Cognitive bias modification of interpretations for anxiety and depression in children and adolescents: A meta-analysis.

Background: Evidence suggests that cognitive bias modification of interpretations (CBM-I) is effective in modifying interpretation biases and has a small effect on reducing anxiety in children and adolescents. However, most evidence to date is based on studies which report anxiety or general distress using ad-hoc Likert-type or Visual Analogue Scales, which are useful but do not reliably index symptoms of clinical importance. This meta-analysis aimed to establish the effects of CBM-I for children and adolescents on both anxiety and depression using psychometrically validated symptom measures, as well as state negative affect and negative and positive interpretation bias. Methods: We identified studies through a systematic search. To be eligible for inclusion, studies needed to target interpretation biases, not combine CBM-I with another intervention, randomly allocate participants to CBM-I or a control condition, assess a mental health outcome (i.e., anxiety or depression symptoms using validated measures or state measures of negative affect) and/or interpretation bias and have a mean age less than 18 years. Results: We identified 36 studies for inclusion in the meta-analysis. CBM-I had a small and non-significant unadjusted effect on anxiety symptoms (g = 0.16), no effect on depression symptoms (g = -0.03), and small and non-significant unadjusted effects on state negative affect both at post-training (g = 0.16) and following a stressor task (g = 0.23). In line with previous findings, CBM-I had moderate to large unadjusted effects on negative and positive interpretations (g = 0.78 and g = 0.52). No significant moderators were identified. Conclusions: CBM-I is effective at modifying interpretation bias, however there were no effects on mental health outcomes. The substantial variability across studies and paucity of studies using validated symptom measures highlight the need to establish randomized controlled trial protocols that evaluate CBM-I in clinical youth samples to determine its future as a clinical intervention.

Centrosome amplification promotes cell invasion via cell-cell contact disruption and Rap-1 activation.

Centrosome amplification (CA) is a prominent feature of human cancers linked to tumorigenesis in vivo. Here, we report mechanistic contributions of CA induction alone to tumour architecture and extracellular matrix (ECM) remodelling. CA induction in non-tumorigenic breast cells MCF10A causes cell migration and invasion, with underlying disruption of epithelial cell-cell junction integrity and dysregulation of expression and subcellular localisation of cell junction proteins. CA also elevates expression of integrin ß-3, its binding partner fibronectin-1 and matrix metalloproteinase enzymes, promoting cell-ECM attachment, ECM degradation, and a migratory and invasive cell phenotype. Using a chicken embryo xenograft model for in vivo validation, we show that CA-induced (+CA) MCF10A cells invade into the chick mesodermal layer, with inflammatory cell infiltration and marked focal reactions between chorioallantoic membrane and cell graft. We also demonstrate a key role of small GTPase Rap-1 signalling through inhibition using GGTI-298, which blocked various CA-induced effects. These insights reveal that in normal cells, CA induction alone (without additional oncogenic alterations) is sufficient to confer early pro-tumorigenic changes within days, acting through Rap-1-dependent signalling to alter cell-cell contacts and ECM disruption.

Interventions for Young Children's Mental Health: A Review of Reviews.

To determine the efficacy of intervention programs for young children (4-9 years) with emerging mental health needs, we conducted a review of meta-analytic and systematic reviews of the intervention literature. Of 41,061 abstracts identified and 15,076 screened, 152 review articles met the inclusion criteria. We reviewed interventions across multiple disciplines targeting: (1) general mental health concerns; (2) internalizing symptoms; (3) externalizing symptoms; (4) anxiety; (5) depression; (6) trauma; (7) symptoms of attention-deficit/hyperactivity disorder; and (8) mental health concerns associated with autism spectrum disorder. Substantial evidence was found for the efficacy of behavioral and cognitive behavioral interventions for general mental health concerns, externalizing symptoms (generally, as well as ADHD, conduct, and other behavioral symptoms) and internalizing symptoms (generally, as well as anxiety) aged 4-9 years. Emerging evidence was identified for interventions targeting trauma symptoms, depression symptoms, and social, emotional and behavioral symptoms in autism spectrum disorder in children aged 4-9 years. Currently there is only limited emerging evidence regarding non-behavioral or non-cognitive behavioral interventions for programs targeting children ages 4-9 years where the aim is to deliver an evidence-based program to improve child social, emotional and/or behavioral functioning. Given the recent rises in mental health needs reported in children, targeted behavioral-and/or cognitive behavior therapy-based interventions should be made widely available to children (and their families) who experience elevated symptoms.

