The emotionally exhausted treating the mentally unwell? A systematic review of burnout and stress interventions for psychologists.

Healthcare providers are at high risk of occupational burnout, which has negative implications on the individual, their profession, the organisation and their patients. Psychologists are particularly susceptible to the repercussions of burnout due to the emotionally draining nature and content of their work. However, research has failed to outline and evaluate effective interventions for burnout within the profession. This study aimed to investigate the treatment effectiveness of burnout through a systematic literature review. Systematic searches of four databases using Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were conducted. A total of 4832 articles were identified, and 15 were included in the final analysis. The search was limited to scholarly and peer-reviewed journals published in the English language, which measured and utilised a form of intervention for the treatment of burnout or stress and included participants within the psychology profession. Interventions identified included mindfulness, training courses, self-care and other therapy-based forms of interventions. Approximately 60% of study participants reported moderate to high levels of stress. Interventions were largely variable in modality, frequency and duration of sessions and follow-up period. Of the 15 studies included within the review, only four measured burnout as an outcome variable, while the others measured stress. Findings of this systematic review indicate that mindfulness-based interventions may be a starting point for reducing stress; however, the most effective intervention for psychologists who have reached burnout is largely unclear. It is recommended that future studies focus on the identification and measurement of burnout, are more rigorously designed and reported and consider peer-based online support approaches.

Debiased ambient vibrations optical coherence elastography to profile cell, organoid and tissue mechanical properties.

The role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in on-line tissue mechanical assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering.

Factor structure of the Young Positive Schema Questionnaire in an eating disorder sample.

PURPOSE: The Young Positive Schema Questionnaire (YPSQ) measures early adaptive schemas (EAS) which could be used to develop positive psychology and schema-based interventions to benefit the treatment of eating disorders (EDs). METHODS: The present study investigated the factor structure of the YPSQ in a sample of 826 participants (18-73 years; n = 753 women) with ED symptomatology (e.g., restricting, binging, and purging). The sample was randomly split into two groups for exploratory and confirmatory factor analyses. Full sample analysis using Pearson correlations was conducted to explore convergent validity of the new YSPQ factor structure with ED symptomatology, emotional regulation, and cognitive flexibility. RESULTS: A nine-factor model was found, demonstrating good fit indices and internal consistency (α = 0.77-0.92). The YPSQ showed an inverse relationship to ED symptomatology and emotional suppression, and a positive relationship with cognitive flexibility and emotion reappraisal. CONCLUSION: Further research is needed to explore the clinical benefits of the YPSQ to identify EAS deficits in individuals with EDs to improve treatment outcomes. LEVEL OF EVIDENCE: Level V, descriptive study.

Exploring the association between early adaptive schemas and self-reported eating disorder symptomatology.

OBJECTIVE: The current study aimed to examine the relationship between early adaptive schemas and eating disorder symptomatology in adults. METHOD: A cross-sectional, correlational design was used to collect data from 352 females and 36 males aged between 18 and 49 years (M = 25.70, SD = 7.04). Participants completed an online questionnaire, which included The Young Positive Schema Questionnaire (YPSQ), Eating Disorder Examination-Questionnaire (EDE-Q) and demographic measures. RESULTS: Four separate hierarchical multiple regression analyses showed that high levels of Healthy Boundaries and low levels of Optimism significantly predicted lower Restraint, Eating Concern, Shape Concern and Weight Concern scores. Additionally, higher scores in Emotional Openness and Social Belonging significantly predicted lower Eating Concern, while higher scores in Self-Care significantly predicted lower levels of Shape Concern. CONCLUSION: The findings highlight the protective function that certain early adaptive schemas may play in mitigating eating disorder symptomatology. Moreover, the findings allude to potential modifiable therapy targets in the treatment of eating disorders. Further research is needed to investigate any differences in early adaptive schemas between eating disorder diagnoses.

Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes.

A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.

Early maladaptive schemas in eating disorders: A systematic review.

OBJECTIVE: Research and theory suggest the aetiological nature and symptomatic profile of eating disorders (EDs) can be explained by multiple factors, including the development of early maladaptive schemas (EMS). Yet, there is lack of consensus regarding the evidence supporting the relationship between EMS and EDs. Therefore, this systematic review aimed to examine existing literature concerning the relationship between different ED diagnoses and EMS to provide a synthesis and evaluation of relevant research. METHOD: A comprehensive literature search of four electronic databases was conducted and studies were included that examined the association between EMS and EDs. Studies were required to use a variant of Young Schema Questionnaire and establish ED diagnosis or symptomology using self-report questionnaires or clinical interview. RESULTS: A total of 29 studies were included in the review. Compared to healthy controls and varying clinical populations, individuals with EDs generally reported significantly higher scores across all EMS except for Entitlement. Furthermore, Unrelenting Standards consistently appeared as a significant EMS across all ED diagnoses whilst Insufficient Self-Control was significantly lower in ED diagnoses with restrictive behaviour compared to diagnoses with binge eating or purging behaviour. DISCUSSION: Research supports significant associations between EMS and EDs, which may contribute to our understanding of ED aetiology, including different diagnostic categories. This review underscores the need for studies to explore more gender and age diverse samples and highlights important implications for practitioners.

