BE-WEL trial (breast: evaluation of weight and exercise for lymphoedema) testing weight control and exercise programmes for women with breast cancer related lymphoedema: a feasibility trial.

PURPOSE: A combined body weight loss and upper body/arm exercise programme is a potential strategy for managing Breast cancer related lymphoedema (BCRL), but there is limited data on the best method for delivery or its potential efficacy. METHODS: Fifty-seven women with overweight/obesity and BCRL were randomised to a 12 week supervised (n = 12) or home-based combined weight loss and upper body/arm exercise programme (n = 16), a home-based upper-body arm exercise only programme (n = 17) or standard care (n = 12). Primary outcomes were uptake, retention and changes in weight and change in Relative Arm Volume Increase (RAVI) using analysis of covariance (ANCOVA). RESULTS: Sixteen percent of women invited joined the study and 49 completed the trial (85% retention). Reductions in weight occurred in the supervised and home-based weight control and exercise programmes; Mean (95% CI) change compared to standard care - 1.68 (- 4.36 to - 1.00), - 2.47(- 4.99 to - 0.04) Kg. Reductions in perometer assessed RAVI were seen in the supervised and home-based combined weight control and arm exercise groups and the weight stable home-based arm exercise only group: mean (95% CI) change compared to standard care - 2.4 (- 5.0 to + 0.4),- 1.8 (- 4.3 to + 0.7), - 2.5(- 4.9 to - 0.05)%. CONCLUSION: Women with BCRL and overweight and obesity engaged in diet and exercise weight loss programmes. Both weight loss/arm exercise programmes led to modest changes in weight and BCRL. Comparable reductions in BCRL were reported in the weight stable group undertaking arm exercise only. The independent and combined effects of weight loss and exercise on BCRL need further study. TRIAL REGISTRATION: ISRCTN86789850 https://doi.org/10.1186/ISRCTN86789850 , registered 2011.

The long-term effectiveness of a personality-targeted substance use prevention program on aggression from adolescence to early adulthood.

BACKGROUND: 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 Preventure on aggressive behavior from ages 13 to 20. METHODS: In total, 339 young people from nine independent schools (M 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 (n = 145 in Preventure, n = 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. RESULTS: Across the 7-year follow-up period, the average yearly reduction in the frequency of aggressive behaviors (b = -0.42; 95% confidence interval [CI] -0.64 to -0.20; p < 0.001), reactive aggression (b = -0.22; 95% CI 0.35 to -0.10; p = 0.001), and proactive aggression (b = -0.14; 95% CI -0.23 to -0.05; p = 0.002) was greater for the Preventure group compared to the control group. CONCLUSIONS: 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.

It's time for change: inequities and determinants of health-related quality of life among gender and sexually diverse young people in Australia.

