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Background: To provide precision cognitive remediation therapy (CR) for schizophrenia, we need to understand whether the mechanism for improved functioning is via cognition improvements. This mechanism has not been rigorously tested for potential moderator effects., Study Design: We used data (n = 377) from a randomized controlled trial using CIRCuiTS, a therapist-supported CR, with participants from first-episode psychosis services. We applied structured equation modeling to test whether: (1) CR hours explain the goal attainment functional outcome (GAS) at posttreatment, (2) global cognitive improvement mediates GAS, and if (3) total symptoms moderate the CR hours to cognitive improvement pathway, and/or negative symptoms moderate the cognition to functioning pathway, testing moderator effects via the mediator or directly on CR hours to functioning path., Study Results: CR produced significant functioning benefit for each therapy hour (Coeff = 0.203, 95% CI 0.101-0.304, P < .001). The mediated path from CR hours to cognition and cognition to functioning was small and nonsignificant (Coeff = 0.014, 95% CI = -0.010, 0.037, P = .256). Total symptoms did not moderate the path to cognition (P = .211) or the direct path to outcome (P = .896). However, negative symptoms significantly moderated the effect of cognitive improvements on functioning (P = .015) with high negative symptoms reducing the functional gains of improved cognition., Conclusions: Although cognitive improvements were correlated with functioning benefit, they did not fully explain the positive effect of increased therapy hours on functioning, suggesting additional CR factors also contribute to therapy benefit. Negative symptoms interfere with the translation of cognitive improvements into functional gains so need consideration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Digital health interventions (DHIs) have significant potential to upscale treatment access to people experiencing psychosis but raise questions around patient safety. Adverse event (AE) monitoring is used to identify, record, and manage safety issues in clinical trials, but little is known about the specific content and context contained within extant AE reports. This study aimed to assess current AE reporting in DHIs., Study Design: A systematic literature search was conducted by the iCharts network (representing academic, clinical, and experts by experience) to identify trials of DHIs in psychosis. Authors were invited to share AE reports recorded in their trials. A content analysis was conducted on the shared reports., Study Results: We identified 593 AE reports from 18 DHI evaluations, yielding 19 codes. Only 29 AEs (4.9% of total) were preidentified by those who shared AEs as being related to the intervention or trial procedures. While overall results support the safety of DHIs, DHIs were linked to mood problems and psychosis exacerbation in a few cases. Additionally, 27% of studies did not report information on relatedness for all or at least some AEs; 9.6% of AE reports were coded as unclear because it could not be determined what had happened to participants., Conclusions: The results support the safety of DHIs, but AEs must be routinely monitored and evaluated according to best practice. Individual-level analyses of AEs have merit to understand safety in this emerging field. Recommendations for best practice reporting in future studies are provided., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Assessing cognition with interview-based measures could be a low-resource alternative to traditional cognitive tests. We previously adapted the Cognitive Assessment Interview (CAI) into Amharic (CAI-A) for use with people with schizophrenia (PWS) in Ethiopia. This study examined the convergent and structural validity of the CAI-A in a group of 350 PWS sub-sampled from the Neuropsychiatric Genetics of African Populations - Psychosis (NeuroGAP-Psychosis) study, who fulfilled the inclusion criteria. Data were analyzed using confirmatory factor analysis (CFA), Spearman's correlation coefficient (ρ), multiple regression, and Item Response Theory (IRT). A one-factor solution best fits the items in the tool (factor loadings between 0.58 and 0.79), suggesting structural validity. The total score of the CAI-A moderately correlated with functioning (ρ = 0.44, p < 0.001) and symptom dimensions (ρ between 0.38 and 0.46, p < 0.001), suggesting convergent validity. Multiple regression showed that age (β = -0.06, 95 % CI (-0.12, 0.00), p = 0.044), the duration of illness (β = 0.08, 95 % CI (0.01, 0.14), p = 0.033), and medication side effects (β = 0.35, 95 % CI (0.21, 0.50), p < 0.001) were positively and significantly associated with the CAI-A total score. The IRT analysis suggested that the tool best functions among participants with moderate to severe impairment (difficulty coefficient between 0.05 and 2.73). We found that the CAI-A is a valid tool for use in Ethiopia. The moderate correlation with symptom and functional measures suggested that self-reported cognitive symptoms parallel other symptom dimensions and functional disability. The CAI-A can be used in clinical practice and research activities in PWS in Ethiopia when subjective assessment of cognition is desired., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38 hi expression universally identified CD8 + and CD4 + RTEs. We further determined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-associated transcriptional reprogramming and shifts in cytokine production. Spectral cytometry profiling revealed two axes of aging common to naive CD8 + and CD4 + T cells: (1) a decrease in CD38 ++ cells (RTEs) and (2) an increase in CXCR3 hi cells. Identification of RTEs enables direct assessment of thymic health. Furthermore, resolving the dynamics of naive T cell remodeling yields insight into vaccination and infection responsiveness throughout aging., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To understand CD's underlying mechanisms, we investigated the link between CD and the FGFR1OP gene, which encodes a centrosome protein. FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypt architecture, resulting in crypt loss, inflammation, and fatality. FGFR1OP insufficiency hindered epithelial resilience during colitis. FGFR1OP was crucial for preserving non-muscle myosin II activity, ensuring the integrity of the actomyosin cytoskeleton and crypt cell adhesion. This role of FGFR1OP suggests that its deficiency in genetically predisposed individuals may reduce epithelial renewal capacity, heightening susceptibility to inflammation and disease., Competing Interests: Declaration of interests R.J.X. is co-founder of Jnana Therapeutics and Celsius Therapeutics, scientific advisory board member at Nestlé, and board director at MoonLake Immunotherapeutics. These organizations had no roles in this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Virtual reality (VR) is a technology that allows to interact with recreated digital environments and situations with enhanced realism. VR has shown good acceptability and promise in different mental health conditions. No systematic review has evaluated the use of VR in Bipolar Disorder (BD). This PRISMA-compliant systematic review searched PubMed and Web of Science databases (PROSPERO: CRD42023467737) to identify studies conducted in individuals with BD in which VR was used. Results were systematically synthesized around four categories (cognitive and functional evaluation, clinical assessment, response to VR and safety/acceptability). Eleven studies were included (267 individuals, mean age = 36.6 years, 60.7% females). Six studies using VR to carry out a cognitive evaluation detected impairments in neuropsychological performance and delayed reaction times. VR was used to assess emotional regulation. No differences in well-being between VR-based and physical calm rooms were found. A VR-based stress management program reduced subjective stress, depression, and anxiety levels. VR-based cognitive remediation improved cognition, depressive symptoms, and emotional awareness. 48.7% of the individuals with BD considered VR-based cognitive remediation 'excellent', whereas 28.2% considered it 'great'. 87.2% of individuals did not report any side effects. 81.8% of studies received a global quality rating of moderate. Emerging data point towards a promising use of VR in BD as an acceptable assessment/intervention tool. However, multiple unstudied domains as comorbidity, relapse and prodromal symptoms should be investigated. Research on children and adolescents is also recommended. Further research and replication of findings are required to disentangle which VR-interventions for which populations and outcomes are effective.

