The strawberry-derived permeation enhancer pelargonidin enables oral protein delivery.

Although patients generally prefer oral drug delivery to injections, low permeability of the gastrointestinal tract makes this method impossible for most biomacromolecules. One potential solution is codelivery of macromolecules, including therapeutic proteins or nucleic acids, with intestinal permeation enhancers; however, enhancer use has been limited clinically by modest efficacy and toxicity concerns surrounding long-term administration. Here, we hypothesized that plant-based foods, which are well tolerated by the gastrointestinal tract, may contain compounds that enable oral macromolecular absorption without causing adverse effects. Upon testing more than 100 fruits, vegetables, and herbs, we identified strawberry and its red pigment, pelargonidin, as potent, well-tolerated enhancers of intestinal permeability. In mice, an oral capsule formulation comprising pelargonidin and a 1 U/kg dose of insulin reduced blood glucose levels for over 4 h, with bioactivity exceeding 100% relative to subcutaneous injection. Effects were reversible within 2 h and associated with actin and tight junction rearrangement. Furthermore, daily dosing of mice with pelargonidin for 1 mo resulted in no detectable side effects, including weight loss, tissue damage, or inflammatory responses. These data suggest that pelargonidin is an exceptionally effective enhancer of oral protein uptake that may be safe for routine pharmaceutical use.

Head-to-Head Comparison of Caco-2 Transwell and Gut-on-a-Chip Models for Assessing Oral Peptide Formulations.

Oral delivery of potent peptide drugs provides key formulation challenges in the pharmaceutical industry: stability, solubility, and permeability. Intestinal permeation enhancers (PEs) can overcome the low oral bioavailability by improving the drug permeability. Conventional in vitro and ex vivo models for assessing PEs fail to predict efficacy in vivo. Here, we compared Caco-2 cells cultured in the conventional static Transwell model to a commercially available continuous flow microfluidic Gut-on-a-Chip model. We determined baseline permeability of FITC-Dextan 3 kDa (FD3) in Transwell (5.3 ± 0.8 × 10-8 cm/s) vs Chip (3.2 ± 1.8 × 10-7 cm/s). We screened the concentration impact of two established PEs sodium caprate and sucrose monolaurate and indicated a requirement for higher enhancer concentration in the Chip model to elicit equivalent efficacy e.g., 10 mM sodium caprate in Transwells vs 25 mM in Chips. Fasted and fed state simulated intestinal fluids (FaSSIF/FeSSIF) were introduced into the Chip and increased basal FD3 permeability by 3-fold and 20-fold, respectively, compared to 4-fold and 4000-fold in Transwells. We assessed the utility of this model to peptides (Insulin and Octreotide) with PEs and observed much more modest permeability enhancement in the Chip model in line with observations in ex vivo and in vivo preclinical models. These data indicate that microfluidic Chip models are well suited to bridge the gap between conventional in vitro and in vivo models.

SEMA3: A free smartphone platform for daily life surveys.

Traditionally, behavioral, social, and health science researchers have relied on global/retrospective survey methods administered cross-sectionally (i.e., on a single occasion) or longitudinally (i.e., on several occasions separated by weeks, months, or years). More recently, social and health scientists have added daily life survey methods (also known as intensive longitudinal methods or ambulatory assessment) to their toolkit. These methods (e.g., daily diaries, experience sampling, ecological momentary assessment) involve dense repeated assessments in everyday settings. To facilitate research using daily life survey methods, we present SEMA3 ( http://www.SEMA3.com ), a platform for designing and administering intensive longitudinal daily life surveys via Android and iOS smartphones. SEMA3 fills an important gap by providing researchers with a free, intuitive, and flexible platform with basic and advanced functionality. In this article, we describe SEMA3's development history and system architecture, provide an overview of how to design a study using SEMA3 and outline its key features, and discuss the platform's limitations and propose directions for future development of SEMA3.

The effect of psychological treatment on repetitive negative thinking in youth depression and anxiety: a meta-analysis and meta-regression.