Canadian medical student perceptions of the Choosing Wisely Canada campaign.

Background: Medical student investment in resource stewardship (RS) is essential as resource overuse continues among physicians, but it is unclear whether this is influenced by hidden curriculum. This study investigated medical student perceptions of Choosing Wisely Canada (CWC). Methods: Canadian Medical students completed a bilingual questionnaire. Chi-square and student's T-tests were used to analyze Likert responses capturing student attitudes toward questions grouped by theme, including the importance of the CWC campaign, the amount of CWC represented in undergraduate medical curriculum, the application of CWC recommendations in medicine, and the barriers which exist to student advocacy for CWC in practice. Results: There were 3,239/11,754 (26.9%) respondents. While most students (n = 2,720/3,171; 85.8%) endorsed the importance of CWC, few students felt that their institution had sufficiently integrated CWC into pre-clerkship (47.0%) and clerkship (63.5%) curricula. Overall, 61.4% of students felt that it is reasonable to expect physicians to apply CWC recommendations given the workplace culture in medicine. Only 35.1% students were comfortable addressing resource misuse with their preceptor. The most common barriers included the assumption that their preceptor was more knowledgeable (86.4%), concern over evaluations (66.0%), and concern for their reputation (31.2%). Conclusions: Canadian medical students recognize the importance of CWC. However, many trainees feel that the workplace culture in medicine does not support the application of CWC recommendations. A power imbalance exists that prevents students from advocating for RS in practice.

Contexte: Il est essentiel que les étudiants en médecine se préoccupent de la gestion des ressources, qui sont encore surutilisées par les médecins, sans qu'il soit clair qu'il s'agisse d'un effet du curriculum caché. La présente étude examine sure des étudiants en médecine concernant la campagne Choisir avec soin (CWC). Méthodes: Des étudiants en médecine canadiens ont été invités à répondre à un questionnaire bilingue. Le test du chi carré et le test de Student ont été utilisés pour analyser leurs réponses, exprimées sur une échelle de Likert, reflétant leur position sur des questions regroupées par thème, notamment l'importance de la campagne CWC, le degré d'intégration des principes de la CWC dans le programme d'études médicales de premier cycle, l'application des recommandations de la CWC en médecine et les facteurs qui peuvent freiner la promotion de la CWC par les étudiants. Résultats: Parmi les 3 239 répondants (soit 26,9% des 11 754 étudiants sondés) la plupart (n=2 720/3 171 ; 85,8 %) reconnaissaient l'importance de la CWC, mais peu d'étudiants estimaient que leur établissement avait suffisamment intégré la CWC au pré-externat (47,0 %) et à l'externat (63,5 %). Dans l'ensemble, 61,4 % des étudiants estimaient qu'il était raisonnable d'attendre des médecins qu'ils appliquent les recommandations de la CWC, compte tenu de la culture du milieu médical. Seuls 35,1 % des étudiants étaient à l'aise d'aborder la question de la mauvaise utilisation des ressources avec leur précepteur. Les obstacles les plus courants étaient l'idée que leur superviseur était sans doute mieux informé qu'eux (86,4 %), et des craintes quant à leur évaluation (66,0%) ou à leur réputation (31,2%). Conclusions: Les étudiants en médecine canadiens reconnaissent l'importance de la CWC. Cependant, ils sont nombreux à croire que la culture du lieu de travail en médecine ne favorise pas la mise en pratique des recommandations de la CWC. Le rapport de pouvoir qui y existe empêche les étudiants de défendre l'IR dans la pratique.

In Vitro Evolution of Listeria monocytogenes Reveals Selective Pressure for Loss of SigB and AgrA Function at Different Incubation Temperatures.

The alternative sigma factor B (σB) contributes to the stress tolerance of the foodborne pathogen Listeria monocytogenes by upregulating the general stress response. We previously showed that σB loss-of-function mutations arise frequently in strains of L. monocytogenes and suggested that mild stresses might favor the selection of such mutations. In this study, we performed in vitro evolution experiments (IVEE) where L. monocytogenes was allowed to evolve over 30 days at elevated (42°C) or lower (30°C) incubation temperatures. Isolates purified throughout the IVEE revealed the emergence of sigB operon mutations at 42°C. However, at 30°C, independent alleles in the agr locus arose, resulting in the inactivation of Agr quorum sensing. Colonies of both sigB mutants and agr mutants exhibited a greyer coloration on 7-days-old agar plates than those of the parental strain. Scanning electron microscopy revealed a more complex colony architecture in the wild type than in the mutant strains. sigB mutant strains outcompeted the parental strain at 42°C but not at 30°C, while agr mutant strains showed a small increase in competitive fitness at 30°C. Analysis of 40,080 L. monocytogenes publicly available genome sequences revealed a high occurrence rate of premature stop codons in both the sigB and agrCA loci. An analysis of a local L. monocytogenes strain collection revealed 5 out of 168 strains carrying agrCA alleles. Our results suggest that the loss of σB or Agr confer an increased competitive fitness in some specific conditions and this likely contributes to the emergence of these alleles in strains of L. monocytogenes. IMPORTANCE To withstand environmental aggressions, L. monocytogenes upregulates a large regulon through the action of the alternative sigma factor B (σB). However, σB becomes detrimental for L. monocytogenes growth under mild stresses, which confer a competitive advantage to σB loss-of-function alleles. Temperatures of 42°C, a mild stress, are often employed in mutagenesis protocols of L. monocytogenes and promote the emergence of σB loss-of-function alleles in the sigB operon. In contrast, lower temperatures of 30°C promote the emergence of Agr loss-of-function alleles, a cell-cell communication mechanism in L. monocytogenes. Our findings demonstrate that loss-of-function alleles emerge spontaneously in laboratory-grown strains. These alleles rise in the population as a consequence of the trade-off between growth and survival imposed by the activation of σB in L. monocytogenes. Additionally, our results demonstrate the importance of identifying unwanted hitchhiker mutations in newly constructed mutant strains.

Plastid ribosome protein L5 is essential for post-globular embryo development in Arabidopsis thaliana.

Plastid ribosomal proteins (PRPs) can play essential roles in plastid ribosome functioning that affect plant function and development. However, the roles of many PRPs remain unknown, including elucidation of which PRPs are essential or display redundancy. Here, we report that the nuclear-encoded PLASTID RIBOSOMAL PROTEIN L5 (PRPL5) is essential for early embryo development in A. thaliana, as homozygous loss-of-function mutations in the PRPL5 gene impairs chloroplast development and leads to embryo failure to develop past the globular stage. We confirmed the prpl5 embryo-lethal phenotype by generating a mutant CRISPR/Cas9 line and by genetic complementation. As PRPL5 underwent transfer to the nuclear genome early in the evolution of Embryophyta, PRPL5 can be expected to have acquired a chloroplast transit peptide. We identify and validate the presence of an N-terminal chloroplast transit peptide, but unexpectedly also confirm the presence of a conserved and functional Nuclear Localization Signal on the protein C-terminal end. This study highlights the fundamental role of the plastid translation machinery during the early stages of embryo development in plants and raises the possibility of additional roles of plastid ribosomal proteins in the nucleus.

Stromal Cells Promote Matrix Deposition, Remodelling and an Immunosuppressive Tumour Microenvironment in a 3D Model of Colon Cancer.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. CRC develops in a complex tumour microenvironment (TME) with both mesenchymal stromal cells (MSCs) and immune infiltrate, shown to alter disease progression and treatment response. We hypothesised that an accessible, affordable model of CRC that combines multiple cell types will improve research translation to the clinic and enable the identification of novel therapeutic targets. A viable gelatine-methacrloyl-based hydrogel culture system that incorporates CRC cells with MSCs and a monocyte cell line was developed. Gels were analysed on day 10 by PCR, cytokine array, microscopy and flow cytometry. The addition of stromal cells increased transcription of matrix remodelling proteins FN1 and MMP9, induced release of tumour-promoting immune molecules MIF, Serpin E1, CXCL1, IL-8 and CXCL12 and altered cancer cell expression of immunotherapeutic targets EGFR, CD47 and PD-L1. Treatment with PD153035, an EGFR inhibitor, revealed altered CRC expression of PD-L1 but only in gels lacking MSCs. We established a viable 3D model of CRC that combined cancer cells, MSCs and monocytic cells that can be used to research the role the stroma plays in the TME, identify novel therapeutic targets and improve the transitional efficacy of therapies.

The Effectiveness of an Interprofessional Education Course in Teaching the Importance of Choosing Wisely and Resource Stewardship: A Pilot Study.

Objectives Rising health care costs and an increase in unnecessary testing have sparked interest in resource stewardship (RS) and subsequently the Choosing Wisely Canada (CWC) campaign. Currently, all Canadian medical schools have student representatives for CWC; however, the same is not true in other health professions. Interprofessional care learned through interprofessional education (IPE) can lead to better patient outcomes. This study assessed whether an IPE course for health profession students was effective in teaching undergraduate students both interprofessional competencies and CWC principles. Methods An approximately seven-hour-long, four-session course was administered to Dalhousie University health profession students (N= 30). A validated survey for IPE competencies and a general survey about CWC principles were administered to assess the course. Descriptive statistics were used to assess the general CWC views, and paired samples t-tests were employed to compare pre- and post-IPE competencies. Results The full survey was completed by 25 (83%) students. Of these, 52% were female, within five health disciplines, and 13 (52%) had heard of CWC prior. Overall, the students agreed that CWC was important and relevant to their profession. They also reported significant improvements in multiple IPE competencies, including communication, collaboration, roles and responsibilities, patient-/family-centered care, conflict management/resolution, and team function. Conclusion Participants in our pilot Choosing Wisely IPE course valued the importance of the CWC campaign and reported improvement in multiple IPE competencies. This adaptable, simple, and low-cost course may be an effective way to integrate RS teaching across multiple health professions.

Investigating the Potential and Pitfalls of EV-Encapsulated MicroRNAs as Circulating Biomarkers of Breast Cancer.

Extracellular vesicles (EVs) shuttle microRNA (miRNA) throughout the circulation and are believed to represent a fingerprint of the releasing cell. We isolated and characterized serum EVs of breast tumour-bearing animals, breast cancer (BC) patients, and healthy controls. EVs were characterized using transmission electron microscopy (TEM), protein quantification, western blotting, and nanoparticle tracking analysis (NTA). Absolute quantitative (AQ)-PCR was employed to analyse EV-miR-451a expression. Isolated EVs had the appropriate morphology and size. Patient sera contained significantly more EVs than did healthy controls. In tumour-bearing animals, a correlation between serum EV number and tumour burden was observed. There was no significant relationship between EV protein yield and EV quantity determined by NTA, highlighting the requirement for direct quantification. Using AQ-PCR to relate miRNA copy number to EV yield, a significant increase in miRNA-451a copies/EV was detected in BC patient sera, suggesting potential as a novel biomarker of breast cancer.