Objectives: Cognitive remediation (CR) can reduce the cognitive difficulties experienced by people with psychosis. Adapting CR to be delivered remotely provides new opportunities for extending its use. However, doing so requires further evaluation of its acceptability from service users' views. We evaluate the acceptability of therapist-supported remote CR from the perspectives of service users using participatory service user-centred methods., Method: After receiving 12 weeks of therapist-supported remote CR, service users were interviewed by a service user researcher following a semi-structured 18-question interview guide. Transcripts were analysed using reflexive thematic analysis with themes and codes further validated by a Lived Experience Advisory Panel and member checking., Results: The study recruited 26 participants, almost all of whom reported high acceptability of remote CR, and some suggested improvements. Four themes emerged: (1) perceived treatment benefits, (2) remote versus in-person therapy, (3) the therapist's role, and (4) how it could be better., Conclusions: This study used comprehensive service user involvement methods. For some participants, technology use remained a challenge and addressing these difficulties detracted from the therapy experience. These outcomes align with existing research on remote therapy, suggesting that remote CR can expand choice and improve access to treatment for psychosis service users once barriers are addressed. Future use of remote CR should consider technology training and equipment provision to facilitate therapy for service users and therapists.

Background: Psychotic-like experiences (PLEs) are subtle, subclinical perturbations of perceptions and thoughts and are common in the general population. Their characterisation and unidimensionality are still debated., Methods: This study was conducted by the Electronic-halluCinations-Like Experiences Cross-culTural International Consortium (E-CLECTIC) and aimed at measuring the Community Assessment of Psychic Experiences (CAPE) factorial structure across five European countries (Belgium; Czech Republic, Germany; Greece, and Spain) and testing the adequacy of the unidimensional polytomous Rasch model of the tool via Partial Credit Model (PCM) of the CAPE to detect people with a high risk for developing psychosis., Results: The sample included 1461 participants from the general population. The factorial analysis confirmed the best fit for the bifactor implementation of the three-factor model, including the positive, negative and depressive dimensions and a general factor. Moreover, the unidimensional polytomous Rasch analysis confirmed that CAPE responses reflected one underlying psychosis proneness., Conclusions: The study proved that the CAPE measures a single latent dimension of psychosis-proneness. The CAPE might help locate and estimate psychosis risk and can be used as a screening tool in primary care settings/education settings., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In our previous paper on the Future of Cognitive Remediation published more than 10 years ago, we envisaged an imminent and wide implementation of cognitive remediation therapies into mental health services. This optimism was misplaced. Despite evidence of the benefits, costs, and savings of this intervention, access is still sparse. The therapy has made its way into some treatment guidance, but these documents weight the same evidence very differently, causing confusion, and do not consider barriers to implementation. This paper revisits our previous agenda and describes how some challenges were overcome but some remain. The scientific community, with its commitment to Open Science, has produced promising sets of empirical data to explore the mechanisms of treatment action. This same community needs to understand the specific and nonspecific effects of cognitive remediation if we are to provide a formulation-based approach that can be widely implemented. In the last 10 years we have learned that cognitive remediation is not "brain training" but is a holistic therapy that involves an active therapist providing motivation support, and who helps to mitigate the impact of cognitive difficulties through metacognition to develop awareness of cognitive approaches to problems. We conclude that, of course, more research is needed but, in addition and perhaps more importantly at this stage, we need more public and health professionals' understanding of the benefits of this therapy to inform and include this approach as part of treatment regimens., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Microglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and to persist throughout life without much contribution from definitive hematopoiesis. Here, using lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and characteristics of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation, and defined the core transcriptional signatures of brain-engrafted MDMs. Lineage tracing mouse models revealed that MDMs transiently express CD206 during brain engraftment as CD206 + microglia precursors in the YS. We found that brain-engrafted MDMs exhibit transcriptional and epigenetic characteristics akin to meningeal macrophages, likely due to environmental imprinting within the meningeal space. Utilizing parabiosis and skull transplantation, we demonstrated that monocytes from both peripheral blood and skull bone marrow can repopulate microglia-depleted brains. Our results reveal the heterogeneous origins and cellular dynamics of brain parenchymal macrophages at baseline and in models of microglia depletion.

