Behavioral Studies of p62 KO Animals with Implications of a Modulated Function of the Endocannabinoid System.

Elementary emotional states and memory can be regulated by the homeostasis of the endocannabinoid system (ECS). Links between the ECS and the autophagy receptor p62 have been found at the molecular level and in animal studies. This project aimed to validate the anxiety and memory phenotype of p62 knockout (KO) animals and whether the ECS plays a role in this. We examined the behavior of p62 KO animals and analyzed whether endocannabinoid levels are altered in the responsible brain areas. We discovered in age-dependent obese p62 KO mice decreased anandamide levels in the amygdala, a brain structure important for emotional responses. Against our expectation, p62 KO animals did not exhibit an anxiety phenotype, but showed slightly increased exploratory behavior as evidenced in novel object and further tests. In addition, KO animals exhibited decreased freezing responses in the fear conditioning. Administration of the phytocannabinoid delta9-tetrahydrocannabinol (THC) resulted in lesser effects on locomotion but in comparable hypothermic effects in p62 KO compared with WT littermates. Our results do not confirm previously published results, as our mouse line does not exhibit a drastic behavioral phenotype. Moreover, we identified further indications of a connection to the ECS and hence offer new perspectives for future investigations.

Impact of the Endocannabinoid System on Bone Formation and Remodeling in p62 KO Mice.

Several studies have shown that the G-protein coupled cannabinoid receptor CB2 and its interaction partner p62 are molecularly involved in bone remodeling processes. Pharmacological activation of the CB2 receptor enhanced bone volume in postmenopausal osteoporosis and arthritis models in rodents, whereas knockout or mutation of the p62 protein in aged mice led to Paget's disease of bone-like conditions. Studies of pharmacological CB2 agonist effects on bone metabolism in p62 KO mice have not been performed to date. Here, we assessed the effect of the CB2-specific agonist JWH133 after a short-term (5 days in 3-month-old mice) or long-term (4 weeks in 6-month-old mice) treatment on structural, dynamic, and cellular bone morphometry obtained by µCT of the femur and histomorphometry of the vertebral bodies in p62 KO mice and their WT littermates in vivo. A genotype-independent stimulatory effect of CB2 on bone formation, trabecular number, and trabecular thickness after short-term treatment and on tissue mineral density after long-term treatment was detected, indicating a weak osteoanabolic function of this CB2 agonist. Moreover, after short-term systemic CB2 receptor activation, we found significant differences at the cellular level in the number of osteoblasts and osteoclasts only in p62 KO mice, together with a weak increase in trabecular number and a decrease in trabecular separation. Long-term treatment showed an opposite JWH133 effect on osteoclasts in WT versus p62 KO animals and decreased cortical thickness only in treated p62 KO mice. Our results provide new insights into CB2 receptor signaling in vivo and suggest that CB2 agonist activity may be regulated by the presence of its macromolecular binding partner p62.

Young children's screen time during the first COVID-19 lockdown in 12 countries.

Older children with online schooling requirements, unsurprisingly, were reported to have increased screen time during the first COVID-19 lockdown in many countries. Here, we ask whether younger children with no similar online schooling requirements also had increased screen time during lockdown. We examined children's screen time during the first COVID-19 lockdown in a large cohort (n = 2209) of 8-to-36-month-olds sampled from 15 labs across 12 countries. Caregivers reported that toddlers with no online schooling requirements were exposed to more screen time during lockdown than before lockdown. While this was exacerbated for countries with longer lockdowns, there was no evidence that the increase in screen time during lockdown was associated with socio-demographic variables, such as child age and socio-economic status (SES). However, screen time during lockdown was negatively associated with SES and positively associated with child age, caregiver screen time, and attitudes towards children's screen time. The results highlight the impact of the COVID-19 lockdown on young children's screen time.

Doctor at Your Fingertips: An Exploration of Digital Visits from Stakeholders' Perspectives.

Technological advances and the evolution of mobile technologies enable patients to meet their doctors through their smartphones. While offering the opportunity of digital visits to patients, there are also challenges for this development. The purpose of this study is to enhance the understanding of digital visits, as perceived by experts working in telemedicine companies. To serve this purpose, the authors conducted semi-structured interviews with managers and employees in eight telemedicine companies. The analysis of the empirical data confirmed the importance of digital visits and their efficiency. The potential of digital visits is expected to increase significantly, should they make use of remote devices to transfer real-time data from patients to physicians. In such a case, digital visits are expected to cover approximately 70-75% of medical cases. However, the use of remote devices must be taken with caution and specific conditions need to be taken into account. We encourage researchers to perform research on promising technologies such as artificial intelligence and remote diagnostic devices, which could make more diagnoses and conditions possible to be treated by digital visits. This is even more important in light of the ongoing Covid-19 pandemic.

Promotion by Education: Adolescent Mental Health Policy Translation in a Local Context of China.

The purpose of this paper is to describe how Chinese national adolescent mental health policy is translated into local plans and practice by means of the theoretical perspective of the policy triangle. Document analysis of national, provincial and local policy documents and semi-structured interviews with local policy actors were performed. National policies were implemented by a top-down process. The ministries were strong policy-makers on the national level, while the policy actors at the local level were mainly found in the educational sector. The content of the policy actions was moral education, knowledge dissemination and learning, rather than counselling and treatment.

Correction to: Mitochondrial phylogeography of baboons (Papio spp.) - Indication for introgressive hybridization?

Following publication of the original article [1], we have been notified that some of the NCB accession numbers were incorrectly associated to their corresponding taxon in the Additional file 1.

Systematic Affinity Purification Coupled to Mass Spectrometry Identified p62 as Part of the Cannabinoid Receptor CB2 Interactome.

The endocannabinoid system (ECS) consists particularly of cannabinoid receptors 1 and 2 (CB1 and CB2), their endogenous ligands, and enzymes that synthesize and degrade their ligands. It acts in a variety of organs and disease states ranging from cancer progression over neuropathic pain to neurodegeneration. Protein components engaged in the signaling, trafficking, and homeostasis machinery of the G-protein coupled CB2, are however largely unknown. It is therefore important to identify further interaction partners to better understand CB2 receptor functions in physiology and pathophysiology. For this purpose, we used an affinity purification and mass spectrometry-based proteomics approach of Strep-HA-CB2 receptor in HEK293 cells. After subtraction of background interactions and protein frequency library assessment we could identify 83 proteins that were classified by the identification of minimally 2 unique peptides as highly probable interactors. A functional protein association network analysis obtained an interaction network with a significant enrichment of proteins functionally involved in protein metabolic process, in endoplasmic reticulum, response to stress but also in lipid metabolism and membrane organization. The network especially contains proteins involved in biosynthesis and trafficking like calnexin, Sec61A, tubulin chains TUBA1C and TUBB2B, TMED2, and TMED10. Six proteins that were only expressed in stable CB2 expressing cells were DHC24, DHRS7, GGT7, HECD3, KIAA2013, and PLS1. To exemplify the validity of our approach, we chose a candidate having a relatively low number of edges in the network to increase the likelihood of a direct protein interaction with CB2 and focused on the scaffold/phagosomal protein p62/SQSTM1. Indeed, we independently confirmed the interaction by co-immunoprecipitation and immunocytochemical colocalization studies. 3D reconstruction of confocal images furthermore showed CB2 localization in close proximity to p62 positive vesicles at the cell membrane. In summary, we provide a comprehensive repository of the CB2 interactome in HEK293 cells identified by a systematic unbiased approach, which can be used in future experiments to decipher the signaling and trafficking complex of this cannabinoid receptor. Future studies will have to analyze the exact mechanism of the p62-CB2 interaction as well as its putative role in disease pathophysiology.

Stable Adult Hippocampal Neurogenesis in Cannabinoid Receptor CB2 Deficient Mice.

The G-protein coupled cannabinoid receptor 2 (CB2) has been implicated in the regulation of adult neurogenesis in the hippocampus. The contribution of CB2 towards basal levels of proliferation and the number of neural progenitors in the subgranular zone (SGZ) of the dentate gyrus, however, remain unclear. We stained hippocampal brain sections of 16- to 17-week-old wildtype and CB2-deficient mice, for neural progenitor and immature neuron markers doublecortin (DCX) and calretinin (CR) and for the proliferation marker Ki67 and quantified the number of positive cells in the SGZ. The quantification revealed that CB2 deficiency neither altered overall cell proliferation nor the size of the DCX+ or DCX and CR double-positive populations in the SGZ compared to control animals. The results indicate that CB2 might not contribute to basal levels of adult neurogenesis in four-month-old healthy mice. CB2 signaling might be more relevant in conditions where adult neurogenesis is dynamically regulated, such as neuroinflammation.