PURPOSE: This study was guided by three research aims: firstly, to examine the longitudinal trends of health-related quality of life (HR-QoL) among gender and sexuality diverse (LGBTQA2S+) young people through adolescence (ages 14-19); secondly, to assess longitudinal associations between poor mental health and HR-QoL among LGBTQA2S+ young people through adolescence; and thirdly, to examine differences in HR-QoL among LGBTQA2S+ young people during early adolescence (ages 14 and 15) depending on select school-, peer-, and parent-level factors. METHODS: This study used three of nine available waves of data from a large population-level, probability sample-based, longitudinal cohort study, namely the K' cohort: children aged 4-5 years old at time of study enrolment followed-up biennially (~ 61% retention rate). HR-QoL weighted means and standard deviations were calculated using Child Health Utility 9D (CHU-9D) scores for LGBTQA2S+ participants at ages 14 and 15 (Wave 6), ages 16 and 17 (Wave 7), and ages 18 and 19 (Wave 8). To strategically identify policy-relevant modifiable behavioural factors suitable for prevention and early intervention, non-parametric Wilcoxon signed-rank tests tested differences in mean CHU-9D ranks at ages 14 and 15 (Wave 6) between groups (gender identity: trans vs. cis; identity-level sexuality: gay, lesbian, bisexual, or other diverse sexuality vs. heterosexual; group-level sexuality: sexually diverse vs. not sexually diverse) and selected school factors (school acceptance, belonging, freedom of expression), peer factors (peer relationship quality, trust, respect), and family factors (parental acceptance, understanding, trust), with Hedge's g correction statistics computed for effect sizes. Longitudinal associations between gender, sexuality, and poor mental health (depressive symptoms, anxiety, symptoms, self-harm thoughts/behaviour, and suicidal thoughts/behaviour) and HR-QoL were tested using mixed-effects models with random intercepts and random slopes for nested clustering (participants within postcodes). RESULTS: HR-QoL disparities disproportionately affecting LGBTQA2S+ groups relative to their cisgender, heterosexual peers, were well-established by age 14 to 15 relatively steeper reductions in HR-QoL were observed throughout adolescence among all LGBTQA2S+ groups, with HR-QoL widening the most for trans participants. Poor mental health was significantly associated with HR-QoL declines. LGBTQA2S+ participants with positive school- and parent factors related to feelings of acceptance, belonging, and freedom of self-expression, reported significantly higher HR-QoL during early adolescence. CONCLUSION: Evidence-based public health policy responses are required to address the dire HR-QoL inequities among LGBTQA2S+ young people, particularly trans young people. Prioritising the promotion of school- and family-based interventions which foster LGBTQA2S+ inclusivity, acceptance, and a sense of belonging from early adolescence through young adulthood, represents a feasible, evidence-based, and cost-effective response to address these HR-QoL disparities.

Mental ill-health and substance use among sexuality diverse adolescents: The critical role of school climate and teacher self-efficacy.

INTRODUCTION: Mental ill-health, substance use and their co-occurrence among sexuality diverse young people during earlier adolescence is relatively understudied. The preventive utility of positive school climate for sexuality diverse adolescents' mental health is also unclear, as well as the role of teachers in conferring this benefit. METHOD: Using Wave 8 'B Cohort' data from the Longitudinal Study of Australian children (N = 3127, Mage = 14.3), prevalence ratios and odds ratios were used to assess prevalence and disparities in mental ill-health and substance use, and multinomial logistic regression for co-occurring outcomes, among sexuality diverse adolescents relative to heterosexual peers. Logistic regression was used to assess associations between school climate and teacher self-efficacy with sexuality diverse adolescents' mental health. RESULTS: Mental ill-health prevalence ranged from 22% (suicidal thoughts/behaviour) to 46% (probable depressive disorders) and substance use between 66% (cigarette use) and 97% (alcohol use). Sexuality diverse participants were significantly more likely to report self-harm and high levels of emotional symptoms in co-occurrence with cigarette, alcohol and/or cannabis use. For each 1-point increase in school climate scores as measured by the Psychological Sense of School Membership scale, there was 10% reduction in sexuality diverse adolescents reporting high levels of emotional symptoms, probable depressive disorder, self-harm thoughts/behaviour and suicidal thoughts/behaviour. For each 1-point increase in lower perceived (worse) teacher self-efficacy scores as measured by four bespoke teacher self-efficacy items, odds of sexuality diverse adolescent-reported suicidal thoughts/behaviour increased by 80%. DISCUSSION: Mental ill-health, substance use and especially their co-occurrence, are highly prevalent and pose significant and inequitable health and well-being risks. Schools represent a potential site for focusing future prevention efforts and educating and training teachers on sexuality diversity is a promising pathway towards optimising these.

What set some young adults apart during the COVID-19 pandemic? Mental health trajectories, risk and protective factors in an Australian longitudinal study.

