A systematic review of callous-unemotional traits and attachment in children and adolescents.

METHODS: The systematic review and meta-analysis included 17 research articles from 1994 to 2022. Results were summarized by developmental periods. RESULTS: Attachment insecurity was associated with CU traits across development (r = .17). This association was marginally stronger for high-risk samples (e.g., clinical, justice) and for continuous attachment measures versus coding schemes. From early to middle childhood, attachment disorganization was associated with CU traits (r = .17). IMPLICATIONS: Research on attachment and CU traits in childhood is still in its infancy. Changes in attachment measures from childhood to adolescence make developmental comparisons difficult. Results suggest attachment as a potential developmental mechanism for youth with CU traits, however, the area requires more research.

Topographic analysis of pancreatic cancer by TMA and digital spatial profiling reveals biological complexity with potential therapeutic implications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput biomarker interrogation in tissues but may not capture histological features of cancer with potential biological relevance. Topographic TMAs (T-TMAs) representing pathophysiological hallmarks of cancer were constructed from representative, retrospective PDAC diagnostic material, including 72 individual core tissue samples. The T-TMA was interrogated with tissue hybridization-based experiments to confirm the accuracy of the topographic sampling, expression of pro-tumourigenic and immune mediators of cancer, totalling more than 750 individual biomarker analyses. A custom designed Next Generation Sequencing (NGS) panel and a spatial distribution-specific transcriptomic evaluation were also employed. The morphological choice of the pathophysiological hallmarks of cancer was confirmed by protein-specific expression. Quantitative analysis identified topography-specific patterns of expression in the IDO/TGF-ß axis; with a heterogeneous relationship of inflammation and desmoplasia across hallmark areas and a general but variable protein and gene expression of c-MET. NGS results highlighted underlying genetic heterogeneity within samples, which may have a confounding influence on the expression of a particular biomarker. T-TMAs, integrated with quantitative biomarker digital scoring, are useful tools to identify hallmark specific expression of biomarkers in pancreatic cancer.

Adherence to and Motivations for Complying With Public Health Measures Among Adolescents During the Coronavirus Disease (COVID-19) Pandemic in Canada.

Background: Public health measures (e.g., minimizing social interactions, social distancing, and mask wearing) have been implemented in Canada to reduce the transmission of COVID-19. Given that adolescents may be a high-risk demographic for spreading COVID-19, this study investigated adherence to and motivations for complying with public health measures among Canadian youth at two points of the COVID-19 pandemic. Methods: Adolescents (N = 1,484, 53% girls, Mage = 15.73 [SD = 1.41]) completed an online survey in either Summer 2020 (Cohort 1 [C1]; n = 809, 56% girls) or Winter 2020/2021 (Cohort 2 [C2]; n = 675, 50% girls). We investigated differences in adherence across cohorts using independent sample t-tests and predictors of adherence using a path analysis. Results: Youth engaged in similar levels of social interaction in C1 and C2. Relative to adolescents in C1, adolescents in C2 reported more mask wearing, but less social distancing. Social responsibility was associated with adherence to almost all public health measures across both cohorts, with one exception: it did not predict minimizing social interactions in C2. Not wanting to get sick predicted minimizing social interactions and mask wearing. Concern with population health predicted adherence to all public health measures in C1 and all but mask wearing in C2. Maintaining social ties was negatively associated with minimizing social interactions in both cohorts, and with social distancing in C1. Conclusions: Youth engaged in more mask wearing but less social distancing as the pandemic progressed. Social responsibility and not wanting to get sick were consistent predictors of adherence to most public health measures throughout the pandemic. Youth shifted away from adhering to mask wearing measures due to concern with population health over the course of the pandemic. These results can inform targeted campaigns to bolster compliance with public health measures among adolescents.

Development and validation of a multivariable model for prediction of malignant transformation and recurrence of oral epithelial dysplasia.

BACKGROUND: Oral epithelial dysplasia (OED) is the precursor to oral squamous cell carcinoma which is amongst the top ten cancers worldwide. Prognostic significance of conventional histological features in OED is not well established. Many additional histological abnormalities are seen in OED, but are insufficiently investigated, and have not been correlated to clinical outcomes. METHODS: A digital quantitative analysis of epithelial cellularity, nuclear geometry, cytoplasm staining intensity and epithelial architecture/thickness is conducted on 75 OED whole-slide images (252 regions of interest) with feature-specific comparisons between grades and against non-dysplastic/control cases. Multivariable models were developed to evaluate prediction of OED recurrence and malignant transformation. The best performing models were externally validated on unseen cases pooled from four different centres (n = 121), of which 32% progressed to cancer, with an average transformation time of 45 months. RESULTS: Grade-based differences were seen for cytoplasmic eosin, nuclear eccentricity, and circularity in basal epithelial cells of OED (p < 0.05). Nucleus circularity was associated with OED recurrence (p = 0.018) and epithelial perimeter associated with malignant transformation (p = 0.03). The developed model demonstrated superior predictive potential for malignant transformation (AUROC 0.77) and OED recurrence (AUROC 0.74) as compared with conventional WHO grading (AUROC 0.68 and 0.71, respectively). External validation supported the prognostic strength of this model. CONCLUSIONS: This study supports a novel prognostic model which outperforms existing grading systems. Further studies are warranted to evaluate its significance for OED prognostication.

