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Childhood adversity is a strong, and concerningly prevalent, risk factor for the later development of substance misuse. Yet despite substantial accumulating evidence for causal mechanisms, there has been little attempt to synthesize the strength of the evidence. Importantly, these mechanisms may be amenable to intervention, providing targets for substance use prevention among those exposed to childhood adversity. The present review aimed to systematically identify mediating and moderating mechanisms operating between childhood adversity and substance use. A systematic review was conducted. Electronic databases (PubMed, MEDLINE, PsycINFO, Web of Science and CINAHL) were searched from 1998 to 2020 for modifiable mediators and moderators of the relationship between childhood adversity and substance use in people aged 10-24. Data was qualitatively synthesised, using a socio-ecological perspective to group mediators/moderators into individual, interpersonal, community, and public policy/cultural levels of behaviour. After screening against eligibility criteria, 50 studies were included in the current review. The mediators at the individual level of behaviour showing the largest and most consistent effect sizes included externalising behaviour, anger, coping motives for substance use, and post-traumatic stress symptoms. Among individual-level moderators, religiosity, future orientation and depressive symptoms all attenuated the relationship between childhood adversity and substance use. At the interpersonal level, peer relationships and mother-child relationships mediated the effect of adversity on substance use. Moderators included family cohesion and relationship quality. Community factors were less commonly studied, though school mobility and educational achievement mediated 14% and 28% of the total effect of childhood adversity on substance use respectively. No mediators or moderators were identified for public policy/culture. A substantial proportion of the relationship between childhood adversity and substance use in youth is mediated through individual, interpersonal and community factors. Coupled with the knowledge that existing, evidence-based programs effectively address many of the identified mediators and moderators, this review advances knowledge on optimal targets to prevent substance misuse among those exposed to childhood adversity.

Background Childhood trauma is a pervasive issue contributing to adverse mental health outcomes. Obtaining optimal sleep supports healthy development and protects against mood-related disorders. Whether sleep serves as a potential buffer between trauma and adverse mental health outcomes holds promise for informing targeted interventions and prevention for adolescents. Methods Data were drawn from the baseline assessment of a randomised controlled trial of a mental health prevention program. A total sample of 752 adolescents completed an online, self-report survey in 2023. Participants were students (M age =13.8 years), attending independent schools in Australia and comprised of 37% girls and 60% boys. Australian sleep guidelines were used to dichotomise nightly sleep duration into whether adolescents met, or did not meet, the sleep guidelines for their age. Mixed-effects linear regression was used to examine whether sleep moderated the association between trauma and symptoms of anxiety, depression, and mental wellbeing. Results The majority of participants (82%) reported exposure to at least one traumatic event. The mean number of traumatic events was 1.8. Trauma was independently associated with higher depressive and anxiety symptoms and lower mental wellbeing scores. Those reporting exposure to one or more traumatic events were more likely to report difficulties falling asleep and less likely to report meeting nightly sleep duration guidelines. We found a significant interaction between meeting nightly sleep duration guidelines and any trauma exposure on depressive and anxiety scores, such that depression and anxiety symptoms were lower in trauma-exposed adolescents who met sleep duration guidelines compared to those who did not meet sleep guidelines. Conclusions Obtaining optimal amounts of sleep each night may help mitigate anxiety and depressive symptoms for non-clinical adolescents exposed to trauma, however, longitudinal research is needed to confirm the directionality of the relationships between trauma, sleep, and mental health symptoms. Future research should examine the effectiveness of public health interventions targeting sleep behaviours in adolescents to promote mental wellbeing.

Background There is a paucity of translational research programmes to improve implementation of evidence-based care in drug and alcohol settings. This systematic review aimed to provide a synthesis and evaluation of the effectiveness of implementation programmes of treatment for patients with drug and alcohol problems using the Consolidated Framework for Implementation Research (CFIR). Methods A comprehensive systematic review was conducted using five online databases (from inception onwards). Eligible studies included clinical trials and observational studies evaluating strategies used to implement evidence-based psychosocial treatments for alcohol and substance use disorders. Extracted data were qualitatively synthesised for common themes according to the CFIR. Primary outcomes included the implementation, service system or clinical practice. Risk of bias of individual studies was appraised using appropriate tools. A protocol was registered with (PROSPERO) (CRD42019123812) and published previously (Louie et al. Systematic 9:2020). Results Of the 2965 references identified, twenty studies were included in this review. Implementation research has employed a wide range of strategies to train clinicians in a few key evidence-based approaches to treatment. Implementation strategies were informed by a range of theories, with only two studies using an implementation framework (Baer et al. J Substance Abuse Treatment 37:191-202, 2009) used Context-Tailored Training and Helseth et al. J Substance Abuse Treatment 95:26-34, 2018) used the CFIR). Thirty of the 36 subdomains of the CFIR were evaluated by included studies, but the majority were concerned with the Characteristics of Individuals domain (75%), with less than half measuring Intervention Characteristics (45%) and Inner Setting constructs (25%), and only one study measuring the Outer Setting and Process domains. The most common primary outcome was the effectiveness of implementation strategies on treatment fidelity. Although several studies found clinician characteristics influenced the implementation outcome (40%) and many obtained clinical outcomes (40%), only five studies measured service system outcomes and only four studies evaluated the implementation. Conclusions While research has begun to accumulate in domains such as Characteristics of Individuals and Intervention Characteristics (e.g. education, beliefs and attitudes and organisational openness to new techniques), this review has identified significant gaps in the remaining CFIR domains including organisational factors, external forces and factors related to the process of the implementation itself. Findings of the review highlight important areas for future research and the utility of applying comprehensive implementation frameworks.

