 4,6), stable with pharmacotherapy over the previous month, and who will remain stable for the next 3 months in the doctor's opinion, having signed informed consent. Intervention: Control group: Standardized recommended treatment for somatization disorder in primary care (Smith's norms). Intervention group: 10 weekly sessions of CBT, following a protocol designed by Prof. Escobar's group at UMDNJ, USA. There are 2 different treatment conditions: individual and group format. Measurements: Survey on the use of health services, number and severity of somatic symptoms, anxiety, depression, quality of life and clinical global impression. The interviewers will not know which group the patient belongs to (blind). The assessments will be carried out at baseline, post-treatment, 6 months and 12 post-treatment. Main variables: Utilization of health services, number and severity of somatic symptoms. Analysis: The analysis will be per intent to treat. We will use the general linear models of the SPSS v.15 statistical package, to analyse the effect of treatment on the result variable (utilization of health services, number and severity of somatic symptoms). Discussion It is necessary to develop more effective psychological treatments for somatoform disorders. This randomised clinical trial will determine whether cognitive behaviour therapy, both in group or in individual format, is effective for the treatment of these patients. Trial registration Current controlled trials ISRCTN69944771</p

Effect of Fibrin Glue on the Biomechanical Properties of Human Descemet's Membrane

10.1371/journal.pone.0037456PLoS ONE75

EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19

OBJECTIVES: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies. METHODS: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting. RESULTS: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates. CONCLUSIONS: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19

Study protocol of psychometric properties of the Spanish translation of a competence test in evidence based practice: The Fresno test

<p>Abstract</p> <p>Background</p> <p>There are few high-quality instruments for evaluating the effectiveness of Evidence-Based Practice (EBP) curricula with objective outcomes measures. The Fresno test is an instrument that evaluates most of EBP steps with a high reliability and validity in the English original version. The present study has the aims to translate the Fresno questionnaire into Spanish and its subsequent validation to ensure the equivalence of the Spanish version against the English original.</p> <p>Methods and design</p> <p>The questionnaire will be translated with the back translation technique and tested in Primary Care Teaching Units in Catalonia (PCTU). Participants will be: (a) tutors of Family Medicine residents (expert group); (b) Family Medicine residents in their second year of the Family Medicine training program (novice group), and (c) Family Medicine physicians (intermediate group). The questionnaire will be administered before and after an educational intervention. The educational intervention will be an interactive four half-day sessions designed to develop the knowledge and skills required to EBP. Responsiveness statistics used in the analysis will be the effect size, the standardised response mean and Guyatt's method. For internal consistency reliability, two measures will be used: corrected item-total correlations and Cronbach's alpha. Inter-rater reliability will be tested using Kappa coefficient for qualitative items and intra-class correlation coefficient for quantitative items and the overall score. Construct validity, item difficulty, item discrimination and feasibility will be determined.</p> <p>Discussion</p> <p>The validation of the Fresno questionnaire into different languages will enable the expansion of the questionnaire, as well as allowing comparison between countries and the evaluation of different teaching models.</p

Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

\ua9 The Author(s) 2024. The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer’s Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer’s Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis