A census of human soluble protein complexes.

Cellular processes often depend on stable physical associations between proteins. Despite recent progress, knowledge of the composition of human protein complexes remains limited. To close this gap, we applied an integrative global proteomic profiling approach, based on chromatographic separation of cultured human cell extracts into more than one thousand biochemical fractions that were subsequently analyzed by quantitative tandem mass spectrometry, to systematically identify a network of 13,993 high-confidence physical interactions among 3,006 stably associated soluble human proteins. Most of the 622 putative protein complexes we report are linked to core biological processes and encompass both candidate disease genes and unannotated proteins to inform on mechanism. Strikingly, whereas larger multiprotein assemblies tend to be more extensively annotated and evolutionarily conserved, human protein complexes with five or fewer subunits are far more likely to be functionally unannotated or restricted to vertebrates, suggesting more recent functional innovations.

Co-design and evaluation of a digital serious game to promote public awareness about pancreatic cancer.

BACKGROUND: Pancreatic cancer, ranking seventh in global cancer-related deaths, poses a significant public health challenge with increasing incidence and mortality. Most cases are diagnosed at an advanced stage, resulting in low survival rates. Early diagnosis significantly impacts prognosis, making symptom awareness crucial. Symptoms are often subtle, leading to delayed help-seeking behaviour. Patients and their carers prioritise increased public awareness, indicating a need for innovative approaches to promote awareness of the disease. METHODS: This study employed a quasi-experimental pre-test/post-test design to assess the relationship between a serious game and pancreatic cancer awareness. Members of the public (N = 727) were recruited internationally, via social media and with signposting by relevant organisations. Participants completed measures of symptom awareness and help-seeking intentions before and after playing the game. The serious game, co-designed with experts by lived experience, patient advocates and healthcare professionals, presented participants with a human anatomy diagram, with each section linked to a question about pancreatic cancer. RESULTS: The serious game demonstrated a statistically significant improvement on pancreatic cancer awareness based on matched paired t-tests. Due to missing data, paired comparisons were only possible for 489 cases. Symptom awareness scores exhibited a statistically significant increase from pre-test to post-test, with a large effect size (p < 0.001, d = 1.43). Help-seeking intentions also markedly improved, showing a significant increase from pre-test to post-test, with a large effect size (p < 0.001, d = 1.10). Independent-samples t-tests were also conducted to determine if there were any group differences on pre- to post-test changes based on age, gender, and previous knowledge and/or experience of pancreatic cancer. Participants overwhelmingly endorsed the game's usability and educational value, suggesting its potential as an effective tool for enhancing public awareness and proactive health-seeking behaviour. DISCUSSION: This study is the first to explore a serious game's utility in pancreatic cancer awareness. Results suggest that such interventions can effectively increase public awareness and influence help-seeking intentions. The co-design process ensured content relevance, and participant satisfaction was high. Findings highlight the game's potential as an accessible and convenient tool for diverse populations.

Evaluation of a dementia awareness game for health professions students in Northern Ireland: a pre-/post-test study.

BACKGROUND: Dementia is a prevalent global health issue, necessitating comprehensive education for healthcare practitioners and students. Nursing and pharmacy students, provide support across healthcare settings often working as frontline caregivers. Therefore, it is imperative to equip these students with a profound understanding of dementia. The aim of this study was to evaluate whether a serious dementia game co-designed with stakeholders, students, and people living with dementia improved the attitudes of nursing and pharmacy students. METHODS: A pretest-posttest design was used to assess the attitudes of health professions students (nursing and pharmacy) towards dementia. The Approaches to Dementia Questionnaire (ADQ) was administered before and after playing a serious Dementia Game. The ADQ measured the total score, Hope subscale, and Recognition of Personhood subscale. Matched pairs t-test was used for analysis conducted with IBM SPSS statistics 27. RESULTS: A diverse cohort of 505 participants from one university in Northern Ireland participated, with 461 matched pairs used for analysis. Both nursing and pharmacy students demonstrated a significant increase in overall dementia attitudes post-gameplay, with nursing students showing an increase from 79.69 to 83.59 and pharmacy students from 75.55 to 79.86. Subscales for Hope (Nursing = 28.77 to 31.22, Pharmacy = 26.65 to 29.20). and Recognition of Personhood also exhibited significant improvement (Nursing = 50.93 to 52.38, Pharmacy = 48.89 to 50.67). Demographic data revealed predominantly female participants, a lack of personal connections to dementia, and varied training experiences. DISCUSSION: The study highlights the efficacy of the serious Dementia Game in enhancing attitudes to dementia amongst health professions students, indicating its potential as an educational tool. The study contributes to the growing body of evidence supporting serious games and gamification in healthcare education.