Group 1 innate lymphoid cells (ILC1s) are cytotoxic and interferon gamma-producing lymphocytes lacking antigen-specific receptors, which include ILC1s and natural killer (NK) cells. In mice, ILC1s differ from NK cells, as they develop independently of the NK-specifying transcription factor EOMES, while requiring the repressor ZFP683 (ZNF683 in humans) for tissue residency. Here we identify highly variable ILC1 subtypes across tissues through investigation of human ILC1 diversity by single-cell RNA sequencing and flow cytometry. The intestinal epithelium contained abundant mature EOMES - ILC1s expressing PRDM1 rather than ZNF683, alongside a few immature TCF7 + PRDM1 - ILC1s. Other tissues harbored NK cells expressing ZNF683 and EOMES transcripts; however, EOMES protein content was variable. These ZNF683 + NK cells are tissue-imprinted NK cells phenotypically resembling ILC1s. The tissue ILC1-NK spectrum also encompassed conventional NK cells and NK cells distinguished by PTGDS expression. These findings establish a foundation for evaluating phenotypic and functional changes within the NK-ILC1 spectrum in diseases., (© 2024. Springer Nature America, Inc.)

Abstract: Stigma is common in people experiencing chronic pain and there are indications that it may adversely affect pain outcomes. However, to date, there is no systematic review exploring the impact of stigma on chronic pain-related outcomes. This systematic review and meta-analysis aimed to examine the association between stigma and key chronic pain outcomes and differences in stigma between pain conditions. Seven databases were searched for studies reporting a measure of association between stigma and at least one pain outcome in adults with chronic pain. Studies were screened by 2 independent researchers. Nineteen studies met eligibility criteria and data were extracted, quality-assessed, and narratively synthesised and meta-analysed where possible. Meta-analyses of bivariate cross-sectional correlations demonstrated significant positive correlations between stigma and pain intensity, disability, and depression, with small to moderate effects. Data from 2 prospective studies and those only reporting multivariate analyses that were not included in meta-analyses further supported these findings. There was some evidence that individuals who experience pain conditions with less clear pathophysiology may report greater stigma, although more research is needed. The review highlights that there is a growing number of studies on stigma in the pain field showing an adverse association between stigma and chronic pain outcomes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background & Aims: The pathophysiology of Crohn's-like disease of the pouch (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single-cell analyses., Methods: Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum) of 50 patients with an ileal pouch-anal anastomosis. Single-cell RNA sequencing was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, and those with familial adenomatous polyposis after pouch formation. Findings were independently validated using immunohistochemistry., Results: The cell populations/states in the pouch body differed from those in the prepouch ileum, likely secondary to increased microbial burden. Compared with the familial adenomatous polyposis pouch, the UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in T helper 17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1 + monocytes, clonal expansion of effector T cells, and overexpression of T helper 17 cells-inducing cytokine genes such as IL23, IL1B, and IL6 by mononuclear phagocytes. Ligand-receptor analysis further revealed a stromal-mononuclear phagocytes-lymphocyte circuit in CDP. Integrated analysis showed that up-regulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum stress across all major cell compartments., Conclusions: CDP likely represents a distinct entity of inflammatory bowel disease with heightened endoplasmic reticulum stress in both immune and nonimmune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Hypothesis: Cognitive difficulties significantly burdened people with schizophrenia (PWS). However, cognitive assessment is often unavailable in low- and middle-income counties (LMICs) due to a lack of validated and culturally adapted cognitive assessment tools. In this study, we developed and evaluated a culturally sensitive cognitive battery for PWS in Ethiopia., Study Design: This study was conducted in three phases. First, we selected appropriate tests through an instrument selection procedure and created a new battery. Then, we rigorously adapted the tests using culturally competent procedures, including cognitive interviewing and expert meetings. Finally, we tested the new battery in 208 PWS and 208 controls. We evaluated its psychometric properties using advanced statistical techniques, including Item Response Theory (IRT)., Study Results: The Ethiopian Cognitive Assessment battery for Schizophrenia (ECAS) was developed from three different batteries. Participants reported tests were easy to complete, and the raters found them easy to administer. All tests had good inter-rater reliability, and the composite score had very high test-retest reliability (ICC = 0.91). One-factor structure better represented the data with excellent internal consistency (α = .81). ECAS significantly differentiated PWS from controls with 77% sensitivity and 62% specificity at a Z-score ≤0.12 cut-off value. IRT analysis suggested that the battery functions best among moderately impaired participants (difficulty between -0.06 and 0.66)., Conclusions: ECAS is a practical, tolerable, reliable, and valid assessment of cognition. ECAS can supplement current assessment tools in LAMICs for PWS and can be used to measure cognitive intervention outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8 + and CD4 + T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300c iCre-hCD2 R26 tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3 Cre R26 tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Cognitive remediation (CR) improves cognition and aids recovery in people with psychosis. An active therapist provides increased benefit, but CR training for therapists is not routinely available, so CR has limited scalability. This study describes the development and evaluation of the first online CR therapist training programme., Methods: An online CR training, based on expert and novice therapist consultations, was developed, and then pilot tested with novice trainees and changes made to produce the evaluation version. Feasibility, acceptability, and training benefits were assessed in a group of naïve UK NHS mental health professionals. Training engagement with a group of clinicians who accessed the programme for professional development was compared to those who paid fees., Results: Most mental health professionals finished training and passed the knowledge test, indicating that training enhanced clinicians' knowledge. Fee-paying trainees had significantly faster completion times and a higher proportion finished in the recommended time. Those who were successful at passing the knowledge questionnaire had significantly fewer years in practice. The majority were satisfied with the programme, felt they had made considerable progress and that training would allow them to begin practicing CR, and would recommend the training to colleagues., Conclusions: This online CR training programme was feasible, acceptable to participants and showed benefits for clinicians. It improved knowledge even in the most junior of staff who have had less time to develop clinical know-how., (© 2023 The Authors. Psychology and Psychotherapy: Theory, Research and Practice published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Objective: Auditory hallucinations (hearing voices) have been associated with a range of altered cognitive functions, pertaining to signal detection, source-monitoring, memory, inhibition and language processes. Yet, empirical results are inconsistent. Despite this, several theoretical models of auditory hallucinations persist, alongside increasing emphasis on the utility of a multidimensional framework. Thus, clarification of current evidence across the broad scope of proposed mechanisms is warranted., Method: A systematic search of the Web of Science, PubMed and Scopus databases was conducted. Records were screened to confirm the use of an objective behavioural cognitive task, and valid measurement of hallucinations specific to the auditory modality., Results: Auditory hallucinations were primarily associated with difficulties in perceptual decision-making (i.e. reduced sensitivity/accuracy for signal-noise discrimination; liberal responding to ambiguity), source-monitoring (i.e. self-other and temporal context confusion), working memory and language function (i.e. reduced verbal fluency). Mixed or limited support was observed for perceptual feature discrimination, imagery vividness/illusion susceptibility, source-monitoring for stimulus form and spatial context, recognition and recall memory, executive functions (e.g. attention, inhibition), emotion processing and language comprehension/hemispheric organisation., Conclusions: Findings were considered within predictive coding and self-monitoring frameworks. Of concern was the portion of studies which - despite offering auditory-hallucination-specific aims and inferences - employed modality-general measures, and/or diagnostic-based contrasts with psychologically healthy individuals. This review highlights disparities within the literature between theoretical conceptualisations of auditory hallucinations and the body of rigorous empirical evidence supporting such inferences. Future cognitive investigations, beyond the schizophrenia-spectrum, which explicitly define and measure the timeframe and sensory modality of hallucinations, are recommended., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4 + T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.

Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2 -/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2 -/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2 -/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2 -/- -associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Cognitive Remediation (CR) is an evidence-based therapy targeting cognitive difficulties in people with psychosis to promote functional recovery, but it is rarely implemented routinely. To reach more individuals, CR is beginning to be delivered remotely, but there is limited evidence to support the acceptability of this method., Aims: To evaluate the acceptability and feasibility of remote therapist-supported CR in people with psychosis and estimate its cost and potential benefits., Methods: A case-series with all participants assessed before and after therapy with measures of personal goal attainment (main outcome), cognition, functioning and symptoms. Acceptability was assessed with post-therapy interviews. Feasibility was assessed using proportions and confidence intervals on pre-specified parameters. Indication of benefits was assessed with exploratory analyses comparing baseline and post-therapy scores on the pre-specified outcomes. The cost of providing remote CR was assessed from both healthcare and societal perspectives., Results: Twenty-nine participants started therapy with two dropping out; on average participants attended 25.5 sessions. Interviews suggested that remote CR had good acceptability and led to perceived benefits. Significant and large improvements were observed on goal attainment. Cost analyses suggest that remote CR has the same health care cost as face-to-face therapy but a lower societal cost., Conclusions: Our results support the use of remote CR in psychosis services as an alternative delivery modality. This method may improve adherence, attendance and be more convenient for service users. Possible barriers such as poor digital literacy or appropriate device ownership should be addressed before starting therapy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cognitive impairment is common in people with schizophrenia (PWS). To detect the presence and its consequences, cognitive measures with sound psychometric properties are needed. However, these are lacking especially in low-income countries. Hence, we developed the Ethiopian Cognitive Assessment battery in Schizophrenia (ECAS). In this study, we evaluated the psychometric properties of the ECAS in a cross-sectional study involving 350 PWS. Confirmatory factor analysis demonstrated a one-factor solution. ECAS score correlated significantly but weakly with a disability measure (r = -0.13, p = 0.02) and symptom dimensions of PANSS (r between -0.12 and -0.29, p < 0.05), except for positive symptoms (r = -0.10, p > 0.05). Years of education (β = 0.12, 95% CI (0.09, 0.14), p < 0.001), male sex (β = 0.22, 95% CI (0.05, 0.39)), age β = -0.02, 95% CI (-0.03, -0.01), and medication side effects (β = -0.03, 95% CI (-0.06, -0.01), p = 0.021) were significantly associated with the composite score of ECAS. The Item Response Theory analysis showed that the tool best functions among participants with moderate cognitive impairment (difficulty coefficient between -1.12 and 0.27). The Differential Item Functioning analyses showed that education had a positive contribution on Digit Symbol Substitution Test (MH OR = 2.64, 95% CI (1.34, 5.20)). The results showed that ECAS is valid in assessing cognition in PWS in low-resource settings., (© 2024. The Author(s).)

In Brief: The cervix plays a crucial role not only in the maintenance of pregnancy but also during delivery, when it undergoes extensive changes. This study highlights the involvement of the endocannabinoidome in cervical remodeling, emphasizing its relevance in the shift from a nonpregnant to pregnant state and its potential contribution to preterm delivery in inflammatory contexts., Abstract: During pregnancy, the main role of the cervix is to isolate the fetus from outside pathogens and maintain the relatively closed system of uterine gestation. Conversely, toward the end of pregnancy, the cervix must be remodeled to increase flexibility and allow the delivery. This process is called cervical remodeling and dysregulation of the process plays a role in premature delivery. The endocannabinoidome plays an important role in several reproductive events; however, its function on cervical tissue throughout pregnancy is poorly understood. The goal of this study was to evaluate the presence and participation of the endocannabinoidome in lipopolysaccharide (LPS)-induced cervical changes. Therefore, we evaluated key components of the endocannabinoidome in cervical tissue from nonpregnant mice and pregnant mice with and without LPS treatment. Using mass spectrometric analysis, we found an increase in anandamide and 2-arachidonoylglycerol in the cervix of pregnant mice when compared to nonpregnant mice. We have also found a reduction in FAAH protein expression in these tissues. Furthermore, when treated with LPS, we observed a reduction in the cervical immunostaining with anti-CB1 and anti-CB2 antibodies. Likewise, using cervix explants from pregnant mice, we found that LPS significantly increased cervical metalloprotease activity and cyclooxygenase 2, which were subsequently modulated by cannabinoid receptor antagonists. Collectively, our findings suggest that an LPS-induced imbalance of cervix endocannabinoidome likely contributes to premature cervical remodeling, which is part of the key components that contribute to premature delivery.