OBJECTIVE: Evidence suggests that young adults (aged 18-34) were disproportionately impacted by the COVID-19 pandemic, but little is known about their longer-term mental health changes beyond the early pandemic period. This article investigates heterogeneous trajectories of mental health among Australian young adults across 2 years of the pandemic and identifies a broad range of associated risk and protective factors. METHOD: Young adults (N = 653, Mage = 27.8 years) from the longitudinal Alone Together Study were surveyed biannually between July 2020 and June 2022. Measures assessed anxiety (7-item Generalised Anxiety Disorder scale) and depression (9-item Patient Health Questionnaire) symptoms at Waves 1-4, as well as demographic, psychological, adversity and COVID-19 factors at baseline. RESULTS: Four and three distinct trajectories of anxiety and depressive symptoms, respectively, were identified through growth mixture modelling. The proportion of participants in each anxiety trajectory were Asymptomatic (45.9%), Mild Stable (17.9%), Moderate-Severe Stable (31.1%) and Initially Severe/Recovering (5.1%). For depression, Mild Stable (58.3%), Moderate-Severe Stable (30.5%) and Reactive/Recovering (11.2%). Baseline factors associated with severe symptom trajectories included a lifetime mental health disorder, pre-pandemic stressful events, identifying as LGBTQIA+ and/or female, and experiencing one or more infection-control measures. Higher household income was protective. CONCLUSION: Most young adults demonstrated stable trajectories of low or high symptoms during the pandemic, with smaller groups showing initially severe or reactive symptoms followed by marked improvements over time. Vulnerable subgroups (gender- or sexuality-diverse, those with prior adversity or pre-existing mental ill-health) may face ongoing impacts and require targeted psychosocial supports to assist their mental health recovery post-COVID-19 and in the event of future crises.

Minority stressors, traumatic events, and associations with mental health and school climate among gender and sexuality diverse young people in Australia: Findings from a nationally representative cohort study.

INTRODUCTION: Population-level, nationally representative data on the prevalence of minority stressors and traumatic events, mental ill-health effects, and the preventative utility of school climate, among gender and sexuality diverse young people in Australia, is significantly lacking. In this study, we estimated the prevalence and distribution of minority stressors and traumatic events among young people by sexuality identity (gay/lesbian, bisexual, other sexuality, heterosexual), sexuality diversity (sexuality diverse, not sexuality diverse), and gender identity (transgender, cisgender) and assessed associations with mental ill-health and the moderating role of school climate factors. METHODS: Using Wave 8 (2018) follow-up data from a population-level, nationally representative longitudinal cohort study, the sample comprised 3037 young people aged 17-19 years in Australia. Prevalence ratios for minority stressors and traumatic events were calculated for gender and sexuality diverse categories using logistic regression models. Linear regression models were used to test associations between traumatic events and minority stressors, and mental ill-health. Multivariate linear regression tested school climate factors as effect modifier between minority stressors and mental ill-health among sexuality diverse young people. RESULTS: Rates of traumatic events and minority stressors were highest among bisexual and gay/lesbian young people and were significantly associated with mental ill-health among all gender and sexuality diverse young people. Highest mental ill-health effects were observed among trans young people. Among sexuality diverse young people, positive and negative feelings toward school climate were associated with decreased and increased mental ill-health, respectively. After accounting for sexuality diversity, positive overall school climate appeared protective of mental ill-health effects of sexuality-based discrimination. DISCUSSION: Minority stressors, traumatic events, and associated mental ill-health are prevalent among gender and sexuality diverse young people in Australia, especially trans, bisexual, and gay/lesbian young people. Promotion of affirmative, safe, and inclusive school climate demonstrates significant promise for the prevention and early intervention of mental ill-health among gender and sexuality diverse young people.

Randomised controlled trial of breast cancer and multiple disease prevention weight loss programmes vs written advice amongst women attending a breast cancer family history clinic.