Prevalence and correlates of positive mental health in Chinese adolescents.

BACKGROUND: Studies investigating the prevalence of positive mental health and its correlates are still scarce compared to the studies on mental disorders, although there is growing interest of assessing positive mental health in adolescents. So far, no other study examining the prevalence and determinants of positive mental health in Chinese adolescents has been found. The purpose of this study was to assess the prevalence and correlates of positive mental health in Chinese adolescents. METHODS: This cross-sectional study used a questionnaire including Mental Health Continuum-Short Form (MHC-SF) and items regarding multiple aspects of adolescent life. The sample involved a total of 5399 students from grade 8 and 10 in Weifang, China. Multivariate Logistic regression analyses were performed to evaluate the associations between potential indicators regarding socio-economic situations, life style, social support and school life and positive mental health and calculate odds ratios and 95% confidence intervals. RESULTS: More than half (57.4%) of the participants were diagnosed as flourishing. The correlated factors of positive mental health in regression models included gender, perceived family economy, the occurrence of sibling(s), satisfaction of self-appearance, physical activity, sleep quality, stress, social trust, desire to learn, support from teachers and parents as well as whether being bullied at school (OR ranging from 1.23 to 2.75). The Hosmer-Lemeshow p-value for the final regression model (0.45) indicated adequate model fit. CONCLUSION: This study gives the first overview on prevalence and correlates of positive mental health in Chinese adolescents. The prevalence of positive mental health in Chinese adolescents is higher than reported in most of the previous studies also using MHC-SF. Our findings suggest that adolescents with advantageous socio-economic situations, life style, social support and school life are experiencing better positive mental health than others.

Staffs' and managers' perceptions of how and when discrete event simulation modelling can be used as a decision support in quality improvement: a focus group discussion study at two hospital settings in Sweden.

OBJECTIVE: To explore healthcare staffs' and managers' perceptions of how and when discrete event simulation modelling can be used as a decision support in improvement efforts. DESIGN: Two focus group discussions were performed. SETTING: Two settings were included: a rheumatology department and an orthopaedic section both situated in Sweden. PARTICIPANTS: Healthcare staff and managers (n=13) from the two settings. INTERVENTIONS: Two workshops were performed, one at each setting. Workshops were initiated by a short introduction to simulation modelling. Results from the respective simulation model were then presented and discussed in the following focus group discussion. RESULTS: Categories from the content analysis are presented according to the following research questions: how and when simulation modelling can assist healthcare improvement? Regarding how, the participants mentioned that simulation modelling could act as a tool for support and a way to visualise problems, potential solutions and their effects. Regarding when, simulation modelling could be used both locally and by management, as well as a pedagogical tool to develop and test innovative ideas and to involve everyone in the improvement work. CONCLUSIONS: Its potential as an information and communication tool and as an instrument for pedagogic work within healthcare improvement render a broader application and value of simulation modelling than previously reported.

Psychometric evaluation of the Mental Health Continuum-Short Form (MHC-SF) in Chinese adolescents - a methodological study.

BACKGROUND: In epidemiological surveillance of mental health there is good reason to also include scales that measure the presence of well-being rather than merely symptoms of ill health. The Mental Health Continuum-Short Form (MHC-SF) is a self-reported scale to measure emotional, psychological and social well-being and conduct categorical diagnosis of positive mental health. This particular instrument includes the three core components of the World Health Organization's definition of mental health and had previously not been psychometrically evaluated on adolescents in China. METHODS: In total 5,399 students (51.1% female) from schools in the urban areas of Weifang in China were included in the study (mean age = 15.13, SD = 1.56). Participants completed a comprehensive questionnaire with several scales, among them the MHC-SF. Statistical analyses to evaluate reliability, structural validity, measurement invariance, presence of floor and ceiling effects and to some extent external validity of the MHC-SF were carried out. RESULTS: The Cronbach's α coefficients for sub-scales as well as the total scale were all above 0.80 indicating good reliability. Confirmative factor analysis confirmed the three-dimensional structure of the Chinese version of MHC-SF and supported the configural and metric invariance across gender and age. Noteworthy ceiling effects were observed for single items and sub-scales although not for the total scale. More importantly, observed floor effects were negligible. The stronger correlation found between MHC-SF and Minneapolis-Manchester Quality of Life Instrument (as measure of positive mental health) than between MHC-SF and Hospital Anxiety Depression Scale (as measure of mental illness and distress) yielded support for external validity. CONCLUSION: In conclusion, the main findings of this study are in line with studies from other countries that evaluated the psychometric properties of the MHC-SF and show that this instrument, that includes the three core components of the WHO definition of mental health, is useful in assessing positive adolescent mental health also in China.

