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The high frequency of aberrant PI3K pathway activation in hormone receptor–positive (HR+) breast cancer has led to the development, clinical testing, and approval of the p110α-selective PI3K inhibitor alpelisib. The limited clinical efficacy of alpelisib and other PI3K inhibitors is partially attributed to the functional antagonism between PI3K and estrogen receptor (ER) signaling, which is mitigated via combined PI3K inhibition and endocrine therapy. We and others have previously demonstrated chromatin-associated mechanisms by which PI3K supports cancer development and antagonizes ER signaling through the modulation of the H3K4 methylation axis, inhibition of KDM5A promoter H3K4 demethylation and KMT2D/MLL4-directed enhancer H3K4 methylation. Here we show that inhibition of the H3K4 histone methyltransferase MLL1 in combination with PI3K inhibition impairs HR+ breast cancer clonogenicity and cell proliferation. While combined PI3K/MLL1 inhibition reduces PI3K/AKT signaling and H3K4 methylation, MLL1 inhibition increases PI3K/AKT signaling through the dysregulation of gene expression associated with AKT activation. These data reveal a feedback loop between MLL1 and AKT whereby MLL1 inhibition reactivates AKT. We show that combined PI3K and MLL1 inhibition synergizes to cause cell death in in vitro and in vivo models of HR+ breast cancer, which is enhanced by the additional genetic ablation of the H3K4 methyltransferase and AKT target KMT2D/MLL4. Together, our data provide evidence of a feedback mechanism connecting histone methylation with AKT and may support the preclinical development and testing of pan-MLL inhibitors. Significance: Here the authors leverage PI3K/AKT-driven chromatin modification to identify histone methyltransferases as a therapeutic target. Dual PI3K and MLL inhibition synergize to reduce clonogenicity and cell proliferation, and promote in vivo tumor regression. These findings suggest patients with PIK3CA-mutant, HR+ breast cancer may derive clinical benefit from combined PI3K/MLL inhibition.

Lithium isotopic ratios have wide ranging applications as chemical signatures, including improved understanding of geochemical processes and battery development. Measurement of isotope ratios using optical spectroscopies would provide an alternative to traditional mass spectrometric methods, which are expensive and often limited to a chemical laboratory. Raman spectra of 7Li2CO3, 6Li2CO3, 7LiOH*H2O, and 6LiOH*H2O have been measured to determine the effect of lithium isotope substitution on the Raman molecular vibrations. Thirteen peaks were observed in the spectrum of lithium carbonate, with discernable isotopic shifts occurring in eleven of the 13 vibrations, two of which have not been previously reported in the literature. The spectrum of lithium hydroxide monohydrate contained nine peaks, with discernable isotopic shifts occurring in eight of the nine vibrations, four of which have not been previously reported in the literature. The Raman spectral data reported here for lithium carbonate and lithium hydroxide monohydrate are in agreement with the previously reported works in the literature, in which the Raman active modes of these molecules were first identified and assigned. However, due to the stability and resolution of the detection system used in this work, isotopic shifts with a magnitude less than one wavenumber have been identified. Principal component regression was used to evaluate the sensitivity to isotopic content of small Raman peak shifts in Li2CO3 and indicates differences greater than 2 atom% could be reliably determined. These measurements add to the body of work on lithium isotope Raman spectroscopy for these two compounds and increases the number of Raman bands which could be used for lithium isotope content analysis.