Background: Hallucinations have been linked to failures in metacognitive reflection suggesting an association between hallucinations and overestimation of performance, although the cross-sectional findings are inconsistent. This inconsistency may relate to the fluctuating hallucinatory experiences that are not captured in cross-sectional studies. Ecological Momentary Assessment (EMA) captures in-the-moment experiences over time so can identify causal relationships between variables such as the associations between metacognition and hallucinatory experience in daily life and overcome problems in cross-sectional designs., Methods: Participants (N = 41) experiencing daily hallucinations completed baseline questionnaires and smartphone surveys 7 times per day for 14 days. They were prompted to identify a task they would complete in the next 4 h and to make metacognitive predictions around the likelihood of completing the task, the difficulty of the task, and how well they would complete it (standard of completion)., Results: 76 % finished the 14-days of assessment with an average of 42.2 % survey completion. Less accurate metacognition was associated with more hallucinations, but less accurate likelihood and standard of completion was associated with fewer hallucinations. Using a cross-lagged analysis, metacognitive predictions around the likelihood of completion (p < .001) and standard of completion (p = .01) predicted hallucination intensity at the following timepoint, and metacognitive predictions regarding likelihood of completion (p = .02) predicted hallucination control at the following timepoint., Discussion: Interventions that aim to improve metacognitive ability in-the-moment may serve to reduce the intensity and increase the control of hallucinations., Competing Interests: Declaration of competing interest No conflicts to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

NKp44 is a human receptor originally found on activated NK cells, group 1 and group 3 innate lymphoid cells that binds dimers of platelet-derived growth factor D (PDGF-DD). NKp44 is also expressed on tissue plasmacytoid dendritic cells (PDCs), but NKp44-PDGF-DD interaction on PDCs remains unstudied. Engagement of NKp44 with PDGF-DD in vitro enhanced PDC secretion of IFN-α, TNF, and IL-6 in response to the TLR9 ligand CpG-ODN, but not TLR7/8 ligands. In tissues, PDCs were found in close contact with PDGF-DD-expressing cells in the high endothelial venules and epithelium of tonsils, melanomas, and skin lesions infected with Molluscum contagiosum. Recombinant PDGF-DD enhanced the serum IFN-α response to systemic HSV-1 infection in a humanized mouse model. We conclude that NKp44 integrates with TLR9 signaling to enhance PDC cytokine production. These findings may have bearings for immune responses to TLR9-based adjuvants, therapy for tumors expressing PDGF-DD, and infections with DNA viruses that induce PDGF-DD expression to enhance viral spread., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background: Cognitive impairment is common with schizophrenia spectrum disorders. Cognitive remediation (CR) is effective in improving global cognition, but not all individuals benefit from this type of intervention. A better understanding of the potential mechanism of action of CR is needed. One proposed mechanism is reward learning (RL), the cognitive processes responsible for adapting behavior following positive or negative feedback. It is proposed that the structure of CR enhances RL and motivation to engage in increasingly challenging tasks, and this is a potential mechanism by which CR improves cognitive functioning in schizophrenia., Objective: Our primary objective is to examine reward processing in individuals with schizophrenia before and after completing CR and to compare this with a group of matched clinical controls. We will assess whether RL mediates the relationship between CR and improved cognitive function and reduced negative symptoms. Potential differences in social RL and nonsocial RL in individuals with schizophrenia will also be investigated and compared with a healthy matched control group., Methods: We propose a clinical, nonrandomized, pre-post pilot study comparing the impact of CR on RL and neurocognitive outcomes. The study will use a combination of objective and subjective measures to assess neurocognitive, psychiatric symptoms, and neurophysiological domains. A total of 40 individuals with schizophrenia spectrum disorders (aged 18-35 years) will receive 12 weeks of CR therapy (n=20) or treatment as usual (n=20). Reward processing will be evaluated using a reinforcement learning task with 2 conditions (social reward vs nonsocial reward) at baseline and the 12-week follow-up. Functional magnetic resonance imaging responses will be measured during this task. To validate the reinforcement learning task, RL will also be assessed in 20 healthy controls, matched for age, sex, and premorbid functioning. Mixed-factorial ANOVAs will be conducted to evaluate treatment group differences. For the functional magnetic resonance imaging analysis, computational modeling will allow the estimation of learning parameters at each point in time, during each task condition, for each participant. We will use a variational Bayesian framework to measure how learning occurred during the experimental task and the subprocesses that underlie this learning. Second-level group analyses will examine how learning in patients differs from that observed in control participants and how CR alters learning efficiency and the underlying neural activity., Results: As of September 2023, this study has enrolled 15 participants in the CR group, 1 participant in the treatment-as-usual group, and 11 participants in the healthy control group. Recruitment is expected to be completed by September 2024. Data analysis is expected to be completed and published in early 2025., Conclusions: The results of this study will contribute to the knowledge of CR and RL processes in severe mental illness and the understanding of the systems that impact negative symptoms and cognitive impairments within this population., International Registered Report Identifier (irrid): DERR1-10.2196/52505., (©Frances Dark, Graham Galloway, Marcus Gray, Matteo Cella, Veronica De Monte, Victoria Gore-Jones, Gabrielle Ritchie. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.01.2024.)

Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3 -/- CD8αα + IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3 -/- and Ikzf3 +/+ IELs showed an amplified effector machinery in Ikzf3 -/- CD8αα + IELs compared to Ikzf3 +/+ counterparts. Ikzf3 -/- CD8αα + IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aim: Psychosis spectrum disorders continue to rank highly among causes of disability. This has resulted in efforts to expand the range of treatment targets beyond symptom remission to include other recovery markers, including social and occupational function and quality of life. Although the efficacy of psychosocial interventions in early psychosis has been widely reported, the acceptability of these interventions is less well-known. This study explores the participant perspective on a novel, psychosocial intervention combining cognitive remediation and social recovery therapy., Methods: We employed a qualitative research design, based on semi-structured interviews and reflexive thematic analysis. Six participants with early psychosis were recruited from the intervention arm of a randomized pilot study, three women and three men, aged between 22 and 27 years., Results: Four themes were developed through the analytical process, namely, (1) a solid therapeutic foundation, (2) multi-directional flow of knowledge, (3) a tailored toolset, and (4) an individual pathway to recovery. Participants also provided pragmatic feedback about how to improve the delivery of the therapy assessments and intervention. Both the themes and pragmatic feedback are described., Conclusions: People with early psychosis described the intervention as acceptable, engaging, helpful and person-centred, suggesting its potential role in a multicomponent therapy model of early intervention in psychosis services. Participants in this study also highlight the importance of an individualized approach to therapy, the vital role of the therapeutic relationship and the ecological validity and value of adopting an assertive outreach delivery, providing therapy outside a conventional clinic setting., (© 2023 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Objective: Sublingual buprenorphine has demonstrated efficacy for treatment of the neonatal opioid withdrawal syndrome (NOWS), but the current formulation used in clinical practice contains 30% ethanol. Ethanol as a pharmacologically active excipient ideally should be removed from neonatal formulations. The objective of this study was to determine the relative bioavailability of a novel ethanol-free -formulation (CHF6563) compared with the commonly used ethanolic solution in a phase I, open-label, 2-period, -single-dose, crossover study in healthy adults., Methods: Eighteen adult opioid-naïve volunteers were administered one of the formulations in a randomized crossover treatment. After a 10-day washout period, subjects received the other formulation. Serial blood samples were drawn for pharmacokinetic analysis over 48 hours., Results: The geometric mean ratio (90% CIs) of the ethanol-free buprenorphine solution AUC 0-last was 0.80 (0.65-0.99) and C max was 0.81 (0.66-0.99) compared with reference ethanolic formulation. The -ethanol-free formulation had a greater degree of intersubject variability than the ethanol-containing -reference formulation (coefficient of variation of 59% vs 31.5%, respectively, for AUC 0-last )., Conclusions: In an adult population, a novel ethanol-free formulation of buprenorphine containing widely used excipients demonstrated a slight decrease in bioavailability when compared with an ethanolic solution. These results will inform those seeking to develop ethanol-free pediatric drug formulations., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org.)

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt + MHCII + type 3 innate lymphoid cells (ILC3) have also been implicated in the instruction of microbiota-specific Tregs. While RORγt + APCs have been actively investigated in mice, the identity and function of these cell subsets in humans remain elusive. Herein, we identify a rare subset of RORγt + cells with dendritic cell (DC) features through integrated single-cell RNA sequencing and single-cell ATAC sequencing. These cells, which we term RORγt + DC-like cells (R-DC-like), exhibit DC morphology, express the MHC class II machinery, and are distinct from all previously reported DC and ILC3 subsets, but share transcriptional and epigenetic similarities with DC2 and ILC3. We have developed procedures to isolate and expand them in vitro, enabling their functional characterization. R-DC-like cells proliferate in vitro, continue to express RORγt, and differentiate into CD1c + DC2-like cells. They stimulate the proliferation of allogeneic T cells. The identification of human R-DC-like cells with proliferative potential and plasticity toward CD1c + DC2-like cells will prompt further investigation into their impact on immune homeostasis, inflammation, and autoimmunity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects., Methods: CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30-40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models., Discussion: This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action., Trial Registration: Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331 . Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting., (© 2023. The Author(s).)

Assessment of cognitive impairment in people with schizophrenia (PWS) is limited in low and middle-income countries due to lack of context-appropriate measures. This study aimed to select, adapt, and evaluate an interview-based cognitive tool for PWS in Ethiopia. The study was carried out in three phases. In the first phase, we followed a rigorous instrument selection procedure to select a tool for adaptation. We then applied a rigorous instrument adaption procedure, including interviews with 24 participants. Finally, we evaluated the psychometric properties of the adapted tool with 208 PWS and 208 matched controls. The Cognitive Assessment Interview was selected as the appropriate tool for adaptation. This tool is practical and tolerable, with short time of administration. We reported high inter-rater reliability and test-retest reliability for the adapted scale. One-factor structure better represented the data with excellent internal consistency. Weak but significant correlation with a performance-based battery was reported. At a cut-off value of > 13, the tool significantly differentiated PWS from controls (62 % sensitivity and 82 % specificity). Item Response Theory-based analysis showed that the tool gives much information among severely impaired participants. The findings show that the tool is reliable, valid, and practical in resource-scarce settings., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In ambulatory care, monitoring process performance measures (PPMs) is essential to meet regulatory requirements, establish targets for care, seek reimbursement, and evaluate patient care responsibilities. We implemented a comprehensive program, "Engage to Sustain," for licensed practical nurses (LPNs) and certified medical assistants (CMAs) to practice at the top of their licensure/certification. Screening rates for 4 key PPMs (depression screening, fall risk screening, and tobacco use screening and counseling) markedly increased following this intervention across 18 ambulatory departments with more than 2 million patient visits. These results suggest that shifting responsibilities for patient screening from physicians and advanced practitioners to LPNs and CMAs may improve screening rates., Competing Interests: All authors report no conflict of interest related to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach's alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design., (© 2023. Springer Nature Limited.)