Posttraumatic stress disorder (PTSD) and substance use disorders (SUD) frequently co-occur in youth. Integrated, trauma-focused treatments are recommended, but evidence in youth is limited and the dynamics of symptom change are poorly understood. We investigated within-treatment changes in PTSD and substance use, and their temporal sequencing, in a randomised controlled trial (RCT) comparing integrated treatment with supportive counselling among youth aged 13-25 years. Participants (  = 55) were randomised to an integrated, exposure-based treatment, Concurrent Treatment of PTSD and SUD Using Prolonged Exposure - Adolescent version (COPE-A); or supportive counselling, Person-Centred Therapy (PCT). PTSD and substance use symptoms were assessed at each session. Generalised estimating equations were used to analyse symptom change over time, and Spearman's correlations were used to examine associations between early (sessions 1-5) and later (sessions 5-11) change. COPE-A showed significantly greater reductions in total PTSD symptom severity during treatment (  = -17.00, 95% CI -29.50 to -4.46); with no between-group differences in substance use quantity or frequency. PTSD symptom clusters improved concurrently, but no temporal relationships were observed. Temporal relationships for substance use change were limited, and changes in PTSD symptoms were not associated with concurrent or subsequent changes in substance use. Integrated, trauma-focused treatment reduced PTSD symptoms, reinforcing the safety and tolerability of exposure-based therapy in this youth sample with comorbid PTSD-SUD. PTSD improvement was not associated with either concurrent or subsequent reductions in substance use. Understanding temporal patterns of change may help refine models of PTSD-SUD comorbidity and optimise intervention delivery.

We have yet to understand fully how conditions during different periods of development interact to influence life-history structure. Can the negative effects of poor juvenile nutrition be overcome by a good adult diet, or are life-history strategies set by early experience? Here, we tested the influence and interaction of different nutritional quality during juvenile and sexual development on female resource allocation physiology, life history and courtship behaviour in the cockroach, Nauphoeta cinerea. Nymphs were raised on either a good-quality or poor-quality diet. After adult eclosion, females were either switched to the opposite diet or remained on their original diet. We assessed mating behaviour and lifetime reproductive success for half of the females from each treatment. We evaluated reproductive investment, somatic investment and resource reallocation from reproduction to the soma via oocyte apoptosis in the remaining females. We found that poor juvenile conditions resulted in a fat phenotype with slow juvenile growth and short reproductive lifespan that could not be retrieved with a change in diet. Good juvenile conditions resulted in the converse, but again fixed, phenotype in adulthood. Thus, juvenile nutrition sets adult patterns of resource allocation.

The COVID-19 pandemic has resulted in significant and unprecedented mental health impacts in Australia. However, there is a paucity of research directly asking Australian community members about their mental health experiences, and what they perceive to be the most important mental health issues in the context of the pandemic. This study utilises qualitative data from Alone Together , a longitudinal mixed-methods study investigating the effects of COVID-19 on mental health in an Australian community sample (N = 2,056). A total of 1,037 participants, ranging in sex (69.9% female), age (M = 40–49 years), state/territory of residence, and socioeconomic status, shared responses to two open-ended questions in the first follow up survey regarding their mental health experiences and priorities during COVID-19. Responses were analysed using thematic analysis. Participants described COVID-19 as primarily impacting their mental health through the disruption it posed to their social world and financial stability. A key concern for participants who reported having poor mental health was the existence of multiple competing barriers to accessing high quality mental health care. According to participant responses, the pandemic placed additional pressures on an already over-burdened mental health service system, leaving many without timely, appropriate support. Absent or stigmatising rhetoric around mental health, at both a political and community level, also prevented participants from seeking help. Insights gained from the present research provide opportunities for policymakers and health practitioners to draw on the expertise of Australians’ lived experience and address priority issues through targeted policy planning. This could ultimately support a more responsive, integrated, and effective mental health system, during and beyond the COVID-19 pandemic.