A comparative study of segmentation techniques for the quantification of brain subcortical volume.

Manual tracing of magnetic resonance imaging (MRI) represents the gold standard for segmentation in clinical neuropsychiatric research studies, however automated approaches are increasingly used due to its time limitations. The accuracy of segmentation techniques for subcortical structures has not been systematically investigated in large samples. We compared the accuracy of fully automated [(i) model-based: FSL-FIRST; (ii) patch-based: volBrain], semi-automated (FreeSurfer) and stereological (Measure®) segmentation techniques with manual tracing (ITK-SNAP) for delineating volumes of the caudate (easy-to-segment) and the hippocampus (difficult-to-segment). High resolution 1.5 T T1-weighted MR images were obtained from 177 patients with major psychiatric disorders and 104 healthy participants. The relative consistency (partial correlation), absolute agreement (intraclass correlation coefficient, ICC) and potential technique bias (Bland-Altman plots) of each technique was compared with manual segmentation. Each technique yielded high correlations (0.77-0.87, p < 0.0001) and moderate ICC's (0.28-0.49) relative to manual segmentation for the caudate. For the hippocampus, stereology yielded good consistency (0.52-0.55, p < 0.0001) and ICC (0.47-0.49), whereas automated and semi-automated techniques yielded poor ICC (0.07-0.10) and moderate consistency (0.35-0.62, p < 0.0001). Bias was least using stereology for segmentation of the hippocampus and using FreeSurfer for segmentation of the caudate. In a typical neuropsychiatric MRI dataset, automated segmentation techniques provide good accuracy for an easy-to-segment structure such as the caudate, whereas for the hippocampus, a reasonable correlation with volume but poor absolute agreement was demonstrated. This indicates manual or stereological volume estimation should be considered for studies that require high levels of precision such as those with small sample size.

SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts.

Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

Volume and shape analysis of subcortical brain structures and ventricles in euthymic bipolar I disorder.

Previous structural magnetic resonance imaging (S-MRI) studies of bipolar disorder have reported variable morphological changes in subcortical brain structures and ventricles. This study aimed to establish trait-related subcortical volumetric and shape abnormalities in a large, homogeneous sample of prospectively confirmed euthymic bipolar I disorder (BD-I) patients (n=60), compared with healthy volunteers (n=60). Participants were individually matched for age and gender. Volume and shape metrics were derived from manually segmented S-MR images for the hippocampus, amygdala, caudate nucleus, and lateral ventricles. Group differences were analysed, controlling for age, gender and intracranial volume. BD-I patients displayed significantly smaller left hippocampal volumes and significantly larger left lateral ventricle volumes compared with controls. Shape analysis revealed an area of contraction in the anterior head and medial border of the left hippocampus, as well as expansion in the right hippocampal tail medially, in patients compared with controls. There were no significant associations between volume or shape variation and lithium status or duration of use. A reduction in the head of the left hippocampus in BD-I patients is interesting, given this region's link to verbal memory. Shape analysis of lateral ventricular changes in patients indicated that these are not regionally specific.

Level of agreement between patient-reported EQ-5D responses and EQ-5D responses mapped from the SF-12 in an injury population.

