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WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1 R394W/+ ). Podocytes were the most dysregulated cell-type in the early stages of Wt1 R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1 R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1 R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1 R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1 R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Presenting unpaired unconditional stimuli (US) during extinction training reduces the renewal of conditional fear due to context change and slows re-acquisition. The present study investigated whether this reduced return of fear is mediated by Pavlovian inhibitory conditioning to the conditional stimulus paired with the US during acquisition (CS+) that is acquired when this stimulus is presented without the US in an excitatory extinction context. Using an ABA renewal paradigm that trained extinction in a context different from acquisition and renewal test, participants either received no USs (Standard), five unsignalled US presentations (Unsignalled) or five presentations of the US preceded by a novel, third CS (Signalled) during extinction training. Extinction was followed by tests for renewal and re-acquisition. Replicating previous results, renewal of electrodermal conditional responses was observed in group Standard, but not in group Unsignalled. Signalling the additional USs, and thus reducing context conditioning and the potential for inhibitory conditioning, did not reduce their effect in that renewal was absent in group Signalled. These results are inconsistent with an inhibitory conditioning account of the effects of unpaired US presentations during extinction. A trial sequence learning account or an arousal account may explain the effects of unpaired presentations of the US during extinction., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The benefit of targeting high ratio fresh frozen plasma (FFP)/red blood cell (RBC) transfusion in pediatric trauma resuscitation is unclear as existing studies are limited to patients who retrospectively met criteria for massive transfusion. The purpose of this study is to evaluate the use of high ratio FFP/RBC transfusion and the association with outcomes in children presenting in shock., Methods: A post hoc analysis of a 24-institution prospective observational study (April 2018 to September 2019) of injured children younger than 18 years with elevated age-adjusted shock index was performed. Patients transfused within 24 hours were stratified into cohorts of low (<1:2) or high (≥1:2) ratio FFP/RBC. Nonparametric Kruskal-Wallis and χ 2 were used to compare characteristics and mortality. Competing risks analysis was used to compare extended (≥75th percentile) ventilator, intensive care, and hospital days while accounting for early deaths., Results: Of 135 children with median (interquartile range) age 10 (5-14) years and weight 40 (20-64) kg, 85 (63%) received low ratio transfusion and 50 (37%) high ratio despite similar activation of institutional massive transfusion protocols (low-38%, high-46%, p = 0.34). Most patients sustained blunt injuries (70%). Median injury severity score was greater in high ratio patients (low-25, high-33, p = 0.01); however, hospital mortality was similar (low-24%, high-20%, p = 0.65) as was the risk of extended ventilator, intensive care unit, and hospital days (all p > 0.05)., Conclusion: Despite increased injury severity, patients who received a high ratio of FFP/RBC had comparable rates of mortality. These data suggest high ratio FFP/RBC resuscitation is not associated with worst outcomes in children who present in shock. Massive transfusion protocol activation was not associated with receipt of high ratio transfusion, suggesting variability in MTP between centers., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Timely diagnosis of systemic mastocytosis (SM) remains challenging because of care heterogeneity. We implemented a standardized approach for SM screening and diagnosis using a novel health care system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and 2 years after care standardization. The accuracy of individual and combined SM screening tests, basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM (MPCM), and elevated BST based upon tryptase genotype, was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially 2 years after care standardization. SM diagnoses doubled from 47 to 94, and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM before care standardization (4/30 [13.3%]) but reflected the general population prevalence 2 years later at (5/76 [6.6%]). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. The presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM (ISM) diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any ISM screening test and improved the REMA score specificity.

Children prone to irritability experience significant functional impairments and internalising and externalising problems. Contemporary models have sought to elucidate the underlying mechanisms in irritability, such as aberrant threat and reward biases to improve interventions. However, the cognitive control processes that underlie threat (e.g., attention towards threats) and reward (e.g., attention towards reward-related cues) biases and the factors which influence the differential activation of positive and negative valence systems and thus leading to maladaptive activation of cognitive control processes (i.e., proactive and reactive control) are unclear. Thus, we aim to integrate extant theoretical and empirical research to elucidate the cognitive control processes underlying threat and reward processing that contribute to irritability in middle childhood and provide a guiding framework for future research and treatment. We propose an expanded conceptual framework of irritability that includes broad intraindividual and environmental vulnerability factors and propose proximal 'setting' factors that activate the negative valence and positive valence systems and proactive and reactive cognitive control processes which underpin the expression and progression of irritability. We consider the implications of this expanded conceptualisation of irritability and provide suggestions for future research., (© 2024. The Author(s).)

Young people face multiple challenges, including appearance dissatisfaction, academic stressors, anxiety and depression. These challenges may increase during the final year of high school and may have become further exacerbated by the COVID-19 pandemic. This study examines the preliminary effectiveness of a brief, uncontrolled school-based intervention aimed at enhancing Psychological Capital (PsyCap), consisting of positive resources of hope, self-efficacy, resilience and optimism (HERO), and reducing mental health symptoms among female year 12 students (n = 95, Mage = 16.78, SD = 0.45). Outcomes on measures of HERO and secondary outcomes of flourishing, appearance dissatisfaction, anxiety and depression were measured at pre and post-intervention. In the overall cohort, no significant changes were found on the HERO outcomes or flourishing post-intervention, while symptoms of depression, anxiety and appearance dissatisfaction decreased significantly. For students with higher baseline anxiety, optimism and anxiety symptoms improved significantly at post-intervention. However, students with lower baseline anxiety experienced significant decreases in self-efficacy and optimism, as well as a significant increase in anxiety symptoms post-intervention. Baseline depression levels did not impact intervention outcomes. The findings, although mixed and limited by the lack of control group, suggest that a brief intervention grounded in PsyCap theory may improve student wellbeing under challenging circumstances., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs., (© 2024. The Author(s).)

Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world's deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Long, Amparo, Goodhart, Ahmad and Waters.)

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61 1 . Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer 2,3 . Nevertheless, KRAS G12C mutations account for only around 15% of KRAS-mutated cancers 4,5 , and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRAS G12X ). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRAS G12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985)., (© 2024. The Author(s).)

Given diverse symptom expression and high rates of comorbid conditions, the present study explored underlying commonalities among OCD-affected children and adolescents to better conceptualize disorder presentation and associated features. Data from 830 OCD-affected participants presenting to OCD specialty centers was aggregated. Dependent mixture modeling was used to examine latent clusters based on their age- and gender adjusted symptom severity (as measured by the Children's Yale-Brown Obsessive-Compulsive Scale; CY-BOCS), symptom type (as measured by factor scores calculated from the CY-BOCS symptom checklist), and comorbid diagnoses (as assessed via diagnostic interviews). Fit statistics favored a four-cluster model with groups distinguished primarily by symptom expression and comorbidity type. Fit indices for 3-7 cluster models were only marginally different and characteristics of the clusters remained largely stable between solutions with small clusters of distinct presentations added in more complex models. Rather than identifying a single classification system, the findings support the utility of integrating dimensional, developmental, and transdiagnostic information in the conceptualization of OCD-affected children and adolescents. Identified clusters point to the centrality of contamination concerns to OCD, relationships between broader symptom expression and higher levels of comorbidity, and the potential for complex/neurodevelopmental presentations., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Adolescents report using digital technologies for emotion regulation (digital ER), with the aim of feeling better (i.e., improving emotions and reducing loneliness). In this 7-day diary study, we investigated associations of digital ER, emotions, and loneliness, and tested whether prior emotional problems moderated these associations., Method: Participants were 312 Australian adolescents (M age  = 13.91, SD = 1.52; 44% boys). Daily surveys measured digital ER; end-of-day happiness, sadness, worry, anger, and loneliness; and peak sadness, worry, and anger. End-of day emotions were subtracted from peak emotions to calculate emotion recovery for sadness, worry, and anger. Participants were randomly selected from two symptom strata (high/low) defined by depression and social anxiety measures collected before the diary. Data were analyzed using multilevel path modeling. Cross-level interactions tested whether symptom strata moderated associations., Results: Digital ER was associated with more recovery from peak to end-of-day sadness and worry, but also with increased sadness, worry, anger, and loneliness by the next end-of-day. Higher end-of-day loneliness was associated with increased next-day digital ER. Prior emotional symptoms were not a significant moderator of daily digital ER and emotion associations., Conclusion: Adolescents who report more digital ER in a day show more recovery from the peak of negative emotion that day, but this recovery dissipates, with digital ER also associated with increased negative emotion and loneliness by the next day for all adolescents, regardless of prior symptom status. Lonelier adolescents use more digital ER by the next day, suggesting they need support to make social connections-online or offline., (© 2023 The Authors. Journal of Adolescence published by Wiley Periodicals LLC on behalf of Foundation for Professionals in Services to Adolescents.)

Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum. Here, we provide evidence that podocin R138Q (but not wild-type podocin) complexes with the intermediate filament protein keratin 8 (K8) thereby preventing its correct trafficking to the plasma membrane. We have also identified a small molecule (c407), a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator protein defect, that interrupts this complex and rescues mutant protein mistrafficking. This results in both the correct localization of podocin at the plasma membrane and functional rescue in both human patient R138Q mutant podocyte cell lines, and in a mouse inducible knock-in model of the R138Q mutation. Importantly, complete rescue of proteinuria and histological changes was seen when c407 was administered both via osmotic minipumps or delivered orally prior to induction of disease or crucially via osmotic minipump two weeks after disease induction. Thus, our data constitute a therapeutic option for patients with NS bearing a podocin mutation, with implications for other misfolding protein disorders. Further studies are necessary to confirm our findings., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fear conditioning is a common experimental paradigm for modelling the development, and exposure-based treatment, of anxiety disorders. Measures of fear such as threat-expectancy, physiological arousal, and fear ratings typically extinguish, however feared stimuli may still be evaluated negatively (i.e. retain negative valence). This systematic review provides the first investigation of the relationship between fear conditioning methodology and extinction of negative stimulus valence. Principal findings were that type of CS (conditioned stimulus) and the CS-US pairing (i.e. specific combination of CS and unconditioned stimulus) predicted extinction outcome. Extinction of absolute negative CS valence was always achieved with shape CSs; often achieved with low fear-relevant animals as CSs, and less frequently achieved with faces as CSs - particularly neutral faces paired with a shock US. Modified extinction procedures typically achieved the same outcome as standard extinction procedures, except for partially-reinforced extinction, which was less effective than standard extinction, and positive imagery training, which was more effective than standard extinction. Further studies are warranted to evaluate the influence of fear conditioning methodology on extinction of absolute negative CS valence., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). They are responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from jamiah.hyde@griffithuni.edu.au., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Embedding mental health and wellbeing programs within youth sports development programs can help provide more young people with mental health support. However, delivering such programs in multiple locations across metropolitan, regional, and rural areas requires novel solutions to overcome geographic and logistical barriers. We examined the delivery of an integrated system delivered within an Australian junior rugby league program. The program included online assessment and feedback about youth mental health, as well as connection with evidence-informed resources and referral sources via parent telephone and email support. There were four methods of delivering player workshops during training sessions: (a) In-person Delivery Only, (b) In-person + Remote Real-time (video-conferenced), (c) In-person + Remote Prerecorded (video-recorded), and (d) Remote Delivery Only (video-conferenced and/or video-recorded). In-person delivered player workshops were facilitated by local rugby league personnel. Remote delivered workshops were facilitated by psychologists from the mental health research team. Participants were 671 boys (12-15 years; M age = 13.35; SD = 0.35) in 21 metropolitan, regional and rural locations. Regardless of delivery condition, players with elevated anxiety, depression and behavioural problems reported significant declines in symptoms from pre- to post-program, and those within healthy ranges did not change from pre- to post-program. Player workshop enjoyment ratings were higher in the In-person + Remote Real-time condition and the Remote Delivery Only condition than the In-person Delivery Only condition. However, non-completion of the post-program assessment across all conditions was higher than in prior studies and a comparison group of players who did not complete the program was not included. Mental health benefits may be observed across in-person and remote modes of delivering mental health workshops within youth sports programs. However, the involvement of mental health personnel, whether in-person or remotely, and mixed delivery modes, may be important for young people's retention and satisfaction., (© 2024. The Author(s).)

Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to and long-term efficacy of direct inhibitors of the KRASG12C mutant in cancer. To identify potential mechanisms of resistance, we applied a CRISPR/Cas9 loss-of-function screen and observed loss of multiple components of the Hippo tumor suppressor pathway, which acts to suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired the antiproliferative and proapoptotic effects of KRASG12C inhibitor (G12Ci) treatment in KRASG12C-mutant cancer cell lines. Conversely, genetic suppression of YAP1/WWTR1 (TAZ) enhanced G12Ci sensitivity. YAP1/TAZ activity overcame KRAS dependency through two distinct TEAD transcription factor-dependent mechanisms, which phenocopy KRAS effector signaling. First, TEAD stimulated ERK-independent transcription of genes normally regulated by ERK (BIRC5, CDC20, ECT2, FOSL1, and MYC) to promote progression through the cell cycle. Second, TEAD caused activation of PI3K-AKT-mTOR signaling to overcome apoptosis. G12Ci treatment-induced acquired resistance was also caused by YAP1/TAZ-TEAD activation. Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRASG12C inhibitor antitumor activity in vitro and prolonged tumor suppression in vivo. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the antitumor efficacy of KRAS-targeted therapies., Significance: YAP1/TAZ-TEAD activation compensates for loss of KRAS effector signaling, establishing a mechanistic basis for concurrent inhibition of TEAD to enhance the efficacy of KRASG12C-selective inhibitor treatment of KRASG12C-mutant cancers. See related commentary by Johnson and Haigis, p. 4005., (©2023 American Association for Cancer Research.)

Short and long nightly sleep durations are associated with anxiety and depression symptoms among adolescents. However, studies have not used recommended hours of nightly sleep or focused on sleep patterns across weekdays and weekends in examining links with anxiety and depression symptoms. The present study included 709 adolescents in Grade 11 (402 females; 307 males) who self-reported hours of sleep on weeknights and weekends and anxiety and depression symptoms. Using the recommended 8-10 h to define average nightly sleep for adolescents, sleep patterns across weekdays and weekends were categorised into seven classes: short stable, short increasing, average decreasing, average stable, average increasing, long decreasing, and long stable. Relative to average stable sleepers, short stable, short increasing, and long stable sleepers had significantly higher anxiety and depression. Adolescents require 8-10 h of sleep on weeknights, regardless of weekends, for optimal emotional wellbeing., (© 2023. The Author(s).)

Considerable work has advanced understanding of the nature, causes, management, and prevention of anxiety disorders in children and adolescents over the past 30 years. Prior to this time the primary focus was on school refusal and specific phobias. It is now recognised that children and adolescents experience the full gamut of anxiety disorders in very similar ways to adults and that anxiety disorders in the paediatric years can predict a lifelong mental-health struggle. Given the vast array of specific studies in this field, the current review summarises current knowledge about these high prevalence disorders, points to overarching limitations, and suggests potentially important future directions. Following a brief historical overview, the review summarises knowledge about demographic and epidemiological characteristics, distal and proximal risk factors, current treatment directions, and prevention. There is still a great deal to learn about the causes and treatments of child and adolescent anxiety disorders. By amalgamating our current knowledge, this review provides a window to the research directions that are likely to lead to future advances., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr Pine was supported by NIMH-IRP Project ZIA-MH002781. Dr Creswell receives funding from the National Institute for Health and Care Research (NIHR) Applied Research Collaboration Oxford and Thames Valley and Oxford Health NIHR Biomedical Research Collaboration at Oxford Health NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Childhood obsessive-compulsive disorder (OCD) is among the most prevalent and disabling mental health conditions affecting children and adolescents. Although the distress and burden associated with childhood OCD are well documented and empirically supported treatments are available, there remains an unacceptable "treatment gap" and "quality gap" in the provision of services for youth suffering from OCD. The treatment gap represents the large number of children who never receive mental health services for OCD, while the quality gap refers to the children and young people who do access services, but do not receive evidence-based, cognitive behavioural therapy with exposure and response prevention (CBT-ERP). We propose a novel staged-care model of CBT-ERP that aims to improve the treatment access to high-quality CBT-ERP, as well as enhance the treatment outcomes for youth. In staged care, patients receive hierarchically arranged service packages that vary according to the intensity, duration, and mix of treatment options, with provision of care from prevention, early intervention, through to first and second-line treatments. Based on a comprehensive review of the literature on treatment outcomes and predictors of treatments response, we propose a preliminary staging algorithm to determine the level of clinical care, informed by three key determinants: severity of illness, comorbidity, and prior treatment history. The proposed clinical staging model for paediatric OCD prioritises high-quality care for children at all stages and levels of illness, utilising empirically supported CBT-ERP, across multiple modalities, combined with evidence-informed, clinical decision-making heuristics. While informed by evidence, the proposed staging model requires empirical validation before it is ready for prime time., (© 2023. The Author(s).)

Background: The association between anxious mood and aberrant fear learning mechanisms has not been fully elucidated. Studying how fear conditioning and extinction constructs relate to anxiety symptoms and reactivity to stressful and benign moments in everyday life provides a powerful addition to experimental paradigms., Method: Fifty-one young adults completed laboratory-based differential conditioning and extinction tasks with (CS + ) and without (CS-) an aversive unconditional stimulus (US). Electrodermal skin conductance responses were measured during each phase, followed by ecological momentary assessment (EMA) tapping anxiety and stressors six times daily for seven days (2, 142 moments)., Results: Conditioned electrodermal reactivity to the CS + and overgeneralisation to the CS- were associated with greater change in anxiety (measured via EMA), across non-stressful situations, remaining the same across stressful situations. Likewise, during extinction when the CS + is now safe, more electrodermal reactivity to the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations. Also, during extinction when threat is absent, more electrodermal reactivity at the late stage of the CS- was associated with less momentary anxiety change in response to stressful situations; more electrodermal activity at the late stage of the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations., Conclusions: Sampling 'in vivo' emotion and stress experiences, study findings revealed links between conditioned electrodermal reactivity and overgeneralisation to safe stimuli and heightened anxious reactivity during non-stressful (i.e. safe) moments in daily life, coupled with less change in response to actual stressors.

Introduction: Many adolescents are concerned about global and future crises, such as the health of the planet or terrorism/safety. Yet, adolescents can also express hope about the future. Thus, asking adolescents about their concern and hope could yield subgroups with different ways of coping and personal adjustment., Method: Australian adolescents (N = 863; age 10-16) completed surveys to report their concern (worry and anger) and hope about the planet, safety, jobs, income, housing, and technology, as well as their active and avoidant coping, depression, and life satisfaction., Results: Four distinct subgroups were identified using cluster analysis: Hopeful (low on concern and high on hope across all issues, 32%), Uninvolved (low in concern and hope; 26%), Concerned about the Planet (CP, 27%), and Concerned about Future Life (CFL, 15%). When compared (adjusting for age, sex, and COVID timing), the CP subgroup was highest in active coping (e.g., taking action) but moderate in personal adjustment. Hopeful had the most positive adjustment, whereas CFL had the poorest adjustment. Uninvolved were lowest in coping but moderate in adjustment., Conclusions: Findings suggest ways of coping and adjustment may not always align, in that CP is connected with more active coping but also some cost to personal adjustment, whereas Hopeful is associated with optimal adjustment but perhaps at the cost of active coping. In addition, although CFL adolescents emerged as the at-risk group, the low levels of hope and coping in Uninvolved adolescents raise the possibility that they are at risk of future problems., (© 2023 The Authors. Journal of Adolescence published by Wiley Periodicals LLC on behalf of Foundation for Professionals in Services to Adolescents.)