BACKGROUND: Overweight and obesity are common amongst women attending breast cancer Family History, Risk and Prevention Clinics (FHRPCs). Overweight increases risk of breast cancer (BC) and conditions including1 cardiovascular disease (CVD) and type-2 diabetes (T2D). Clinics provide written health behaviour advice with is likely to have minimal effects. We assessed efficacy of two remotely delivered weight loss programmes vs. written advice. METHOD: 210 women with overweight or obesity attending three UK FHRPCs were randomised to either a BC prevention programme (BCPP) framed to reduce risk of BC (n = 86), a multiple disease prevention programme (MDPP) framed to reduce risk of BC, CVD and T2D (n = 87), or written advice (n = 37). Change in weight and health behaviours were assessed at 12-months. RESULTS: Weight loss at 12 months was -6.3% (-8.2, -4.5) in BCPP, -6.0% (-7.9, -4.2) in MDPP and -3.3% (-6.2, -0.5) in the written group (p = 0.451 across groups). The percentage losing ≥10% weight in these groups were respectively 34%, 23% and 14% (p = 0.038 across groups). DISCUSSION: BCPP and MDPP programmes resulted in more women achieving ≥10% weight loss, but no evidence of additional benefits of MDPP. A multicentre RCT to test the BCPP across UK FHRPCs is warranted. Clinical Trial Registration ISRCTN16431108.

Wire- and magnetic-seed-guided localization of impalpable breast lesions: iBRA-NET localisation study.

BACKGROUND: Wire localization is historically the most common method for guiding excision of non-palpable breast lesions, but there are limitations to the technique. Newer technologies such as magnetic seeds may allow some of these challenges to be overcome. The aim was to compare safety and effectiveness of wire and magnetic seed localization techniques. METHODS: Women undergoing standard wire or magnetic seed localization for non-palpable lesions between August 2018 and August 2020 were recruited prospectively to this IDEAL stage 2a/2b platform cohort study. The primary outcome was effectiveness defined as accurate localization and removal of the index lesion. Secondary endpoints included safety, specimen weight and reoperation rate for positive margins. RESULTS: Data were accrued from 2300 patients in 35 units; 2116 having unifocal, unilateral breast lesion localization. Identification of the index lesion in magnetic-seed-guided (946 patients) and wire-guided excisions (1170 patients) was 99.8 versus 99.1 per cent (P = 0.048). There was no difference in overall complication rate. For a subset of patients having a single lumpectomy only for lesions less than 50 mm (1746 patients), there was no difference in median closest margin (2 mm versus 2 mm, P = 0.342), re-excision rate (12 versus 13 per cent, P = 0.574) and specimen weight in relation to lesion size (0.15 g/mm2versus 0.138 g/mm2, P = 0.453). CONCLUSION: Magnetic seed localization demonstrated similar safety and effectiveness to those of wire localization. This study has established a robust platform for the comparative evaluation of new localization devices.

Selective personality-targeted prevention of suicidal ideation in young adolescents: post hoc analysis of data collected in a cluster randomised controlled trial.

OBJECTIVE: To assess the efficacy of a selective, personality-targeted intervention for reducing suicidal ideation in adolescents. DESIGN: Post hoc analysis of survey data collected in the Climate and Preventure (CAP) study, a cluster randomised controlled trial that compared strategies for reducing alcohol misuse by adolescents, 2012-2015. SETTING, PARTICIPANTS: Year 8 students at 16 New South Wales non-government schools and one Victorian non-government school. INTERVENTION: Preventure, a selective, personality-targeted intervention designed to help adolescents with personality risk factors for alcohol misuse, comprising two 90-minute sessions, one week apart. For our post hoc analysis, we combined data from the two CAP trial groups in which Preventure was offered (the Preventure and the Preventure/Climate Schools [a non-selective prevention strategy] groups) as the intervention group; and data from the two groups in which Preventure was not offered (usual health education only [control] and Climate Schools groups) as the control group. MAIN OUTCOME MEASURE: Difference between post hoc control and intervention groups in the change in proportions of students reporting suicidal ideation during the preceding six months (single item of Brief Symptom Inventory depression subscale) over three years. RESULTS: A total of 1636 students (mean age at baseline, 13.3 years; standard deviation, 0.5 years) were included in our analysis, of whom 1087 (66%) completed the suicidal ideation item in the three-year follow-up assessment. The post hoc control group included 755 students (nine schools), the intervention group 881 students (eight schools). After adjusting for nesting of students in schools and sex, reporting of suicidal ideation by students who had received Preventure had declined over three years, compared with the control group (per year: adjusted odds ratio, 0.80; 95% CI, 0.66-0.97). CONCLUSION: Personality-targeted selective prevention during early secondary school can have a lasting impact on suicidal ideation during adolescence. TRIAL REGISTRATION (CAP STUDY ONLY): Australian and New Zealand Clinical Trials Registry, ACTRN12612000026820 (prospective).