BACKGROUND: Comparing health-related quality of life (HRQL) outcomes between studies is difficult due to the wide variety of instruments used. Comparing study outcomes and facilitating pooled data analyses requires valid "crosswalks" between HRQL instruments. Algorithms exist to map 12-item Short Form Health Survey (SF-12) responses to EQ-5D item responses and preference weights, but none have been validated in populations where disability is prevalent, such as injury. METHODS: Data were extracted from the Validating and Improving injury Burden Estimates Study (Injury-VIBES) for 10,166 adult, hospitalized trauma patients, with both the three-level EQ-5D (EQ-5D-3L) and SF-12 data responses at six and 12-months postinjury. Agreement between actual (patient-reported) and estimated (mapped from SF-12) EQ-5D-3L item responses and preference weights was assessed using Kappa, Prevalence-Adjusted Bias-Adjusted Kappa statistics and Bland-Altman plots. RESULTS: Moderate agreement was observed for usual activities, pain/discomfort, and anxiety/depression. Agreement was substantial for mobility and self-care items. The mean differences in preference weights were -0.024 and -0.012 at six and 12 months (p < 0.001), respectively. The Bland-Altman plot limits of agreement were large compared to the range of valid preference weight values (-0.56 to 1.00). Estimated EQ-5D-3L responses under-reported disability for all items except pain/discomfort. CONCLUSIONS: Caution should be taken when using EQ-5D-3L responses mapped from the SF-12 to describe patient outcomes or when undertaking economic evaluation, due to the underestimation of disability associated with mapped values. The findings from this study could be used to adjust expected EQ-5D-3L preference weights when estimated from SF-12 item responses when combining data from studies that use either instrument.

Incorporating novel solutions to lower-limb problems into compression formularies.

This study investigates the effect of a new short-stretch two-layer compression system in eight patients with common chronic lower-limb conditions in three locations in the UK. Chronic leg ulcers are the most common type of lower-limb ulceration with 70% caused by chronic venous hypertension. An appropriate level of compression is proven to heal chronic venous leg ulcers. The study was only a small sample of patients; however, the underlying conditions included chronic venous eczema, diabetes, sarcoma, cellulitis and mixed-aetiology ulcers. During the study, the UK experienced some of the hottest temperatures in the last 30 years. This had an impact on five patients, who noted an increase in malodour associated with their leg ulcers. CoFlex TLC (Aspen Medical Europe Ltd) foam comfort layer is impregnated with cyclodextrin-a naturally based oligosaccharide known to reduce malodour. The zinc-impregnated foam bandages in this study were viewed very favourably by both patients and staff, particularly those who had chronic venous eczema.

Impaired neuronal glucose uptake in pathogenesis of schizophrenia - can GLUT 1 and GLUT 3 deficits explain imaging, post-mortem and pharmacological findings?

The largely empirical dopamine theory has limited value in clarifying the pathogenesis of schizophrenia, due to its inability to explain consistent imaging findings, such as cortical grey matter loss, reduced frontal and thalamic activity, and, reduced D1 receptor load. Furthermore, the most effective drug for treating positive and negative symptoms - clozapine - has minimal dopaminergic activity. We present an alternative hypothesis centring on presumed deficits in membrane bound glucose transporter proteins GLUT 1 and GLUT 3, either in absolute numbers or functional capacity. In situations of high demand, intracellular hypoglycaemia in neurones and astrocytes will produce acute symptoms of misperceptions, misinterpretations, anxiety and irritability - the usual features of prodromal and first onset schizophrenia. Furthermore, reduced glucose uptake will disrupt production of glutamate--functionally similar to the schizophrenia-like syndrome produced by PCP, a glutamate antagonist. In the longer term, reduced neuronal growth and poor synaptic contacts will produce chronic cognitive difficulties and perpetuate acute symptoms. A backlog effect due to reduced brain uptake of glucose would produce systemic hyperglycaemia observed in drug nai ve subjects. Rat studies have shown that clozapine and similar compounds block GLUT proteins in the brain and peripherally, more so than selective dopamine blockers. By blocking GLUT proteins, clozapine would break malfunctioning circuits, resulting in the disappearance of cognitive and perceptual symptoms. Unfortunately, these drugs would also raise systemic glucose levels, increasing the risk of diabetes, as observed in longer term studies of clozapine in particular. We summarise potentially useful research strategies, including studying the genotype of GLUT proteins with respect to schizophrenia phenotypes, activation studies involving fMRI using deoxyglucose as a substrate, and investigating clinical features of schizophrenic patients prior to and following treatment for co-existing diabetes.