Prevalence and risk factors of parental mental health problems: A cross-sectional study.

An understanding of the prevalence and risk factors of parental mental health problems is important for early intervention and prevention measures and shaping services for parents and their children. However, large representative surveys of parental mental health problems and associated risk factors are lacking. The aim of this study was to estimate prevalence rates of parental mental health problems using a standardised measure of psychiatric morbidity (General Health Questionnaire; GHQ-12), in a representative sample of parents and caregivers of children and young people (2-19 years) in Northern Ireland. Further, this study explored associated risk factors of parental mental health problems. A random household survey of parents and children was conducted between June 2019 and March 2020. Parental responses on demographic, economic, familial and psychological measures were collected (N = 2815) and 22% of parents and caregivers screened positive for mental health problems. The STROBE checklist for observational research was adhered to. Multivariate logistic regression indicated that being in receipt of benefits, having poor family support, a history of adverse childhood experiences, a history of exposure to politically motivated violence (the Troubles), and a child with conduct problems and poor health were all independent risk factors of increased parental mental health problems. Findings will help to inform future commissioning and development of services and broaden understanding of the correlates of parental mental health problems.

Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology.

Recent evidence suggests that Alzheimer's disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aß40, worse blood-brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer's Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aß40 (ß = -0.44, p-value = 0.017) and replicated this interaction in ADNI (ß = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aß peptides in brain (Aß total ß = -0.14, p = 0.629; Aß1-38, ß = 0.11, p = 0.200). In contrast to the effects on Aß, the minor allele of this same variant seemed to enhance the association with blood-brain barrier dysfunction (ß = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aß levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

Liposome-enabled bufalin and doxorubicin combination therapy for trastuzumab-resistant breast cancer with a focus on cancer stem cells.

Breast cancer stem cells (BCSCs) play a key role in therapeutic resistance in breast cancer treatments and disease recurrence. This study aimed to develop a combination therapy loaded with pH-sensitive liposomes to kill both BCSCs and the okbulk cancer cells using trastuzumab-sensitive and resistant human epidermal growth factor receptor 2 positive (HER2+) breast cancer cell models. The anti-BCSCs effect and cytotoxicity of all-trans retinoic acid, salinomycin, and bufalin alone or in combination with doxorubicin were compared in HER2+ cell line BT-474 and a validated trastuzumab-resistant cell line, BT-474R. The most potent anti-BCSC agent was selected and loaded into a pH-sensitive liposome system. The effects of the liposomal combination on BCSCs and bulk cancer cells were assessed. Compared with BT-474, the aldehyde dehydrogenase positive BCSC population was elevated in BT-474R (3.9 vs. 23.1%). Bufalin was the most potent agent and suppressed tumorigenesis of BCSCs by ∼50%, and showed strong synergism with doxorubicin in both BT-474 and BT-474R cell lines. The liposomal combination of bufalin and doxorubicin significantly reduced the BCSC population size by 85%, and inhibited both tumorigenesis and self-renewal, although it had little effect on the migration and invasiveness. The cytotoxicity against the bulk cancer cells was also enhanced by the liposomal combination than either formulation alone in both cell lines (p < 0.001). The liposomal bufalin and doxorubicin combination therapy may effectively target both BCSCs and bulk cancer cells for a better outcome in trastuzumab-resistant HER2+ breast cancer.

The structure of the Prodromal Questionnaire-16 (PQ-16) in a non-help-seeking youth population: Exploratory and confirmatory factor analyses study.

AIMS: The present study aimed to examine the structure of the Prodromal Questionnaire-16 (PQ-16) in a non-help-seeking youth population through exploratory and confirmatory factor analysis. Previous studies have not examined the structure of this self-report measure in this age group outside a clinical setting. METHODS: Participants (n = 1165) aged 11-19 years were recruited to an epidemiological study of young people in Northern Ireland, and completed the PQ-16 alongside other measures. The dataset was split randomly in two for separate factor analyses. A polychoric correlation matrix was created and exploratory factor analysis was used to identify the optimal number of factors. In addition, based on previous studies, six models were tested through confirmatory factor analysis to determine best fit. A one-factor, 3 two-factor, a three-factor and a four-factor model were all tested. RESULTS: The exploratory factor analysis indicated a two-factor structure of the PQ-16 in this population, which we have labelled 'general unusual experiences' and 'hallucinations'. Confirmatory analysis indicated that the two-factor model identified through the exploratory analysis was the best fit for the data. DISCUSSION: The present study suggests that the structure of the PQ-16 may vary across age groups in non-clinical settings, and adds further support to the validity of the PQ-16 is a cost-effective, easy to administer self-report measure that is suitable for use in non-help-seeking populations as a screening tool for prodromal symptoms.

The influence of adverse and positive childhood experiences on young people's mental health and experiences of self-harm and suicidal ideation.

BACKGROUND: Few studies have examined the interaction of adverse childhood experiences (ACEs) and positive childhood experiences (PCEs) with mental health outcomes in nationally representative European populations. OBJECTIVE: The primary objective was to test models of resilience through investigating associations between ACEs and PCEs and young people's risk of common mood and anxiety disorders, self-harm and suicidal ideation. PARTICIPANTS AND SETTING: Data were from the Northern Ireland Youth Wellbeing Survey (NIYWS), a stratified random probability household survey conducted between June 2019 and March 2020. Analysis is based on data from adolescents aged 11-19 years (n = 1299). METHOD: Logistic regression was used to test the direct effects of ACEs and PCEs on mental health outcomes and the moderating effect of PCEs at different levels of ACE exposure. RESULTS: Prevalence rates of mental health outcomes were: common mood and anxiety disorders (16 %); self-harm (10 %); suicidal ideation (12 %). ACEs and PCEs both independently predicted common mood and anxiety disorders, self-harm and suicidal ideation. Every additional ACE increased the likelihood of a common mood and anxiety disorder (81 %), self-harm (88 %) and suicidal ideation (88 %). Every additional PCE reduced common mood and anxiety disorders (14 %), self-harm (13 %) and suicidal ideation (7 %). There was no moderating effect of PCEs on ACEs and mental health outcomes. CONCLUSION: The findings suggest that PCEs act largely independently of ACEs and that initiatives to increase PCEs can assist in the prevention of mental health problems.

Deciphering breast cancer: from biology to the clinic.

Breast cancer remains a leading cause of cancer-related mortality in women, reflecting profound disease heterogeneity, metastasis, and therapeutic resistance. Over the last decade, genomic and transcriptomic data have been integrated on an unprecedented scale and revealed distinct cancer subtypes, critical molecular drivers, clonal evolutionary trajectories, and prognostic signatures. Furthermore, multi-dimensional integration of high-resolution single-cell and spatial technologies has highlighted the importance of the entire breast cancer ecosystem and the presence of distinct cellular "neighborhoods." Clinically, a plethora of new targeted therapies has emerged, now being rapidly incorporated into routine care. Resistance to therapy, however, remains a crucial challenge for the field.

Mechanisms of Organ-Specific Metastasis of Breast Cancer.

Cancer metastasis, or the development of secondary tumors in distant tissues, accounts for the vast majority of fatalities in patients with breast cancer. Breast cancer cells show a striking proclivity to metastasize to distinct organs, specifically the lung, liver, bone, and brain, where they face unique environmental pressures and a wide variety of tissue-resident cells that together create a strong barrier for tumor survival and growth. As a consequence, successful metastatic colonization is critically dependent on reciprocal cross talk between cancer cells and host cells within the target organ, a relationship that shapes the formation of a tumor-supportive microenvironment. Here, we discuss the mechanisms governing organ-specific metastasis in breast cancer, focusing on the intricate interactions between metastatic cells and specific niche cells within a secondary organ, and the remarkable adaptations of both compartments that cooperatively support cancer growth. More broadly, we aim to provide a framework for the microenvironmental prerequisites within each distinct metastatic site for successful breast cancer metastatic seeding and outgrowth.

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling.

Metabolic rewiring is often considered an adaptive pressure limiting metastasis formation; however, some nutrients available at distant organs may inherently promote metastatic growth. We find that the lung and liver are lipid-rich environments. Moreover, we observe that pre-metastatic niche formation increases palmitate availability only in the lung, whereas a high-fat diet increases it in both organs. In line with this, targeting palmitate processing inhibits breast cancer-derived lung metastasis formation. Mechanistically, breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a-dependent manner. Concomitantly, lysine acetyltransferase 2a expression is promoted by palmitate, linking the available acetyl-CoA to the acetylation of the nuclear factor-kappaB subunit p65. Deletion of lysine acetyltransferase 2a or carnitine palmitoyltransferase 1a reduces metastasis formation in lean and high-fat diet mice, and lung and liver metastases from patients with breast cancer show coexpression of both proteins. In conclusion, palmitate-rich environments foster metastases growth by increasing p65 acetylation, resulting in a pro-metastatic nuclear factor-kappaB signaling.

Prevalence of probable eating disorders and associated risk factors: An analysis of the Northern Ireland Youth Wellbeing Survey using the SCOFF.