Associations of childhood emotional and physical neglect with mental health and substance use in young adults.

BACKGROUND: Childhood neglect is a risk factor for subsequent mental health problems. However, research on the unique contribution of emotional and physical subtypes of neglect is lacking. Importantly, if emotional and physical neglect have different impacts on mental health, they must be examined separately to understand how to prevent and treat their effects. OBJECTIVE: This study aimed to examine associations of emotional and physical neglect with depression, anxiety, stress, alcohol and drug use in 18- to 20-year-olds. METHODS: Participants (N = 569, mean age = 18.9, 70% female) responded in an online survey to questions on childhood emotional and physical neglect, childhood abuse, symptoms of depression, anxiety and stress, and alcohol and drug use and problems. Procedures were approved by the University of Sydney Human Ethics Committee. Hierarchical linear regressions were performed, controlling for socio-demographic characteristics and other adverse childhood experiences. RESULTS: Combined neglect was associated with depression (B = 2.895, p < 0.001), anxiety (B = 1.572, p = 0.003) and stress (B = 1.781, p = 0.001). However, a second model entering emotional and physical neglect as separate exposures revealed emotional neglect was driving this association with depression (B = 2.884, p < 0.001), anxiety (B = 1.627, p = 0.001) and stress (B = 1.776, p = 0.001), and that physical neglect was not associated with any outcome. Neither emotional nor physical neglect were associated with alcohol or drug use. CONCLUSION: Emotional neglect is a risk factor for mental health problems in early adulthood. Research that combines emotional and physical neglect into a single exposure may be obscuring relationships with mental health. Mental health prevention and treatment must screen for, and address, emotional neglect.

Is Adolescent Alcohol Use Linked to Spikes in Aggressive Behaviour? A Growth Curve Analysis.

A relationship between alcohol use and aggression is well-established; however, less is known about how these factors develop and influence each other over time. This study examined the immediate and delayed effects of alcohol use on aggression during adolescence. Alcohol use and aggression were measured in a subset of students (n = 1560) from the Climate and Preventure study, Australia. Participants completed self-report surveys across five assessments (ages 13, 13.5, 14, 15 and 16). In a two-stage analysis, parallel and auto-regressive latent growth curve models were applied to investigate person-specific trajectories (or between-person effects) of alcohol use and aggression and identify the time-varying impact (or within-person effects) of alcohol use on aggression. Average alcohol consumption increased between ages 13 and 16, while average aggression levels decreased over time. Overall growth in alcohol use was positively related to heightened aggression at age 16, and vice versa. Spikes (time-varying increases) in alcohol use were linked to corresponding increases in aggression at each time point. There was evidence of a prospective effect where aggression was associated with hazardous alcohol use a year later, but no evidence that alcohol use was associated with subsequent aggression. Change in hazardous alcohol consumption and aggression beginning early in adolescence are interrelated and are predictive of one another at age 16. The time-varying effects of alcohol on aggression appear to be immediate rather than delayed; however, there is evidence for a prospective relationship where aggression influences later alcohol use. Implications for the timing and nature of novel harm reduction intervention approaches for young people are discussed.

Evaluating the differential effectiveness of social influence and personality-targeted alcohol prevention on mental health outcomes among high-risk youth: A novel cluster randomised controlled factorial design trial.

