Embedding nurse home visiting in universal healthcare: 6-year follow-up of a randomised trial.

OBJECTIVE: Nurse home visiting (NHV) is designed to redress child and maternal health inequities. Of the previous trials to investigate NHV benefits beyond preschool, none were designed for populations with universal healthcare. To address this evidence gap, we investigated whether the Australian 'right@home' NHV programme improved child and maternal outcomes when children turned 6 and started school. METHODS: A screening survey identified pregnant women experiencing adversity from antenatal clinics across two states (Victoria, Tasmania). 722 were randomised: 363 to the right@home programme (25 visits promoting parenting and home learning environment) and 359 to usual care. Child measures at 6 years (first school year): Strengths and Difficulties Questionnaire (SDQ), Social Skills Improvement System (SSIS), Childhood Executive Functioning Inventory (CHEXI) (maternal/teacher-reported); general health and paediatric quality of life (maternal-reported) and reading/school adaptation items (teacher-reported). Maternal measures: Personal Well-being Index (PWI), Depression Anxiety Stress Scales, warm/hostile parenting, Child-Parent Relationship Scale (CPRS), emotional abuse and health/efficacy items. Following best-practice methods for managing missing data, outcomes were compared between groups (intention-to-treat) using regression models adjusted for stratification factors, baseline variables and clustering (nurse/site level). RESULTS: Mothers reported on 338 (47%) children, and teachers on 327 (45%). Patterns of group differences favoured the programme arm, with small benefits (effect sizes ranging 0.15-0.26) evident for SDQ, SSIS, CHEXI, PWI, warm parenting and CPRS. CONCLUSIONS: Four years after completing the right@home programme, benefits were evident across home and school contexts. Embedding NHV in universal healthcare systems from pregnancy can offer long-term benefits for families experiencing adversity. TRIAL REGISTRATION NUMBER: ISRCTN89962120.

Longitudinal relationships between sub-clinical depression, sub-clinical eating disorders and health-related quality of life in early adolescence.

OBJECTIVE: A comprehensive understanding of the relationship between depressive symptoms and eating disorder (ED) symptoms requires consideration of additional variables that may influence this relationship. Health-related quality of life (HRQOL) has been associated with both depression and EDs; however, there is limited evidence to demonstrate how all three variables interact over time. This study sought to explore the bi-directional relationships between depressive symptoms, ED symptoms and HRQOL in a large community sample of young adolescents METHOD: Adolescents (N = 1393) aged between 11 and 14 years (M = 12.50, SD = 0.38) completed an online survey measuring depressive symptoms, ED symptoms and HRQOL. Two-level autoregressive cross-lagged models with three variables (i.e., depressive symptoms, HRQOL and ED) assessed across two time points (T1 and T2) were created to address the study aims. RESULTS: HRQOL was found to predict depressive symptoms and depressive symptoms were found to predict ED symptoms. Components of HRQOL (i.e., social relationships and ability to cope) were found to share a differential relationship with depressive symptoms. Inability to cope predicted depressive symptoms and depressive symptoms predicted negative social relationships. EDs were found to predict reduced HRQOL and negative social relationships. DISCUSSION: Findings suggest prevention and early intervention programs designed to address adolescent depression should focus on improving HRQOL. Future research should assess the relationship between HRQOL and individual ED symptoms (e.g., body-related ED symptoms, restrictive symptoms) as a means of exploring relationships that may have been masked by assessing ED symptoms using a total score. PUBLIC SIGNIFICANCE: This study sought to explore how eating disorders, depressive symptoms, and health-related quality of life (HRQOL) relate over time in a sample of young adolescents. Findings indicate adolescents who self-reported lower levels of HRQOL, including a reduced ability to cope, are at risk of experiencing depressive symptoms. Adolescents should be provided with the tools to develop problem-focused coping strategies as a means of reducing depressive symptoms.

Nurse home visiting to improve child and maternal outcomes: 5-year follow-up of an Australian randomised controlled trial.