Aberrant threat processing is a known cognitive characteristic of anxiety disorders and irritability. Youth with more severe symptomatology show greater allocation of attention towards threat relative to neutral stimuli. Although irritability contributes to poorer outcomes among anxious youths, irritability has not been considered as a contributing factor to threat processing in anxiety disorders. Thus, the current study examined the role of irritability in predicting attention biases for threat among clinically anxious youth. Our study included 84 clinically anxious youth (M = 9.31 years old, SD = 2.44) who completed a dot-probe task to determine attention biases. Anxiety disorders were assessed using semi-structured diagnostic interviews. Well validated measures were used to assess the severity of anxiety and irritability symptoms via child- and parent-report, respectively. Findings indicated that more severe irritability predicted greater attention biases toward threat among clinically anxious youth, covarying for age, anxiety severity, and the number of comorbid diagnoses. At a trend-level, anxiety severity also predicted attention bias for threat. Among clinically anxious youth, irritability severity was the strongest predictor of attention bias toward threat. Findings point to the salience of irritability, and to some extent anxiety severity, in relation to threat processing among youth with clinical anxiety disorders., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Recent studies have shown that extinction training including the conditional stimulus (CS+) and stimuli that are similar to the CS + enhances extinction retention and generalisation to novel stimuli. However, in a clinical setting, the CS+ is rarely available for use during exposure therapy. The aim of the present study was to determine if replacing the CS+ with a similar versus different stimulus, and including other similar stimuli during extinction, could reduce fear at test on par with extinction using the original CS+ with and without other similar stimuli. In an experiment conducted in a single session, participants completed a habituation phase followed by an acquisition phase using two dog images presented with (CS+) and without (CS-) an acoustic unconditional stimulus (US). Participants were randomly allocated to four extinction conditions: similar CS + dog with novel dog images (Similar replacement extinction condition); different CS + dog with novel dog images (Different replacement extinction condition); original CS + dog with novel dog images (Multiple extinction control condition); and original CS + without novel dog images (Standard extinction control condition). All participants completed a test phase with the original CSs followed by a generalisation test with another two novel dog images. All groups acquired, and then extinguished differential skin conductance responses (SCRs) with no differences observed between groups. Whereas the Similar replacement extinction group and the Multiple and Standard extinction control groups did not exhibit significant differential SCRs when re-exposed to the original CS + relative to the CS- at test, differential responding to the CSs was significant at test in the Different replacement extinction group. There were no significant differences between groups in SCRs to the two novel dog images during the generalisation phase and in between-phase subjective ratings. Findings suggest that replacement stimuli used during extinction should be as similar as possible to the CS + to reduce physiological arousal to the original CS+., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study tested the efficacy of a 5 × 1.5 h/session, group-based, parent-focused, behavioural intervention (BI) targeting sleep problems in preschool children. Parents were randomised to either the BI (N = 62) or care as usual (CAU; N = 66) conditions. Outcomes included sleep, anxiety, behavioural problems, internalising and externalising symptoms, transition to school and academic achievement. Assessments were conducted at pre- and post-BI intervention (in the year prior to formal schooling), and then at follow-ups 1 and 2 in the first year of formal schooling. Relative to the CAU, the BI condition demonstrated significantly greater improvements in sleep, anxiety, behaviour problems and internalising and externalising symptoms from pre-to post-intervention. Improvements in sleep, anxiety, and internalising symptoms were maintained, while behaviour and externalising symptoms were further improved upon at school follow-up 2. For the BI group, improvements in sleep at post-intervention were found to mediate improvements in anxiety, internalising, and externalising symptoms, but not behaviour problems, at school follow-ups 1 and 2. There were no significant effects of condition on school transition or academic outcome measures. The results suggest that the BI is effective for sleep, anxiety, behaviour, internalising and externalising symptoms, but not for school transition or academic outcomes. ANZCTR NUMBER: ACTRN12618001161213., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Studies indicate the COVID-19 pandemic has resulted in rises in adolescent mental health symptoms globally, although the impact of the pandemic on subjective wellbeing is under-researched in this population. Psychological capital (PsyCap), a cluster of four positive psychological constructs comprising hope, efficacy, resilience and optimism (HERO), has demonstrated preventative and promotive qualities on mental health symptoms and subjective wellbeing outcomes with adult populations (employees, university students). However, PsyCap's influence on these outcomes in young people is unclear. The present exploratory study investigated changes in self-reported anxiety and depressive symptoms (measured via the RCADS-SV) and subjective wellbeing (measured by the Flourishing Scale) from pre-pandemic levels to 3 months into the pandemic and explored gender differences at each time point in a sample of Australian Year 10 students (N = 56, Mage = 14.93 years, SD = 0.50, 51.8% male). The longitudinal predictive role of baseline PsyCap on follow-up assessments of anxiety symptoms, depressive symptoms and flourishing were also examined. There were no significant changes in levels of anxiety and depressive symptoms between the timepoints, but flourishing significantly declined from T1 to T2. Baseline PsyCap was not a significant predictor of T2 anxiety and depressive symptoms but was a significant predictor of T2 flourishing. Further, different baseline HERO constructs predicted T2 mental health symptoms and flourishing. Future larger studies building on the current preliminary findings investigating the roles of student PsyCap, mental health and subjective wellbeing are warranted to better understand these constructs in the COVID-19 era and beyond., (© 2023. The Author(s).)

This study examined the preliminary acceptability and efficacy of an intensive, group-based, disorder-specific cognitive behavioural therapy (CBT) intervention for adolescents with social anxiety disorder (SAD). Fourteen Australian adolescents with SAD (78.6% female, M age = 13.93 years) and their parents completed the program plus measures of treatment satisfaction, and provided feedback. Clinical interviews and surveys were administered pre-treatment, post-treatment, and at 6-month follow-up to determine diagnostic status and assess related variables. Post-treatment satisfaction scores were very high for adolescents and parents. Post-treatment, 32.3% of participants no longer met criteria for SAD diagnosis, increasing to 42.9% at follow-up. Participants showed sizeable reductions in comorbid diagnoses, significant improvements in global functioning, social anxiety symptoms, and internalising symptoms from pre- to post-treatment (maintained at follow-up), and significant improvements in social skills and social competence from pre-treatment to follow-up. This study supports the use of an intensive CBT program for adolescents with SAD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Academic stress is linked to adolescent distress and perfectionism during the final years at school, with girls being at greater risk. The onset of the COVID-19 pandemic was an additional stressor that impacted student learning on a global scale. The present study examines the effectiveness of an intervention targeting Psychological Capital (PsyCap), comprising hope, efficacy, resilience, and optimism (HERO) to increase these HERO resources and assess its impact on mental health symptoms and subjective wellbeing outcomes among a cohort of Year 12 students (n = 82, Mage = 17.09, SD = 0.28, 99% identifying as female) from a girls school during the first year of the pandemic. Primary outcomes of anxiety symptoms, depressive symptoms, and flourishing and secondary outcomes of HERO variables and perfectionism were examined. There were no significant changes in primary outcomes. Significant changes in efficacy, optimism, omnibus PsyCap (HERO combined) and perfectionism were found at post-intervention. Findings indicate the intervention targeting HERO constructs may be promising for developing HERO capabilities in youth and reducing common areas of concern for students (e.g., perfectionism). Future research directions addressing limitations are discussed., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK-MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K-AKT-mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor-based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC., Significance: CRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer., (©2022 American Association for Cancer Research.)