BackgroundBorderline personality disorder is a severe mental health condition characterised by a pattern of emotional instability, interpersonal dysfunction, disturbed self-image and impulsive behaviour, including self-harm. Symptoms of borderline personality disorder typically emerge during adolescence. Although there is compelling evidence in support of early intervention for borderline personality disorder, current evidence-based interventions are resource intensive, with the result that few young people access timely treatment. Therefore, there is an urgent need for accessible interventions to facilitate early intervention for adolescents with borderline personality disorder symptoms.ObjectivesThe first objective was to adapt a brief psychological treatment for adolescent borderline personality disorder that had previously been delivered within secondary mental health services for co-delivery within schools and colleges. The second objective was to assess the feasibility of evaluating the clinical effectiveness and cost-effectiveness of this intervention in a future randomised controlled trial.DesignWe first conducted a rapid evidence synthesis of barriers to and facilitators of the implementation of indicated mental health interventions for adolescents within educational settings and piloted the prototype intervention with three schools/colleges. Based on the findings of the evidence synthesis and pilot, we refined the intervention and study procedures in preparation for a feasibility randomised controlled trial. The feasibility randomised controlled trial involved 12 schools and colleges, whose pastoral staff members received training to deliver the intervention alongside a mental health practitioner. Participants were randomised in a 1 : 1 ratio to receive either the BEST (Brief Education Supported Treatment) intervention plus treatment as usual or treatment as usual alone. Participants were assessed pre randomisation (baseline) and at 12 and 24 weeks post randomisation. Mixed-methods process data were collected to understand how the intervention was implemented, to assess acceptability and to monitor contamination of the control arm.ParticipantsYoung people eligible to participate were aged 13–18 years, reported symptoms of borderline personality disorder above an established threshold and had a history of repeated self-harm.ResultsThe intervention was refined based on findings of the rapid evidence synthesis, which included 50 studies, feedback from staff participants in the pilot and analysis of session recordings. In the feasibility randomised controlled trial, we randomised 32 participants prior to the premature closure of recruitment. The rate of recruitment was slower than anticipated but would probably have narrowly surpassed our progression criterion over the full recruitment window. Participant retention was high (89.5% at 12 weeks and 73.7% at 24 weeks) and the performance of the proposed outcome measures was satisfactory. We did not find any evidence that participants allocated to the treatment-as-usual arm received the BEST intervention or its components. Fidelity of intervention delivery was high (93.5% of recordings rated as adherent) and the intervention was viewed as offering benefits for individual participants, practitioners involved in co-delivery and the wider school/college.LimitationsThe feasibility randomised controlled trial was disrupted by the closure of schools and colleges in response to the COVID-19 pandemic. This reduced the window for participant recruitment and limited the data that could be collected.ConclusionsThe refined BEST intervention was able to be delivered successfully within schools and colleges and was found to be acceptable to staff and young people. The findings provide support for continuing this programme of research and would inform the design of a future trial.Trial registrationThis trial is registered as ISRCTN16862589.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full inHealth and Social Care Delivery Research; Vol. 10, No. 37. See the NIHR Journals Library website for further project information.

To assess the effectiveness of a hospital physical therapy (PT) referral triggered by scores on a mobility assessment embedded in the electronic health record (EHR) and completed by nursing staff on hospital admission.EHR and billing data from 12 acute care hospitals in a western Pennsylvania health system (January 2017-February 2018) and 11 acute care hospitals in a northeastern Ohio health system (August 2019-July 2021).We utilized a regression discontinuity design to compare patients admitted to PA hospitals with stroke who reached the mobility score threshold for an EHR-PT referral (treatment) to those who did not (control). Outcomes were hospital length of stay (LOS) and 30-day readmission or mortality. Control variables included demographics, insurance, income, and comorbidities. Hospital systems with EHR-PT referrals were also compared to those without (OH hospitals as alternative control). Subgroup analyses based on age were also conducted.We identified adult patients with a primary or secondary diagnosis of stroke and mobility assessments completed by nursing (n = 4859 in PA hospitals, n = 1749 in OH hospitals) who completed their inpatient stay.In the PA hospitals, patients with EHR-PT referrals had an 11.4 percentage-point decrease in their 30-day readmission or mortality rates (95% CI -0.57, -0.01) relative to the control. This effect was not observed in the OH hospitals for 30-day readmission (β = 0.01; 95% CI -0.25, 0.26). Adults over 60 years old with EHR-PT referrals in PA had a 26.2 percentage-point (95% CI -0.88, -0.19) decreased risk of readmission or mortality compared to those without. Unclear relationships exist between EHR-PT referrals and hospital LOS in PA.Health systems should consider methodologies to facilitate early acute care hospital PT referrals informed by mobility assessments.