BACKGROUND: Depression and anxiety are prevalent in youth populations and typically emerge during adolescence. Repetitive negative thinking (RNT) is a putative transdiagnostic mechanism with consistent associations with depression and anxiety. Targeting transdiagnostic processes like RNT for youth depression and anxiety may offer more targeted, personalised and effective treatment. METHODS: A meta-analysis was conducted to examine the effect of psychological treatments on RNT, depression and anxiety symptoms in young people with depression or anxiety, and a meta-regression to examine relationships between outcomes. RESULTS: Twenty-eight randomised controlled trials examining 17 different psychological interventions were included. Effect sizes were small to moderate across all outcomes (Hedge's g depression = -0.47, CI -0.77 to -0.17; anxiety = -0.42, CI -0.65 to -0.20; RNT = -0.45, CI -0.67 to -0.23). RNT-focused and non-RNT focused approaches had comparable effects; however, those focusing on modifying the process of RNT had significantly larger effects on RNT than those focusing on modifying negative thought content. Meta-regression revealed a significant relationship between RNT and depression outcomes only across all intervention types and with both depression and anxiety for RNT focused interventions only. CONCLUSION: Consistent with findings in adults, this review provides evidence that reducing RNT with psychological treatment is associated with improvements in depression and anxiety in youth. Targeting RNT specifically may not lead to better outcomes compared to general approaches; however, focusing on modifying the process of RNT may be more effective than targeting content. Further research is needed to determine causal pathways.

Do mindfulness-based interventions change brain function in people with substance dependence? A systematic review of the fMRI evidence.

BACKGROUND: Substance use disorders (SUDs) affect ~ 35 million people globally and are associated with strong cravings, stress, and brain alterations. Mindfulness-based interventions (MBIs) can mitigate the adverse psychosocial outcomes of SUDs, but the underlying neurobiology is unclear. Emerging findings were systematically synthesised from fMRI studies about MBI-associated changes in brain function in SUDs and their associations with mindfulness, drug quantity, and craving. METHODS: PsycINFO, Medline, CINAHL, PubMed, Scopus, and Web of Science were searched. Seven studies met inclusion criteria. RESULTS: Group by time effects indicated that MBIs in SUDs (6 tobacco and 1 opioid) were associated with changes in the function of brain pathways implicated in mindfulness and addiction (e.g., anterior cingulate cortex and striatum), which correlated with greater mindfulness, lower craving and drug quantity. CONCLUSIONS: The evidence for fMRI-related changes with MBI in SUD is currently limited. More fMRI studies are required to identify how MBIs mitigate and facilitate recovery from aberrant brain functioning in SUDs.

Using EMPOWER in daily life: a qualitative investigation of implementation experiences.

BACKGROUND: Digital self-management tools blended with clinical triage and peer support have the potential to improve access to early warning signs (EWS) based relapse prevention in schizophrenia care. However, the implementation of digital interventions in psychosis can be poor. Traditionally, research focused on understanding how people implement interventions has focused on the perspectives of mental health staff. Digital interventions are becoming more commonly used by patients within the context of daily life, which means there is a need to understand implementation from the perspectives of patients and carers. METHODS: Semi-structured one-on-one interviews with 16 patients who had access to the EMPOWER digital self-management intervention during their participation in a feasibility trial, six mental health staff members who supported the patients and were enrolled in the trial, and one carer participant. Interviews focused on understanding implementation, including barriers and facilitators. Data were coded using thematic analysis. RESULTS: The intervention was well implemented, and EMPOWER was typically perceived positively by patients, mental health staff and the carer we spoke to. However, some patients reported negative views and reported ideas for intervention improvement. Patients reported valuing that the app afforded them access to things like information or increased social contact from peer support workers that went above and beyond that offered in routine care. Patients seemed motivated to continue implementing EMPOWER in daily life when they perceived it was creating positive change to their wellbeing, but seemed less motivated if this did not occur. Mental health staff and carer views suggest they developed increased confidence patients could self-manage and valued using the fact that people they support were using the EMPOWER intervention to open up conversations about self-management and wellbeing. CONCLUSIONS: The findings from this study suggest peer worker supported digital self-management like EMPOWER has the potential to be implemented. Further evaluations of these interventions are warranted, and conducting qualitative research on the feasibility gives insight into implementation barriers and facilitators, improving the likelihood of interventions being usable. In particular, the views of patients who demonstrated low usage levels would be valuable.

Neuroticism may not reflect emotional variability.

Neuroticism is one of the major traits describing human personality, and a predictor of mental and physical disorders with profound public health significance. Individual differences in emotional variability are thought to reflect the core of neuroticism. However, the empirical relation between emotional variability and neuroticism may be partially the result of a measurement artifact reflecting neuroticism's relation with higher mean levels-rather than greater variability-of negative emotion. When emotional intensity is measured using bounded scales, there is a dependency between variability and mean levels: at low (or high) intensity, it is impossible to demonstrate high variability. As neuroticism is positively associated with mean levels of negative emotion, this may account for the relation between neuroticism and emotional variability. In a metaanalysis of 11 studies (N = 1,205 participants; 83,411 observations), we tested whether the association between neuroticism and negative emotional variability was clouded by a dependency between variability and the mean. We found a medium-sized positive association between neuroticism and negative emotional variability, but, when using a relative variability index to correct for mean negative emotion, this association disappeared. This indicated that neuroticism was associated with experiencing more intense, but not more variable, negative emotions. Our findings call into question theory, measurement scales, and data suggesting that emotional variability is central to neuroticism. In doing so, they provide a revisionary perspective for understanding how this individual difference may predispose to mental and physical disorders.

The role of insight, social rank, mindfulness and self-compassion in depression following first episode psychosis.

Gaining awareness of psychosis (i.e., insight) is linked to depression, particularly in the post-acute phase of psychosis. Informed by social rank theory, we examined whether the insight-depression relationship is explained by reduced social rank related to psychosis and whether self-compassion (including uncompassionate self-responding [UCS] and compassionate self-responding [CSR]) and mindfulness buffered the relationship between social rank and depression in individuals with first episode psychosis during the post-acute phase. Participants were 145 young people (Mage  = 20.81; female = 66) with first episode psychosis approaching discharge from an early psychosis intervention centre. Questionnaires and interviews assessed insight, depressive symptoms, perceived social rank, self-compassion, mindfulness and illness severity. Results showed that insight was not significantly associated to depression and thus no mediation analysis was conducted. However, lower perceived social rank was related to higher depression, and this relationship was moderated by self-compassion and, more specifically, UCS. Mindfulness was related to depression but had no moderating effect on social rank and depression. Results supported previous findings that depressive symptoms are common during the post-acute phase. The role of insight in depression for this sample is unclear and may be less important during the post-acute phase than previously considered. Supporting social rank theory, the results suggest that low perceived social rank contributes to depression, and reducing UCS may ameliorate this effect. UCS, social rank and possibly mindfulness may be valuable intervention targets for depression intervention and prevention efforts in the recovery of psychosis.

Integrating digital interventions with clinical practice in youth mental health services.

OBJECTIVE: Integrating digital technologies with clinical practice promises to improve access and enhance care in the context of high service demand and constrained capacity. METHOD: We outline the emerging research in the integration of digital tools in clinical care, known as blended care, and provide case examples of mental health technology platforms currently in use, summarise findings regarding novel technologies such as virtual reality, and outline real-world implementation challenges and potential solutions. RESULTS: Recent evidence shows that blended care approaches are clinically effective and improve service efficiency. Youth-specific technologies such as moderated online social therapy (MOST) are achieving a range of positive clinical and functional outcomes, while emerging technologies like virtual reality have strong evidence in anxiety disorder, and accumulating evidence in psychotic conditions. Implementation science frameworks show promise in helping overcome the common challenges faced in real-world adoption and ongoing use. CONCLUSION: The integrated, blended use of digital mental health technologies with face-to-face clinical care has the potential to improve care quality for young people while helping overcome the growing challenges faced by youth mental health service providers.

A Comparison of Adolescent versus Young Adult Outpatients with First-Presentation Borderline Personality Disorder: Findings from the MOBY Randomized Controlled Trial.

OBJECTIVE: The increasing focus on adolescent personality disorder has tended to ignore evidence of the developmental continuity of the period from puberty to young adulthood. This study aims to: (1) describe the characteristics of a sample of young people with borderline personality disorder (BPD) who had no previous history of evidence-based treatment for the disorder and (2) compare their characteristics by participant age group. METHODS: One hundred and thirty-nine young people (15 to 25 years) with BPD, newly enrolled in the Monitoring Outcomes of BPD in Youth randomized controlled trial, completed semi-structured interview and self-report measures assessing demographic, clinical, and functional characteristics. Younger (aged 15 to 17 years; n = 64) and older (aged 18 to 25 years; n = 75) participants were compared on these same variables using t-tests, chi-square tests, and logistic regression. RESULTS: Young outpatients with BPD had extensive and severe psychopathology and were functioning poorly. Adolescents and young adults with BPD showed substantial similarities on 20 key aspects of their presentation. Significant between-groups differences were observed in household makeup, treatment history, antisocial personality disorder, emotion dysregulation, substance use, age of commencement and extent of self-harm, and achievement of age-appropriate educational milestones. Adolescent BPD group membership was predicted by family composition and self-harm, whereas young adult BPD group membership was predicted by not achieving age-appropriate milestones, vocational disengagement, and emotion dysregulation. The final model explained 54% of the variance and correctly classified 80.2% of the sample by age. CONCLUSIONS: Both adolescents and young adults with early stage BPD present with severe and often similar problems to one another, supporting developmental continuity across this age range. However, there are also meaningful differences in presentation, suggesting that pathways to care might differ by age and/or developmental stage. Detection and intervention for personality disorder should not be delayed until individuals reach 18 years of age.

A comparison of experiences of care and expressed emotion among caregivers of young people with first-episode psychosis or borderline personality disorder features.

OBJECTIVE: Caregivers of individuals with severe mental illness often experience significant negative experiences of care, which can be associated with higher levels of expressed emotion. Expressed emotion is potentially a modifiable target early in the course of illness, which might improve outcomes for caregivers and patients. However, expressed emotion and caregiver experiences in the early stages of disorders might be moderated by the type of severe mental illness. The aim was to determine whether experiences of the caregiver role and expressed emotion differ in caregivers of young people with first-episode psychosis versus young people with 'first-presentation' borderline personality disorder features. METHOD: Secondary analysis of baseline (pre-treatment) data from three clinical trials focused on improving caregiver outcomes for young people with first-episode psychosis and young people with borderline personality disorder features was conducted (ACTRN12616000968471, ACTRN12616000304437, ACTRN12618000616279). Caregivers completed self-report measures of experiences of the caregiver role and expressed emotion. Multivariate generalised linear models and moderation analyses were used to determine group differences. RESULTS: Data were available for 265 caregivers. Higher levels of negative experiences and expressed emotion, and stronger correlations between negative experiences and expressed emotion domains, were found in caregivers of young people with borderline personality disorder than first-episode psychosis. Caregiver group (borderline personality disorder, first-episode psychosis) moderated the relationship between expressed emotion and caregiver experiences in the domains of need to provide backup and positive personal experiences. CONCLUSION: Caregivers of young people with borderline personality disorder experience higher levels of negative experiences related to their role and expressed emotion compared with caregivers of young people with first-episode psychosis. The mechanisms underpinning associations between caregiver experiences and expressed emotion differ between these two caregiver groups, indicating that different supports are needed. For borderline personality disorder caregivers, emotional over-involvement is associated with both negative and positive experiences, so a more detailed understanding of the nature of emotional over-involvement for each relationship is required to guide action.

Digital Interventions for Psychological Well-being in University Students: Systematic Review and Meta-analysis.

BACKGROUND: Life at university provides important opportunities for personal growth; however, this developmental phase also coincides with the peak period of risk for the onset of mental health disorders. In addition, specific university lifestyle factors, including impaired sleep and academic and financial stress, are known to exacerbate psychological distress in students. As a result, university students have been identified as a vulnerable population who often experience significant barriers to accessing psychological treatment. Digital psychological interventions are emerging as a promising solution for this population, but their effectiveness remains unclear. OBJECTIVE: This systematic review and meta-analysis aimed to assess digital interventions targeting psychological well-being among university students. METHODS: Database searches were conducted on December 2, 2021, via Embase, MEDLINE, PsycINFO, and Web of Science. RESULTS: A total of 13 eligible studies were identified, 10 (77%) of which were included in the meta-analysis. Mean pre-post effect sizes indicated that such interventions led to small and significant improvement in psychological well-being (Hedges g=0.32, 95% CI 0.23-0.4; P<.001). These effects remained, albeit smaller, when studies that included a wait-list control group were excluded (Hedges g=0.22, 95% CI 0.08-0.35; P=.002). An analysis of acceptance and commitment therapy approaches revealed small and significant effects (k=6; Hedges g=0.35, 95% CI 0.25-0.45; P<.001). CONCLUSIONS: Digital psychological interventions hold considerable promise for university students, although features that optimize service delivery and outcomes require further assessment. TRIAL REGISTRATION: PROSPERO CRD42020196654; https:/www.crd.york.ac.uk/prospero/display_record.php?RecordID=196654.

Formulation, Characterisation and Evaluation of the Antihypertensive Peptides, Isoleucine-Proline-Proline and Leucine-Lysine-Proline in Chitosan Nanoparticles Coated with Zein for Oral Drug Delivery.

Isoleucine-Proline-Proline (IPP) and Leucine-Lysine-Proline (LKP) are food-derived tripeptides whose antihypertensive functions have been demonstrated in hypertensive rat models. However, peptides display low oral bioavailability due to poor intestinal epithelial permeability and instability. IPP and LKP were formulated into nanoparticles (NP) using chitosan (CL113) via ionotropic gelation and then coated with zein. Following addition of zein, a high encapsulation efficiency (EE) (>80%) was obtained for the NP. In simulated gastric fluid (SGF), 20% cumulative release of the peptides was achieved after 2 h, whereas in simulated intestinal fluid (SIF), ~90% cumulative release was observed after 6 h. Higher colloidal stability (39−41 mV) was observed for the coated NP compared to uncoated ones (30−35 mV). In vitro cytotoxicity studies showed no reduction in cellular viability of human intestinal epithelial Caco-2 and HepG2 liver cells upon exposure to NP and NP components. Administration of NP encapsulating IPP and LKP by oral gavage to spontaneously hypertensive rats (SHR) attenuated systolic blood pressure (SBP) for 8 h. This suggests that the NP provide appropriate release to achieve prolonged hypotensive effects in vivo. In conclusion, chitosan-zein nanoparticles (CZ NP) have potential as oral delivery system for the encapsulation of IPP and LKP.

A pilot digital intervention targeting loneliness in young people with psychosis.

PURPOSE: Loneliness has been identified as a significant challenge for people with psychosis. Interventions targeting loneliness are lacking but adopting a positive psychology approach may reduce loneliness, promote well-being, and support meaningful social interactions. Together with youth mental health consumers, we developed a digital smartphone application (app) called +Connect, which delivers positive psychology content daily for 6 weeks. MATERIALS AND METHODS: Twelve participants diagnosed with a psychotic disorder were recruited from early psychosis services. Loneliness was assessed pre-intervention, post-intervention, and 3-month post-intervention. Acceptability, feasibility, and usability were measured post-intervention, including a semi-structured interview on the user's experience of +Connect. RESULTS: We found evidence for the feasibility of +Connect. All but two participants completed the +Connect program, completing 95% (40.10 out of 42 days) of the program. Furthermore, 66.67% (8 out of the 12 participants) remained engaged with the program 3-months post-intervention. Our data indicates preliminary evidence that +Connect may reduce loneliness, with scores from pre-intervention (M = 50.00, SD = 8.47) to post-intervention (M = 48.10, SD = 10.38) and 3-months post-intervention (M = 42.89, SD = 7.04). We found that positive reinforcement of in-game rewards and evidence of positive mood changes added to the feasibility of the app. Regarding acceptability, while 10% (1/10 participants) reported not finding +Connect useful or enjoyable, 90% of participants agreed that +Connect helped them to increase their social confidence, enjoy life, look forward to being with other people, and feel more connected with others. Participant interviews supported these results, with participants highlighting the app's strengths in providing useful information, stimulating self-reflection, fostering positive affect, and encouraging transfer of skills into their social interactions. DISCUSSION: While preliminary findings indicated that +Connect yielded high levels of acceptability and feasibility, it is important to consider that we recruited a small and selected sample of lonely young people. Further iterations of this proof of concept app, which can incorporate participant feedback such preferences for increased personalisation, in-app feedback, and gamification, may allow an opportunity to test an improved version in the future.