OBJECTIVE: This study examined the secondary mental health outcomes of two contrasting alcohol prevention approaches, whereby one intervention targets common underlying personality risk for alcohol use and mental health problems (Preventure) and the other targets alcohol- and drug-related behaviours and cognitions (Climate Schools). METHODS: A 2 × 2 cluster randomised controlled factorial design trial was conducted in 26 Australian schools randomised to the following 4 conditions: Climate Schools (n = 6), Preventure (n = 7), combined Climate Schools and Preventure (CAP; n = 6) or treatment as usual (TAU; n = 7). Participants completed questionnaires at baseline, 6, 12, 24 and 36 months post-baseline including the Brief Symptom Inventory anxiety and depression scales and hyperactivity and conduct scales of the Strengths and Difficulties Questionnaire. Analyses focused on students who were at high-risk based on personality traits (n = 947; Mage = 13.3). The effectiveness of each approach in reducing symptoms of internalising and externalising problems was assessed using multi-level mixed effects analysis. RESULTS: Main effects for each intervention relative to not receiving that intervention revealed significant main effects of Preventure in reducing anxiety symptoms (d = -0.27, 95% confidence interval [CI] = [-0.53, -0.01], p < 0.05) and a marginal effect in reducing depressive symptoms (d = -0.24, 95% CI = [-0.49, 0.01], p = 0.06) over 3 years. Interaction effects revealed that when delivered alone, Preventure significantly reduced conduct problems (d = -0.45, 95% CI = [-0.78, -0.11], p < 0.05) and hyperactivity symptoms (d = -0.38, 95% CI = [-0.70,-0.07], p < 0.05) compared to TAU. CONCLUSION: This study is the first to report the effectiveness of personality-targeted alcohol prevention in reducing internalising and externalising symptoms relative to an active control, providing evidence in favour of its specificity in preventing concurrent substance use and mental health problems among high-risk youth.

Pathways to prevention: protocol for the CAP (Climate and Preventure) study to evaluate the long-term effectiveness of school-based universal, selective and combined alcohol misuse prevention into early adulthood.

BACKGROUND: Alcohol use and associated harms are among the leading causes of burden of disease among young people, highlighting the need for effective prevention. The Climate and Preventure (CAP) study was the first trial of a combined universal and selective school-based approach to preventing alcohol misuse among adolescents. Initial results indicate that universal, selective and combined prevention were all effective in delaying the uptake of alcohol use and binge drinking for up to 3 years following the interventions. However, little is known about the sustainability of prevention effects across the transition to early adulthood, a period of increased exposure to alcohol and other drug use. This paper describes the protocol for the CAP long-term follow-up study which will determine the effectiveness of universal, selective and combined alcohol misuse prevention up to 7 years post intervention, and across the transition from adolescence into early adulthood. METHODS: A cluster randomized controlled trial was conducted between 2012 and 2015 with 2190 students (mean age: 13.3 yrs) from 26 Australian high schools. Participants were randomized to receive one of four conditions; universal prevention for all students (Climate); selective prevention for high-risk students (Preventure); combined universal and selective prevention (Climate and Preventure; CAP); or health education as usual (Control). The positive effect of the interventions on alcohol use at 12-, 24- and 36-month post baseline have previously been reported. This study will follow up the CAP study cohort approximately 5- and 7-years post baseline. The primary outcome will be alcohol use and related harms. Secondary outcomes will be cannabis use, alcohol and other drug harms including violent behavior, and mental health symptomatology. Analyses will be conducted using multi-level, mixed effects models within an intention-to-treat framework. DISCUSSION: This study will provide the first ever evaluation of the long-term effectiveness of combining universal and selective approaches to alcohol prevention and will examine the durability of intervention effects into the longer-term, over a 7-year period from adolescence to early adulthood. TRIAL REGISTRATION: This trial was registered in the Australian New Zealand Clinical Trials Registry ( ACTRN12612000026820 ) on January 6th 2012.

A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor.

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.

An exploration of paediatric nurses' views of caring for infants who have suffered nonaccidental injury.