OBJECTIVES: Nurse home visiting (NHV) is widely implemented to address inequities in child and maternal health. However, few studies have examined longer-term effectiveness or delivery within universal healthcare systems. We evaluated the benefits of an Australian NHV program ("right@home") in promoting children's language and learning, general and mental health, maternal mental health and wellbeing, parenting and family relationships, at child ages 4 and 5 years. SETTING AND PARTICIPANTS: Randomised controlled trial of NHV delivered via universal, child and family health services (the comparator). Pregnant women experiencing adversity (≥2 of 10 risk factors) were recruited from 10 antenatal clinics across 2 states (Victoria, Tasmania) in Australia. INTERVENTION: Mothers in the intervention arm were offered 25 nurse home visits (mean 23·2 home visits [SD 7·4, range 1-43] received) of 60-90 minutes, commencing antenatally and continuing until children's second birthdays. PRIMARY AND SECONDARY OUTCOMES MEASURED: At 4 and 5 years, outcomes were assessed via parent interview and direct assessment of children's language and learning (receptive and expressive language, phonological awareness, attention, and executive function). Outcomes were compared between intervention and usual care arms (intention to treat) using adjusted regression with robust estimation to account for nurse/site. Missing data were addressed using multiple imputation and inverse probability weighting. RESULTS: Of 722 women enrolled in the trial, 225 of 363 (62%) intervention and 201 of 359 (56%) usual care women provided data at 5 years. Estimated group differences showed an overall pattern favouring the intervention. Statistical evidence of benefits was found across child and maternal mental health and wellbeing, parenting and family relationships with effect sizes ranging 0·01-0·27. CONCLUSION: An Australian NHV program promoted longer-term family functioning and wellbeing for women experiencing adversity. NHV can offer an important component of a proportionate universal system that delivers support and intervention relative to need. TRIAL REGISTRATION: 2013-2016, registration ISRCTN89962120.

Bi-directional associations between depressive symptoms and eating disorder symptoms in early adolescence.

Despite frequently co-occurring, the temporal relationship between depression and eating disorder symptoms remains poorly understood. This exploratory study sought to investigate the reciprocal relationship between depressive symptoms and (1) shape and weight dissatisfaction, (2) shape and weight overvaluation, (3) preoccupation with shape or weight, (4) preoccupation with food, (5) dietary restraint and (6) binge eating in early adolescence. Adolescents (N = 1393) aged between 11.4 and 13.9 years (M = 12.50, SD = 0.38) completed the Centre for Epidemiological Depression Scale-Revised and Eating Disorder Examination Questionnaire-Adolescent version at the beginning of secondary school (T1) and 12-months later (T2). Cross-lagged models were created to assess the reciprocal relationship between depressive symptoms and ED symptoms. Depressive symptoms at T1 predicted shape and weight dissatisfaction, shape and weight overvaluation, preoccupation with shape or weight, preoccupation with food, dietary restraint and binge eating at T2. Shape and weight dissatisfaction and binge eating were the only ED symptoms at T1 to predict depressive symptoms at T2. Findings suggest young adolescents who experience depressive symptoms in their first year of secondary school are at-risk of developing ED symptoms over the subsequent 12-month period.

Risk factors in body image dissatisfaction: gender, maladaptive perfectionism, and psychological wellbeing.