Young People's Experience of a Long-Term Social Media-Based Intervention for First-Episode Psychosis: Qualitative Analysis.

BACKGROUND: Digital mental health interventions present a unique opportunity to address the lack of social connection and loneliness experienced by young people with first-episode psychosis (FEP). The first generation of digital interventions, however, is associated with high attrition rates. Social media presents an opportunity to target this issue. A new generation of digital intervention has harnessed the popularity of social media to both promote engagement and foster social connectedness in youth mental health interventions. Despite their potential, little is known about how young people engage with, and experience, social media-based interventions as well as the optimal design, implementation, and management needed to ensure young people with psychosis receive benefit. OBJECTIVE: This study aimed to explore how young people engage with, and experience, a long-term social media-based mental health intervention designed to address social functioning in individuals with FEP. METHODS: This qualitative study was based on 12 interviews with young people who used Horyzons, a long-term social media-based mental health intervention, as part of a previous randomized controlled trial. A semistructured phenomenological interview guide with open-ended questions was used to explore young people's subjective experience of the intervention. All interviews were recorded and transcribed verbatim. Data were analyzed using interpretative phenomenological analysis. RESULTS: A total of 4 superordinate themes emerged during the analysis including (1) shared experience as the catalyst for a cocreated social space, (2) the power of peer support, (3) an upbeat environment, and (4) experiences that interrupt being in Horyzons. CONCLUSIONS: We found that Horyzon's therapeutic social network fostered a connection and an understanding among young people. It also aided in the creation of an embodied experience that afforded young people with FEP a sense of self-recognition and belonging over the long term. However, although we found that most young people had strong positive experiences of a social connection on Horyzons, we also found that they experienced significant barriers that could substantively interrupt their ability to use the platform. We found that social anxiety, paranoia, internalized stigma, lack of autonomy, and social protocol confusion interfered with young people's usage of the platform. From a design perspective, digital interventions are flexible and thus equipped to begin addressing these implications by providing customizable and personalized treatment options that account for varying levels of social connection and psychological need that could otherwise interrupt young people's usage of social media-based interventions.

A Novel Multimodal Digital Service (Moderated Online Social Therapy+) for Help-Seeking Young People Experiencing Mental Ill-Health: Pilot Evaluation Within a National Youth E-Mental Health Service.

BACKGROUND: Mental ill-health is the leading cause of disability worldwide. Moreover, 75% of mental health conditions emerge between the ages of 12 and 25 years. Unfortunately, due to lack of resources and limited engagement with services, a majority of young people affected by mental ill-health do not access evidence-based support. To address this gap, our team has developed a multimodal, scalable digital mental health service (Enhanced Moderated Online Social Therapy [MOST+]) merging real-time, clinician-delivered web chat counseling; interactive user-directed online therapy; expert and peer moderation; and peer-to-peer social networking. OBJECTIVE: The primary aim of this study is to ascertain the feasibility, acceptability, and safety of MOST+. The secondary aims are to assess pre-post changes in clinical, psychosocial, and well-being outcomes and to explore the correlations between system use, perceived helpfulness, and secondary outcome variables. METHODS: Overall, 157 young people seeking help from a national youth e-mental health service were recruited over 5 weeks. MOST+ was active for 9 weeks. All participants had access to interactive online therapy and integrated web chat counseling. Additional access to peer-to-peer social networking was granted to 73 participants (46.5%) for whom it was deemed safe. The intervention was evaluated via an uncontrolled single-group study. RESULTS: Overall, 93 participants completed the follow-up assessment. Most participants had moderate (52/157, 33%) to severe (96/157, 61%) mental health conditions. All a priori feasibility, acceptability, and safety criteria were met. Participants provided mean scores of ≥3.5 (out of 5) on ease of use (mean 3.7, SD 1.1), relevancy (mean 3.9, SD 1.0), helpfulness (mean 3.5, SD 0.9), and overall experience (mean 3.9, SD 0.8). Moreover, 98% (91/93) of participants reported a positive experience using MOST+, 82% (70/93) reported that using MOST+ helped them feel better, 86% (76/93) felt more socially connected using it, and 92% (86/93) said they would recommend it to others. No serious adverse events or inappropriate use were detected, and 97% (90/93) of participants reported feeling safe. There were statistically significant improvements in 8 of the 11 secondary outcomes assessed: psychological distress (d=-0.39; P<.001), perceived stress (d=-0.44; P<.001), psychological well-being (d=0.51; P<.001), depression (d=-0.29; P<.001), loneliness (d=-0.23; P=.04), social support (d=0.30; P<.001), autonomy (d=0.36; P=.001), and self-competence (d=0.30; P<.001). There were significant correlations between system use, perceived helpfulness, and a number of secondary outcome variables. CONCLUSIONS: MOST+ is a feasible, acceptable, and safe online clinical service for young people with mental ill-health. The high level of perceived helpfulness, the significant improvements in secondary outcomes, and the correlations between indicators of system use and secondary outcome variables provide initial support for the therapeutic potential of MOST+. MOST+ is a promising and scalable platform to deliver standalone e-mental health services as well as enhance the growing international network of face-to-face youth mental health services.