AIMS AND OBJECTIVES: To explore paediatric nurses' views of caring for infants who have suffered nonaccidental injury. BACKGROUND: Children less than two years of age are at greater risk of serious abuse than those in any other age group. An infant's physical and mental immaturity makes them especially vulnerable. Abuse in this age group is often caused by a parent who does not report the abuse. The experience of caring for abused children is recognised as being both personally and professionally challenging. However, despite the increased risk of serious or fatal injury, caring for these infants who have suffered abuse is relatively unexplored. DESIGN: A qualitative research design using purposive sampling was adopted. The setting for this research was a paediatric unit in Ireland. METHOD: Semi-structured interviews were conducted with 10 paediatric nurses and data were analysed using the framework approach. RESULTS: Paediatric nurses' views of caring for infants who have suffered a nonaccidental injury were established under four main themes: (1) 'Personal impact', (2) 'Professional roles', (3) 'Nurse-client relationship' and (4) 'Resources'. CONCLUSION: Findings highlighted that the experience for the nurse is complex. Personal emotions are evoked and the experience influenced reflection on their own lives. Communication with the parents of the infant is often difficult. Professional relationships were sometimes hindered by poor sharing of information. However, nurses strived to maintain their professionalism and to provide nursing care for the infant and their parents that was holistic. Paediatric nurses relied heavily on each other for support and their nursing experience was a valuable resource for managing nonaccidental injuries. RELEVANCE TO CLINICAL PRACTICE: The general consensus was that a nurse could never fully be prepared to care for an infant who had suffered a nonaccidental injury. However, recommendations for future practice and education are identified and include frequent and practical education sessions.

The long-term effectiveness of a selective, personality-targeted prevention program in reducing alcohol use and related harms: a cluster randomized controlled trial.

BACKGROUND: This study investigated the long-term effectiveness of Preventure, a selective personality-targeted prevention program, in reducing the uptake of alcohol, harmful use of alcohol, and alcohol-related harms over a 3-year period. METHODS: A cluster randomized controlled trial was conducted to assess the effectiveness of Preventure. Schools were block randomized to one of two groups: the Preventure group (n = 7 schools) and the Control group (n = 7 schools). Only students screening as high-risk on one of four personality profiles (anxiety sensitivity, negative thinking, impulsivity, and sensation seeking) were included in the analysis. All students were assessed at five time points over a 3-year period: baseline; immediately after the intervention; and 12, 24, and 36 months after baseline. Students were assessed on frequency of drinking, binge drinking, and alcohol-related harms. Two-part latent growth models were used to analyze intervention effects, which included all students with data available at each time point. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000026820; www.anzctr.org.au). RESULTS: A total of 438 high-risk adolescents (mean age, 13.4 years; SD = 0.47) from 14 Australian schools were recruited to the study and completed baseline assessments. Relative to high-risk Control students, high-risk Preventure students displayed significantly reduced growth in their likelihood to consume alcohol [b = -0.225 (0.061); p < .001], to binge drink [b = -0.305 (.096); p = 0.001], and to experience alcohol-related harms [b = -0.255 (0.096); p = .008] over 36 months. CONCLUSIONS: Findings from this study support the use of selective personality-targeted preventive interventions in reducing the uptake of alcohol, alcohol misuse, and related harms over the long term. This trial is the first to demonstrate the effects of a selective alcohol prevention program over a 3-year period and the first to demonstrate the effects of a selective preventive intervention in Australia.

A cross-validation trial of an Internet-based prevention program for alcohol and cannabis: Preliminary results from a cluster randomised controlled trial.