OBJECTIVES: Eating disorders (ED) are associated with significant morbidity and mortality rates and are most common in young people aged between 15 and 19 years. Large representative surveys on disordered eating in youth are lacking. The main aims were to estimate the prevalence of disordered eating in a representative sample of 11-19 year olds in Northern Ireland and investigate the associations between probable eating disorder and a range of risk factors. DESIGNS AND METHODS: A large nationally representative household survey was conducted, and the bivariate and multivariate associations between demographic, familial, economic and psychological risk factors and probable eating disorder were assessed. RESULTS: A total of 16.2% (n = 211) of the sample met the SCOFF screening criteria for disordered eating. Probable eating disorder was associated with being female (OR = 2.44), having a parent with mental health problems (OR = 1.68), suffering from certain psychological problems, such as mood or anxiety disorder (OR = 2.55), social media disorder (OR = 2.95), being the victim of physical bullying (OR = 1.71) and having smoked (OR = 2.46). CONCLUSIONS: This study provides the first prevalence estimates of probable eating disorder among youth in Northern Ireland. Furthermore, the study identifies unique risk factors for probable eating disorder among this representative sample.

Nutrient deficiency profiles and depression: A latent class analysis study of American population.

BACKGROUND: Research into the effects of nutrition on depression is often performed by examining the effects of singular nutrients and dietary styles (e.g.: vegan, Mediterranean). The present study is the first one to establish the effects of patterns of nutritional deficiency within the American population and examines their effects on depression. METHODS: Data was drawn from National Health and Nutrition Examination Survey (NHANES). Latent class analysis was performed to identify homogeneous groups of nutrient deficiency. A 3-step analysis was performed to establish class-dependant differences in depression severity. BCH analysis revealed unique predictors of depression dependant on most probable class. RESULTS: Analysis revealed 4 classes of nutrient deficiency. Magnesium and dietary fibre were the least endorsed. 'Nutrient deprived' individuals showed the highest depression severity (Mean = 4.137, SD = 0.337). Profiles were predicted by different socioeconomic and anthropogenic predictors with meeting minimum calories showing the strongest odds of not being nutrient deprived (OR between 5.44 and 11.11). Overall, age (ß = -0.115, p ≤ 0.01) and income (ß = -0.147, p ≤ 0.01) were the strongest protecting factors while being female (ß = 0.128, p ≤ 0.01) and arthritis (ß = 0.130, p ≤ 0.01) were the strongest risk factors. LIMITATIONS: The study involved binary variables based on minimum daily intakes and did not account for positive effects of exceeding minimum recommended doses. CONCLUSIONS: The study supports the notion of a negative relationship between good nutrition and depression. Finding unique risk factors for depression symptoms supports the utility of nutrient deficiency profiling.

How is loneliness related to anxiety and depression: A population-based network analysis in the early lockdown period.

High risk of mental health problems is associated with loneliness resulting from social distancing measures and "lockdowns" that have been imposed globally due to the COVID-19 pandemic. This study explores the interconnectedness of loneliness, anxiety and depression on a symptom level using network analysis. A representative sample of participants (N = 1041), who were of at least 18 years of age, was recruited from the Republic of Ireland (ROI). Loneliness, anxiety and depression were assessed using validated instruments. Network analysis was used to identify the network structure of loneliness, anxiety and depression. Loneliness was found to be largely isolated from anxiety and depression nodes in the network. Anxiety and depression were largely interconnected. "Trouble relaxing," "feeling bad about oneself" and "not being able to stop or control worrying" were suggested as the most influential nodes of the network. Despite the expectation that loneliness would be implicated more robustly in the anxiety and depression network of symptoms, the results suggest loneliness as a distinct construct that is not interwoven with anxiety and depression.

Prevalence and risk factors of mood and anxiety disorders in children and young people: Findings from the Northern Ireland Youth Wellbeing Survey.

OBJECTIVE: This paper presents the key findings from the Northern Ireland Youth Wellbeing Prevalence Survey (NIYWS), specifically the prevalence of common mental health disorders and their association with personal, familial and socio-economic risk factors. METHODS: The Northern Ireland Youth Wellbeing Survey (NIYWS) is a large nationally representative household survey of young people aged 2-19 years (N = 3074) and their parents (N = 2816). Data collection was by means of a stratified random probability household survey. Children and young people were eligible to take part if they were aged 2 to 19 and lived in Northern Ireland. Mood and anxiety disorders were measured using the Revised Children's Anxiety and Depression Scale (RCADS: Chorpita et al., 2000). RESULTS: Based on the cut-off scores for the RCADS 11.5% of the sample met the criteria for any mental health disorder. The most prevalent disorder was panic disorder (6.76%) and the least common was generalised anxiety disorder (2.69%). Poor child health, special educational needs, parental separation, living in a household in receipt of benefits, living in an area of deprivation and living in an urban area were all significant predictors of any mood or anxiety disorder. CONCLUSIONS: The results indicate somewhat elevated prevalence rates of mood and anxiety disorders in children and young people in Northern Ireland compared to England and other international countries. These findings can be used to help inform mental health policy and practice.