Exploring the immune microenvironment in small bowel adenocarcinoma using digital image analysis.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare malignancy of the small intestine associated with late stage diagnosis and poor survival outcome. High expression of immune cells and immune checkpoint biomarkers especially programmed cell death ligand-1 (PD-L1) have been shown to significantly impact disease progression. We have analysed the expression of a subset of immune cell and immune checkpoint biomarkers in a cohort of SBA patients and assessed their impact on progression-free survival (PFS) and overall survival (OS). METHODS: 25 patient samples in the form of formalin fixed, paraffin embedded (FFPE) tissue were obtained in tissue microarray (TMAs) format. Automated immunohistochemistry (IHC) staining was performed using validated antibodies for CD3, CD4, CD8, CD68, PD-L1, ICOS, IDO1 and LAG3. Slides were scanned digitally and assessed in QuPath, an open source image analysis software, for biomarker density and percentage positivity. Survival analyses were carried out using the Kaplan Meier method. RESULTS: Varying expressions of biomarkers were recorded. High expressions of CD3, CD4 and IDO1 were significant for PFS (p = 0.043, 0.020 and 0.018 respectively). High expression of ICOS was significant for both PFS (p = 0.040) and OS (p = 0.041), while high PD-L1 expression in tumour cells was significant for OS (p = 0.033). High correlation was observed between PD-L1 and IDO1 expressions (Pearson correlation co-efficient = 1) and subsequently high IDO1 expression in tumour cells was found to be significant for PFS (p = 0.006) and OS (p = 0.034). CONCLUSIONS: High levels of immune cells and immune checkpoint proteins have a significant impact on patient survival in SBA. These data could provide an insight into the immunotherapeutic management of patients with SBA.

Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an 'Immune Cold' Phenotype Associated with Poor Survival.

New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an 'immune cold' tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC.

Developmental Precursors of Primary and Secondary Callous-Unemotional Traits in Youth.

There is growing evidence of diverse etiological pathways to the development of callous-unemotional (CU) traits, known as primary and secondary CU variants. The purpose of the present study was to extend previous cross-sectional research and examine theoretical predictors of CU variants prospectively from childhood to adolescence. Participants included high-risk control and normative samples from the Fast Track project (N = 754, male = 58%, Black = 46%). Using structural equation modelling, primary CU traits, identified in early adolescence, were associated with higher levels of childhood emotion regulation and lower levels of prosocial behavior. Secondary CU traits were associated with lower levels of childhood emotion regulation and low parental warmth, but not prosocial behaviour. Neither CU variant was related to harsh parenting. Parental warmth moderated emotion regulation and prosocial behavior on secondary CU traits. Results were not moderated by sex. A greater understanding of theoretical developmental precursors of CU variants may better guide intervention efforts.

Primary and secondary callous-unemotional traits in adolescence are associated with distinct maladaptive and adaptive outcomes in adulthood.

While phenotypically indistinguishable with respect to callousness, individuals with primary and secondary callous-unemotional (CU) traits may show different developmental outcomes. This research predominantly comprised cross-sectional studies of male participants with a focus on maladaptive correlates. Thus, the present study examined whether youth with primary and secondary CU traits identified in Grade 7 reported distinct maladaptive outcomes (internalizing, externalizing, and substance use problems; criminal offenses; and sexual and partner experiences) and adaptive outcomes (health and wellbeing, education, and employment) in adulthood at age 25. We also examined sex differences. Participants included the high-risk control and normative samples from the Fast Track project (N = 754, male = 58%, Black = 46%). Youth with secondary CU traits reported higher levels of adult internalizing and externalizing psychopathology, a greater number of sexual partners and risky sexual behavior, and a greater number of violent offenses, compared with individuals with primary CU traits and those with low CU and anxiety symptoms. Conversely, youth with primary CU traits and low symptoms had higher wellbeing and happiness scores than those with secondary CU traits. Finally, there was differentiation on outcomes between female primary and secondary CU variants and male primary and secondary CU variants.