Behavioral and emotional dyscontrol commonly occur following traumatic brain injury (TBI). Neuroimaging and electrophysiological correlates of dyscontrol have not been systematically summarized in the literature to date.To complete a systematic review of the literature examining neuroimaging and electrophysiological findings related to behavioral and emotional dyscontrol due to TBI.A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature search was conducted in PubMed (MEDLINE), PsycINFO, EMBASE, and Scopus databases prior to May 2019. The database query yielded 4392 unique articles. These articles were narrowed based on specific inclusion criteria (e.g., clear TBI definition, statistical analysis of the relationship between neuroimaging and dyscontrol).A final cohort of 24 articles resulted, comprising findings from 1552 patients with TBI. Studies included civilian (n = 12), military (n = 10), and sport (n = 2) samples with significant variation in the severity of TBI incorporated. Global and region-based structural imaging was more frequently used to study dyscontrol than functional imaging or diffusion tensor imaging. The prefrontal cortex was the most common neuroanatomical region associated with behavioral and emotional dyscontrol, followed by other frontal and temporal lobe findings.Frontal and temporal lesions are most strongly implicated in the development of postinjury dyscontrol symptoms although they are also the most frequently investigated regions of the brain for these symptom categories. Future studies can make valuable contributions to the field by (1) emphasizing consistent definitions of behavioral and emotional dyscontrol, (2) assessing premorbid dyscontrol symptoms in subjects, (3) utilizing functional or structural connectivity-based imaging techniques, or (4) restricting analyses to more focused brain regions.

The EU-GEI Project was funded by grant agreement Health-F2-2010-241909 from the European Community’s Seventh Framework program. The Brazilian study was funded by grant 2012-0417-0 from the São Paulo Research Foundation, D'Andrea, Giuseppe; Lal, Jatin; Tosato, Sarah;Gayer-Anderson, Charlotte;Jongsma, Hannah E.;Stilo, Simona A.; van der Ven, Els;Quattrone, Diego;Velthorst, Eva;Berardi, Domenico;Rossi Menezes, Paulo; Arango, Celso; Parellada, Mara; Lasalvia, Antonio; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Sideli, Lucia; Bobes, Julio; Bernardo, Miguel; Sanjuan, Julio; Santos, Jose Luis; Arrojo, Manuel; Marta Del-Ben, Cristina; Tripoli, Giada; Llorca, Pierre-Michel; de Haan, Lieuwe; Selten, Jean-Paul; Tortelli, Andrea; Szoke, Andrei; Muratori, Roberto; Rutten, Bart P.; van Os, Jim; Jones, Peter B.; Kirkbride, James B.; Murray, Robin M.; di Forti, Marta; Tarricone, Ilaria; Morgan, Craig

Identifying patients at risk for mortality from COVID-19 is crucial to triage, clinical decision-making, and the allocation of scarce hospital resources. The 4C Mortality Score effectively predicts COVID-19 mortality, but it has not been validated in a United States (U.S.) population. The purpose of this study is to determine whether the 4C Mortality Score accurately predicts COVID-19 mortality in an urban U.S. adult inpatient population.This retrospective cohort study included adult patients admitted to a single-center, tertiary care hospital (Philadelphia, PA) with a positive SARS-CoV-2 PCR from 3/01/2020 to 6/06/2020. Variables were extracted through a combination of automated export and manual chart review. The outcome of interest was mortality during hospital admission or within 30 days of discharge.This study included 426 patients; mean age was 64.4 years, 43.4% were female, and 54.5% self-identified as Black or African American. All-cause mortality was observed in 71 patients (16.7%). The area under the receiver operator characteristic curve of the 4C Mortality Score was 0.85 (95% confidence interval, 0.79-0.89).Clinicians may use the 4C Mortality Score in an urban, majority Black, U.S. inpatient population. The derivation and validation cohorts were treated in the pre-vaccine era so the 4C Score may over-predict mortality in current patient populations. With stubbornly high inpatient mortality rates, however, the 4C Score remains one of the best tools available to date to inform thoughtful triage and treatment allocation.