Model Unity and the Unity of Consciousness: Developments in Expected Float Entropy Minimisation.

The unity of consciousness, or, more precisely, phenomenal unity, is an important property of consciousness and an important area of research in mathematical consciousness science and the scientific study of consciousness. Due to the numerous aspects and complexity of consciousness, the property tends to engender loose or inadequate characterizations. In this article, we introduce the concept and mathematical formulation of model unity. A system has model unity if a single relational model, stretched across the whole system, is optimal. Alternatively, model unity may only be present for subsystems, although there may still be unity at some higher level. As a development in the theory of expected float entropy minimisation, such relational models provide an interpretation of system states and the theory may help to provide insights into questions such as why experience of the visual field is unified and why different people do not have a unified consciousness, for example. This article constitutes a relatively small initial study of model unity. Four investigations were undertaken and are given as examples. A postulate is also given, distilling the foundations of EFE minimisation into a clear statement allowing others to consider whether or not the postulate identifies a self-evident fundamental property of consciousness.

Self-perceptions of aging: A systematic review of longitudinal studies.

As the population of older adults increases, it is important to understand what may assist every older person to live well and longer. Using a systematic review, this study examined the longitudinal consequences of self-perceptions of aging (SPA), a measure of internalized stereotypes of aging, in participants 50 years or older. The sample comprised 21 studies published in English that used the Attitudes Toward Own Aging (ATOA) scale to measure SPA. Studies were conducted in the United States (10), Germany (7), Australia (2), and one each from Israel and Switzerland. Risk of bias was low, study design and assessment showed good to high quality, and the ATOA scale was reliable in all studies. Primary outcomes were physiological (N = 15; longevity and better health, health behaviors, and diseases) and psychological (N = 6; depression, cognitive function, and other psychological outcomes) rather than social. More positive SPA was consistently associated with healthier longitudinal outcomes, including better self-rated health and less obesity, greater longevity, better performance of the activities of daily living, less depression, and better cognitive functioning (including reductions in cognitive decline and incidence of dementia). These were both direct and indirect pathways and provide support for the consequences of aging stereotypes, providing support for Levy's Stereotype Embodiment theory. The results have public health implications, broadly as community messaging about the benefits of positive SPA and usual and healthy aging, and more narrowly in using ATOA to screen for middle-aged adults with negative SPA to prevent future physical and psychological decline. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Massively Multiplayer Online Games and Well-Being: A Systematic Literature Review.

Background: Massively multiplayer online games (MMOs) evolve online, whilst engaging large numbers of participants who play concurrently. Their online socialization component is a primary reason for their high popularity. Interestingly, the adverse effects of MMOs have attracted significant attention compared to their potential benefits. Methods: To address this deficit, employing PRISMA guidelines, this systematic review aimed to summarize empirical evidence regarding a range of interpersonal and intrapersonal MMO well-being outcomes for those older than 13. Results: Three databases identified 18 relevant English language studies, 13 quantitative, 4 qualitative and 1 mixed method published between January 2012 and August 2020. A narrative synthesis methodology was employed, whilst validated tools appraised risk of bias and study quality. Conclusions: A significant positive relationship between playing MMOs and social well-being was concluded, irrespective of one's age and/or their casual or immersed gaming patterns. This finding should be considered in the light of the limited: (a) game platforms investigated; (b) well-being constructs identified; and (c) research quality (i.e., modest). Nonetheless, conclusions are of relevance for game developers and health professionals, who should be cognizant of the significant MMOs-well-being association(s). Future research should focus on broadening the well-being constructs investigated, whilst enhancing the applied methodologies.

Internet Use by People with Intellectual Disability: Exploring Digital Inequality-A Systematic Review.

Many people with intellectual disability experience digital inequality due to a lack of Internet access; this is known as the digital divide. Digital inequality is also apparent when people with intellectual disability have Internet access, but only use it for a small number of applications (e.g., watching videos and playing games). Recently, it has been suggested that digital inequality also occurs in situations where some Internet users are less likely than others to translate their online activities to offline resources, including educational outcomes and social capital. The extent to which people with intellectual disability are translating their online activities to offline resources has not been examined. We conducted a systematic and critical review using PRISMA guidelines. The search strategy terms "intellectual disability" and "Internet use" were used to search the databases: Scopus; Wiley Online Library; Psychiatry Online; Web of Science; CINAHL; and PubMed. Twenty-four studies were found, which described 53 types of Internet use, 48 risks of Internet use, and 28 benefits of Internet use. The data were identified thematically and categorized to facilitate comparisons. The most frequently reported types of Internet use were in the category of social media/social networking (23%), the most common Internet risks were in the category of emotional distress (24%), and the most often reported benefits were in the category of friendships and social connection (33%). The findings indicate that the benefits of Internet use for people with intellectual disability have received much less attention than the risks.

