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Background: The role of alcohol use in the development of depression is unclear. We aimed to investigate whether alcohol dependence, but not high frequency or quantity of consumption, during adolescence increased the risk of depression in young adulthood., Methods: In this prospective cohort study, we included adolescents who were born to women recruited to the Avon Longitudinal Study of Parents and Children in Avon, UK, with delivery dates between April 1, 1991, and Dec 31, 1992. Alcohol dependence and consumption were measured at about age 16 years, 18 years, 19 years, 21 years, and 23 years using the self-reported Alcohol Use Disorders Identification Test, and at about age 18 years, 21 years, and 23 years using items corresponding to DSM-IV symptoms. The primary outcome was depression at age 24 years, assessed using the Clinical Interview Schedule Revised. Analyses were probit regressions between growth factors for alcohol dependence and consumption and depression, before and after adjustments for confounders: sex, housing tenure, maternal education, maternal depressive symptoms, parents' alcohol use, conduct problems at age 4 years, being bullied from age 12-16 years, and frequency of smoking cigarettes or cannabis. Adolescents were included in analyses if they had data from at least one timepoint for alcohol use and confounders., Findings: We included 3902 adolescents (2264 [58·0%] female; 1638 [42·0%] male) in our analysis, and 3727 (96·7%) of 3853 participants with data on ethnicity were White. After adjustments, we found a positive association between alcohol dependence at 18 years of age (latent intercept) and depression at 24 years of age (probit coefficient 0·13 [95% CI 0·02 to 0·25]; p=0·019), but no association between rate of change (linear slope) and depression (0·10 [-0·82 to 1·01]; p=0·84). There was no evidence of an association between alcohol consumption and depression (latent intercept probit coefficient -0·01 [-0·06 to 0·03]; p=0·60; linear slope 0·01 [-0·40 to 0·42]; p=0·96) after adjustments., Interpretation: Psychosocial or behavioural interventions that reduce the risk of alcohol dependence during adolescence could contribute to preventing depression in young adulthood., Funding: UK Medical Research Council and Alcohol Research UK (grant number MR/L022206/1)., Competing Interests: Declaration of interests MH has served as Trustee of Society of Study of Addiction and Regional Editor of Addiction in the past 3 years. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Parental alcohol use and problems are risk factors for alcohol use disorder (AUD), and these effects may be mediated by adolescent alcohol expectancies and consumption. In the present study, we tested the direct effects of mothers' and fathers' alcohol consumption on young adult AUD, as well as the indirect effects through adolescent maximum alcohol use, alcohol consumption, and alcohol expectancies., Methods: Participants were 5160 individuals (49.1% female) and their biological parents from the Avon Longitudinal Study of Parents and Children, a cohort study of children born in southwestern England during 1991 and 1992. Structural equation modeling (SEM) was used to test associations of mothers' and fathers' alcohol use (assessed when children were 12 years old) with age 24 AUD. Potential mediator variables included the maximum number of alcoholic drinks consumed within a 24-h period by age 13.5 and alcohol expectancies and alcohol consumption at ages 17 and 20., Results: Higher maternal and paternal alcohol use were associated with higher levels of alcohol consumption at age 17. Greater alcohol consumption, in turn, was related to a more severe presentation of AUD. The overall indirect effects of mothers' (b = 0.033, 95% confidence interval [CI] = 0.006, 0.059) and fathers' drinking (b = 0.041, 95% CI = 0.018, 0.064) on AUD were modest but significant, and were primarily comprised of adolescent alcohol consumption rather than alcohol expectancies., Conclusions: Our findings underscore the importance of both mothers' and fathers' drinking for the development of alcohol use and problems across adolescence and young adulthood., (© 2023 The Authors. Journal of Adolescence published by Wiley Periodicals LLC on behalf of Foundation for Professionals in Services to Adolescents.)

Cognitive abilities are markers of brain development and psychopathology. Abilities, across executive, and social domains need better characterization over development, including factors that influence developmental change. This study is based on the cVEDA [Consortium on Vulnerability to Externalizing Disorders and Addictions] study, an Indian population based developmental cohort. Verbal working memory, visuo-spatial working memory, response inhibition, set-shifting, and social cognition (faux pas recognition and emotion recognition) were cross-sectionally assessed in > 8000 individuals over the ages 6-23 years. There was adequate representation across sex, urban-rural background, psychosocial risk (psychopathology, childhood adversity and wealth index, i.e. socio-economic status). Quantile regression was used to model developmental change. Age-based trajectories were generated, along with examination of the impact of determinants (sex, childhood adversity, and wealth index). Development in both executive and social cognitive abilities continued into adulthood. Maturation and stabilization occurred in increasing order of complexity, from working memory to inhibitory control to cognitive flexibility. Age related change was more pronounced for low quantiles in response inhibition (β∼4 versus  -1 versus -0.25 for lower quantiles). Wealth index had the largest influence on developmental change across cognitive abilities. Sex differences were prominent in response inhibition, set-shifting and emotion recognition. Childhood adversity had a negative influence on cognitive development. These findings add to the limited literature on patterns and determinants of cognitive development. They have implications for understanding developmental vulnerabilities in young persons, and the need for providing conducive socio-economic environments., Competing Interests: Conflict of interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Depression often first emerges in adolescence and, for many, is a lifelong disorder. The long-term clinical course of depression is highly variable. We aimed to examine the adult outcomes of adolescent-onset trajectories of clinically significant depressive symptoms and to identify factors differentiating trajectories that persist and desist in adulthood., Methods: We included participants from the English population-based Avon Longitudinal Study of Parents and Children with data on depressive symptoms. Self-reported depression symptoms were assessed on ten occasions when participants were age 10·5-25 years using the short Mood and Feelings Questionnaire, and major depressive disorder episodes were assessed at age 13·0 years, 15·0 years, 17·5 years, and 25·0 years. We characterised trajectories of depression symptoms using latent class growth analysis, for which we required depression data at least once from each of three key phases: ages 10·5-13·5 years; 16·5-18·5 years; and 21-25 years. We examined adult outcomes by assessing lifetime suicidal self-harm and functional impairment at age 24·0 years, and employment, education, and the self-reported Strengths and Difficulties Questionnaire at age 25·0 years., Findings: We studied 4234 participants: 2651 (63%) female, 1582 (37%) male, and one individual with missing sex data. The mean age was 10·6 years (SD 0·2) at baseline and 25·8 years (SD 0·5) at the final timepoint. Data on ethnicity were not available in our data set. We identified four depression trajectory classes: adolescent-persistent depression with onset early in adolescence (7%, n≈279), adolescent-limited depression with onset later in adolescence and remittance by adult life (14%, n≈592), adult-increasing depression (25%, n≈1056), and stable-low levels of depression (54%, n≈2307). The adolescent-persistent class was associated with poor adult outcomes for functional impairment (62%), suicidal self-harm (27%), mental health difficulties (25%), and not being in education, employment, or training (16%). Adolescent-limited depression was associated with transient adolescent stress, but by early adulthood functional impairment and mental health difficulties were similar to the stable-low group. Major depressive disorder polygenic score (odds ratio [OR] 1·36, 95% CI 1·04-1·79), adolescent educational attainment (OR 0·47, 0·30-0·74), and any early childhood adversity (OR 2·60, 1·42-4·78), that persisted into adulthood (OR 1·60, 1·38-1·87) distinguished the adolescent-persistent and adolescent-limited groups., Interpretation: The future course of adolescent depression can be differentiated by age at onset during adolescence, adolescent academic attainment, early and persistent adversity, and genetic loading. A detailed social and educational history could be helpful in making clinical decisions about the intensity of interventions for young people with clinically elevated depressive symptoms who seek help., Funding: Medical Research Council, Wolfson Centre for Young People's Mental Health, Wolfson Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Although studies have examined the association between tobacco and cannabis use in adolescence with subsequent cognitive functioning, study designs are usually not able to distinguish correlation from causation., Methods: Separate patterns of tobacco and cannabis use were derived using longitudinal latent class analysis based on measures assessed on five occasions from age 13-18 in a large UK population cohort (Avon Longitudinal Study of Parents and Children). Cognitive functioning measures comprised of working memory, response inhibition, and emotion recognition assessed at 24 years of age. Mendelian randomization was used to examine the possible causal relationship between smoking initiation, lifetime cannabis use and cognitive functioning., Results: We found evidence of a relationship between tobacco and cannabis use and diminished cognitive functioning for each of the outcomes in the observational analyses. There was evidence to suggest that late-onset regular tobacco smokers (b=-0.29, 95 %CI=-0.45 to -0.13), early-onset regular tobacco smokers (b=-0.45, 95 %CI=-0.84 to -0.05), and early-onset regular cannabis users (b=-0.62, 95 %CI=-0.93 to -0.31) showed poorer working memory. Early-onset regular tobacco smokers (b = 0.18, 95 %CI = 0.07 to 0.28), and early-onset regular cannabis users (b = 0.30, 95 %CI = 0.08 to 0.52) displayed poorer ability to inhibit responses. Late-onset regular (b=-0.02, 95 %CI=-0.03 to - 0.00), and early-onset regular tobacco smokers (b=-0.04, 95 %CI=-0.08 to -0.01) showed poorer ability to recognise emotions. Mendelian randomization analyses were imprecise and did not provide additional support for the observational results., Conclusion: There was some evidence to suggest that adolescent tobacco and cannabis use were associated with deficits in working memory, response inhibition and emotion recognition. Better powered genetic studies are required to determine whether these associations are causal., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The causal role of inflammatory markers on self-harm and suicidal risk has been studied using observational data, with conflicting results. Confounding and reverse causation can lead to bias, so we appraised question from a genetic perspective to protect against these biases. We measured associations between genetic liability for high levels of inflammatory markers Interleukin-6 (IL-6) and C-reactive protein (CRP) on self-harm, and conducted a secondary analysis restricted to self-harm with suicidal intent., Methods: We conducted two sample and multivariable Mendelian randomisation (MR) to assess the effects of IL-6 and CRP on self-harm utilising existing data and conducting new genome wide association studies to instrument IL-6 and CRP, and for the outcome of self-harm., Results: No single nucleotide polymorphisms (SNPs) reached genome-wide significance for self-harm, however 193 SNPs met suggestive significance levels (p < 5 × 10 -6 ). We found no evidence of an association between our instruments for IL-6 and self-harm in the two-sample MR, however we found an inverse association between instruments for CRP and self-harm, indicating that higher levels of circulating CRP may protect against self-harm (inverse variance weighted OR 0.92, 95%CI 0.84, 1.01, p = 0.08; MR Egger OR 0.86, 95% CI 0.74, 1.00, p = 0.05). The direct effect estimate for IL-6 was slightly smaller in the multivariable MR than in the two sample MR, while the CRP effect estimates were consistent with the two sample MR (OR 0.92, SE 1.05, p = 0.09)., Conclusions: Our findings are conflicting and indicate that IL-6 and CRP are not robust etiological markers of increased self-harm or suicide risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The negative control design can be used to provide evidence for whether a prenatal exposure-outcome association occurs by in utero mechanisms. Assortative mating has been suggested to influence results from negative control designs, although how and why has not yet been adequately explained. We aimed to explain why mutual adjustment of maternal and paternal exposure in regression models can account for assortative mating., Study Design and Setting: We used directed acyclic graphs to show how bias can occur when modeling maternal and paternal effects separately. We empirically tested our claims using a simulation study. We investigated how increasing assortative mating influences the bias of effect estimates obtained from models that do and do not use a mutual adjustment strategy., Results: In models without mutual adjustment, increasing assortative mating led to increased bias in effect estimates. The maternal and paternal effect estimates were biased by each other, making the difference between them smaller than the true difference. Mutually adjusted models did not suffer from such bias., Conclusions: Mutual adjustment for maternal and paternal exposure prevents bias from assortative mating influencing the conclusions of a negative control design. We further discuss issues that mutual adjustment may not be able to resolve., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between anxiety and alcohol use is unclear, and moderating factors, such as drinking to cope (DTC) motives, may explain mixed findings., Methods: Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined associations between generalized anxiety disorder (GAD) at age 18 and frequent drinking, frequent bingeing, hazardous drinking, and harmful drinking at ages 18 (unadjusted n = 3462) and 21 (unadjusted n = 2076), in a sample of late adolescent drinkers. Analyses were adjusted for sociodemographic, parental, and adolescent confounders. We also examined whether DTC motives influenced the strength and direction of associations between GAD and alcohol use., Results: GAD was positively associated with all alcohol outcomes at baseline (unadjusted OR (95% CI): frequent drinking 1.40 (1.02-1.91); frequent bingeing 1.40 (0.96-2.04); hazardous drinking 1.44 (1.08-1.92); harmful drinking 1.98 (1.22-3.23)). GAD increased the odds of harmful drinking at age 21 (unadjusted OR 1.72, 95% CI 1.09-2.73), but there was no clear evidence of a longitudinal relationship between GAD and the other alcohol use outcomes. There was no clear evidence of a GAD x DTC interaction on alcohol use at ages 18 or 21. Findings were consistent across various multiply imputed datasets., Conclusions: In adolescence, GAD symptoms are associated with frequent drinking, frequent bingeing, hazardous drinking, and harmful drinking. In early adulthood, associations remain for harmful drinking only. DTC motives do not appear to moderate the relationship at either age., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Researchers are concerned whether multiple imputation (MI) or complete case analysis should be used when a large proportion of data are missing. We aimed to provide guidance for drawing conclusions from data with a large proportion of missingness., Study Design and Setting: Via simulations, we investigated how the proportion of missing data, the fraction of missing information (FMI), and availability of auxiliary variables affected MI performance. Outcome data were missing completely at random or missing at random (MAR)., Results: Provided sufficient auxiliary information was available; MI was beneficial in terms of bias and never detrimental in terms of efficiency. Models with similar FMI values, but differing proportions of missing data, also had similar precision for effect estimates. In the absence of bias, the FMI was a better guide to the efficiency gains using MI than the proportion of missing data., Conclusion: We provide evidence that for MAR data, valid MI reduces bias even when the proportion of missingness is large. We advise researchers to use FMI to guide choice of auxiliary variables for efficiency gain in imputation analyses, and that sensitivity analyses including different imputation models may be needed if the number of complete cases is small., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Suicidal thoughts and non-suicidal self-harm are common in adolescents and are strongly associated with suicide attempts. We aimed to identify predictors of future suicide attempts in these high-risk groups., Methods: Participants were from the Avon Longitudinal Study of Parents and Children, a population-based birth cohort study in the UK. The sample included 456 adolescents who reported suicidal thoughts and 569 who reported non-suicidal self-harm at 16 years of age. Logistic regression analyses were used to explore associations between a wide range of prospectively recorded risk factors and future suicide attempts, assessed at the age of 21 years., Findings: 38 (12%) of 310 participants with suicidal thoughts and 46 (12%) of 380 participants who had engaged in non-suicidal self-harm reported having attempted suicide for the first time by the follow-up at 21 years of age. Among participants with suicidal thoughts, the strongest predictors of transition to attempts were non-suicidal self-harm (odds ratio [OR] 2·78, 95% CI 1·35-5·74; p=0·0059), cannabis use (2·61, 1·11-6·14; p=0·029), other illicit drug use (2·47, 1·02-5·96; p=0·045), exposure to self-harm (family 2·03, 0·93-4·44, p=0·076; friend 1·85, 0·93-3·69, p=0·081), and higher levels of the personality type intellect/openness (1·62, 1·06-2·46; p=0·025). Among participants with non-suicidal self-harm at baseline, the strongest predictors were cannabis use (OR 2·14, 95% CI 1·04-4·41; p=0·038), other illicit drug use (2·17, 1·10-4·27; p=0·025), sleep problems (waking in the night 1·91, 0·95-3·84, p=0·069; insufficient sleep 1·97, 1·02-3·81, p=0·043), and lower levels of the personality type extraversion (0·71, 0·49-1·03; p=0·068)., Interpretation: Most adolescents who think about suicide or engage in non-suicidal self-harm will not make an attempt on their life. Many commonly cited risk factors were not associated with transition to suicide attempt among these high-risk groups. Our findings suggest that asking about substance use, non-suicidal self-harm, sleep, personality traits, and exposure to self-harm could inform risk assessments, and might help clinicians to identify which adolescents are at greatest risk of attempting suicide in the future., Funding: American Foundation for Suicide Prevention, National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service Foundation Trust, and the University of Bristol., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To examine the hypothesis that autism spectrum disorders (ASD) diagnosis and traits in childhood are associated with suicidal thoughts, plans and self-harm at 16 years, and that any observed associations are explained by depression at 12 years., Method: We examined associations between ASD diagnosis and 4 dichotomized ASD traits (social communication, pragmatic language, repetitive behavior, and sociability) with suicidal and nonsuicidal self-harm, suicidal thoughts, and suicidal plans at age 16 years in 5,031 members of the United Kingdom-based birth cohort study the Avon Longitudinal Study of Parents and Children. We assessed whether any associations were explained by depressive symptoms in early adolescence measured by the Short Moods and Feelings Questionnaire at 12 years., Results: Children with impaired social communication had a higher risk of self-harm with suicidal intent (relative risk [RR] = 2.14, 95% CI = 1.28-3.58), suicidal thoughts (RR = 1.42, 95% CI = 1.06-1.91), and suicidal plans (RR = 1.95, 95% CI = 1.09-3.47) by age 16 years as compared to those without. There was no evidence for an association between ASD diagnosis and outcomes, although these analyses were imprecise because of small numbers. There was also no evidence of an association between other autism traits and the outcomes. Approximately 32% of the total estimated association between social communication impairment and self-harm was explained by depressive symptoms at 12 years., Conclusion: Social communication impairments are an important autistic trait in relation to suicidality. Early identification and management of depression may be a preventative mechanism, and future research identifying other potentially modifiable mechanisms may lead to interventions against suicidal behavior in this high-risk group., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Antisocial behavior (ASB) decreases with age in most of the population; however, excessive alcohol use can inhibit the desistance process. This study investigated whether excessive early drinking might slow a young person's overall pattern of crime desistance compared with that of others ("between-person effects") and whether short-term increases in alcohol consumption might result in short-term increases in ASB ("within-person effects")., Method: Frequency of ASB and typical alcohol consumption were assessed repeatedly in young people 15 to 21 years old in a population-based birth cohort (Avon Longitudinal Study of Parents and Children). Longitudinal trajectories showed ASB decreasing and alcohol use increasing across adolescence, which stabilized in adulthood. The parallel growth model was re-parameterized to simultaneously estimate the person-specific (or "between-person") and time-specific (or "within-person") influences of alcohol on ASB., Results: Typical alcohol consumption by young people 15 years old was positively associated with ASB cross-sectionally and into young adulthood (i.e., there were between-person effects of initial levels of alcohol consumption on initial [b 1.64, standard error 0.21; p < .001] and final [b 0.53, standard error 0.14; p < .001] levels of ASB). Within-person effects also were identified in early adulthood (b 0.06, standard error 0.02; p = .001), showing that when a young person reported consuming more alcohol than normal across the past year, that person also reported engaging in higher than usual levels of ASB., Conclusion: The results are consistent with between- and within-person effects of excessive alcohol use on ASB desistence. Future research should further investigate this relation by investigating pathways into excessive alcohol use and ASB in adolescence., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Smoking influences body weight, but there is little evidence as to whether body mass index (BMI) and body dissatisfaction increase smoking initiation in adolescents., Methods: We evaluated the association between measured BMI, body dissatisfaction and latent classes of smoking initiation (never smokers, experimenters, late onset regular smokers, early onset regular smokers) in the Avon Longitudinal Study of Parents and Children. In observational analyses we used BMI (N=3754) and body dissatisfaction at age 10.5 years (N=3349). In Mendelian randomisation (MR) analysis, we used a BMI genetic risk score of 76 single nucleotide polymorphisms (N=4017)., Results: In females, higher BMI was associated with increased odds of early onset regular smoking (OR: 1.11, 95% CI: 1.04, 1.18) compared to being a never smoker, but not clearly associated with experimenting with smoking (OR: 1.04, 95% CI: 0.99, 1.10) or late onset regular smoking (OR: 1.01, 95% CI: 0.94, 1.09). No clear evidence was found for associations between BMI and smoking initiation classes in males (p-value for sex interaction≤0.001). Body dissatisfaction was associated with increased odds of late-onset regular smoking (OR: 1.71, 95% CI: 1.32, 1.99) in males and females combined (P-value for sex interaction=0.32). There was no clear evidence for an association between the BMI genetic risk score and smoking latent classes in males or females but estimates were imprecise., Conclusions: BMI in females and body dissatisfaction in males and females are associated with increased odds of smoking initiation, highlighting these as potentially important factors for consideration in smoking prevention strategies., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous research has suggested that deliberate self-harm is associated with contemporary goth subculture in young people; however, whether this association is confounded by characteristics of young people, their families, and their circumstances is unclear. We aimed to test whether self-identification as a goth is prospectively associated with emergence of clinical depression and self-harm in early adulthood., Methods: We used data from the Avon Longitudinal Study of Parents and Children, a UK community-based birth cohort of 14 541 pregnant women with expected delivery between April 1, 1991, and Dec 31, 1992. All children in the study were invited to attend yearly follow-up visits at the research clinic from age 7 years. At 15 years of age, participants reported the extent to which they self-identified as a goth. We assessed depressive mood and self-harm at 15 years with the Development and Wellbeing Assessment (DAWBA) questionnaire, and depression and self-harm at 18 years using the Clinical Interview Schedule-Revised. We calculated the prospective association between goth identification at 15 years and depression and self-harm at 18 years using logistic regression analyses., Findings: Of 5357 participants who had data available for goth self-identification, 3694 individuals also had data for depression and self-harm outcomes at 18 years. 105 (6%) of 1841 adolescents who did not self-identify as goths met criteria for depression compared with 28 (18%) of 154 who identified as goths very much; for self-harm, the figures were 189 (10%) of 1841 versus 57 (37%) of 154. We noted a dose-response association with goth self-identification both for depression and for self-harm. Compared with young people who did not identify as a goth, those who somewhat identified as being a goth were 1·6 times more likely (unadjusted odds ratio [OR] 1·63, 95% CI 1·14-2·34, p<0·001), and those who very much identified as being a goth were more than three times more likely (unadjusted OR 3·67, 2·33-4·79, p<0·001) to have scores in the clinical range for depression at 18 years; findings were similar for self-harm. Associations were not attenuated after adjustment for a range of individual, family, and social confounders., Interpretation: Our findings suggest that young people identifying with goth subculture might be at an increased risk for depression and self-harm. Although our results suggest that some peer contagion operates within the goth community, our observational findings cannot be used to claim that becoming a goth increases risk of self-harm or depression. Working with young people in the goth community to identify those at increased risk of depression and self-harm and provide support might be effective., Funding: Wellcome Trust, Medical Research Council Programme., (Copyright © 2015 Bowes et al. Open Acess article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: School exclusion is a disciplinary method used to remove a child from the school environment. It is known to affect certain groups disproportionately, including boys, some ethnic minorities, children in care, children in poverty, and children with special educational needs. Population-based studies on wider characteristics of excluded pupils are scarce. The aim of this study was to describe factors associated with school exclusion in the Avon Longitudinal Study of Parents and Children (ALSPAC), focussing on neurodevelopment and mental health., Methods: ALSPAC is a prospective population-based British birth cohort study, with the initial sample consisting of 14 541 pregnancies. The study has data for whether a child has been permanently excluded from school up to the age of 8 years as reported by parents and also permanent and fixed period exclusions in the preceding 12 months as reported by parents and young people at age 16 years. Upstream risk factors were assessed for associations with exclusion on univariable analysis. The association with social communication difficulties was investigated with multivariable logistic regression., Findings: Data for exclusions up to the age of 8 years were available for 8245 ALSPAC participants and 4482 participants for exclusion at age 16 years. 53 pupils (0·6%) were excluded from school by age 8 years, and 390 (8·7%) at age 16 years. The odds of exclusion by 8 years and at 16 years were increased with male sex (p=0·001 and p<0·0001, respectively), low family income (p=0·014 and p<0·0001), family adversity (p<0·0001 for both), maternal psychopathology (p=0·013 and p=0·004), low intelligence quotient (p=0·041 and p<0·0001), mental health difficulties (p<0·0001 for both), psychiatric disorder (p<0·0001 for both), social communication difficulties (p<0·0001 for both), antisocial activities (p=0·004 and p<0·0001), bullying or being bullied (p=0·005 and p<0·0001), low educational attainment (p<0·0001 for both), and increased special educational needs (p<0·0001 for both). On multivariable analysis, having social communication difficulties above a clinical threshold on the Social Communication Disorders Checklist was strongly associated with exclusion by 8 years (odds ratio 7·4, 95% CI 3·6-15·4) and at 16 years (2·3, 1·5-3·5), after adjustment for relevant confounders., Interpretation: Although cohort attrition and small numbers of exclusions at 8 years are limitations, this study suggests that school exclusion is associated with numerous risk factors identifiable at or before primary school entry. Child health professionals have an important role in the holistic assessment of children who are excluded, or who are at risk of school exclusion. There is particular need to ensure that mental health and neurodevelopmental difficulties are appropriately recognised and supported., Funding: National Institute for Health Research Academic Clinical Fellowship., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: One's peer group can have a strong impact on depressed mood and harmful drinking in adolescence. It remains unclear whether affiliation with deviant peers explains the link between these traits. Our study aims to (1) explore the developmental relationship between harmful drinking and depressed mood in adolescence and (2) establish to which extent affiliation with deviant peers explains this relationship., Methods: A total of 4,863 adolescents from the Avon Longitudinal Study of Parents and Children were assessed between the ages of 14 and 16 years. Harmful drinking was established using age-appropriate measures: the Semi-Structured Assessment for the Genetics of Alcoholism in mid-adolescence (age, 14 years) and the Alcohol Use Disorders Identification Test in late adolescence (age, 16 years). Depressed mood was measured by the Short Mood and Feelings Questionnaire at both ages. Affiliation with deviant peers was assessed at the age of 15 years., Results: Harmful drinking at the age of 14 years predicted depressed mood 2 years later. This association was explained by affiliation with deviant peers and remained present even after adjustment for earlier depressed mood. Depressed mood at the age of 14 years predicted harmful drinking at the age of 16 years via affiliation with deviant peers; however, this indirect effect disappeared when adjusting for adolescents' earlier harmful alcohol use (age, 14 years). No gender differences were observed., Conclusions: Adolescents who engage in early harmful drinking and subsequently become affiliated with a deviant peer group may be at particular risk of later depressed mood., (Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Overgeneral autobiographical memory has repeatedly been identified as a risk factor for adolescent and adult psychopathology but the factors that cause such over-generality remain unclear. This study examined the association between childhood exposure to traumatic events and early adolescent overgeneral autobiographical memory in a large population sample., Methods: Thirteen-year-olds, n = 5,792, participating in an ongoing longitudinal cohort study (ALSPAC) completed a written version of the Autobiographical Memory Test. Performance on this task was examined in relation to experience of traumatic events, using data recorded by caregivers close to the time of exposure., Results: Results indicated that experiencing a severe event in middle childhood increased the likelihood of an adolescent falling into the lowest quartile for autobiographical memory specificity (retrieving 0 or 1 specific memory) at age 13 by approximately 60%. The association persisted after controlling for a range of potential socio-demographic confounders., Limitations: Data on the traumatic event exposures was limited by the relatively restricted range of traumas examined, and the lack of contextual details surrounding both the traumatic event exposures themselves and the severity of children's post-traumatic stress reactions., Conclusions: This is the largest study to date of the association between childhood trauma exposure and overgeneral autobiographical memory in adolescence. Findings suggest a modest association between exposure to traumatic events and later overgeneral autobiographical memory, a psychological variable that has been linked to vulnerability to clinical depression., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Parental suicidal behavior is associated with offspring's risk of suicidal behavior. However, much of the available evidence is from population registers or clinical samples. We investigated the associations of self-reported parental suicide attempt (SA) with offspring self-harm and suicidal thoughts in the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort., Method: Parental SA was self-reported on 10 occasions from pregnancy until their child was 11 years of age. Offspring self-reported lifetime self-harm, with and without suicidal intent, suicidal thoughts, and suicide plans, at age 16 to 17 years. Multivariable regression models quantified the association between parental SA and offspring outcomes controlling for confounders., Results: Data were available for 4,396 mother-child and 2,541 father-child pairs. Adjusting for confounders including parental depression, maternal SA was associated with a 3-fold increased risk of self-harm with suicidal intent in their children (adjusted odds ratio [aOR] = 2.94, 95% confidence interval [CI] = 1.43-6.07) but not with self-harm without suicidal intent (aOR = 0.83, 95% CI = 0.35-1.99). Children whose mother attempted suicide were more likely to report suicidal thoughts and plans (aOR = 5.04, 95% CI = 2.24-11.36; aOR = 2.17, 95% CI = 1.07-4.38, respectively). Findings in relation to paternal SA were somewhat weaker and not significant., Conclusions: Maternal SA increased their offspring's risk of self-harm with suicidal intent and of suicidal thoughts, but was unrelated to self-harm without intent; findings for paternal suicide attempt were weaker and not significant. Maternal SA, which may not come to the attention of health care professionals, represents a major risk for psychiatric morbidity in their offspring., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