OBJECTIVE: Replication is an important step in evaluating evidence-based preventive interventions and is crucial for establishing the generalizability and wider impact of a program. Despite this, few replications have occurred in the prevention science field. This study aims to fill this gap by conducting a cross-validation trial of the Climate Schools: Alcohol and Cannabis course, an Internet-based prevention program, among a new cohort of Australian students. METHOD: A cluster randomized controlled trial was conducted among 1103 students (Mage: 13.25 years) from 13 schools in Australia in 2012. Six schools received the Climate Schools course and 7 schools were randomized to a control group (health education as usual). All students completed a self-report survey at baseline and immediately post-intervention. Mixed-effects regressions were conducted for all outcome variables. Outcomes assessed included alcohol and cannabis use, knowledge and intentions to use these substances. RESULTS: Compared to the control group, immediately post-intervention the intervention group reported significantly greater alcohol (d = 0.67) and cannabis knowledge (d = 0.72), were less likely to have consumed any alcohol (even a sip or taste) in the past 6 months (odds ratio = 0.69) and were less likely to intend on using alcohol in the future (odds ratio = 0.62). However, there were no effects for binge drinking, cannabis use or intentions to use cannabis. CONCLUSION: These preliminary results provide some support for the Internet-based Climate Schools: Alcohol and Cannabis course as a feasible way of delivering alcohol and cannabis prevention. Intervention effects for alcohol and cannabis knowledge were consistent with results from the original trial; however, analyses of longer-term follow-up data are needed to provide a clearer indication of the efficacy of the intervention, particularly in relation to behavioral changes.

Suicidality, internalizing problems and externalizing problems among adolescent bullies, victims and bully-victims.

OBJECTIVE: The aim of this study is to compare suicidality, internalizing problems and externalizing problems among adolescent victims, bullies and bully-victims. METHOD: This study examined bullying involvement among a subset of the baseline sample of the Climate and Preventure study, a trial of a comprehensive substance use prevention intervention for adolescents in 2012. The sample included 1588 Year 7-9 students in New South Wales and Victoria, Australia. RESULTS: Victims, bullies and bully-victims had more problems than uninvolved students. Students with internalizing problems were more likely to be a victim than a bully. Some externalizing problems (alcohol and tobacco use) were associated with increased odds of being a bully, but not others (cannabis use and conduct/hyperactivity symptoms). Suicidal ideation, internalizing problems and some externalizing problems increased the odds of being a bully-victim compared to being a bully or a victim. CONCLUSION: Early intervention for adolescents frequently involved in bullying may reduce the onset of substance use and other mental disorders. It would be advisable for bullying interventions to include a focus on substance use and mental health problems. A reduction in these chronic and detrimental problems among adolescents could potentially lead to a concomitant reduction in bullying involvement.

A recently collected Xanthomonas translucens isolate encodes TAL effectors distinct from older, less virulent isolates.

Xanthomonas translucens, the causal agent of bacterial leaf streak disease (BLS) in cereals, is a re-emerging pathogen that is becoming increasingly destructive across the world. While BLS has caused yield losses in the past, there is anecdotal evidence that newer isolates may be more virulent. We observed that two X. translucens isolates collected from two sites in Colorado, USA, are more aggressive on current wheat and barley varieties compared to older isolates, and we hypothesize that genetic changes between recent and older isolates contribute to the differences in isolate aggressiveness. To test this, we phenotyped and genetically characterized two X. translucens isolates collected from Colorado in 2018, which we designated CO236 (from barley) and CO237 (from wheat). Using pathovar-specific phenotyping and PCR primers, we determined that CO236 belongs to pathovar translucens (Xtt) and CO237 belongs to pathovar undulosa (Xtu). We sequenced the full genomes of the isolates using Oxford Nanopore long-read sequencing, and compared their whole genomes against published X. translucens genomes. This analysis confirmed our pathovar designations for Xtt CO236 and Xtu CO237, and showed that, at the whole-genome level, there were no obvious genomic structural changes between Xtt CO236 and Xtu CO237 and other respective published pathovar genomes. Focusing on pathovar undulosa (Xtu CO237), we then compared putative type III effectors among all available Xtu isolate genomes and found that they were highly conserved. However, there were striking differences in the presence and sequence of various transcription activator-like effectors between Xtu CO237 and published undulosa genomes, which correlate with isolate virulence. Here, we explore the potential implications of the differences in these virulence factors, and provide possible explanations for the increased virulence of recently emerged isolates.