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.

Pediatric Critical Care Referrals for Tertiary Inpatient and Transport Services in Canada's Maritime Provinces: A Retrospective Cohort Study.

OBJECTIVE: Accurate triage of children referred for tertiary pediatric critical care services is crucial to ensure optimal disposition and resource conservation. We aimed to explore the characteristics and level of care needs of children referred to tertiary pediatric critical care inpatient and transport services and the characteristics of referring physicians and hospitals to which these children present. METHODS: We conducted a 1-year retrospective cohort study of children (< 16 years) with documented referral to pediatric critical care and specialized transport services at a tertiary pediatric hospital from regional (24/7 pediatrician on-call coverage) and community (no pediatric specialty services) hospitals in Canada's Maritime provinces. RESULTS: We identified 205 documented referrals resulting in 183 (89%) transfers; 97 (53%) were admitted to the pediatric intensive care unit (PICU). Of 150 children transferred from centers with 24/7 pediatric specialist coverage, 45 (30%) were admitted to the tertiary hospital pediatric medical unit with no subsequent admission to the PICU. Of 20 children transferred from community hospitals and admitted to the tertiary hospital general pediatric medical unit, 9 (45%) bypassed proximate regional hospitals with specialist pediatric care capacity. The specialized pediatric critical care transport team performed 151 (83%) of 183 interfacility transfers; 83 (55%) were admitted to the PICU. CONCLUSION: One third of the children accepted for interfacility transfer after pediatric critical care referral were triaged to a similar level of care as could be provided at the sending or nearest regional hospital. Improved utilization of pediatric expertise in regional hospitals may reduce unnecessary pediatric transports and conserve valuable health care resources.

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.

Exploring the experiences of people living with dementia in Dementia Friendly Communities (DFCs) in Northern Ireland: a realist evaluation protocol.

BACKGROUND: The aim of this study is to 1) explore the experiences of people living with dementia interacting with DFCs and 2) identify factors that influence empower and support people living with dementia to live successfully in DFCs. The main elements of a DFC are related to people; communities; organisations and partnerships. There are over 200 organisations recognised as dementia-friendly in Northern Ireland (NI). This realist evaluation is to understand how DFCs work for people living with dementia, how positive outcomes are achieved, for whom and in what contexts do DFCs work best. METHODS: A realist evaluation using case study methodology. The process evaluation includes a realist review of the literature, non-participant observation of people living with dementia in their local communities, semi-structured interviews to explore the facilitators and barriers to living well in DFCs and focus groups comprised of people living with dementia, family caregivers and people working in DFCs to support Context- Mechanisms and Outcomes (CMOs). This four-stage realist assessment cycle is used, including iterative rounds of theory development, data gathering, and theory testing. In the end, analysis will reveal context mechanisms that influence how dementia-friendly communities operate and present an initial theory of how people think, which, if adopted, may be able to alter current contexts so that "key" mechanisms are activated to generate desired outcomes. DISCUSSION: To give confidence in moving from hypothetical constructions about how DFCs could function to explanations of possible or observable causal mechanisms, the realist evaluation of a complex intervention incorporates a variety of evidence and perspectives. Despite playing a significant role in a person with dementia's everyday life, it appears that little is known about how communities function to achieve intended results. Even though there has been a lot of work to pinpoint the fundamentals and crucial phases of building DFCs, it is still unclear how people living with dementia benefit the most from these communities. This study intends to advance our understanding of how outcomes are produced for people living with dementia by contributing to the underlying theory of DFCs as well as addressing the primary research objectives.

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.

Translating 'dementia friends' programme to undergraduate medical and nursing practice: a qualitative exploration.