Psychometric Evaluation of the Affect Regulation Checklist: Clinical and Community Samples, Parent-Reports and Youth Self-Reports.

The Affect Regulation Checklist (ARC) was designed to capture affect dysregulation, suppression, and reflection. Importantly, affect dysregulation has been established as a transdiagnostic mechanism underpinning many forms of psychopathology. We tested the ARC psychometric properties across clinical and community samples and through both parent-report and youth self-report information. Clinical sample: Participants included parents (n = 814; Mage = 43.86) and their child (n = 608; Mage = 13.98). Community sample: Participants included independent samples of parents (n = 578; Mage = 45.12) and youth (n = 809; Mage = 15.67). Exploratory structural equation modeling supported a three-factor structure across samples and informants. Dysregulation was positively associated with all forms of psychopathology. In general, suppression was positively associated with many forms of psychopathology, and reflection was negatively associated with externalizing problems and positively associated with internalizing problems.

Associations between physical activity, affect regulation difficulties, and mental health among Canadian adolescents at two different points of the COVID-19 pandemic.

Objective. Although physical activity declined with social distancing measures and stay-at-home orders during the COVID-19 pandemic, youth who engaged in more physical activity experienced fewer mental health problems. If and how physical activity maintained its protective role throughout the ongoing pandemic remains unclear. This study models associations between three types of physical activity (indoor, outdoor, with parents), affect regulation, and anxious and depressive symptoms in two independent adolescent samples (T1: Summer 2020; T2: Winter 2020/21).Methods and Measures. Six hundred sixty-two Canadian adolescents (T1: Mage = 15.69, SD = 1.36; 52% girls; 5% trans+) and 675 Canadian adolescents (T2: Mage = 15.80, SD = 1.46; 50% girls; 6% trans+) participated in an online survey. Data included frequency of physical activity indoors, outdoors, and with parents, affect regulation difficulties, and measures of anxious and depressive symptoms.Results. Multiple-group path analysis showed indoor physical activity had an indirect effect on anxiety and depressive symptoms through affect dysregulation, but only at T1. Physical activity with parents was protective for adolescent anxiety and depressive symptoms at both T1 and T2 and had an indirect effect through affect dysregulation and suppression.Conclusion. Findings contribute to our understanding of how physical activity protects adolescent mental health, and point to strengthening family supports and recreation opportunities.

ICOSeg: Real-Time ICOS Protein Expression Segmentation from Immunohistochemistry Slides Using a Lightweight Conv-Transformer Network.

In this article, we propose ICOSeg, a lightweight deep learning model that accurately segments the immune-checkpoint biomarker, Inducible T-cell COStimulator (ICOS) protein in colon cancer from immunohistochemistry (IHC) slide patches. The proposed model relies on the MobileViT network that includes two main components: convolutional neural network (CNN) layers for extracting spatial features; and a transformer block for capturing a global feature representation from IHC patch images. The ICOSeg uses an encoder and decoder sub-network. The encoder extracts the positive cell's salient features (i.e., shape, texture, intensity, and margin), and the decoder reconstructs important features into segmentation maps. To improve the model generalization capabilities, we adopted a channel attention mechanism that added to the bottleneck of the encoder layer. This approach highlighted the most relevant cell structures by discriminating between the targeted cell and background tissues. We performed extensive experiments on our in-house dataset. The experimental results confirm that the proposed model achieves more significant results against state-of-the-art methods, together with an 8× reduction in parameters.

A Two-Way Street? Reciprocal Associations Between Parental Warmth and Hostility with Substance Use Among Justice-Involved Adolescents.

Transactional developmental theories propose that poor parenting behaviors contribute to youth substance use, and youth substance use contributes to poor parenting behaviors. However, research aimed at testing these theories has not distinguished: (1) between- and within-person sources of variance; (2) maternal and paternal parenting behaviors; and (3) alcohol, marijuana, and other illicit drug use. This study addressed these limitations by investigating the reciprocal associations between maternal and paternal warmth and hostility with alcohol, marijuana, and other illicit drug use among justice-involved adolescents, an at-risk population for substance use. 1354 justice-involved adolescents (86.4% male; Mage = 16.04 [SD = 0.14], range = 14-17; 41.4% Black, 33.5% Hispanic, 20.2% White, 4.8% other race/ethnicity) completed self-reports assessing parental warmth, parental hostility, and substance use every six months for 36 months. Random-intercept structural equation models disaggregated between- and within-person associations. At the between-person level, maternal and paternal warmth were negatively associated with alcohol, marijuana, and other illicit drug use, whereas maternal and paternal hostility were positively associated with alcohol, marijuana, and other illicit drug use. At the within-person level, maternal and paternal warmth predicted decreases in marijuana and other illicit drug use, and paternal warmth predicted decreases in alcohol use six months later. Maternal hostility predicted increases in subsequent marijuana and other illicit drug use. Marijuana and other illicit drug use predicted decreases in subsequent paternal hostility. The results are partially consistent with transactional developmental models proposing recursive influences between parenting behaviors and youth substance use. Evocative effects were in the opposite direction than expected and specific to fathers, such that youth drug use was related to improvements in the father-youth relationship. The results support the potential utility of family-based interventions for substance use among justice-involved adolescents.