Background: Currently there is no first-line treatment recommended for the negative symptoms of schizophrenia. Psychosocial and behavioural interventions are widely used to reduce the burden of negative symptoms. Meta-analytic studies have summarised the evidence for specific approaches but not compared evidence quality and benefit., Aim: To review and evaluate the evidence from meta-analytic studies of psychosocial and behavioural interventions for the negative symptoms of schizophrenia., Method: A systematic literature search was undertaken to identify all meta-analyses evaluating psychosocial and behavioural interventions reporting on negative symptom outcomes in people with schizophrenia. Data on intervention, study characteristics, acceptability and outcome were extracted. Risk of bias was evaluated. Results were summarised descriptively, and evidence ranked on methodological quality., Results: In total, 31 systematic reviews met the inclusion criteria evaluating the efficacy of negative symptom interventions on 33 141 participants. Exercise interventions showed effect sizes (reduction in negative symptoms) ranging from -0.59 to -0.24 and psychological interventions ranging from -0.65 to -0.04. Attrition ranged between 12% to 32%. Across the studies considered heterogeneity varied substantially (range 0-100). Most of the reviews were of very low to low methodological quality. Methodological quality ranking suggested that the effect size for cognitive remediation and exercise therapy may be more robust compared with other approaches., Conclusions: Most of the interventions considered had a small-to-moderate effect size, good acceptability levels but very few had negative symptoms as the primary intervention target. To improve the confidence of these effect sizes being replicated in clinical settings future studies should minimise risk of bias.

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases., (© 2023. The Author(s).)

Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages., Competing Interests: Declaration of interests A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Hypothesis: Cognitive remediation (CR) benefits cognition and functioning in psychosis but we do not know the optimal level of therapist contact, so we evaluated the potential benefits of different CR modes., Study Design: A multi-arm, multi-center, single-blinded, adaptive trial of therapist-supported CR. Participants from 11 NHS early intervention psychosis services were independently randomized to Independent, Group, One-to-One, or Treatment-as-usual (TAU). The primary outcome was functional recovery (Goal Attainment Scale [GAS]) at 15-weeks post randomization. Independent and TAU arms were closed after an interim analysis, and three informative contrasts tested (Group vs One-to-One, Independent vs TAU, Group + One-to-One vs TAU). Health economic analyses considered the cost per Quality Adjusted Life Year (QALY). All analyses used intention-to-treat principles., Study Results: We analyzed 377 participants (65 Independent, 134 Group, 112 One-to-One, 66 TAU). GAS did not differ for Group vs One-to-One: Cohen's d: 0.07, -0.25 to 0.40 95% CI, P = .655; Independent vs TAU: Cohen's d: 0.07, -0.41 to 0.55 95% CI, P = .777. GAS and the cognitive score improved for Group + One-to-One vs TAU favoring CR (GAS: Cohen's d: 0.57, 0.19-0.96 95% CI, P = .003; Cognitive score: Cohens d: 0.28, 0.07-0.48 95% CI, P = .008). The QALY costs were £4306 for Group vs TAU and £3170 for One-to-One vs TAU. Adverse events did not differ between treatment methods and no serious adverse events were related to treatment., Conclusions: Both active therapist methods provided cost-effective treatment benefiting functional recovery in early psychosis and should be adopted within services. Some individuals benefited more than others so needs further investigation., Trial Registration: ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860Now closed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

TREM2 is a myeloid cell receptor that has been extensively described in the context of neuroinflammation and neurodegenerative diseases. Recently, TREM2 emerged as a crucial regulator of macrophage function in tumors. TREM2-deficiency or blockade provide protection and promote the response to anti-PD1 in different murine models. In human tumors, TREM2-expressing macrophages are present in numerous cohorts and tumor types and are generally associated with immunosuppression and poor prognosis. Here, we provide an overview of the impact of TREM2 in tumors considering current literature, with a focus on both murine models and human cancer., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr -/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr -/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr -/- IELs. Loss of IELs in Ahrr -/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses., Competing Interests: Declaration of interests M. Colonna receives research support from Pfizer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Bipolar disorder (BD) is associated with cognitive and functional difficulties, persistent beyond mood episodes. Cognitive remediation (CR) is a psychological therapy targeting cognitive and functioning difficulties. Recent evidence suggests that CR may enhance long-term functioning but transfer mechanisms on functional outcomes have not been explored. We aim to investigate whether and how cognitive gains after CR transfer to functional improvement., Methods: We considered data from a randomized controlled trial comparing CR ( n = 40) to treatment-as-usual (TAU; n = 40) in euthymic people with BD. Treatment outcomes included individual cognitive domains and global cognition, psychosocial functioning, and goal attainment. Regression-based mediation and moderation modelling were used to assess whether and how post-treatment cognitive changes translate into functional improvement at follow-up, three months after treatment end., Results: Cognitive gains after CR transferred to functional changes three months later: improvement in post-treatment global cognition partially mediated the effect of CR on psychosocial functioning (standardized indirect effect: -0.23, 95% CI -0.51 to -0.04). Goal attainment was not significantly mediated by changes in cognition, but post-treatment cognitive performance moderated the effect of CR on the GAS at follow-up (interaction effect: 0.78, 95% CI 0.08-1.55)., Conclusions: Our findings suggest that cognitive improvements contribute to functional improvement but transfer mechanisms differ between psychosocial functioning and idiosyncratic recovery goals. Cognition accounted for only a proportion of the total CR effect on functional outcomes. Future studies should consider other variables, such as metacognition, that may drive the transfer of CR effects to functional outcomes.

Previously youth-orientated, UK early intervention in psychosis (EI) services expanded care in 2016 to adults of any age. To compare EI care offering, clinical characteristics, and potential benefits for under-35s and over-35s, an observational study considering anonymised data for users of London-based EI services between April 2016 and December 2019 was conducted. Descriptive statistics and between groups comparisons are reported. The analysis considered 692 service users (32.5% over-35). Over-35s were more likely to be female, of poorer physical health, with severer problems at intake (Health of the Nation Outcome Scale, HoNOS). Under-35s had poorer appointment attendance, required increased use of inpatient facilities, and demonstrated greater risks to themselves and others. At discharge, HoNOS ratings indicated improvements for both groups. Over-35s constitute a considerable proportion of EI service-users, their care may involve less crisis management, more recovery-oriented intervention and physical health needs consideration. Care offering should reflect these needs., (© 2022. The Author(s).)