INTRODUCTION: Dementia awareness is a key priority of medical and nursing pre-registration education. The 'dementia friends' programme is an internationally recognised and accredited dementia awareness workshop that is led by a trained facilitator. While this programme has been associated with positive outcomes, few studies have examined how medical and nursing students apply their learning in practice after the workshop. The aim of his study was to explore how nursing and medical students apply the dementia friend's programme into practice when caring for people living with dementia. METHODS: Seven focus-group interviews were conducted with 36 nursing students and 14 medical students at one university in Northern Ireland (n = 50), following 'the dementia friends programme. Interview guides were co-designed alongside people living with dementia. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. Ethical approval was granted for this study. RESULTS: Four themes emerged: 'reframing dementia', which highlighted how the education had enabled students to actively empower and support people living with dementia in practice; 'dementia friendly design', which focused on how students had modified their clinical environments when providing care for people living with dementia, 'creative communication', which considered how students had used their education to adapt their verbal and non-verbal communication with people living with dementia and 'realities of advanced dementia' which contemplated how students believed their dementia education could be improved within their current curriculum. DISCUSSION: The Dementia Friends programme has actively supported nursing and medical students to improve the lives of people with dementia in their care through environmental adaptions and creative approaches to communication. This study provides an evidence base that supports the provision of 'a dementia friends programme to healthcare professional students. The study also highlights how this education can actively influence how nursing and medical students support people living with dementia in their practice in the months and years after education.

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.

Evaluation of a dementia awareness game for undergraduate nursing students in Northern Ireland: a Pre-/Post-Test study.

INTRODUCTION: Although it is possible to live well with dementia and many individuals with dementia lead active lives with the help of family, friends, and communities, the general impression of dementia is frequently negative. Dementia is a global health issue. Despite this, little research has been done on the effects of innovative dementia education strategies among undergraduate nursing students. The aim of this study was therefore to assess if this serious digital game, originally intended for the public, could increase knowledge about dementia in first-year nursing students. METHODS: The intervention was a digital serious game called "The Dementia Game", which was available to students throughout February 2021, to a convenience sample of first-year undergraduate nursing students (n = 560) completing a BSc Honours Nursing Degree programme in one university in Northern Ireland. The game was evaluated using a pretest-posttest design. The questionnaire comprised of a 30- item true- false Alzheimer's Disease Knowledge Scale (ADKS), which covers risk factors, assessment and diagnosis, symptoms, course, life impact, caregiving and treatment and management. Data were analysed using paired t-tests and descriptive statistics. RESULTS: Overall dementia knowledge increased significantly after playing the game. Pre-test to post-test increases were observed across a range of seven categories of dementia knowledge (life impact, risk factors, symptoms, treatment, assessment, caregiving and trajectory), with particularly large increases in knowledge of trajectory and risk factors, as shown using paired t-tests. All pre-test to post-test comparisons were significant at the p < 0.001 level. CONCLUSIONS: A short serious digital game on dementia improved first-year student's knowledge about dementia. Undergraduate students also expressed that this approach to dementia education was effective in improving their knowledge about the disease.

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.

Are American Indian/Alaska Native Adolescent Health Behaviors Different? A Review of AI/AN Youth Involved in Native STAND Curriculum, 2014-2017 United States.

OBJECTIVES: To explore health behavior profiles of AI/AN youth involved in native students together against negative decisions (STAND), a national culture-based curriculum. METHODS: We analyzed data from 1236 surveys conducted among AI/AN youth at 40 native STAND implementation sites located in 16 states throughout the US from 2014 to 2017. Health profiles included demographics, sexual orientation, sexual activity, STI testing, cigarette use, and suicide attempts in the past 12-months. We used t-tests and chi square tests of independence to compare risk behavior prevalence among the sample. RESULTS: Health behavior profiles of AI/AN youth indicate that 45.6% of youth did not use condoms the last time they had sex, and 82.7% have never been tested for STIs. Differences in cigarette smoking were observed in questioning youth (questioning: 80.3%, straight/heterosexual: 63.8%, LGBTQ2S + : 49.9%, p = 0.03). CONCLUSIONS FOR PRACTICE: Health behaviors related to sex, substance, violence and self-harm, are at least as common for AI/AN youth as those observed in other US teens. Future research should consider similarities and differences in health profiles of AI/AN youth when designing interventions that affect them. Further, our findings underscore the need for culturally-relevant curricula like native STAND, not because their health behavior is different, but because their socio-ecologic environment is different.

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.