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention.

Prostate cancer is a major cause of disease for men globally. Inflammation, an established hallmark of cancer, is frequently observed in the prostate, though its contribution to prostate cancer risks and outcomes is not fully understood. Prostate cancer is biologically and clinically heterogeneous, and there is now evidence that inflammation and immunological characteristics vary by the genomic and mutational landscape of the tumor. Moreover, it is now recognized that risk factor profiles vary between tumor subgroups, as defined by histopathological and molecular features. Here, we provide a review centered around the relationship between inflammation and prostate cancer, with a consideration of molecular tumor features and a particular focus on the advanced and lethal stages of disease. We summarize findings from epidemiological studies of the etiology and role of inflammation in prostate cancer. We discuss the pathology of prostate inflammation, and consider approaches for assessing the tumor immune microenvironment in epidemiological studies. We review emerging clinical therapies targeting immune biology within the context of prostate cancer. Finally, we consider potentially modifiable risk factors and corresponding lifestyle interventions that may affect prostate inflammation, impacting outcomes. These emerging insights will provide some hints for the development of treatment and prevention strategies for advanced and lethal prostate cancer.

Identification of a prognostic signature in colorectal cancer using combinatorial algorithm-driven analysis.

Colorectal carcinoma is one of the most common types of malignancy and a leading cause of cancer-related death. Although clinicopathological parameters provide invaluable prognostic information, the accuracy of prognosis can be improved by using molecular biomarker signatures. Using a large dataset of immunohistochemistry-based biomarkers (n = 66), this study has developed an effective methodology for identifying optimal biomarker combinations as a prognostic tool. Biomarkers were screened and assigned to related subsets before being analysed using an iterative algorithm customised for evaluating combinatorial interactions between biomarkers based on their combined statistical power. A signature consisting of six biomarkers was identified as the best combination in terms of prognostic power. The combination of biomarkers (STAT1, UCP1, p-cofilin, LIMK2, FOXP3, and ICOS) was significantly associated with overall survival when computed as a linear variable (χ2  = 53.183, p < 0.001) and as a cluster variable (χ2  = 67.625, p < 0.001). This signature was also significantly independent of age, extramural vascular invasion, tumour stage, and lymph node metastasis (Wald = 32.898, p < 0.001). Assessment of the results in an external cohort showed that the signature was significantly associated with prognosis (χ2  = 14.217, p = 0.007). This study developed and optimised an innovative discovery approach which could be adapted for the discovery of biomarkers and molecular interactions in a range of biological and clinical studies. Furthermore, this study identified a protein signature that can be utilised as an independent prognostic method and for potential therapeutic interventions.

Patterns and Predictors of Different Youth Responses to Attachment-Based Parent Intervention.

OBJECTIVE: Few studies have evaluated attachment-based parent interventions for pre-teens and teens, and in particular, differential adolescent trajectories of response. This study examined distinct patterns, and multi-level predictors, of intervention response among youth with serious behavioral and mental health problems whose parents participated in Connect, an attachment- and trauma-informed parent program. METHOD: Participants included 682 parents (Mage = 42.83, 86% mothers) and 487 youth (Mage = 13.95, 53% female, 28.1% ethnic minority) enrolled in a community-based evaluation of Connect. Parents and youth reported on youth externalizing and internalizing problems (EXT and INT) at six time points from baseline through 18-months post-intervention. Demographic and youth and family level predictors were assessed at baseline. RESULTS: Growth mixture modeling revealed three distinct trajectory classes in both the parent and youth models based on different patterns of co-occurring EXT and INT and degree of improvement over time. Youth with severe EXT showed the largest and fastest improvement, and, interestingly, were characterized by higher callous-unemotional traits and risk-taking at program entry. Youth with comorbid EXT/INT demonstrated a partial or moderate response to intervention in the parent and youth model, respectively, and were characterized by more attachment anxiety at baseline. Most youth showed relatively moderate/low levels of EXT/INT at baseline which gradually improved. Caregiver strain also predicted trajectory classes. CONCLUSIONS: These results have significance for tailoring and personalizing interventions for high-risk youth and provide new understanding regarding the profiles of subgroups of youth who show different responses to an attachment-based parent intervention.