Development of Physiologically Responsive Human iPSC-Derived Intestinal Epithelium to Study Barrier Dysfunction in IBD.

In inflammatory bowel disease (IBD), the intestinal epithelium is characterized by increased permeability both in active disease and remission states. The genetic underpinnings of this increased intestinal permeability are largely unstudied, in part due to a lack of appropriate modelling systems. Our aim is to develop an in vitro model of intestinal permeability using induced pluripotent stem cell (iPSC)-derived human intestinal organoids (HIOs) and human colonic organoids (HCOs) to study barrier dysfunction. iPSCs were generated from healthy controls, adult onset IBD, and very early onset IBD (VEO-IBD) patients and differentiated into HIOs and HCOs. EpCAM+ selected cells were seeded onto Transwell inserts and barrier integrity studies were carried out in the presence or absence of pro-inflammatory cytokines TNFα and IFNγ. Quantitative real-time PCR (qRT-PCR), transmission electron microscopy (TEM), and immunofluorescence were used to determine altered tight and adherens junction protein expression or localization. Differentiation to HCO indicated an increased gene expression of CDX2, CD147, and CA2, and increased basal transepithelial electrical resistance compared to HIO. Permeability studies were carried out in HIO- and HCO-derived epithelium, and permeability of FD4 was significantly increased when exposed to TNFα and IFNγ. TEM and immunofluorescence imaging indicated a mislocalization of E-cadherin and ZO-1 in TNFα and IFNγ challenged organoids with a corresponding decrease in mRNA expression. Comparisons between HIO- and HCO-epithelium show a difference in gene expression, electrophysiology, and morphology: both are responsive to TNFα and IFNγ stimulation resulting in enhanced permeability, and changes in tight and adherens junction architecture. This data indicate that iPSC-derived HIOs and HCOs constitute an appropriate physiologically responsive model to study barrier dysfunction and the role of the epithelium in IBD and VEO-IBD.

Developing a Hypothetical Implementation Framework of Expectations for Monitoring Early Signs of Psychosis Relapse Using a Mobile App: Qualitative Study.