Discontent with one's appearance (body image dissatisfaction) has become a global phenomenon, associated with the development of extreme behaviours in order to correct perceived body image problems. Much of the literature has focused on associated destructive behaviours that result from body image dissatisfaction; however, there has been a dearth of research examining risk factors for body image problems in adults. Thus, the current study aimed to investigate risk factors associated with adult body image problems, focusing on two variables highlighted in the literature (gender and maladaptive perfectionism). The current study (1) compared gender differences in body image dissatisfaction and (2) investigated psychological wellbeing as a mediator between maladaptive perfectionism and body image dissatisfaction. The sample included 139 Australian adults from universities (55.7%) and the community (44.3%). Participants completed demographic questions, the Frost Multidimensional Perfectionism Scale, the Psychological Wellbeing questionnaire, the Multidimensional Body-Self Relations Questionnaire, and Marlowe-Crowne Social Desirability Scale. In contrast to predictions, females had higher body area satisfaction and appearance evaluation scores. Furthermore, in line with the hypotheses, psychological wellbeing fully mediated the relationship between maladaptive perfectionism and poor body image. The findings suggest gender, maladaptive perfectionism, and psychological wellbeing may act as risk factors for body image dissatisfaction.

Depression and eating disorders in early adolescence: A network analysis approach.

OBJECTIVE: Eating disorders (EDs) and depression are among the most debilitating and pervasive mental illnesses. Although they often co-occur, the relationship between EDs and depression remains poorly understood. This study used network analysis to explore the symptom-level relationship between EDs and depression among a sample of Australian adolescents completing their first year of secondary school. METHOD: Adolescents (N = 4,421) aged between 10 and 15 years completed the Centre for Epidemiological Depression Scale and the Eating Disorder Examination-Questionnaire. Network structure was estimated using the Gaussian graphical model and node centrality was assessed using one-step expected influence (EI) and bridge EI. RESULTS: "Depressed," "lonely," and "low energy" were identified as core symptoms of depression. "Shape and weight dissatisfaction," "desire to lose weight," and "preoccupation with shape or weight" were identified as core ED symptoms. "Irritable," "social eating," and "depressed" were identified as the most important nodes connecting (i.e., bridging) symptoms of depression and EDs. DISCUSSION: This study provides an important symptom-level conceptualization of the association between depression and ED symptoms in a community sample of adolescents. This preliminary evidence may guide the development of public health prevention and early intervention programs. Future research should be conducted to address the study limitations (e.g., cross-sectional design).

Clinical, financial and social impacts of COVID-19 and their associations with mental health for mothers and children experiencing adversity in Australia.

BACKGROUND: Australia has maintained low rates of SARS-COV-2 (COVID-19) infection, due to geographic location and strict public health restrictions. However, the financial and social impacts of these restrictions can negatively affect parents' and children's mental health. In an existing cohort of mothers recruited for their experience of adversity, this study examined: 1) families' experiences of the COVID-19 pandemic and public health restrictions in terms of clinical exposure, financial hardship family stress, and family resilience (termed 'COVID-19 impacts'); and 2) associations between COVID-19 impacts and maternal and child mental health. METHODS: Participants were mothers recruited during pregnancy (2013-14) across two Australian states (Victoria and Tasmania) for the 'right@home' trial. A COVID-19 survey was conducted from May-December 2020, when children were 5.9-7.2 years old. Mothers reported COVID-19 impacts, their own mental health (Depression, Anxiety, Stress Scales short-form) and their child's mental health (CoRonavIruS Health and Impact Survey subscale). Associations between COVID-19 impacts and mental health were examined using regression models controlling for pre-COVID-19 characteristics. RESULTS: 319/406 (79%) mothers completed the COVID-19 survey. Only one reported having had COVID-19. Rates of self-quarantine (20%), job or income loss (27%) and family stress (e.g., difficulty managing children's at-home learning (40%)) were high. Many mothers also reported family resilience (e.g., family found good ways of coping (49%)). COVID-19 impacts associated with poorer mental health (standardised coefficients) included self-quarantine (mother: ß = 0.46, child: ß = 0.46), financial hardship (mother: ß = 0.27, child: ß = 0.37) and family stress (mother: ß = 0.49, child: ß = 0.74). Family resilience was associated with better mental health (mother: ß = -0.40, child: ß = -0.46). CONCLUSIONS: The financial and social impacts of Australia's public health restrictions have substantially affected families experiencing adversity, and their mental health. These impacts are likely to exacerbate inequities arising from adversity. To recover from COVID-19, policy investment should include income support and universal access to family health services.