Experiences of childhood adversity across generations - Continuity or change? A study from the Northern Ireland youth wellbeing survey.

BACKGROUND: Although a wealth of international literature consistently links cumulative experiences of adverse childhood experiences (ACEs) with physical, mental and emotional problems in later life, only a few studies have focused on intergenerational ACE exposure and research using nationally representative populations is lacking. OBJECTIVE: This paper examines intergenerational associations between parent and child ACE scores in a large nationally representative sample of parent-child dyads. PARTICIPANTS AND SETTING: Participant comprise 1042 pairs of parents and young people (11-19 year olds) who both completed questions relating to their exposure to ACEs (N = 1042) as part the Northern Ireland Youth Wellbeing Survey (NIYWS) - a stratified random probability household survey of the prevalence of mental health disorders among 2 to 19 year olds in Northern Ireland (N = 3074). METHODS: Hierarchical regression was used to identify the relationship between parent and young people ACE scores and investigate the extent to which this is influenced by child, parent, family and socio-economic variables. RESULTS: In the final model, young person ACE scores were associated with older child age (ß = 0.082, p = .016), younger parental age (ß = -0.083, p = .022), fewer children in the household (ß = -0.120, p < .001), poor child health (ß = 0.160, p < .001), low family support (ß = 0.118, p = .001) and the household being in receipt of benefits (ß = 0.223, p < .001). CONCLUSIONS: This study found a small association between parent and young person ACE exposure which was attenuated through other variables.

Radiation exposure elicits a neutrophil-driven response in healthy lung tissue that enhances metastatic colonization.

Radiotherapy is one of the most effective approaches to achieve tumor control in cancer patients, although healthy tissue injury due to off-target radiation exposure can occur. In this study, we used a model of acute radiation injury to the lung, in the context of cancer metastasis, to understand the biological link between tissue damage and cancer progression. We exposed healthy mouse lung tissue to radiation before the induction of metastasis and observed a strong enhancement of cancer cell growth. We found that locally activated neutrophils were key drivers of the tumor-supportive preconditioning of the lung microenvironment, governed by enhanced regenerative Notch signaling. Importantly, these tissue perturbations endowed arriving cancer cells with an augmented stemness phenotype. By preventing neutrophil-dependent Notch activation, via blocking degranulation, we were able to significantly offset the radiation-enhanced metastases. This work highlights a pro-tumorigenic activity of neutrophils, which is likely linked to their tissue regenerative functions.

CD38 knockout natural killer cells expressing an affinity optimized CD38 chimeric antigen receptor successfully target acute myeloid leukemia with reduced effector cell fratricide.

There is a strong biological rationale for the augmentation of allogeneic natural killer (NK) cell therapies with a chimeric antigen receptor (CAR) to enhance acute myeloid leukemia (AML) targeting. CD38 is an established immunotherapeutic target in multiple myeloma and under investigation as a target antigen in AML. CD38 expression on NK cells and its further induction during ex vivo NK cell expansion represents a barrier to the development of a CD38 CAR-NK cell therapy. We set out to develop a CD38 CAR-NK cell therapy for AML, first by using an NK cell line which has low baseline CD38 expression and subsequently healthy donor expanded NK cells. To overcome anticipated fratricide due to NK cell CD38 expression when using primary expanded NK cells, we applied CRISPR/Cas9 genome editing to disrupt the CD38 gene during expansion achieving a mean knockdown efficiency of 84%. The resulting CD38 KD expanded NK cells, after expression of an affinity optimized CD38 CAR, showed reduced NK cell fratricide and an enhanced ability to target primary AML blasts. Furthermore, the cytotoxic potential of CD38 CAR-NK cells was augmented by pre-treatment of the AML cells with all-trans retinoic acid which drove enhanced CD38 expression offering a rational combination therapy. These findings support the further investigation of CD38 KD - CD38 CAR-NK cells as a viable immunotherapeutic approach to the treatment of AML.

ICD-11 'mixed depressive and anxiety disorder' is clinical rather than sub-clinical and more common than anxiety and depression in the general population.