In a prospective birth cohort study of 5295 girls from the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC), we examined the association between biological father absence in childhood and age at menarche whilst adjusting for antenatal indicators of socioeconomic disadvantage and maternal characteristics. We also examined whether exposure to maternal depression and financial problems during middle childhood mediate the association between father absence and age at menarche. There was stronger evidence for an association between father absence during the first 5 years of life and early timing of menarche compared with father absence between 5 and 10 years. There was evidence that maternal depression and major financial problems explained some of the association between early childhood father absence and age at menarche. Although father absence cannot be a direct target of prevention, family-based programs to address family processes influenced by maternal depression and socioeconomic disadvantage may be effective., (Copyright © 2014 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.)

Background: We consider the strength of the relationship between types of conduct problems in early life and pattern of alcohol use during adolescence., Methods: Children from the Avon Longitudinal Study of Parents and Children, a U.K. birth-cohort, had their level of conduct problems assessed repeatedly from 4 to 13 years using the maternal report Strengths and Difficulties Questionnaire. Developmental trajectories derived from these data were subsequently related to (i) patterns of alcohol use from 13 to 15 years, and (ii) hazardous alcohol used at age 16., Results: Boys with 'Adolescent Onset' or 'Early Onset Persistent' conduct problems were much more likely to be high frequency drinkers between 13 and 15 years (OR 5.00 95% CI=[2.4, 10.6] and 3.9 95% CI=[2.1, 7.3] respectively) compared with those with Low or 'Childhood Limited' conduct. Adolescent Onset/Early Onset Persistent girls also had greater odds of this high-alcohol frequency drinking pattern (2.67 [1.4, 5.0] and 2.14 [1.2, 4.0] respectively). Associations were more moderate for risk of hazardous alcohol use at age 16. Compared to 32% among those with low conduct problems, over 40% of young people classified as showing Adolescent Onset/Early Onset Persistent conduct problems were drinking hazardously (OR 1.52 [1.09, 2.11] and 1.63 [1.22, 2.18] respectively)., Conclusions: Whilst persistent conduct problems greatly increase the risk of adolescent alcohol problems, the majority of adolescents reporting hazardous use at age 16 lack such a history. It is important, therefore, to undertake alcohol prevention among all young people as a priority, as well as target people with manifest conduct problems., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To examine whether early menarche is associated with depressive symptoms from adolescence to young adulthood., Method: The study is based on 3,648 girls from a large UK birth cohort (Avon Longitudinal Study of Parents and Children) who provided data on age at onset of menarche and at least 1 measure of depressive symptoms assessed using the Short Mood and Feelings Questionnaire at ages 13, 14, 16.5, 18, and 19 years. Depressive symptoms were examined as binary outcomes (sum score ≥11) and continuous latent traits (using confirmatory factor analysis). Results were adjusted for socioeconomic disadvantage, paternal absence, and body mass index (BMI)., Results: In early to midadolescence, there was strong evidence for increased odds of depressive symptoms in girls with early compared with late menarche. Differences remained after adjusting for confounders (adjusted odds ratio [OR] = 2.07, 95% confidence interval [CI] = 1.28-3.35 at 13 years; OR = 2.09, 95% CI = 1.41-3.09 at 14 years). At the later time points there was weak evidence for an association between early menarche and depressive symptoms in the unadjusted models. Adjusting for confounders explained a moderate amount of the effect (adjusted OR = 1.26, 95% CI = 0.86-1.85 at 16.5 years; OR = 1.33, 95% CI = 0.91-1.95 at 18 years; and OR = 1.40, 95% CI = 0.93-2.13 at 19 years). Findings were similar when we repeated the analysis using continuous depressive symptom latent traits., Conclusions: Girls who experience earlier menarche than their peers have increased levels of depressive symptoms in early to midadolescence, but there is little evidence for an effect of early menarche on depressive symptoms in later adolescence and young adulthood., (Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether being bullied between 7 and 10 years of age is directly associated with self-harm in late adolescence when controlling for previous exposure to an adverse family environment (domestic violence, maladaptive parenting); concurrent internalizing and externalizing behavior; and subsequent psychopathology (borderline personality disorder and depression symptoms)., Method: A total of 4,810 children and adolescents in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort were assessed to ascertain bullying exposure (between 7 and 10 years of age) and self-harm at 16 to 17 years., Results: A total of 16.5% of 16- to 17-year-olds reported self-harm in the previous year. Being bullied was associated with an increased risk of self-harm directly, and indirectly via depression symptoms in early adolescence. The association between an adverse family environment (exposure to maladaptive parenting and domestic violence) and self-harm was partially mediated by being bullied., Conclusions: Being bullied during childhood increases the risk of self-harm in late adolescence via several distinct pathways, for example, by increasing the risk of depression and by exacerbating the effects of exposure to an adverse family environment; as well as in the absence of these risk exposures. Health practitioners evaluating self-harm should be aware that being bullied is an important potential risk factor., (Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: There is overlap between an autistic and hyperactive-inattentive symptomatology when studied cross-sectionally. This study is the first to examine the longitudinal pattern of association between social-communication deficits and hyperactive-inattentive symptoms in the general population, from childhood through adolescence. We explored the interrelationship between trajectories of co-occurring symptoms, and sought evidence for shared prenatal/perinatal risk factors., Method: Study participants were 5,383 singletons of white ethnicity from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multiple measurements of hyperactive-inattentive traits (Strengths and Difficulties Questionnaire) and autistic social-communication impairment (Social Communication Disorder Checklist) were obtained between 4 and 17 years. Both traits and their trajectories were modeled in parallel using latent class growth analysis (LCGA). Trajectory membership was subsequently investigated with respect to prenatal/perinatal risk factors., Results: LCGA analysis revealed two distinct social-communication trajectories (persistently impaired versus low-risk) and four hyperactive-inattentive trait trajectories (persistently impaired, intermediate, childhood-limited and low-risk). Autistic symptoms were more stable than those of attention-deficit/hyperactivity disorder (ADHD) behaviors, which showed greater variability. Trajectories for both traits were strongly but not reciprocally interlinked, such that the majority of children with a persistent hyperactive-inattentive symptomatology also showed persistent social-communication deficits but not vice versa. Shared predictors, especially for trajectories of persistent impairment, were maternal smoking during the first trimester, which included familial effects, and a teenage pregnancy., Conclusions: Our longitudinal study reveals that a complex relationship exists between social-communication and hyperactive-inattentive traits. Patterns of association change over time, with corresponding implications for removing exclusivity criteria for ASD and ADHD, as proposed for DSM-5., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: Patterns of pubertal development reflect underlying endocrine function and exposures, and could affect future health outcomes. We used data from a longitudinal cohort to describe factors associated with breast and pubic hair stage and estimate average duration of puberty., Methods: Data from the Avon Longitudinal Study of Parents and Children were used to describe timing and duration of pubertal development in girls. Self-reported Tanner stage of breast and pubic hair and menarche status were collected from ages 8-14 through mailed questionnaires. Factors associated with breast and pubic hair stage were identified using ordinal probit models. Age at entry into breast and pubic hair stages, and duration of puberty were estimated using interval-censored parametric survival analysis., Results: Among the 3,938 participants, being overweight or obese, of non-white race, being the firstborn, and younger maternal age at menarche were associated with more advanced breast and pubic hair stages. Having an overweight or obese mother was associated with more advanced breast stages. Time spent in breast stages 2 and 3 was longer (1.5 years) than time spent in pubic hair stages 2 and 3 (1 year). The average age at menarche was 12.9 (95% CI, 12.8-12.9) years, and average duration of puberty (time from initiation of puberty to menarche) was 2.7 years., Conclusions: Girls in Avon Longitudinal Study of Parents and Children had a slightly longer duration of puberty compared to an earlier British cohort study. Various maternal and child characteristics were associated with breast and pubic hair stage, including both child and maternal body mass.