Addressing aggressive behavior in adolescence is a key step toward preventing violence and associated social and economic costs in adulthood. This study examined the secondary effects of the personality-targeted substance use preventive program on aggressive behavior from ages 13 to 20. In total, 339 young people from nine independent schools ( age = 13.03 years, s.d. = 0.47, range = 12-15) who rated highly on one of the four personality traits associated with increased substance use and other emotional/behavioral symptoms (i.e. impulsivity, anxiety sensitivity, sensation seeking, and negative thinking) were included in the analyses ( = 145 in Preventure, = 194 in control). Self-report assessments were administered at baseline and follow-up (6 months, 1, 2, 3, 5.5, and 7 years). Overall aggression and subtypes of aggressive behaviors (proactive, reactive) were examined using multilevel mixed-effects analysis accounting for school-level clustering. Across the 7-year follow-up period, the average yearly reduction in the frequency of aggressive behaviors ( = -0.42; 95% confidence interval [CI] -0.64 to -0.20; < 0.001), reactive aggression ( = -0.22; 95% CI 0.35 to -0.10; = 0.001), and proactive aggression ( = -0.14; 95% CI -0.23 to -0.05; = 0.002) was greater for the Preventure group compared to the control group. The study suggests a brief personality-targeted intervention may have long-term impacts on aggression among young people; however, this interpretation is limited by imbalance of sex ratios between study groups.

Though significant research highlights higher rates of mental ill-health and substance use among trans, non-binary and gender diverse (henceforth ‘trans’) young people, little research has considered patterns, contextual characteristics, and correlates of co-occurring experiences of mental ill-health and substance use among trans young people. Using data from the Trans Pathways study, we used prevalence ratios and age- and gender-adjusted logistic regression models to examine prevalence and differences of co-occurring substance use (past six-month cigarette use, alcohol use, and other drug use) and contextual characteristics of substance use (past six-month solitary alcohol and/or drug use, substance use for coping) by mental ill-health (depression disorder, anxiety disorder, past 12-month self-harm thoughts and behaviours, suicidal thoughts, planning, and attempt/s). Age- and gender-adjusted models assessed associations between co-occurring depressive and anxiety disorders and recent cigarette, alcohol, and other drug use (six co-occurring items total) and 18 interpersonal stressors. Significantly increased odds of smoking or recent use of cannabis or sedatives was observed among trans young people reporting depressive disorder, anxiety disorder (aORs ranging 1.8–3.1). Trans young people who reported recent smoking or use of cannabis, inhalants, or sedatives, had 40% to 80% reduced odds of past 12-month self-harm thoughts, self-harm behaviours, suicidal thoughts, and suicide attempt/s (aORs ranging 0.2–0.6). On the other hand, solitary alcohol and/or other drug use and substance use for coping was significantly associated with increased odds of all mental ill-health outcomes. Issues with school, secure housing, and intimate partner abuse were the most robust correlates of co-occurring mental ill-health and substance use. Trans young people using substances, especially cigarettes, cannabis, and sedatives, often so do with co-occurring experiences of depression and anxiety though limited substance use in more ‘social’ contexts may confer benefits for preventing self-harm and suicide thoughts and behaviours. Continued research in partnership with trans young people is warranted to conceptualise more nuanced and precise conceptual parameters of trans-affirming substance use harm reduction approaches.

Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS - or BRAF -mutant colorectal cancer. Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS , RAF , and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders characterized by mitochondrial dysfunction and chronic inflammation. The transcription factor NF-κB1 is implicated in both neuroprotective and pro-inflammatory processes, with its activity varying between neurons and glial cells. While previous studies have explored the genetic and epigenetic contributions to these diseases, the infection hypothesis has re-emerged as a potential framework for identifying novel biomarkers and therapeutic targets. We conducted bulk RNA sequencing on human postmortem caudate nucleus tissue samples obtained from cognitively normal controls ( = 5), AD patients ( = 6), and PD patients ( = 3). Differential gene expression analysis and pathway enrichment were performed to identify dysregulated signaling mechanisms relevant to neuroinflammation and mitochondrial function. TNFα signaling through the NF-κB pathway was identified as a prominently dysregulated mechanism in both AD and PD samples. Transcript levels of NFE2L2 (NRF2) and NF-κB1 were elevated, coinciding with reduced expression of the mitochondrial transporter gene SLC25A6, suggesting a compensatory response to oxidative stress. Additionally, PLCG2 expression was markedly increased in microglial populations, reflecting heightened immune activation. A significant 10-fold reduction in hemoglobin subunit alpha (HbA1) RNA was observed in disease groups compared to controls, indicating compromised oxygen transport and cellular stress. These findings highlight candidate biomarkers and suggest that therapeutic strategies targeting mitochondrial integrity and neuroinflammation may be effective in AD and PD.