Brief alcohol interventions (BAIs) have historically centered on young adults attending 4-year predominantly white institutions. The purpose of this scoping review is to determine BAIs evaluated among young adults with one or more marginalized/understudied racial, ethnic, sexual, gender, and military/Veteran identities and/or who are embedded in an understudied context based on houselessness, attending a 2-year institution, or not attending college. A secondary objective is to explore definitions of the constructsSources had to be published in English between January 1, 1999 and December 31, 2019 and report the evaluation of an intervention ≤ 5 hr long, delivered over ≤ 4 weeks, among participants aged 18-30 years (or 16-30 in college contexts) within a specified marginalized/understudied subpopulation/context wherein alcohol use and/or consequences were a primary outcome. Systematic searches were conducted in APA PsycNet, the EBSCO Psychology and Behavioral Sciences Collection, PubMed, Sociological Abstracts, and Web of Science. Screening was independently performed by two coders who also extracted data.Of 4,825 identified records, 158 provided data; 86 described interventions fitting our definition of brief; of these, only 21 met criteria based on our definition ofFindings signify a need for additional research evaluating BAIs among young adult subpopulations and highlight the importance of carefully defining and reporting participant characteristics. Increased attention to sociocultural considerations and strengths relevant to the diverse contexts and intersecting identities of young adults may strengthen extant BAIs and equitably mitigate alcohol-related harm. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The coronavirus disease (COVID-19) pandemic has brought immense psychological pressure and disruptions to daily life for all individuals, and particularly children, parents, and families. Despite these difficulties, parents are able to show resilience through adaptive coping and positive parenting behaviors. Although there is robust research on resilience in children, very little research has tested predictors of parental resilience. The present study presents descriptive information about mothers' pandemic-related stressors and positive changes and then tests whether prepandemic maternal well-being and child effortful control predicted mothers' resilient parental outcomes (positive behavior and coping) through the mediators of maternal self-compassion, adherence to family routines, and child coping. The sample comprised 95 mothers (95.38% European American, 3.2% African American, and 1.1% Asian American) with a mean age of 38.21 years (

Spatial prepositions have been studied in some detail from multiple disciplinary perspectives. However, neither the semantic similarity of these prepositions, nor the relationships between the multiple senses of different spatial prepositions, are well understood. In an empirical study of 24 spatial prepositions, we identify the degree and nature of semantic similarity and extract senses for three semantically similar groups of prepositions using t-SNE, DBSCAN clustering, and Venn diagrams. We validate the work by manual annotation with another data set. We find nuances in meaning among proximity and adjacency prepositions, such as the use of close to instead of near for pairs of lines, and the importance of proximity over contact for the next to preposition, in contrast to other adjacency prepositions.

Forest and freshwater ecosystems are tightly linked and together provide important ecosystem services, but climate change is affecting their species composition, structure, and function. Research at nine US Long Term Ecological Research sites reveals complex interactions and cascading effects of climate change, some of which feed back into the climate system. Air temperature has increased at all sites, and those in the Northeast have become wetter, whereas sites in the Northwest and Alaska have become slightly drier. These changes have altered streamflow and affected ecosystem processes, including primary production, carbon storage, water and nutrient cycling, and community dynamics. At some sites, the direct effects of climate change are the dominant driver altering ecosystems, whereas at other sites indirect effects or disturbances and stressors unrelated to climate change are more important. Long-term studies are critical for understanding the impacts of climate change on forest and freshwater ecosystems.