Background: Adverse pregnancy outcomes have been related to environmental and/or genetic factors. Of interest are genes associated with the clotting system as any perturbation in the balance of thrombotic and thrombolytic cascades could affect the placental circulation and hence the viability of the developing fetus. Several previous reports using relatively small numbers of cases and controls have suggested that there is a relationship between poor pregnancy outcomes and two polymorphisms, one in the factor V gene, the 1691G to A change (rs6025) located on chromosome 1q23 (factor V Leiden, FVL), and the other in the prothrombin gene, 20210G to A change (rs1799963) on chromosome 11p11-q12 (PT). These results, however, are conflicting., Methods: We genotyped 6755 mother/infant pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether maternal or fetal FVL or PT, either alone or in combination, are associated with fetal growth restriction (FGR) or pre-eclampsia (PE). We also added the present results to previous cohort studies using meta-analysis., Results: Smoking, primiparity and lower body mass index (BMI) were all associated with FGR, but neither maternal nor fetal FVL or PT, singly or in combination, were associated with FGR in the ALSPAC cohort. Meta-analysis confirmed the lack of association between maternal FVL and FGR with a pooled odds ratio (OR) of 1.15 [95% confidence interval (CI) 0.95-1.39]. High BMI, primiparity, diabetes and chronic hypertension were all associated with pre-eclampsia. Combining ALSPAC results with previous studies in ameta-analysis indicated that maternal FVL is significantly associated with pre-eclampsia, with a pooled OR of 1.49 (95% CI 1.13-1.96)., Conclusion: Neither maternal nor fetal FVL or PT, singly or in combination, are associated with FGR; this contradicts previous case-control studies and meta-analyses based on these studies. In a meta-analysis of all published cohort studies to date, maternal FVL appears to increase the risk of pre-eclampsia by almost 50%. This result is robust, homogeneous and does not appear to be affected by publication bias.