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists.

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2A AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2A AR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A2A AR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2A AR, an emerging target in immuno-oncology.

Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine.

Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.

Accurate Prediction of GPCR Ligand Binding Affinity with Free Energy Perturbation.

The computational prediction of relative binding free energies is a crucial goal for drug discovery, and G protein-coupled receptors (GPCRs) are arguably the most important drug target class. However, they present increased complexity to model compared to soluble globular proteins. Despite breakthroughs, experimental X-ray crystal and cryo-EM structures are challenging to attain, meaning computational models of the receptor and ligand binding mode are sometimes necessary. This leads to uncertainty in understanding ligand-protein binding induced changes such as, water positioning and displacement, side chain positioning, hydrogen bond networks, and the overall structure of the hydration shell around the ligand and protein. In other words, the very elements that define structure activity relationships (SARs) and are crucial for accurate binding free energy calculations are typically more uncertain for GPCRs. In this work we use free energy perturbation (FEP) to predict the relative binding free energies for ligands of two different GPCRs. We pinpoint the key aspects for success such as the important role of key water molecules, amino acid ionization states, and the benefit of equilibration with specific ligands. Initial calculations following typical FEP setup and execution protocols delivered no correlation with experiment, but we show how results are improved in a logical and systematic way. This approach gave, in the best cases, a coefficient of determination (R2) compared with experiment in the range of 0.6-0.9 and mean unsigned errors compared to experiment of 0.6-0.7 kcal/mol. We anticipate that our findings will be applicable to other difficult-to-model protein ligand data sets and be of wide interest for the community to continue improving FE binding energy predictions.

Blur resolved OCT: full-range interferometric synthetic aperture microscopy through dispersion encoding.

We present a computational method for full-range interferometric synthetic aperture microscopy (ISAM) under dispersion encoding. With this, one can effectively double the depth range of optical coherence tomography (OCT), whilst dramatically enhancing the spatial resolution away from the focal plane. To this end, we propose a model-based iterative reconstruction (MBIR) method, where ISAM is directly considered in an optimization approach, and we make the discovery that sparsity promoting regularization effectively recovers the full-range signal. Within this work, we adopt an optimal nonuniform discrete fast Fourier transform (NUFFT) implementation of ISAM, which is both fast and numerically stable throughout iterations. We validate our method with several complex samples, scanned with a commercial SD-OCT system with no hardware modification. With this, we both demonstrate full-range ISAM imaging and significantly outperform combinations of existing methods.

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.

The orexin system, which consists of the two G protein-coupled receptors OX1 and OX2, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX1 and OX2 can be achieved are discussed.

Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design.

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C3476.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.

Understanding Ligand Binding Selectivity in a Prototypical GPCR Family.

Adenosine receptors are involved in many pathological conditions and are thus promising drug targets. However, developing drugs that target this GPCR subfamily is a challenging task. A number of drug candidates fail due to lack of selectivity which results in unwanted side effects. The extensive structural similarity of adenosine receptors complicates the design of selective ligands. The problem of selective targeting is a general concern in GPCRs, and in this respect adenosine receptors are a prototypical example. Here we use enhanced sampling simulations to decipher the determinants of selectivity of ligands in A2a and A1 adenosine receptors. Our model shows how small differences in the binding pocket and in the water network around the ligand can be leveraged to achieve selectivity.

Analysis of tractable allosteric sites in G protein-coupled receptors.

Allosteric modulation of G protein-coupled receptors represent a promising mechanism of pharmacological intervention. Dramatic developments witnessed in the structural biology of membrane proteins continue to reveal that the binding sites of allosteric modulators are widely distributed, including along protein surfaces. Here we restrict consideration to intrahelical and intracellular sites together with allosteric conformational locks, and show that the protein mapping tools FTMap and FTSite identify 83% and 88% of such experimentally confirmed allosteric sites within the three strongest sites found. The methods were also able to find partially hidden allosteric sites that were not fully formed in X-ray structures crystallized in the absence of allosteric ligands. These results confirm that the intrahelical sites capable of binding druglike allosteric modulators are among the strongest ligand recognition sites in a large fraction of GPCRs and suggest that both FTMap and FTSite are useful tools for identifying allosteric sites and to aid in the design of such compounds in a range of GPCR targets.

Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures.

Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu5 receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is rotated by 180° compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and mavoglurant and by the unexpected water-mediated receptor interactions of a new chemotype represented by fenobam. The implications of the new structures for ligand design are discussed, with extensive analysis of the energetics of the water networks of both pseudoapo and bound structures providing a new design strategy for allosteric modulators.