A 2020 World Health Organization report underscored the impact of rising healthcare spending globally and questioned the long-term economic sustainability of current funding models. Increases in costs associated with care of late-stage irreversible diseases and the increasing prevalence of debilitating neurodegenerative disorders, coupled with increases in life expectancy are likely to overload the healthcare systems in many nations within the next decade if not addressed. One option for sustainability of the healthcare system is a change in emphasis from illness to wellness centered care. An attractive model is the P4 (Predictive, Preventative, Personalized and Participatory) medicine approach. Recent advances in connected health technology can help accelerate this transition; they offer prediction, diagnosis, and monitoring of health-related parameters. We explain how to integrate such technologies with conventional approaches and guide public health policy toward wellness-based care models and strategies to relieve the escalating economic burdens of managed care.

BACKGROUND: Sleep deprivation in adolescence is increasing in prevalence and may be linked to subsequent depression. Findings regarding associations between sleep duration, sleep onset time, and the development of depressive symptoms over time in adolescents are mixed, and rely on subjective measures of sleep. METHODS: Sleep onset and duration were assessed using a combined heart rate monitor and accelerometer and self-report in 688 participants from the ROOTS study at age 15. Participants reported depressive symptoms at ages 14.5, 16, and 17.5, using the Mood and Feelings Questionnaire. Latent growth curve modelling was used to model development of depressive symptoms and test associations with baseline sleep onset and duration. RESULTS: Cross-sectionally, falling asleep later and shorter sleep duration were both associated with higher depressive symptoms in males and females, using both device-measured and self-reported sleep. There were no longitudinal associations between baseline sleep duration and change in depressive symptoms. A later sleep onset-time was associated with a decrease in depressive symptoms over time, in females only, using device-measured sleep only. LIMITATIONS: The current sample was more economically advantaged and ethnically white than the UK average, and with lower MFQ symptoms than the original cohort, which may reduce generalisability. CONCLUSIONS: Adolescents who fall asleep later or sleep less have higher levels of depressive symptoms cross-sectionally, but do not show increases in depressive symptoms over time. Interventions targeting sleep onset and duration in adolescence may improve mental health in the short-term but the possibility of reverse causality should be explored further.

Although cultivars possessing recessive resistance alleles provide effective control of bacterial spot of pepper (Capsicum annuum), the deployed resistance gene, bs5, is ineffective against Xanthomonas gardneri, one of the pathogenic species. Resistance against X. gardneri was identified in C. annuum accession PI 163192, and this study sought to characterize this novel resistance and to map the resistance gene(s) to the pepper genome. We crossed PI 163192 with the susceptible cultivar Early Calwonder (ECW) to develop resistant near-isogenic lines (NILs) of ECW, designated ECW80R. The novel resistance in ECW80R was determined to be quantitative, recessively inherited, and non-hypersensitive-response causing, and inhibits lesion expansion and chlorosis. Presence of the resistance in NILs decreased the in planta bacterial population by ninefold compared with ECW. Bulked segregant analysis of resistant and susceptible individuals from an F2 population using whole genome single nucleotide polymorphisms identified a major resistance locus within an approximate 6-Mbp interval on the subtelomeric region of chromosome 11. We developed markers spanning this region and used these to genotype backcross F2 populations, which further delimited the resistance locus within a 2.3-Mbp interval. The novel resistance locus has been designated bs8. ECW80R and the linked markers developed in this study should prove useful for breeders seeking to advance this resistance into commercially relevant germplasm and for pyramiding bs8 with other resistance alleles such as bs5 and bs6. The allele bs8 will help prolong the durability of bacterial spot resistance in pepper and improve resistance to multiple species of Xanthomonas.

Xanthomonas citri is a plant pathogen that causes major economic losses to the citrus industry and sweet orange production in particular. Several subspecies and pathogens are recognized, with host ranges including soybean, common bean, mango, pomegranate, and cashew, among others.

Results from the application of optical potential, relativistic optical potential, relativistic convergent close-coupling, and binary encounter Bethe models to electron scattering from gas-phase cadmium are presented. In particular, integral cross sections for elastic scattering, summed discrete electronic-state excitation, and ionization scattering processes are reported over an extended incident electron-energy range. Total cross sections are constructed by taking their sum. Measurements are presented for elastic scattering and for excitation to the 51P1 state. The theoretical and experimental results are compared to previous calculations and measurements. Recommended electron cross-section datasets are constructed over an incident electron energy range of 0.01–10 000 eV.