A Mobile Internet Service for Self-Management of Physical Activity in People With Rheumatoid Arthritis: Challenges in Advancing the Co-Design Process During the Requirements Specification Phase.

BACKGROUND: User involvement in the development of health care services is important for the viability, usability, and effectiveness of services. This study reports on the second step of the co-design process. OBJECTIVE: The aim was to explore the significant challenges in advancing the co-design process during the requirements specification phase of a mobile Internet service for the self-management of physical activity (PA) in rheumatoid arthritis (RA). METHODS: A participatory action research design was used to involve lead users and stakeholders as co-designers. Lead users (n=5), a clinical physiotherapist (n=1), researchers (n=2) with knowledge in PA in RA and behavioral learning theories, an eHealth strategist (n=1), and an officer from the patient organization (n=1) collaborated in 4 workshops. Data-collection methods included video recordings and naturalistic observations. RESULTS: The inductive qualitative video-based analysis resulted in 1 overarching theme, merging perspectives, and 2 subthemes reflecting different aspects of merging: (1) finding a common starting point and (2) deciding on design solutions. Seven categories illustrated the specific challenges: reaching shared understanding of goals, clarifying and handling the complexity of participants' roles, clarifying terminology related to system development, establishing the rationale for features, negotiating features, transforming ideas into concrete features, and participants' alignment with the agreed goal and task. CONCLUSIONS: Co-designing the system requirements of a mobile Internet service including multiple stakeholders was a complex and extensive collaborative decision-making process. Considering, valuing, counterbalancing, and integrating different perspectives into agreements and solutions (ie, the merging of participants' perspectives) were crucial for moving the process forward and were considered the core challenges of co-design. Further research is needed to replicate the results and to increase knowledge on key factors for a successful co-design of health care services.

Development of a web-based and mobile app to support physical activity in individuals with rheumatoid arthritis: results from the second step of a co-design process.

BACKGROUND: Long-term adherence to physical activity recommendations remains challenging for most individuals with rheumatoid arthritis (RA) despite evidence for its health benefits. OBJECTIVE: The aim of this study was to provide basic data on system requirement specifications for a Web-based and mobile app to self-manage physical activity. More specifically, we explored the target user group, features of the future app, and correlations between the system requirements and the established behavior change techniques (BCTs). METHODS: We used a participatory action research design. Qualitative data were collected using multiple methods in four workshops. Participants were 5 individuals with RA, a clinical physiotherapist, an officer from the Swedish Rheumatism Association, a Web designer, and 2 physiotherapy researchers. A taxonomy was used to determine the degree of correlation between the system requirements and established BCTs. RESULTS: Participants agreed that the future Web-based and mobile app should be based on two major components important for maintaining physical activity: (1) a calendar feature for goal setting, planning, and recording of physical activity performance and progress, and (2) a small community feature for positive feedback and support from peers. All system requirements correlated with established BCTs, which were coded as 24 different BCTs. CONCLUSIONS: To our knowledge, this study is the first to involve individuals with RA as co-designers, in collaboration with clinicians, researchers, and Web designers, to produce basic data to generate system requirement specifications for an eHealth service. The system requirements correlated to the BCTs, making specifications of content and future evaluation of effectiveness possible.

Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker.

Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.

Continuous innovation: developing and using a clinical database with new technology for patient-centred care--the case of the Swedish quality register for arthritis.

OBJECTIVE: We describe and explain the development of a clinical quality database and its use for different clinical, management and patient empowerment purposes. DESIGN: A longitudinal case study covering 1993-2009. SETTING: Rheumatology departments in Swedish hospitals. PARTICIPANTS: Those involved in developing the clinical database and its applications and a limited number of users. INTERVENTION(S): Different methods for inputting and storing clinical and patient data and for analysing and presenting the data to providers and patients. MAIN OUTCOME MEASURE(S): Participants' perceptions of the value of different applications and of influences, which helped and hindered the development of the system. RESULTS: Different innovations were introduced at different times continually to increase the ultility of the clinical data and the clinic- and patient coverage of the clinical data system. Limited interview data show postive patient and provider perceptions of the latest application to collect and present data as time trend visual display in the clinical consultation. CONCLUSIONS: A longitudinal perspective revealed how a clinical quality register was developed and how new technologies not imagined in the early 1990s continue to increase the ultility and value of the clinical database. This historical perspective provided limited evidence of impact, but does provide lessons for current strategies for innovation for quality in health care and of the need to consider innovolution processes, rather than discrete innovations, given the rapid pace of change in new technologies. More evidence is needed of the impact of such registers, and of enhancements, on providers and patients and on costs.