Objective: Postnatal depression in women is associated with adverse effects on both maternal health and children's development. It is unclear whether depression in men at this time poses comparable risks. The present study set out to assess the association between depression in men in the postnatal period and later psychiatric disorders in their children and to investigate predisposing factors for depression in men following childbirth., Method: A population-based cohort of 10,975 fathers and their children from the Avon Longitudinal Study of Parents and Children (ALSPAC) was recruited in the prenatal period and followed for 7 years. Paternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale and later child psychiatric disorder (DSM-IV) with the Development and Well-Being Assessment., Results: Depression in fathers in the postnatal period was significantly associated with psychiatric disorder in their children 7 years later (adjusted OR 1.72, 95% CI 1.07-2.77), most notably oppositional defiant/conduct disorders (adjusted OR 1.94, 95% CI 1.04-3.61), after adjusting for maternal depression and paternal educational level. A history of severe depression and high prenatal symptom scores for depression and anxiety were the strongest predictors of paternal depression in the postnatal period., Conclusions: Depression in fathers in the postnatal period is associated with later psychiatric disorders in their children, independently of maternal postnatal depression. Further research into the risks associated with paternal psychopathology is required because this could represent an important opportunity for public health intervention.

Background: Animal studies suggest that prenatal stress is associated with long-term disturbance in hypothalamic-pituitary-adrenal (HPA) axis function, but evidence in humans is lacking. This study examined the long-term association between prenatal anxiety and measures of diurnal cortisol at age 10 years., Methods: Measures of cortisol were collected at awakening, 30 min after awakening, and at 4 pm and 9 pm on 3 consecutive days in a sample of 10-year-olds (n = 74) from the Avon Longitudinal Study of Parents and Children, a prospective longitudinal cohort study of mothers and children on whom measures of anxiety and depression were collected in pregnancy and the postpartum period. Analyses examined the links between symptoms of prenatal anxiety and multiple indicators of cortisol, an index of HPA axis functioning., Results: Prenatal anxiety was significantly associated with individual differences in awakening and afternoon cortisol after accounting for obstetric and sociodemographic risk (partial correlations were .32 and .25, p < .05). The effect for awakening cortisol remained significant after controlling for multiple postnatal assessments of maternal anxiety and depression., Conclusions: This study provides the first human evidence that prenatal anxiety might have lasting effects on HPA axis functioning in the child and that prenatal anxiety might constitute a mechanism for an increased vulnerability to psychopathology in children and adolescents.

Background: Several studies support the dysbindin (dystrobrevin binding protein 1) gene (DTNBP1) as a susceptibility gene for schizophrenia. We previously reported that variation at a specific 3-locus haplotype influences susceptibility to schizophrenia in a large United Kingdom (UK) Caucasian case-control sample., Methods: Using similar methodology to our schizophrenia study, we have investigated this same 3-locus haplotype in a large, well-characterized bipolar sample (726 Caucasian UK DSM-IV bipolar I patients; 1407 ethnically matched controls)., Results: No significant differences were found in the distribution of the 3-locus haplotype in the full sample. Within the subset of bipolar I cases with predominantly psychotic episodes of mood disturbance (n = 133) we found nominally significant support for association at this haploptype (p < .042) and at SNP rs2619538 (p = .003), with a pattern of findings similar to that in our schizophrenia sample. This finding was not significant after correction for multiple testing., Conclusions: Our data suggest that variation at the polymorphisms examined does not make a major contribution to susceptibility to bipolar disorder in general. They are consistent with the possibility that DTNBP1 influences susceptibility to a subset of bipolar disorder cases with psychosis. However, our subset sample is small and the hypothesis requires testing in independent, adequately powered samples.

Background: Animal studies have shown that prenatal stress is linked with altered laterality in the offspring., Aims: The aim of this study was to test the hypothesis that antenatal maternal anxiety was associated with altered lateralisation in children, as demonstrated by mixed handedness., Study Design and Subjects: We used the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective longitudinal study that has followed women since pregnancy. The final analysis included data on 7431 mother-child pairs. Maternal anxiety was measured at 18- and 32-week gestation and 8 weeks postnatally using a self-report inventory. Child handedness was assessed at 42 months using an established maternal report scale. Information on maternal and paternal handedness, as well as data on possible confounding variables such as obstetric and antenatal risks, were also assessed., Results: Univariable analysis showed that antenatal anxiety at 18 weeks was associated with mixed-handedness in the child, OR=1.28 (95% CI 1.09-1.50, p<0.01). Although boys were more likely than girls to be mixed handed, the link with antenatal anxiety was similar. There was no significant association with antenatal anxiety at 32 weeks. Multivariable analyses indicated that maternal anxiety at 18 weeks of pregnancy predicted an increased likelihood of mixed-handedness in the child (OR=1.23, 95% CI 1.02-1.48, p<0.05), independently of parental handedness, obstetric and other antenatal risks, and postnatal anxiety., Conclusion: This result provides further evidence for a link between antenatal anxiety and fetal programming in humans.

Objective: To examine the hypothesis that the effects of postnatal depression on children's behavioral/emotional problems are explained by antenatal maternal mood., Method: The current study investigated this hypothesis in the Avon Longitudinal Study of Parents and Children, a prospective, community-based study that has followed a cohort of women since pregnancy (n = 7,144) who delivered their baby between April 1, 1991, and December 31, 1992. Self-report measures of maternal anxiety and depression were assessed at repeated intervals in pregnancy and the postnatal period. Children's behavioral/emotional problems were assessed by parent report at age 4 years., Results: After controlling for smoking, alcohol use, birth weight for gestational age, maternal age, child sex, and socioeconomic status, postnatal depression at 8 weeks (OR = 2.27 [1.55-3.31]) and 8 months (OR = 1.68 [1.12-2.54]) was associated with children's behavioral/emotional problems. Subsequent analyses that included antenatal maternal mood indicated that antenatal anxiety in late pregnancy and not antenatal depression was also independently associated with behavioral/emotional problems at age 4 (OR = 1.72 [1.14-2.59]); 8 week postnatal depression remained a significant predictor after antenatal maternal mood was statistically controlled for (OR = 1.56 [1.04-2.32])., Conclusions: Antenatal anxiety and postnatal depression represent separate risks for behavioral/emotional problems in children and act in an additive manner.