The Association between ADHD and the Severity of COVID-19 Infection.

OBJECTIVE: Patients with ADHD are at increased risk of acquiring COVID-19. The present study assessed the possibility that ADHD also increases the risk of severe COVID-19 infection. METHOD: We assessed 1,870 COVID-19 positive patients, aged 5 to 60 years, registered in the database of Leumit Health Services (LHS, Israel), February to -June 2020, of whom 231 with ADHD. Logistic regression analysis models evaluated the association between ADHD and the dependent variables of being symptomatic/referral to hospitalization, controlling for demographic and medical variables. RESULTS: Age, male sex, and BMI were confirmed to be significant risk factors for increased COVID-19 severity. ADHD was found to be associated with increased severity of COVID-19 symptoms (OR = 1.81, 95% CI [1.29, 2.52], p < .05) and referral to hospitalization (OR =1.93, 95% CI [1.06, 3.51], p = .03). CONCLUSION: ADHD is associated with poorer outcomes in COVID-19 infection.

Roles of Family Stress, Maltreatment, and Affect Regulation Difficulties on Adolescent Mental Health During COVID-19.

This study examines the indirect effects of affect dysregulation and suppression on the associations between family stress from confinement, maltreatment, and adolescent mental health during COVID-19. We examined both adolescent and caregiver perspectives to yield a more well-rounded understanding of these associations than afforded in previous research. Using both adolescent (N = 809, Mage = 15.66) and caregiver (N = 578) samples, family stress from confinement, exposure to physical and psychological maltreatment, affect dysregulation and suppression, and youth internalizing and externalizing symptoms were measured in the summer of 2020, following three months of stay-at-home orders due to COVID-19. Affect dysregulation partially accounted for the associations between family stress from confinement and psychological maltreatment on both internalizing and externalizing symptoms for youth and caregiver report. Suppression partially accounted for the associations between family stress and maltreatment on internalizing and externalizing symptoms in the youth sample, but only for internalizing symptoms in the caregiver sample. Understanding family predictors of adolescents' mental health concerns and their underlying mechanisms, affect dysregulation and suppression, can inform mental health interventions during and following the COVID-19 pandemic.

Prevalence and Correlates of Suicidal Ideation and Deliberate Self-harm in Canadian Adolescents During the Coronavirus Disease 2019 Pandemic.

OBJECTIVE: In light of recent evidence that the coronavirus disease 2019 (COVID-19) pandemic has resulted in marked increases in depression, anxiety, substance use, and other mental health concerns among Canadian adolescents, we investigated the rates of self-harm thoughts and behaviours in this population. Specifically, this study explored: (1) the demographic and geographic distributions of suicidal ideation (SI) and deliberate self-harm (DSH), and (2) the associations of mental health and substance use with SI and DSH. METHOD: A total of 809 Canadian adolescents, aged 12-18 years, completed an online survey between June 17, 2020 and July 31, 2020. RESULTS: 44% of adolescents reported experiencing SI since the pandemic began, while 32% reported engaging in DSH. SI and DSH were more common among youth who: identified as transgender, non-binary or gender fluid; who did not reside with both parents; and who reported psychiatric concerns or frequent cannabis use. CONCLUSION: Canadian adolescents appear to be experiencing higher rates of self-harm thoughts and behaviours relative to before the COVID-19 pandemic. It is important for adults who are likely to interact with distressed youth to be aware of potential warning signs that a youth is struggling with self-harm, and to refer youth to specialty mental health services where appropriate.

Fusobacterium nucleatum and oral cancer: a critical review.

There is a growing level of interest in the potential role inflammation has on the initiation and progression of malignancy. Notable examples include Helicobacter pylori-mediated inflammation in gastric cancer and more recently Fusobacterium nucleatum-mediated inflammation in colorectal cancer. Fusobacterium nucleatum is a Gram-negative anaerobic bacterium that was first isolated from the oral cavity and identified as a periodontal pathogen. Biofilms on oral squamous cell carcinomas are enriched with anaerobic periodontal pathogens, including F. nucleatum, which has prompted hypotheses that this bacterium could contribute to oral cancer development. Recent studies have demonstrated that F. nucleatum can promote cancer by several mechanisms; activation of cell proliferation, promotion of cellular invasion, induction of chronic inflammation and immune evasion. This review provides an update on the association between F. nucleatum and oral carcinogenesis, and provides insights into the possible mechanisms underlying it.