BACKGROUND: Relapse is a common experience for people diagnosed with psychosis, which is associated with increased service costs and profound personal and familial distress. EMPOWER (Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery) is a peer worker-supported digital intervention that aims to enable service users to self-monitor their mental health with the aim of encouraging self-management and the shared use of personal data to promote relapse prevention. Digital interventions have not been widely used in relapse prevention and, therefore, little is currently known about their likely implementation-both within trials and beyond. OBJECTIVE: Seeking the perspectives of all relevant stakeholder groups is recommended in developing theories about implementation because this can reveal important group differences in understandings and assumptions about whether and for whom the intervention is expected to work. However, the majority of intervention implementation research has been retrospective. This study aimed to discover and theoretically frame implementation expectations in advance of testing and synthesize these data into a framework. METHODS: To develop a hypothetical implementation framework, 149 mental health professionals, carers, and people diagnosed with psychosis participated in 25 focus groups in both Australia and the United Kingdom. An interview schedule informed by the normalization process theory was used to explore stakeholders' expectations about the implementation of the EMPOWER intervention. Data were analyzed using thematic analysis and then theoretically framed using the Medical Research Council guidelines for understanding the implementation of complex interventions. RESULTS: All groups expected that EMPOWER could be successfully implemented if the intervention generated data that were meaningful to mental health staff, carers, and service users within their unique roles. However, there were key differences between staff, carers, and service users about what facilitators and barriers that stakeholders believe exist for intervention implementation in both the cluster randomized controlled trial stage and beyond. For example, service user expectations mostly clustered around subjective user experiences, whereas staff and carers spoke more about the impact upon staff interactions with service users. CONCLUSIONS: A hypothetical implementation framework synthesized from stakeholder implementation expectations provides an opportunity to compare actual implementation data gathered during an ongoing clinical trial, giving valuable insights into the accuracy of these stakeholders' previous expectations. This is among the first studies to assess and record implementation expectations for a newly developed digital intervention for psychosis in advance of testing in a clinical trial. TRIAL REGISTRATION: ISRCTN Registry ISRCTN99559262; http://www.isrctn.com/ISRCTN99559262.

Meta-analysis of the effects of third-wave behavioural interventions on disordered eating and body image concerns: implications for eating disorder prevention.

Third-wave behavioural interventions are increasingly popular for treating and preventing mental health conditions. Recently, researchers have begun testing whether these interventions can effectively targeting eating disorder risk factors (disordered eating, body image concerns). This meta-analysis examined whether third-wave behavioural interventions (acceptance and commitment therapy; dialectical behaviour therapy; mindfulness-based interventions; compassion-focused therapy) show potential for being effective eating disorder prevention programs, by testing their effects on eating disorder risk factors in samples without an eating disorder. Twenty-four studies (13 randomized trials) were included. Most studies delivered selective prevention programs (i.e. participants who reported elevated risk factor). Third-wave interventions led to significant pre-post (g = 0.59; 95% CI = 0.43, 0.75) and follow-up (g = 0.83; 95% CI = 0.38, 1.28) improvements in disordered eating, and significant pre-post improvements in body image (g = 0.35; 95% CI = 0.13, 0.56). DBT-based interventions were associated with the largest effects. Third-wave interventions were also significantly more efficacious than wait-lists (g = 0.39; 95% CI = 0.09, 0.69) in reducing disordered eating, but did not differ to other interventions (g = 0.25; 95% CI = -0.06, 0.57). Preliminary evidence suggests that third-wave interventions may have a beneficial effect in ameliorating eating disorder risk.

Loneliness in psychosis: a systematic review.

PURPOSE: The aim of the review is to understand the relationships between loneliness and related psychological and social factors in individuals with psychosis. Loneliness is poorly understood in people with psychosis. Given the myriad of social challenges facing individuals with psychosis, these findings can inform psychosocial interventions that specifically target loneliness in this vulnerable group. METHODS: We adhered to the PRISMA guidelines and systematically reviewed empirical studies that measured loneliness either as a main outcome or as an associated variable in individuals with psychosis. RESULTS: A total of ten studies examining loneliness in people diagnosed with a psychotic disorder were examined. Heterogeneity in the assessment of loneliness was found, and there were contradictory findings on the relationship between loneliness and psychotic symptomatology. In individuals with psychosis, loneliness may be influenced by psychological and social factors such as increased depression, psychosis, and anxiety, poor social support, poor quality of life, more severe internalised stigma and perceived discrimination, and low self-esteem. CONCLUSIONS: The relationship between loneliness and psychosis remains poorly understood due to a lack of rigorous studies. Although having strong social relationships is crucial to facilitate recovery from serious mental illness, psychosocial interventions that specifically target loneliness in individuals with psychosis are lacking and sorely needed. Interventions targeting loneliness in those with psychosis will also need to account for additional barriers associated with psychosis (e.g., social skill deficits, impoverished social networks, and negative symptoms).