Objective: The current study utilized a single case series, non-concurrent multiple baseline design to examine the efficacy of training parents via telehealth videoconferencing in exposure and response prevention (ERP) for home delivery of the treatment for their children and adolescents with obsessive compulsive disorder (OCD)., Method: There were nine participants aged 8 to 14  years who had received a primary diagnosis of OCD. The design involved a series of AB replications, whereby following pre-treatment assessments participants were randomly assigned to either a 2-week ( n  = 4) or 3-week ( n  = 5) baseline condition with weekly monitoring of their child's OCD symptoms. Following baseline, parents participated four weekly telehealth parent-training modules in delivering FAST ( F amilies A ccessing S kills T raining) cognitive behavior therapy (CBT) with ERP (CBT-ERP) to children with OCD via videoconferencing with the clinician. Primary outcome measures were OCD symptom severity, diagnostic severity, and global functioning, which were assessed post-treatment and at 2 month follow-up., Results: The stability of the baseline period from pre-treatment to week 2 (for the 2-week condition) or to week 3 (for the 3-week condition) was established as there were no significant differences across baseline scores for parent target obsessions or parent target compulsions ratings. Significant improvements on the primary outcomes of clinician assessed symptom severity, diagnostic ratings, and global functioning were observed from baseline to post-treatment, and continued to 2 months follow-up., Conclusion: These data suggest that brief, parent training in FAST CBT-ERP via telehealth provides an overall effective intervention that is likely to be of most benefit to children and youth who are mild to moderate in severity., Competing Interests: ES discloses the following relationships: consultant for Biohaven Pharmaceuticals and Brainsway; Book royalties from Elsevier, Springer, American Psychological Association, Wiley, Oxford, Kingsley, and Guilford; Stock valued at less than $5,000 from NView; Research support from NIH, IOCDF, Ream Foundation, and Texas Higher Education Coordinating Board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Farrell, Nabinger de Diaz, Mathieu, McKenzie, Miyamoto, Donovan, Waters, March, Bothma, Kroon, Simcock, Ware, Selles, Storch and Ollendick.)

Observational fear learning has been notably understudied in fear learning research, especially the potential benefits of observational extinction. Additionally, no studies have investigated observational extinction during adolescence, a key developmental stage for the emergence of anxiety disorders. This study compared observational and direct fear extinction following observational fear acquisition among adolescents and adults. Participants underwent differential observational fear acquisition. Next, participants underwent one of three fear extinctions: (1) observational extinction, (2) direct extinction, (3) no-extinction. Thereafter, participants underwent a US reminder and finally, a direct exposure test. Skin conductance response (SCR), self-reported fear, and risk assessment were measured. Differential observational fear acquisition was demonstrated by both age groups across all measures. During extinction, the observational and direct extinction groups did not differ in differential extinction, however, during the US reminder the observational group exhibited higher SCR compared to the direct group, but not the no-extinction group. Finally, during the direct exposure test, the no-extinction group showed greater differential risk assessment and higher SCR compared to the observational and direct groups. Additionally, adolescents showed poorer discrimination between the CSs compared to adults. Observational extinction successfully reduced fear and its retention amongst youth and adults pointing to the potential benefit of vicarious exposure therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: none declared. All authors have completed the BMJ online declaration of interests form.

One productive avenue for building adolescents' personal strengths and reducing mental health problems is integrating assessment and intervention into organised sports programs. We investigated the efficacy of the RISE program, a rugby league development program for 12- to 15-year-old boys, which integrated a mental health and wellbeing system called Life-Fit-Learning. The Life-Fit System is designed to measure youth's strengths and mental health symptoms and sends mental health feedback to parents, provides group-based workshops, connects youth and parents to online psychoeducation resources, and provides individual telephone follow-up and referral with parents of youth at high-risk for mental health problems. In this study, mental health and wellbeing outcomes were compared in participants who did (RISE, N = 94) and did not (Comparison, N = 82) receive the RISE/Life-Fit-Learning program. RISE players reported their self-satisfaction, grit, gratitude, prosocial behaviour, anxiety, depression, and behavioural problems using the Life-Fit System pre- and post-program. Comparison participants completed measures twice, 6-months apart. Self-satisfaction did not change in RISE participants but declined among comparison participants. In both groups, 26% of players scored in the high-risk range on at least one mental health measure. On mental health measures, high-risk RISE players' depression and behavioural problems improved from pre-to post-program relative to no change among Comparison players. Among participants who were not high-risk, RISE players' anxiety, depression, and behavioural problems did not change whereas Comparison players' behavioural problems increased significantly. Results underscore the value of integrating strengths-based interventions and targeting youth mental health problems within the context of junior sports development programs., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Past fear conditioning studies have used different types of conditional stimuli (CSs). Whether this choice affects learning outcomes in particular when neutral stimuli (e.g., neutral faces vs. shapes) are used is unclear. Data were aggregated across nine studies using an electric shock unconditional stimulus to test for differences in acquisition and extinction of electrodermal responses and self-reported CS pleasantness when CSs were neutral faces or shapes (Experiment 1, N = 594) and when CSs were angry or neutral faces (Experiment 2, N = 157). Reliable electrodermal conditioning was observed in all stimulus conditions. We found stronger differential conditioning in electrodermal second interval responses and CS pleasantness and more pronounced extinction in CS pleasantness for neutral shape than neutral face CSs, but no differences in electrodermal first interval responses, the most frequently reported index of fear conditioning. For angry and neutral face CSs, there were no differences during acquisition, but the extinction of first and second interval electrodermal conditioning to angry faces was retarded relative to neutral faces. Acquisition of differential CS pleasantness, which was reliably observed for neutral face CSs, was absent for angry face CSs. The current results suggest that fear conditioning with a neutral face and shape CSs yields broadly similar results with differences limited to second interval electrodermal responses and CS pleasantness ratings. Using angry face CSs resulted in impaired extinction of electrodermal indices and no differential CS pleasantness ratings and should only be considered in studies designed to address questions about these specific CS materials., (© 2022 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Past research has shown that Intolerance of Uncertainty (IU) affects Pavlovian fear conditioning processes. In particular, extinction of learned fear is delayed in those reporting high IU. Reports of differences during acquisition are less consistent with most of the studies reporting no evidence for effects of IU. This may be due to past studies' focus on first interval electrodermal responses or fear potentiated startle, rather than on indices that may better capture uncertainty - like the response to the absence of a probabilistic unconditional stimulus. The current analysis combined data across three experiments that employed a 50 % reinforcement schedule and assessed electrodermal responses and (in two experiments) ratings of conditional stimulus pleasantness. Participants scoring high on IU showed overall larger electrodermal first interval responses during habituation and acquisition but did not differ from those scoring low on IU in differential conditioning (the difference between CS+ and CS-), as indicated by electrodermal first or second interval responses or ratings of CS pleasantness. However, participants high in IU showed larger differential third interval electrodermal responses to the omission of the electro-tactile unconditional stimulus during acquisition. Some evidence for this difference emerged in each experiment, supporting the reliability of the result. The current results suggest that effects of IU emerge in conditions of high uncertainty in Pavlovian fear learning tasks, such as during the omission of probabilistic unconditional stimuli., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Hereditary-alpha tryptasemia (HαT) is the most common etiology for elevated basal serum tryptase (BST). However, the utility of tryptase genotyping of individuals with elevated BST in general clinical practice remains undefined. Moreover, studies showing associations between elevated BST and chronic kidney disease (CKD), myelodysplastic syndrome (MDS), rheumatoid arthritis, or eosinophilic esophagitis did not include tryptase genotyping., Objective: To determine the utility of tryptase genotyping among individuals with moderate elevations in BST at a regional health system., Methods: Clinical and laboratory data from 109 subjects with basal tryptase values of 7.5 ng/mL or greater who were tested for HαT or had a disorder previously linked to elevated BST were collected retrospectively by chart review., Results: Fifty-eight subjects had elevated BST defined as 11.5 ng/mL or greater. HαT was found in 63.8% (n = 37), 12.1% (n = 7) had CKD, and 20.7% (n = 12) had clonal myeloid disorders. A total of 6.9% (n = 4) with elevated BST had negative testing for HαT, CKD, and myeloid neoplasms. Two subjects with CKD, 1 subject with MDS, and 1 with myeloid hypereosinophilic syndrome had negative testing for HαT. Among subjects with elevated BST and more than 1 tryptase measurement, 41.5% (n = 22) had BST variability that exceeded the 20% plus 2 formula. Increased BST variability was found in subjects with HαT, all forms of mastocytosis, CKD, MDS, and those with no associated diagnosis., Conclusions: HαT, CKD, and clonal myeloid disorders or a combination of the 3 constitute approximately 90% of individuals with elevated BST in clinical practice. Myeloid neoplasms were over-represented in this cohort relative to population prevalence data suggesting tryptase measurement selection bias by clinicians or higher prevalence. Elevated BST is associated with increased tryptase variability, regardless of etiology., (Published by Elsevier Inc.)

Introduction: Constipation in pediatrics remains a common problem. Antegrade continence enema (ACE) procedures have been shown to decrease the distress of daily therapy. Patients are able to administer more aggressive washouts in the outpatient setting. Therefore, we hypothesize that patients following an ACE procedure would have reduced admissions for constipation., Methods: Patients who underwent an ACE procedure at a large children's hospital from 2015 to 2018 were included. Demographics, diagnosis, procedure, and preoperative/postoperative hospital admissions were analyzed., Results: Forty-eight patients were included in the study. Over half were diagnosed with idiopathic constipation. Majority of patients underwent an appendicostomy (88%, n = 42). Preoperatively, 26 patients were admitted for a combined total of 63 times for constipation. Postoperatively, 4 patients were admitted for a total of 5 visits ( P = .021). Twenty-eight patients required a nonscheduled appendicostomy tube replacement., Conclusion: This study demonstrates ACE procedures can improve constipation-related symptoms in children and are associated with decrease hospital admissions.