BACKGROUND: The new International Classification of Diseases was published in 2018 (ICD-11; World Health Organization, 2018) and now includes 'Mixed depressive and anxiety disorder' (6A73: MDAD) designated as a mood disorder. This disorder is defined by symptoms of both anxiety and depression occurring more days than not, for a period of two weeks, and neither set of symptoms considered separately reaches a diagnostic threshold for either disorder. However, to date no study has examined the validity of these guidelines in a general population sample. METHODS: Using Goldberg et al.'s (2017) guidelines regarding measurement of depression and anxiety, this study used factor mixture modelling (FMM) to examine the validity of the ICD-11 criteria of MDAD. Symptom endorsement rates are provided as well as demographic predictors and somatization outcomes. RESULTS: Fit indices suggested the two-factor four-class solution was the best balance between model complexity and model fit. The results did not support a class that is subsyndromal to both anxiety and depression. On the contrary, we suggest that there exists a 'Comorbid' class that represents endorsement of both anxiety and depression symptoms at a higher level when compared to both 'anxiety' and 'depression' groups. Demographic predictors, as well as somatization and functional impairment outcomes, provided support for this FMM solution. CONCLUSIONS: The 'Comorbid' group was the largest symptomatic group and had the highest levels of both anxiety and depression symptoms. Importantly, this group was larger than either the 'anxiety' or 'depression' group and was associated with high levels of functional impairment and somatization.

A systematic literature review of factor analytic and mixture models of ICD-11 PTSD and CPTSD using the International Trauma Questionnaire.

The 11th version of the International Classification of Diseases (ICD-11; WHO, 2018) describes two distinct trauma related disorders, Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD). This review aims to summarise and synthesize evidence from factor analytic and mixture modelling studies that have investigated the latent structure of the International Trauma Questionnaire. A systematic search of PsycInfo, Web of Science, Scopus and Pubmed databases was conducted to identify relevant articles. Thirty-three studies met the inclusion criteria for this systematic review. The latent structure of the ITQ was best represented by two models; a correlated six-factor model (Re-experiencing, Avoidance, Threat, Affect Dysregulation, Negative Self Concept, and Disturbed Relationships) and a two-factor second-order model (PTSD and Disturbances in Self-Organization). Mixture model studies consistently identified distinct classes representing those displaying PTSD and CPTSD symptoms. Numerous studies demonstrated support for the factorial and discriminant validity of PTSD and CPTSD when analysed in conjunction with other variables. Overall, support was found for the conceptual coherence of PTSD and CPTSD as empirically distinguishable disorders, as measured by the ITQ. The available evidence demonstrates that the ITQ is a valid measure of ICD-11 PTSD and CPTSD. Recommendations for future research are included.

Generation of neighbor-labeling cells to study intercellular interactions in vivo.

Understanding cell-cell interactions is critical in most, if not all, research fields in biology. Nevertheless, studying intercellular crosstalk in vivo remains a relevant challenge, due mainly to the difficulty in spatially locating the surroundings of particular cells in the tissue. Cherry-niche is a powerful new method that enables cells expressing a fluorescent protein to label their surrounding cells, facilitating their specific isolation from the whole tissue as live cells. We previously applied Cherry-niche in cancer research to study the tumor microenvironment (TME) in metastasis. Here we describe how to generate cancer cells with the ability to label their neighboring cells (within the tumor niche) by transferring a liposoluble fluorescent protein. Live niche cells can be isolated and compared with cells distant from the tumor bulk, using a variety of ex vivo approaches. As previously shown, this system has the potential to identify novel components in the TME and improve our understanding of their local interactions. Importantly, Cherry-niche can also be applied to study potential cell-cell interactions due to in vivo proximity in research fields beyond cancer. This protocol takes 2-3 weeks to generate the labeling cells and 1-2 weeks to test their labeling ability.

Connecting the dots: Neutrophils at the interface of tissue regeneration and cancer.

Knowledge about neutrophil biology has exponentially grown over the past decades. A high volume of investigations focusing on the characterization of their initially unappreciated multifaceted functions have grown in parallel with the immunity and the cancer fields. This has led to a significant gain in knowledge about their functions not only in tissue defence against pathogens and the collateral damage their overactivation can cause, but also their role in tissue repair and regeneration especially in the context of sterile injuries. On the other hand, the cancer field has also intensively focused its attention on neutrophil engagement in the many steps of the tumorigenic process. This review aims to draw the readers' attention to the similar functions described for neutrophils in tissue repair and in cancer. By bridging the two fields, we provide support for the hypothesis that the underlying program driving cancer-dependent exploitation of neutrophils is rooted in their physiologic tissue protection functions. In this view, cross-fertilization between the two fields will expedite the discovery of therapeutic interventions based on neutrophil targeting or their manipulation.