A qualitative exploration of the sexual and reproductive health knowledge of adolescent mothers from indigenous populations in Ratanak Kiri Province, Cambodia.

INTRODUCTION: Adolescents from indigenous populations in Ratanak Kiri Province in Cambodia experience worse sexual and reproductive health (SRH) outcomes when compared to their urban counterparts. However, few qualitative studies have been conducted to identify factors that may explain the poor SRH outcomes experienced by this population group. METHODS: The socioecological model was used as the analytical lens to explore the SRH knowledge and sources of SRH information of adolescent mothers (aged 15-19 years) from indigenous populations in north-eastern Cambodia. Adolescent mothers from the Tompoun and Jarai indigenous population groups (n=22) were purposively recruited from seven villages in two districts of Ratanak Kiri Province. All adolescent mothers engaged in a combined body mapping exercise and semi-structured interview; this approach was considered the most appropriate qualitative data collection method to use in this context as it reduced language, cultural and social barriers that have previously restricted qualitative exploration of sensitive issues among this population group. The body maps and semi-structured interview transcripts were analysed using thematic analysis. RESULTS: Adolescent mothers demonstrated limited SRH knowledge including that pertaining to the anatomy of the female reproductive body, the physiology of human reproduction, fertility and pregnancy. Adolescents' primary source of SRH information was interaction with female family members and friends within their community. Adolescents' limited SRH knowledge was influenced by factors on individual (eg educational attainment, child marriage), relationship (eg social interaction with female family members and friends), community (eg access to educational and healthcare services) and societal (eg barriers to accessing national SRH programs and initiatives) levels. CONCLUSION: The%u202Ffindings support the need for SRH education in the primary and secondary school curriculum. In 2018 the Cambodia Ministry of Education, Youth and Sports introduced a Comprehensive Sexuality Education (CSE) program into the government primary and secondary school curriculum. The CSE, which is delivered in the Khmer language, provides Cambodian youth with an avenue to access accurate SRH information that will aid their SRH decision-making. However, indigenous girls face numerous social, cultural, economic and language barriers that restrict or prevent their access to formal education. Therefore, additional SRH materials and resources that are culturally and linguistically appropriate need to be developed for indigenous students attending primary and secondary schools in Ratanak Kiri Province and for young people who have ceased formal education. Educating village chiefs to deliver non-formal, community-based education programs is proposed as a means of increasing SRH knowledge and reducing health inequalities faced by this population group while ensuring that accurate information is delivered in a culturally appropriate manner.

Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions.

Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activated by ICAM-1 engagement, either through lymphocyte adhesion or Ab-mediated clustering. MAPKs were involved in ICAM-1-dependent expression of TNF-α in cerebral and dermal MVECs, and CXCL8, CCL3, CCL4, VCAM-1, and cyclooxygenase 2 (COX-2) in cerebral MVECs. Endothelial JNK and to a much lesser degree p38 were the principal MAPKs involved in facilitating diapedesis of CD4+ lymphocytes across both types of MVECs, whereas ERK was additionally required for TEM across dermal MVECs. JNK activity was critical for ICAM-1-induced F-actin rearrangements. Furthermore, activation of endothelial ICAM-1/JNK led to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1-induced phosphorylation of paxillin was required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation. Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

The blood-brain barrier and methamphetamine: open sesame?