Background: Elevated defensive responding, through startle reflex (SR) and skin conductance response (SCR), may contribute to onset and maintenance of depression and anxiety. Most work examining SR and SCR has predicted psychiatric diagnoses. There is a paucity of research examining links between SR or SCR and dimensional measures of psychopathology., Methods: We used latent growth curve modeling to predict longitudinal change in three symptom factors (i.e., General Distress, Fears, Anhedonia-Apprehension) from SR and SCR measured during a fear-potentiated startle paradigm among adolescents oversampled for neuroticism (N = 129)., Results: Elevated SCR in danger phases before and after an unpleasant muscle contraction predicted increasing Fears over time. Elevated SR in safe phases post-contraction also predicted increasing Fears over time. Attenuated SR in safe phases post-contraction predicted elevated General Distress longitudinally. Attenuated SCR pre-contraction in danger phases predicted elevated Anhedonia-Apprehension over time., Limitations: Our non-clinical sample may limit generalizability of results. Additionally, we did not assess change in SR and SCR over time., Conclusions: The present study demonstrates that SR and SCR during a fear-potentiated startle paradigm predict longitudinal change in dimensional anxiety and depression symptom factors and relatedly, that SR and SCR may represent risk factors for the exacerbation of symptomatology., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Missense mutations at the three hotspots in the guanosine triphosphatase (GTPase) RAS-Gly 12 , Gly 13 , and Gln 61 (commonly known as G12, G13, and Q61, respectively)-occur differentially among the three RAS isoforms. Q61 mutations in KRAS are infrequent and differ markedly in occurrence. Q61H is the predominant mutant (at 57%), followed by Q61R/L/K (collectively 40%), and Q61P and Q61E are the rarest (2 and 1%, respectively). Probability analysis suggested that mutational susceptibility to different DNA base changes cannot account for this distribution. Therefore, we investigated whether these frequencies might be explained by differences in the biochemical, structural, and biological properties of KRAS Q61 mutants. Expression of KRAS Q61 mutants in NIH 3T3 fibroblasts and RIE-1 epithelial cells caused various alterations in morphology, growth transformation, effector signaling, and metabolism. The relatively rare KRAS Q61E mutant stimulated actin stress fiber formation, a phenotype distinct from that of KRAS Q61H/R/L/P , which disrupted actin cytoskeletal organization. The crystal structure of KRAS Q61E was unexpectedly similar to that of wild-type KRAS, a potential basis for its weak oncogenicity. KRAS Q61H/L/R -mutant pancreatic ductal adenocarcinoma (PDAC) cell lines exhibited KRAS-dependent growth and, as observed with KRAS G12 -mutant PDAC, were susceptible to concurrent inhibition of ERK-MAPK signaling and of autophagy. Our results uncover phenotypic heterogeneity among KRAS Q61 mutants and support the potential utility of therapeutic strategies that target KRAS Q61 mutant-specific signaling and cellular output.

Mental health problems affect large numbers of young people. Integrated systems are required that can be applied in diverse settings to reach youth 'where they are'. We evaluated the process of implementing a three-step youth mental health and wellbeing system in diverse community settings according to three implementation outcomes: feasibility, penetration and acceptability. The study describes 49 applications of the 'Life-Fit-Learning system' designed to assess the mental health and wellbeing of youth (Assess step), provide feedback on assessment results (Reflect step), and connect them to resources and services proportionate to their needs (Connect step). Within a participatory research approach, 3798 administrations were conducted with youth between 9 and 18 years and 90 administrations were conducted with adults. Implementation was based on the four phases of the Quality Implementation Framework and was staged to integrate stakeholder and consumer feedback and experience gained from focus groups and two pilot phases before full implementation. Feasibility ratings of successful implementation ranged from 86.7 to 96.4% across applications and settings. High penetration rates were achieved. The Life-Fit-Learning system successfully reached 91.9% to 96% of youth with the Assess and Reflect steps and low intensity Connect step resources. Of those, 14.7% to 23% were identified at-risk for mental health problems and 93% to 97% of those at-risk youth additionally received Connect step co-delivered group-based programs (moderate intensity care) and/or individual treatment (high intensity care). Youth and parents reported high satisfaction across all steps and delivery modes. With strong collaboration, an integrated model of care can be delivered feasibly, effectively and satisfactorily to reach large numbers of young people across settings., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Hearst Health Prize is the first national annual award for excellence in population health. The prize was established "to discover, support, and showcase the work of an individual, group, organization, or institution that has successfully implemented a population health program or intervention that has made a measurable difference" in health outcomes. Now, 5 years since the award's inception, this article reflects on how submissions for the prize collectively mirror - and may even predict - changes within the field of population health. It examines how the most successful programs demonstrated genuine, measurable improvements in health outcomes and/or health behaviors. In exploring the work of these outstanding programs, the aim of this article is to help disseminate best practices, advance the mission of the prize, and inspire improvements in population health practices.

Disruptive behaviors such as conduct problems and aggression are some of the most prevalent childhood psychological concerns. The etiology of disruptive behaviors is heterogenous and the relationships between the myriad risk factors that contribute to these problems are not yet fully understood. This study examined the relationship between inhibitory control and callous-unemotional traits (CU traits) with conduct problems and aggression in a community sample of children (aged 6 to 11 years). Caregivers ( n = 148) completed a survey assessing a range of known risk factors (including hyperactivity and inattention). Children were found to display more conduct problems and aggression if they had greater difficulties with inhibitory control and a higher number of CU traits. Interestingly, when children had CU traits, inhibitory control difficulties exacerbated the severity of conduct problems (but not aggression). Differences in severity between conduct problems and aggression highlight the unique relationships between risk factors such as inhibitory control and CU traits, and lay the groundwork for future studies to explore the trajectories of this relationship.

Background and Objectives: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years., Design, Setting, Participants, & Measurements: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome., Results: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores., Conclusions: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function., (Copyright © 2022 by the American Society of Nephrology.)

A considerable body of research in adults has demonstrated that anxiety disorders are characterised by attentional biases to threat. Findings in children have been inconsistent. The present study examined anxiety-related attention biases using eye tracking methodology in 463 preadolescents between 10 and 12 years of age, of whom 92 met criteria for a DSM-5 anxiety disorder and 371 did not. Preadolescent's gaze was recorded while they viewed adolescent face pairs depicting angry-neutral and happy-neutral expressions with each face pair presented for 5000 ms. No group differences were observed across any eye tracking indices including probability of first fixation direction, latency to first fixation, first fixation duration and dwell time. The sample overall showed faster initial attention towards threat cues, followed by a later broadening of attention away from threat. There is a need to identify the types of threats and the developmental period during which visual attention patterns of anxious and non-anxious youth diverge to inform more developmentally sensitive treatments., (Copyright © 2022 Elsevier Ltd. All rights reserved.)