Background: The efficacies of granisetron plus dexamethasone and dexamethasone alone in controlling delayed nausea and vomiting after cisplatin chemotherapy (> or = 69 mg/m2) were compared in a multicentre, double-blind, placebo-controlled comparative study., Patients and Methods: In all, 654 patients (of whom 619 were evaluable) received prophylactic granisetron plus dexamethasone before chemotherapy on day 0; on day 1 complete responders and non-responders were randomized separately to receive dexamethasone, 8 mg b.d. p.o., with either granisetron, 1 mg b.d. p.o., or matching placebo for six days., Results: Over days 1-6 the complete response rates were 54.5% (dexamethasone group) and 52.1% (dexamethasone plus granisetron group). Response rates were higher over days 4-6 (71.8% and 70.7%, respectively) than over days 1-3 (60.4% and 57.9%, respectively). Significantly more patients who responded to antiemetic treatment during day 0 were responders over days 1-6 (63% vs. 17%; P < 0.001). No other treatment-related differences were found. Adverse events tended to be minor, with constipation and headache the most common. Overall, there were no significant differences in the safety profiles of the two regimens, but constipation and abdominal pain were significantly more common in the dexamethasone plus granisetron group., Conclusions: Granisetron plus dexamethasone did not appear to confer additional benefit over use of dexamethasone alone in controlling delayed nausea and vomiting following cisplatin chemotherapy. Control of acute nausea and vomiting, however, appeared to be an important factor influencing delayed nausea and vomiting.

Patients and Methods: Three anti-emetic treatment regimens were compared in 357 patients receiving cisplatin therapy (mean dose 81 mg/m2) in this double-blind randomized study. Regimens studied were i) granisetron 1 mg bd orally for 7 days (granisetron alone); ii) gran 1 mg bd orally for 7 days plus prophylactic dexamethasone (12 mg i.v.) on the first day only (gran/dex); iii) metoclopramide (3 mg/kg i.v. loading dose; 4 mg/kg i.v. infusion) plus dex (12 mg i.v.) on the first day followed by met 10 mg orally tds for a further 6 days (met/dex)., Results: At 24 hours, gran/dex was significantly superior to met/dex in terms of total anti-emetic control, defined as no nausea, no vomiting, no rescue anti-emetic therapy, not withdrawn (54.7% gran/dex vs. 37.2% met/dex; P < 0.01). There was also a significant delay in time to onset of nausea (P < 0.01) and vomiting (P < 0.01) following gran/dex compared with met/dex. Oral granisetron alone was as effective as met/dex in control of acute emesis in all parameters examined. There were no significant differences between the three groups in the control of delayed nausea and vomiting. The most common adverse experiences in both granisetron groups were headache and constipation, both characteristic of 5-HT3 antagonists. Agitation, somnolence, diarrhoea and decreased appetite were reported more frequently by the met/dex group., Conclusions: Oral granisetron as a single agent is as effective as high doses of i.v. met/dex in preventing cisplatin-induced emesis. Oral granisetron in combination with a corticosteroid provides superior anti-emetic control to the met/dex regimen in patients undergoing highly emetogenic chemotherapy.

Background: Because of its antitumour activity and its pharmacological advantage when administered by the intraperitoneal route, carboplatin was studied in a phase II multicentric trial. The aim of the study was to determine the response rate and the toxicity of carboplatin administered intraperitoneally and to determine if pathological complete response could be attained in women with macroscopic residual ovarian cancer at second-look laparotomy after intravenous cisplatin chemotherapy., Patients and Methods: Twenty-nine patients with macroscopical residual disease after intravenous cisplatin-based chemotherapy at second-look laparotomy, were treated at that time with 300 mg/m2 of carboplatin administered in the abdominal cavity every four weeks for six cycles. In instances of negative findings at physical and CT scan examination, laparotomy evaluation was performed and the catheter was removed. The dose of carboplatin was increased or decreased according to hematological toxicity., Results: Efficacy is evaluable in 25 pts: 2 pts had pathological complete responses and 1 pt had microscopic disease (12% response rate of evaluable patients). Toxicity is evaluable for 135 cycles in 29 patients. No grade 4 hematological toxicity was observed, 2 pts had grade 3 leukopenia and 3 pts had grade 3 thrombocytopenia; grade 3 vomiting was observed in 11% of cycles. No peritoneal complication was observed; catheter dysfunction occurred after the first cycle in one patient who refused a surgical procedure to remove the catheter and to pursue treatment., Conclusion: Intraperitoneal carboplatin demonstrates efficacy in patients with macroscopical residual disease at second-look laparotomy after first-line cisplatin chemotherapy. The recommended dose for further studies is 300 mg/m2 administered every 4 weeks. A low response rate does not favour a randomised study.

Visual function was studied in a group of 15 patients with hereditary motor and sensory neuropathy (HMSN). Psychophysical measures of luminance and chromatic threshold and temporal contrast sensitivity were undertaken, together with visual evoked potentials (VEPs), visual fields and clinical neuro-ophthalmological examination. A patchy loss of visual function was found in individual cases of HMSN. In the group analysis there was evidence of a selective loss of luminance threshold and temporal contrast sensitivity at low temporal frequencies; the VEP P100 latency was not significantly prolonged. The losses of visual function in HMSN were discussed and compared with visual losses in multiple sclerosis, which had been detected using identical experimental techniques.

Visual thresholds and perceptual latencies were determined in patients with multiple sclerosis (MS) and in normal control subjects. Measurements were made under light- and dark-adapted conditions, with stimuli chosen to stimulate rod and cone receptors selectively. More abnormalities in perceptual latency and luminance threshold were recorded in the light-adapted condition than in the dark-adapted condition, but this result was not specific to the rod or cone systems. Possible underlying pathophysiological processes are discussed, and it is suggested that reduced conduction velocity in the demyelinated visual pathway is the most likely explanation of the observed perceptual delays and that there is no evident retinal contribution.

4-Aminopyridine (4-AP) was administered to two groups of patients with multiple sclerosis (MS). The first group consisted of 5 patients with labile visual symptoms, 2 of whom had arcuate scotomata. 4-AP improved visual performance of most patients in this group and reduced the size of scotomata. The second group consisted of 5 patients with the spinal form of MS who were in a stable state; in this group 4-AP had little effect clinically or on tests of visual function.