Implementing organisation and management innovations in Swedish healthcare: lessons from a comparison of 12 cases.

PURPOSE: The purpose of this paper is to compare the implementation of 12 different organisation and management innovations (OMIs) in Swedish healthcare, to discover the generic and specific factors important for successful healthcare improvement change in a public health system. DESIGN/METHODOLOGY/APPROACH: Longitudinal cross-case comparison of 12 case studies was employed, where each case study used a common framework for collecting data about the process of change, the content of the change, the context, and the intermediate and final outcomes. FINDINGS: Clinical leaders played a more important part in the development of these successful service innovations than managers. Strategies for and patterns of change implementation were found to differ according to the type of innovation. Internal organisational context factors played a significant role in the development of nearly all, but external factors did not. "Developmental evolution" better described the change process than "implementation". RESEARCH LIMITATIONS/IMPLICATIONS: The 12 cases were all of relatively successful change processes: some unsuccessful examples would have provided additional testing of the hypotheses about what would predict successful innovation which were used in the case comparison. The cross-case comparative hypothesis testing method allows systematic comparison if the case data are collected using similar frameworks, but this approach to management research requires considerable resources and coordination. PRACTICAL IMPLICATIONS: Management innovations that improve patient care can be carried out successfully by senior clinicians, under certain circumstances. A systematic approach is important both for developing and adapting an innovation to a changing situation. A significant amount of time was required for all involved, which could be reduced by "fast-tracking" approval for some types of change. ORIGINALITY/VALUE: This is the first empirical report comparing longitudinal and contextualised findings from a number of case studies of different organisational and management healthcare innovations. The findings made possible explanations for success factors and useful practical recommendations for conditions needed to nurture such innovation in public healthcare.

Sources of acoustic variation: implications for production specificity and call categorization in chacma baboon (Papio ursinus) grunts.

Elucidating the information content of vocal signals is fundamental to the understanding of animal communication. Acoustically distinct calls produced in specific contexts allow listeners to predict future events and choose adequate responses. However, the vocal repertoires of most terrestrial mammals consist of a limited number of call types that vary within and between categories. These "graded signaling systems" are thought to be rich in information, at the cost of increasing uncertainty regarding call categorization. In this study, patterns of acoustic variation in grunts of wild chacma baboons (Papio ursinus) were assessed in relation to different contexts, callers' arousal, the presence of listeners, and individual identity. Although overall production specificity was low, and sensitive to the number of contexts under consideration, grunts given in three contexts could be statistically distinguished from each other. Contextual differences remained when controlling for caller arousal, suggesting that these differences cannot be explained by variation in arousal. No audience effect was detected, but individual identity was found to have an influence on acoustic structure. Overall, these results support the view that, in comparison to other signaling systems associated with hazardous conditions, lower production specificity might evolve under relaxed circumstances where unambiguous signaling is less important.

Managing health care decisions and improvement through simulation modeling.

Simulation modeling is a way to test changes in a computerized environment to give ideas for improvements before implementation. This article reviews research literature on simulation modeling as support for health care decision making. The aim is to investigate the experience and potential value of such decision support and quality of articles retrieved. A literature search was conducted, and the selection criteria yielded 59 articles derived from diverse applications and methods. Most met the stated research-quality criteria. This review identified how simulation can facilitate decision making and that it may induce learning. Furthermore, simulation offers immediate feedback about proposed changes, allows analysis of scenarios, and promotes communication on building a shared system view and understanding of how a complex system works. However, only 14 of the 59 articles reported on implementation experiences, including how decision making was supported. On the basis of these articles, we proposed steps essential for the success of simulation projects, not just in the computer, but also in clinical reality. We also presented a novel concept combining simulation modeling with the established plan-do-study-act cycle for improvement. Future scientific inquiries concerning implementation, impact, and the value for health care management are needed to realize the full potential of simulation modeling.