Fish stocking occurs in aquatic systems for conservation purposes, to create or enhance recreational fisheries, and to enhance wild-catch commercial fisheries. Identifying and quantifying the contribution of stocking efforts to wild populations is crucial to informing these management objectives. Provenance determination methods trade off accuracy, replicability, and cost-effectiveness at fishery-relevant scales. We present and assess multiple methods for provenance determination using a case study of barramundi (Lates calcarifer) in the Dry Tropics region of northern Australia. A novel application of Near Infra-Red Spectroscopy (NIRS) is compared to two established methods for fish provenance: otolith microchemistry and genetic parentage analysis using microsatellites. The otolith microchemistry method was able to provide extremely high provenance resolution (>99% accuracy). The microsatellite parentage analysis method had a slightly lower overall accuracy (95%), likely as a result of genetic introgression in this region. Provenance determination using otolith NIRS had the lowest overall accuracy (76%). Once limitations regarding spectral noise, image resolution, and sample size are addressed, NIRS may have potential for cost-effectively determining provenance in fish.

Childhood adversity is one of the strongest predictors of adolescent mental illness. Therefore, it is critical that the mechanisms that aid resilient functioning after childhood adversity are better understood. Here, we examined whether resilient functioning was related to structural brain network topology. We quantified resilient functioning at the individual level as psychosocial functioning adjusted for the severity of childhood adversity in a large sample of adolescents (N=2406, aged 14-24). Next, we examined nodal degree (the number of connections that brain regions have in a network) using brain-wide cortical thickness measures in a representative subset (N=275) using a sliding window approach. We found that increases in resilient functioning were convergently associated with decreases in nodal degree of multiple regions including the dorsolateral prefrontal cortex, the medial prefrontal cortex, and the posterior superior temporal sulcus (z> 1.645). During adolescence, decreases in nodal degree are thought to reflect a normative developmental process that is part of the extensive remodelling of structural brain network topology. Therefore, our findings of reductions in nodal degree being related to increases in resilient functioning are compatible with more mature-like structural network topology in more resilient young people.

Bacterial spot is an economically significant disease in tomato and pepper-producing countries globally. We report the whole genome sequence of 11 Xanthomonas strains associated with bacterial spot disease on pepper, tomato, and eggplant in the Southeastern Anatolia Region, Turkey. This genomic information can be used as a reference to study the genetic diversity of these species and contribute to illuminating pathogen evolution with respect to host specificity.

Background Measurement-Based Care (MBC) is an evidence-based practice shown to enhance patient care. Despite being efficacious, MBC is not commonly used in practice. While barriers and facilitators of MBC implementation have been described in the literature, the type of clinicians and populations studied vary widely, even within the same practice setting. The current study aims to improve MBC implementation in adult ambulatory psychiatry by conducting focus group interviews while utilizing a novel virtual brainwriting premortem method. Methods Semi-structured focus group interviews were conducted with clinicians (n = 18) and staff (n = 7) to identify their current attitudes, facilitators, and barriers of MBC implementation in their healthcare setting. Virtual video-conferencing software was used to conduct focus groups, and based on transcribed verbatin, emergent barriers/facilitators and four themes were identified. Mixed methods approach was utilized for this study. Specifically, qualitative data was aggregated and re-coded separately by three doctoral-level coders. Quantitative analyses were conducted from a follow-up questionnaire surveying clinician attitudes and satisfaction with MBC. Results The clinician and staff focus groups resulted in 291 and 91 unique codes, respectively. While clinicians identified a similar number of barriers (40.9%) and facilitators (44.3%), staff identified more barriers (67%) than facilitators (24.7%) for MBC. Four themes emerged from the analysis; (1) a description of current status/neutral opinion on MBC; (2) positive themes that include benefits of MBC, facilitators, enablers, or reasons on why they conduct MBC in their practice, (3) negative themes that include barriers or issues that hinder them from incorporating MBC into their practice, and (4) requests and suggestions for future MBC implementation. Both participant groups raised more negative themes highlighting critical challenges to MBC implementation than positive themes. The follow-up questionnaire regarding MBC attitudes showed the areas that clinicians emphasized the most and the least in their clinical practice. Conclusion The virtual brainwriting premortem focus groups provided critical information on the shortcomings and strengths of MBC in adult ambulatory psychiatry. Our findings underscore implementation challenges in healthcare settings and provide insight for both research and clinical practice in mental health fields. The barriers and facilitators identified in this study can inform future training to increase sustainability and better integrate MBC with positive downstream outcomes in patient care.

