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To examine prenatal APAP exposure in relation to language development in offspring at 30 months of age.
A population-based pregnancy cohort study including 754 women who enrolled in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study in pregnancy week 8–13. Two exposure measures were used: (1) maternally reported number of APAP tablets taken between conception and enrollment; (2) APAP urinary concentration at enrollment. Language development at 30 months was assessed by nurse's evaluation and parental questionnaire, including the number of words the child used (<25, 25–50 and >50). Main study outcome; parental report of use of fewer than 50 words, termed language delay (LD).
59.2% of women enrolled in weeks 8–13 reported taking APAP between conception and enrollment. APAP was measurable in all urine samples and urinary APAP was correlated with the number of APAP taken during pregnancy (P<0.01). Language delay was more prevalent in boys (12.6%) than girls (4.1%) (8.5% in total). Both the number of APAP tablets and urinary APAP concentration were associated with greater LD in girls but not in boys. The adjusted odds ratio (OR) for LD among girls whose mothers reported >6 vs. 0 APAP tablets was 5.92 (95% confidence interval (CI) 1.10–31.94). The OR for LD in girls whose mothers’ urinary APAP was in the highest compared to the lowest quartile was 10.34 (95% CI 1.37–77.86). While it cannot be ruled out, our available data do not support confounding by indication.
Given the prevalence of prenatal APAP use and the importance of language development, these findings, if replicated, would suggest that pregnant women should limit their use of this analgesic during pregnancy.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
To determine the pre- and post-operative prevalence of dizziness, tinnitus and taste disturbances in adult cochlear implant recipients.
A questionnaire regarding pre- and post-operative dizziness, tinnitus and taste disturbances was sent to 170 cochlear implant recipients implanted between January 2003 and March 2009. Seventy-seven patients (41 per cent) responded.
Pre-operatively, 20 per cent of the participants experienced dizziness, 52 per cent experienced tinnitus and 3 per cent experienced taste disturbances. Post-operative dizziness developed in 46 per cent of patients and resolved in the majority of these; however, 15 per cent reported dizziness more than six months after implantation. Tinnitus worsened in 25 per cent of patients, whereas 73 per cent reported attenuation or termination of tinnitus. Post-operatively, tinnitus developed in 12 per cent and taste disturbances developed in 17 per cent of the patients.
The high prevalence of dizziness, tinnitus and taste disturbances reported by cochlear implant recipients necessitates that assessment of symptoms related to inner ear and chorda tympani damage are included when evaluating operative results.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
Social context has a major influence on the detection and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas, particularly where gang culture, community violence, normalisation of drug use and repetitive maladaptive family structures prevail. This paper aims to examine how social context influences the development, identification and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas from the perspectives of health care workers.
Semi-structured interviews were conducted with health care workers (n=37) from clinical settings including: primary care, secondary care and community agencies and analysed thematically using Bronfenbrenner’s Ecological Theory to guide analysis.
Health care workers’ engagement with young people was influenced by the multilevel ecological systems within the individual’s social context which included: the young person’s immediate environment/‘microsystem’ (e.g., family relationships), personal relationships in the ‘mesosystem’ (e.g., peer and school relationships), external factors in the young person’s local area context/‘exosystem’ (e.g., drug culture and criminality) and wider societal aspects in the ‘macrosystem’ (e.g., mental health policy, health care inequalities and stigma).
In socioeconomically disadvantaged urban areas, social context, specifically the micro-, meso-, exo-, and macro-system impact both on the young person’s experience of mental health or substance use problems and services, which endeavour to address these problems. Interventions that effectively identify and treat these problems should reflect the additional challenges posed by such settings.
People with a diagnosis of schizophrenia have limited metacognitive awareness of their symptoms. This is also evident for cognitive difficulties when neuropsychological assessments and self-reports are compared. Unlike for delusions and hallucinations, little attention has been given to factors that may influence the mismatch between objective and subjectively reported cognitive problems. Symptom severity, and also self-esteem and social functioning, can have an impact on cognitive problem perception and help to explain the gap between objective and subjective cognitive assessments in psychosis.
One-hundred participants with a diagnosis of schizophrenia were recruited and assessed with a comprehensive neuropsychological battery, a measure of awareness of cognitive problems and measures of psychotic symptoms, social and behavioural functioning and self-esteem. Regression was used to investigate the influence of symptoms, social functioning and self-esteem, and patients with different levels of cognitive problem awareness were contrasted.
Simple correlation analysis replicated the lack of association between objective cognitive measures and metacognitive awareness of cognitive problems. However, the results of the regression analyses highlight that self-esteem and negative symptoms predict metacognitive awareness. When significant predictors were controlled, individuals with better awareness had more impaired working memory but higher IQ.
Poor self-esteem and high negative symptoms are negatively associated with metacognitive awareness in people with schizophrenia. Interventions that aim to improve cognition should consider that cognitive problem reporting in people with schizophrenia correlates poorly with objective measures and is biased not only by symptoms but also by self-esteem. Future studies should explore the causal pathways using longitudinal designs.
Cannabis varies considerably in levels of its two major constituent cannabinoids – (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Recently, we found evidence that those who smoked cannabis containing detectable levels of CBD had fewer psychotic-like symptoms than those whose cannabis had no CBD. The present study aimed, first, to replicate those findings and, second, to determine whether protective effects of CBD may extend to other harms of cannabis, such as memory impairment and reduced psychological well-being.
A total of 120 current cannabis smokers, 66 daily users and 54 recreational users were classified into groups according to whether analysis of their hair revealed the presence or absence of CBD and high versus low levels of THC. All were assessed on measures of psychosis-like symptoms, memory (prose recall; source memory) and depression/anxiety.
Lower psychosis-like symptoms were found in those whose hair had CBD compared with those without. However, this was seen only in recreational users, who had higher levels of THC in their hair. Higher THC levels in hair were associated with increased depression and anxiety. Prose recall and source memory were poorer in daily users with high THC levels in hair while recognition memory was better in individuals with CBD present in hair.
CBD attenuates the psychotic-like effects of cannabis over time in recreational users. Higher THC negatively impacts on memory and psychological well-being. These findings raise concerns for the harms stemming from use of varieties such as ‘skunk’ (sensimillia), which lack any CBD but currently dominate the supply of cannabis in many countries.
Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.
A major outbreak of tuberculosis occurred in cattle on a farm in Dorset between 1970 and 1976. Six hundred and twenty-six cattle were slaughtered either because they reacted to the tuberculin test or had been exposed to infection. No source of infection was found until 1974 when badgers infected with Mycobacterium bovis were first discovered.
An analysis of the tuberculin test records of this herd and the six surrounding herds indicated that tuberculosis had been a sporadic problem since the early 1960's. Two peaks of infection occurred in the most severely affected herd in 1970 and 1974 when 29·8% and 27·3% of animals, respectively, reacted to the tuberculin test. These figures are exceptionally high. During the last 20 years there have been two periods when all the herds in the area had synchronous outbreaks consistent with a common source.
Analysis indicated that cattle were at greatest risk in April and May and suggest that there was re-exposure to infection at this time each year. In addition the cattle were apparently exposed to M. bovis, at sufficiently high levels for transmission to occur, for only a relatively short period of time.
Following a major outbreak of tuberculosis in cattle on a farm in Dorset, badgers were discovered to be infected with Mycobacterium bovis. Two hundred and forty sets were found in the 1200 hectares of the study area. The sets were found predominantly in areas of Portland Sand. A high prevalence of tuberculosis was found in the badger population which was removed and repopulation prevented for 3 years. The removal of the infected badgers led to the resolution of the problem in cattle. Re-colonization of the area has progressed slowly and the cattle have remained free from infection for a period of 5 years.
A large sample of the wild mammals found on a farm in South Dorset were trapped and examined for the presence of Mycobacterium bovis following the discovery of widespread infection in cattle and badgers. M. bovis was isolated from the lymph nodes of two out of 90 rats (Rattus norvegicus) and one out of seven foxes (Vulpes vulpes) but no lesions of tuberculosis were observed. It was concluded that the badger was the only species of wild mammal which was a reservoir of M. bovis in this area.