Repeated social interactions with conspecifics and/or heterospecifics during early development may drive the differentiation of behavior among individuals. Competition is a major form of social interaction and its impacts can depend on whether interactions occur between conspecifics or heterospecifics and the directionality of a response could be specific to the ecological context that they are measured in. To test this, we reared tungara frog tadpoles ( Engystomops pustulosus ) either in isolation, with a conspecific tadpole or with an aggressive heterospecific tadpole, the whistling frog tadpole ( Leptodactylus fuscus ). In each treatment, we measured the body size and distance focal E. pustulosus tadpoles swam in familiar, novel and predator risk contexts six times during development. We used univariate and multivariate hierarchical mixed effect models to investigate the effect of treatment on mean behavior, variance among and within individuals, behavioral repeatability and covariance among individuals in their behavior between contexts. There was a strong effect of competition on behavior, with different population and individual level responses across social treatments. Within a familiar context, the variance in the distance swam within individuals decreased under conspecific competition but heterospecific competition caused more variance in the average distance swam among individuals. Behavioral responses were also context specific as conspecific competition caused an increase in the distance swam within individuals in novel and predator risk contexts. The results highlight that the impact of competition on among and within individual variance in behavior is dependent on both competitor species identity and context., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Society for Behavioral Ecology.)

Background: Social cognition interventions have shown promise for improving social functioning in people with schizophrenia. However, it is unclear how changes in social cognition affect social functioning. This study evaluates the impact of a social cognition intervention (GRASP - GRoup trAining for Social skills in Psychosis) on social cognition and social functioning outcomes and explores how two mechanisms, affect and physiological arousal, may drive changes., Method: A two-arm single blind (assessor) randomized pilot trial comparing GRASP plus treatment-as-usual (TAU) with TAU alone in people with a diagnosis of schizophrenia. Participants were assessed with measures of social cognition, social functioning, and symptoms. All participants undertook a week-long mobile health assessment (experience sampling method) measuring social behavior and affect and used a wearable device recording autonomic activity. Assessments were performed at baseline and at week 10., Results: Forty-eight participants were randomly allocated to the treatment or control condition. Individuals randomized to GRASP did not show improvements on experience sampled social behavior and social cognition measures compared to controls. However, participants in the GRASP group enjoyed social contact more and had lower levels of negative affect and higher levels of positive affect compared to controls. There was no evidence of autonomic changes (i.e., electrodermal activity) associated with social behavior resulting from the therapy., Conclusion: Social cognition interventions may be helpful in improving the quality of social contacts in people with schizophrenia by decreasing negative affect. Increase in social behavior may require longer periods to be evident. Future studies should consider how social cognition interventions may alter qualitative aspects associated with social behavior., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound after analytic treatment interruption. Moreover, a broadly neutralizing antibody, PGT121, enhanced NK cell function in vivo, consistent with antibody-dependent cellular cytotoxicity. Monoclonal antibody depletion of NK cells resulted in higher viral loads in multiple nonlymphoid organs. Overall, our results in humanized MISTRG-6-15 mice demonstrated that NK cells provided direct anti-HIV-1 responses in vivo but were limited in their responses in lymphoid organs.

Background: Cognitive impairment is a core feature of schizophrenia, associated with poor functional outcomes. The course of cognitive function in the years following illness onset has remained a subject of debate, with a previous analysis finding no worsening, providing support for the neurodevelopmental model of schizophrenia. Since then, many more studies have reported on longitudinal cognitive performance in early psychosis, with some indicating deterioration, which does not align with this view., Aims: This study aims to quantitatively review the literature on the longitudinal trajectory of cognitive deficits in the years following psychosis onset, in comparison with healthy controls. It is the first to also synthesise longitudinal data on social cognition., Method: Electronic databases ('PubMed', 'PsycInfo' and 'Scopus') were searched (to end September 2021). Meta-analyses of 25 longitudinal studies of cognition in early psychosis were conducted (1480 patients, 789 health controls). Unlike previous analyses, randomised controlled trials and those with multiple cognitive testing periods within the first year were excluded to minimise bias (PROSPERO, ID: CRD42021241525)., Results: Small improvements were observed for global cognition ( g = 0.25, 95% CI 0.17-0.33) and individual cognitive domains, but these were comparable with healthy controls and likely an artefact of practice effects., Conclusions: There is no evidence of continued cognitive decline or improvement in the early years following psychosis onset, with a need for more studies over longer follow-up periods. Practice effects highlight the importance of including control samples in longitudinal and intervention studies. Further data are needed to evaluate the course of social cognition subdomains.

Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express Slc7a8 , encoding a transporter for arginine and large amino acids. Slc7a8 was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of Slc7a8 in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, Slc7a8- deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to Slc7a8 deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify Slc7a8 as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.

Background: There is evidence that Cognitive Remediation (CR) is an efficacious approach to reduce cognitive and functioning difficulties in people with schizophrenia. However, there is still a limited understanding of what influences different treatment responses. Treatment adherence has been suggested as one factor but has not been investigated systematically., Aim: To investigate how the number of CR sessions completed influences treatment outcomes., Method: This study used data from six randomised controlled trials comparing CR to a control condition. Instrumental variable analysis was used to evaluate the effect of number of treatment sessions on cognitive and functional outcomes. Logistic regression analysis was conducted to identify significant predictors of session attendance., Results: A total of 440 participants with schizophrenia spectrum diagnosis were considered. Participants were mostly men (71.6%) and had a mean age of 39.6 (SD 10.69). A higher number of CR sessions led to larger improvements in executive function and processing speed at end of therapy. However, number of sessions did not influence outcomes for working memory and functioning. Younger age and higher levels of negative symptoms at baseline were associated with higher treatment attendance., Conclusion: These findings highlight the importance of treatment adherence and underscore the importance of massed practice, at least for some cognitive outcomes. While it may be complex to assess a single session's contribution to outcome in a dose-response fashion, accessing more sessions seems associated with some cognitive benefits. Observing a relationship to functioning may require longer therapy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)