Funder: MQ: Transforming Mental Health; Grant(s): MQDS17/40, Around a quarter of people who experience a first episode of psychosis (FEP) will develop treatment-resistant schizophrenia (TRS), but there are currently no established clinically useful methods to predict this from baseline. We aimed to explore the predictive potential for clozapine use as a proxy for TRS of routinely collected, objective biomedical predictors at FEP onset, and to externally validate the model in a separate clinical sample of people with FEP. We developed and externally validated a forced-entry logistic regression risk prediction Model fOr cloZApine tReaTment, or MOZART, to predict up to 8-year risk of clozapine use from FEP using routinely recorded information including age, sex, ethnicity, triglycerides, alkaline phosphatase levels, and lymphocyte counts. We also produced a least-absolute shrinkage and selection operator (LASSO) based model, additionally including neutrophil count, smoking status, body mass index, and random glucose levels. The models were developed using data from two UK psychosis early intervention services (EIS) and externally validated in another UK EIS. Model performance was assessed via discrimination and calibration. We developed the models in 785 patients, and validated externally in 1,110 patients. Both models predicted clozapine use well at internal validation (MOZART: C 0.70; 95%CI 0.63,0.76; LASSO: 0.69; 95%CI 0.63,0.77). At external validation, discrimination performance reduced (MOZART: 0.63; 0.58,0.69; LASSO: 0.64; 0.58,0.69) but recovered after re-estimation of the lymphocyte predictor (C: 0.67; 0.62,0.73). Calibration plots showed good agreement between observed and predicted risk in the forced-entry model. We also present a decision-curve analysis and an online data visualisation tool. The use of routinely collected clinical information including blood-based biomarkers taken at FEP onset can help to predict the individual risk of clozapine use, and should be considered equally alongside other potentially useful information such as symptom scores in large-scale efforts to predict psychiatric outcomes.

BackgroundMindfulness-based programmes (MBPs) have shown beneficial mental health effects. There is emerging evidence that MBPs may also be associated with marked deviations in the subjective experience of waking consciousness. We aimed to assess whether MBPs can have a causal role in different types of such states. MethodsWe conducted a pragmatic randomised controlled trial (ACTRN12615001160527). University of Cambridge students without severe mental illness were randomised to an 8-week MBP plus mental health support as usual (SAU), or to SAU alone. We adapted the Altered States of Consciousness Rating Scale (OAV) to assess spontaneous experiences in daily life, and included it as a post-hoc secondary outcome at the end of the one-year follow-up questionnaire. ResultsWe randomised 670 participants; 205 (33%) completed the OAV. In comparison with SAU, MBP participants had more intense experiences of unity, (adjusted partial eta squared (n2) 0.04, p=0.001) and disembodiment (n2 0.04, p=0.006). Meditation predicted reports of unity, blissful state, insightfulness, disembodiment, and changed meanings. Findings were robust to corrections for multiple comparisons.ConclusionsResults provide a novel suggestion of causal links between mindfulness practice and specific altered states of consciousness. Practitioners need to anticipate and handle them appropriately. Future studies need to confirm findings.

Figure S1 shows combined effects of PI3K and MLL1 inhibition in clonogenic assays