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.

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.

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.

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.

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.

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.

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.

Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series.

AIMS: Establishing the mismatch repair (MMR) status of colorectal cancers is important to enable the detection of underlying Lynch syndrome and inform prognosis and therapy. Current testing typically involves either polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing or MMR protein immunohistochemistry (IHC). The aim of this study was to compare these two approaches in a large, population-based cohort of stage 2 and 3 colon cancer cases in Northern Ireland. METHODS AND RESULTS: The study used the Promega pentaplex assay to determine MSI status and a four-antibody MMR IHC panel. IHC was applied to tumour tissue microarrays with triplicate tumour sampling, and assessed manually. Of 593 cases with available MSI and MMR IHC results, 136 (22.9%) were MSI-high (MSI-H) and 135 (22.8%) showed abnormal MMR IHC. Concordance was extremely high, with 97.1% of MSI-H cases showing abnormal MMR IHC, and 97.8% of cases with abnormal IHC showing MSI-H status. Under-representation of tumour epithelial cells in samples from heavily inflamed tumours resulted in misclassification of several cases with abnormal MMR IHC as microsatellite-stable. MMR IHC revealed rare cases with unusual patterns of MMR protein expression, unusual combinations of expression loss, or secondary clonal loss of expression, as further illustrated by repeat immunostaining on whole tissue sections. CONCLUSIONS: MSI PCR testing and MMR IHC can be considered to be equally proficient tests for establishing MMR/MSI status, when there is awareness of the potential pitfalls of either method. The choice of methodology may depend on available services and expertise.

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.

The Mediational Effect of Affect Dysregulation on the Association Between Attachment to Parents and Oppositional Defiant Disorder Symptoms in Adolescents.

Oppositional defiant disorder (ODD) is a childhood disorder, commonly occurring in early school aged children with some symptoms becoming normative in adolescence (e.g., irritability, disagreeing). Affect dysregulation is a risk factor in the development of ODD. Affect regulation is nurtured within parent-child relationships, thus disruptions to attachment may derail children's capacity to develop adaptive affect regulation, increasing the risk for ODD. Using a high-risk sample of adolescents, we investigated the association between attachment anxiety and attachment avoidance with ODD through affect dysregulation. Attachment anxiety, but not avoidance, was associated with affect dysregulation and ODD. Affect dysregulation was found to fully mediate the relationship between attachment anxiety and ODD concurrently and prospectively. Similar findings have been demonstrated among children; results show that attachment anxiety, and its effects on affect dysregulation, are associated with ODD symptoms well into adolescence.

Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia.

BACKGROUND: Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy. METHODS: Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology. RESULTS: Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression). CONCLUSIONS: Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.

Chronic loss of STAG2 leads to altered chromatin structure contributing to de-regulated transcription in AML.

BACKGROUND: The cohesin complex plays a major role in folding the human genome into 3D structural domains. Mutations in members of the cohesin complex are known early drivers of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with STAG2 the most frequently mutated complex member. METHODS: Here we use functional genomics (RNA-seq, ChIP-seq and HiChIP) to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming in a clinically relevant model of chronic STAG2 loss. RESULTS: The chronic loss of STAG2 led to loss of smaller loop domains and the maintenance/formation of large domains that, in turn, led to altered genome compartmentalisation. These changes in genome structure resulted in altered gene expression, including deregulation of the HOXA locus and the MAPK signalling pathway, resulting in increased sensitivity to MEK inhibition. CONCLUSIONS: The altered genomic architecture driven by the chronic loss of STAG2 results in altered gene expression that may contribute to leukaemogenesis and may be therapeutically targeted.

The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation.

BACKGROUND: Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. METHODS: Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density. RESULTS: CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223-0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363-0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS. CONCLUSIONS: Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.

ADHD and Exposure to Maltreatment in Children and Youth: a Systematic Review of the Past 10 Years.

PURPOSE OF THE REVIEW: The purpose of the current paper was to review and summarize the literature on ADHD and maltreatment over the past 10 years. RECENT FINDINGS: The majority of research on ADHD and exposure to maltreatment focuses on the high rates of comorbidity, including international studies from Asia, South America, North America, and Europe. Longitudinal studies showed that early exposure to maltreatment is a risk factor for ADHD symptoms later in development; however, this finding was not consistent. There were some preliminary studies on the neurological and genetic mechanisms underlying the link between ADHD and exposure to maltreatment. Finally, ADHD and exposure to maltreatment were found to have an additive effect on clinically salient outcomes (e.g., aggression, suicide attempts). Results from the review have direct clinical and future implications, including the need to understand the effect of comorbid ADHD and exposure to maltreatment in treatment studies.

Recommendations for determining HPV status in patients with oropharyngeal cancers under TNM8 guidelines: a two-tier approach.