This chapter focuses on the mechanisms by which environmental exposures can induce endocrine disruption. It highlights the mechanisms that play important roles in developmental programming. Endocrine-disrupting chemicals, which mimic the activity of endogenous hormones and activate receptors are termed agonists, whereas those that inhibit receptor activity are termed antagonists. During the perinatal period programming of the endocrine axis occurs, making this a vulnerable period of exposure to endogenous and exogenous stimuli. Among the endocrine-disrupting chemicals (EDCs), xenoestrogens have garnered a significant amount of attention due to the well-known effects of the xenoestrogen diethylstilbestrol (DES) in humans, and the identification of many other estrogenic anthropogenic chemicals. Metabolism plays a key role in maintaining hormone homeostasis. Endocrine-disrupting chemicals can disturb normal hormone homeostasis, which can have both direct and indirect effects on the reproductive function of both wildlife and human populations.
Let X1, X2, …, Xn be independent random variables uniformly distributed on [0,1]. We observe these sequentially and have to stop on exactly one of them. No recall of preceding observations is permitted. What stopping rule minimizes the expected rank of the selected observation? What is the value of the expected rank (as a function of n) and what is the limit of this value when n goes to ∞? This full-information expected selected-rank problem is known as Robbins' problem of minimizing the expected rank, and its general solution is unknown. In this paper we provide an alternative approach to Robbins' problem. Our model is similar to that of Gnedin (2007). For this, we consider a continuous-time version of the problem in which the observations follow a Poisson arrival process on ℝ+ × [0,1] of homogeneous rate 1. Translating the previous optimal selection problem in this setting, we prove that, under reasonable assumptions, the corresponding value function w(t) is bounded and Lipschitz continuous. Our main result is that the limiting value of the Poisson embedded problem exists and is equal to that of Robbins' problem. We prove that w(t) is differentiable and also derive a differential equation for this function. Although we have not succeeded in using this equation to improve on bounds on the optimal limiting value, we argue that it has this potential.
Transcriptomic studies are useful for elucidating molecular mechanisms through which changes in nutrient availability produce pleiotropic effects on whole-body and tissue physiology. To further the knowledge of gene-regulatory effects of Zn on tissues important for adult and fetal Zn nutrition, we analysed the responses of human intestinal Caco-2 and placental JAR cells to changes in Zn supply. Analysis of oligonucleotide microarrays demonstrated that, despite the analogous roles of the two tissues in nutrient transfer, different genes respond to changes in Zn availability in intestinal cells compared with placental cells. A number of Fe- and Cu-related genes were identified as targets for regulation by Zn, revealing potential mechanisms underlying reported dietary interactions between Zn and other metals. We established that there are fundamental differences in Zn-regulated transcriptional control in Caco-2 compared with JAR cells. We demonstrated that Zn-induced transcriptional activation of the metallothionein 2A promoter occurs over different, and physiologically relevant, concentration ranges in Caco-2 and JAR cells, indicating that these cell lines sense changes in the extracellular Zn concentration over different ranges. Also, we established that mRNA levels of the Zn-responsive metal response element binding transcription factor (MTF)-1, and its homologue MTF-2, are regulated by Zn in Caco-2 but not JAR cells, which may in part underlie differential gene responses to Zn in intestinal and placental cells. The present study identified a number of novel molecular targets that may underlie symptoms associated with deficient or excessive Zn supply and highlighted the necessity of taking account of cell- and tissue-specific processes when investigating Zn-regulated gene expression in mammals.
Although people with schizophrenia display impaired abilities for consent, it is not known how much impairment constitutes incapacity.
To assess a method for determining the categorical capacity status of potential participants in schizophrenia research.
Expert-judgement validation of capacity thresholds on the sub-scales of the MacArthur Competence Assessment Tool – Clinical Research (MacCAT–CR) was evaluated using receiver operating characteristic (ROC) analysis in 91 people with severe mental illness and 40 controls.
The ROC areas under the curve for the understanding, appreciation and reasoning sub-scales of the MacCAT–CR were 0.94 (95% CI 0.88–0.99), 0.85 (95% CI 0.76–0.94) and 0.80 (95% CI 0.70–0.90). These findings yielded negative and positive predictive values of incapacity that can guide the practice of investigators and research ethics committees.
By performing such validation studies for a few categories of research with varying risks and benefits, it might be possible to create evidence-based capacity determination guidelines for most schizophrenia research.