The chemical and electrical microenvironment of neurons within the central nervous system is protected and segregated from the circulation by the vascular blood-brain barrier. This barrier operates on the level of endothelial cells and includes regulatory crosstalk with neighboring pericytes, astrocytes, and neurons. Within this neurovascular unit, the endothelial cells form a formidable, highly regulated barrier through the presence of inter-endothelial tight junctions, the absence of fenestrations, and the almost complete absence of fluid-phase transcytosis. The potent psychostimulant drug methamphetamine transiently opens the vascular blood-brain barrier through either or both the modulation of inter-endothelial junctions and the induction of fluid-phase transcytosis. Direct action of methamphetamine on the vascular endothelium induces acute opening of the blood-brain barrier. In addition, striatal effects of methamphetamine and resultant neuroinflammatory signaling can indirectly lead to chronic dysfunction of the blood-brain barrier. Breakdown of the blood-brain barrier may exacerbate the neuronal damage that occurs during methamphetamine abuse. However, this process also constitutes a rare example of agonist-induced breakdown of the blood-brain barrier and the adjunctive use of methamphetamine may present an opportunity to enhance delivery of chemotherapeutic agents to the underlying neural tissue.

Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from lipopolysaccharide-stimulated myeloid cells.

Vitamin K-dependent proteases generated in response to vascular injury and infection enable fibrin clot formation, but also trigger distinct immuno-regulatory signaling pathways on myeloid cells. Factor Xa, a protease crucial for blood coagulation, also induces protease-activated, receptor-dependent cell signaling. Factor Xa can bind both monocytes and macrophages, but whether factor Xa-dependent signaling stimulates or suppresses myeloid cell cytokine production in response to Toll-like receptor activation is not known. In this study, exposure to factor Xa significantly impaired pro-inflammatory cytokine production from lipopolysaccharide-treated peripheral blood mononuclear cells, THP-1 monocytic cells and murine macrophages. Furthermore, factor Xa inhibited nuclear factor-kappa B activation in THP-1 reporter cells, requiring phosphatidylinositide 3-kinase activity for its anti-inflammatory effect. Active-site blockade, γ-carboxyglutamic acid domain truncation and a peptide mimic of the factor Xa inter-epidermal growth factor-like region prevented factor Xa inhibition of lipopolysaccharide-induced tumor necrosis factor-α release. In addition, factor Xa anti-inflammatory activity was markedly attenuated by the presence of an antagonist of protease-activated receptor 2, but not protease-activated receptor 1. The key role of protease-activated receptor 2 in eliciting factor Xa-dependent anti-inflammatory signaling on macrophages was further underscored by the inability of factor Xa to mediate inhibition of tumor necrosis factor-α and interleukin-6 release from murine bone marrow-derived protease-activated receptor 2-deficient macrophages. We also show for the first time that, in addition to protease-activated receptor 2, factor Xa requires a receptor-associated protein-sensitive low-density lipoprotein receptor to inhibit lipopolysaccharide-induced cytokine production. Collectively, the findings of this study support a novel function for factor Xa as an endogenous, receptor-associated protein-sensitive, protease-activated receptor 2-dependent regulator of myeloid cell pro-inflammatory cytokine production.

Methamphetamine-induced nitric oxide promotes vesicular transport in blood-brain barrier endothelial cells.

Methamphetamine's (METH) neurotoxicity is thought to be in part due to its ability to induce blood-brain barrier (BBB) dysfunction. Here, we investigated the effect of METH on barrier properties of cultured rat primary brain microvascular endothelial cells (BMVECs). Transendothelial flux doubled in response to METH, irrespective of the size of tracer used. At the same time, transendothelial electrical resistance was unchanged as was the ultrastructural appearance of inter-endothelial junctions and the distribution of key junction proteins, suggesting that METH promoted vesicular but not junctional transport. Indeed, METH significantly increased uptake of horseradish peroxidase into vesicular structures. METH also enhanced transendothelial migration of lymphocytes indicating that the endothelial barrier against both molecules and cells was compromised. Barrier breakdown was only observed in response to METH at low micromolar concentrations, with enhanced vesicular uptake peaking at 1 µM METH. The BMVEC response to METH also involved rapid activation of endothelial nitric oxide synthase and its inhibition abrogated METH-induced permeability and lymphocyte migration, indicating that nitric oxide was a key mediator of BBB disruption in response to METH. This study underlines the key role of nitric oxide in BBB function and describes a novel mechanism of drug-induced fluid-phase transcytosis at the BBB.