BACKGROUND: TNM8 staging for oropharyngeal squamous cell carcinomas (OPSCC) surrogates p16 immunohistochemistry for HPV testing. Patients with p16+ OPSCC may lack HPV aetiology. Here, we evaluate the suitability of TNM8 staging for guiding prognosis in such patients. METHODS: HPV status was ascertained using p16 immunohistochemistry and high-risk HPV RNA and DNA in situ hybridisation. Survival by stage in a cohort of OPSCC patients was evaluated using TNM7/TNM8 staging. Survival of p16+/HPV- patients was compared to p16 status. RESULTS: TNM8 staging was found to improve on TNM7 (log rank p = 0·0190 for TNM8 compared with p = 0·0530 for TNM7) in p16+ patients. Patients who tested p16+ but were HPV- (n = 20) had significantly reduced five-year survival (33%) compared to p16+ patients (77%) but not p16- patients (35%). Cancer stage was reduced in 95% of p16+/HPV- patients despite having a mortality rate twice (HR 2.66 [95% CI: 1.37-5.15]) that of p16+/HPV+ patients under new TNM8 staging criteria. CONCLUSION: Given the significantly poorer survival of p16+/HPV- OPSCCs, these data provide compelling evidence for use of an HPV-specific test for staging classification. This has particular relevance in light of potential treatment de-escalation that could expose these patients to inappropriately reduced treatment intensity as treatment algorithms evolve.

Profiles of primary and secondary callous-unemotional features in youth: The role of emotion regulation.

There is increasing evidence for multiple pathways in the development of callous-unemotional (CU) features, including primary and secondary profiles. Understanding affect regulation strategies among variants may provide further insight to the development and treatment of CU features. This study evaluated whether profiles of CU features could be identified within a clinical sample of youth using measures of affect dysregulation, affect suppression, anxiety, and maltreatment. We also examined whether these profiles were consistent across gender. Participants (N = 418; 56.7% female) ranged in age from 12 to 19 years (M = 15.04, SD = 1.85) and were drawn from a clinical sample. Latent profile analysis (LPA) was conducted using five indicators, including affect regulation, suppression, anxiety, CU features, and maltreatment. The best fitting model, a four-profile solution, included a low (low CU/dysregulation), anxious (low CU/high dysregulation), primary CU (high CU/low dysregulation), and secondary CU profile (high CU/dysregulation/maltreatment). LPAs found the same four-profile model when conducted separately for males and females. This is the first study to examine gender and include affect regulation strategies in the examination of primary and secondary profiles of CU.

An attachment-based intervention for parents of adolescents at risk: mechanisms of change.

Mechanisms that account for treatment effects are poorly understood. The current study examined processes that may underlie treatment outcomes of an attachment-based intervention (Connect) for parents of pre-teens and teens with serious behavior problems. Parents (N = 540) in a non-randomized trial reported on their teen's functioning prior to and following treatment. Results confirmed significant decreases in parents' reports of teens' externalizing and internalizing symptoms, replicating prior evaluations of this program. Reductions in parents' reports of teen attachment avoidance were associated with decreases in externalizing symptoms, while reductions in parents' reports of teen attachment anxiety were associated with decreases in internalizing symptoms. Parents' reports of improved teen affect regulation were also associated with decreases in both internalizing and externalizing symptoms. Results were comparable across gender and for parents of teens with pre-treatment externalizing symptoms in the clinical versus sub-clinical range. A model of therapeutic change in attachment-based parenting programs is discussed.

Insights on Epidemiology, Morbidity and Mortality of Cushing's Disease in Northern Ireland.

Cushing's disease is a rare condition occurring due to an adrenocorticotrophin-producing corticotrophinoma arising from the pituitary gland. The consequent hypercortisolaemia results in multisystem morbidity and mortality. This study aims to report incidence, clinicopathological characteristics, remission outcomes and mortality in a regional pituitary neurosurgical cohort of patients diagnosed with Cushing's disease in Northern Ireland from 2000-2019. Clinical, biochemical and radiological data from a cohort of patients operated for Cushing's disease were retrospectively collected and analysed. Fifty-three patients were identified, resulting in an estimated annual incidence of Cushing's disease of 1.39-1.57 per million population per year. Females accounted for 72% (38/53) of the cohort. The majority (74%, 39/53) of corticotrophinomas were microadenomas and in 44% (17/39) of these no tumour was identified on preoperative magnetic resonance imaging. Histopathological characterisation was similarly difficult, with no tumour being identified in the histopathological specimen in 40% (21/53) of cases. Immediate postoperative remission rates were 53% and 66% when considering serum morning cortisol cut-offs of ≤50nmol/L (1.8µg/dL) and ≤138nmol/L (5µg/dL) respectively in the week following pituitary surgery. Approximately 70% (37/53) of patients achieved longer term remission with a single pituitary surgery. Three patients had recurrent disease. Patients with Cushing's disease had a significantly higher mortality rate compared to the Northern Ireland general population (standardised mortality ratio 8.10, 95% confidence interval 3.3 - 16.7, p<0.001). Annual incidence of Cushing's disease in Northern Ireland is consistent with other Northern European cohorts. Functioning corticotrophinomas are a clinically, radiologically and histopathologically elusive disease with increased mortality compared to the general population.