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Introduction: Epidemiologic and modeling studies suggest that between 45 and 70% of individuals with chronic hepatitis C virus (HCV) infection in Canada remain undiagnosed. The Canadian Association for the Study of the Liver (CASL) recommends one-time screening of baby boomers (1945-1975). Screening programs in the US have shown a very high prevalence of previously undiagnosed HCV among patients seen in the emergency department (ED). We sought to assess the feasibility of implementing a targeted birth-cohort HCV screening program in a Canadian ED setting. Methods: Patients born from 1945 to 1975 presenting to the ED of a downtown Toronto hospital were offered HCV testing. Patients with life-threatening conditions, unable to provide verbal consent in English or intoxication were excluded. Blood samples were collected by finger prick on Dried Blood Spot (DBS) collection cards and tested for anti-HCV antibody with reflex to HCV RNA. Patients with positive HCV RNA were referred to a liver specialist. Results: During a 27-month period (July 2017 - Sept 2019), 8363 patients in the birth cohort presented to the ED during daytime hours. 80% (6714) met eligibility criteria, and 48.4% (3247) were offered testing. Screening was performed by non-medical staff (mean 8/day, median spots on DBS 4). 345 (10.6%) had been previously tested, and 639 (19.7%) declined. 2136 (65.8%) patients underwent testing: median age 58.4 years (40-82), 1117 male (52.3%). Of these, 45 patients (2.1%; 95% CI 1.5%-2.7%) were anti-HCV positive: 32 (76.2%) were HCV RNA positive, 10 (23.8%) negative and 3 not done due to inadequate DBS sample. 26 patients (81.3%) were linked to care and 3 (9.4%) lost to follow-up. HCV prevalence in the ED was significantly higher than the general Canadian population (2.1% vs 0.7%; p < 0.0001) but much lower than reported rates in American EDs (2.1% vs 10.3%; p < 0.0001). Conclusion: Acceptance of HCV screening in the ED birth cohort was high and easily performed using DBS to ensure the majority of positive samples were tested for HCV RNA. Challenges included implementation that limited number of people tested, and linkage to care for HCV positive patients. HCV prevalence among this ED birth cohort was higher than the general population but lower than seen in the ED in the US. This may in part be due to exclusion of individuals with more severe medical issues, refusal by higher risk subgroups, or population and healthcare system differences between countries.
Twenty-six percent of children experience a traumatic event by the age of 4. Negative events during childhood have deleterious correlates later in life, including antisocial behavior. However, the mechanisms that play into this relation are unclear. We explored deficits in neurocognitive functioning, specifically problems in passive avoidance, a construct with elements of inhibitory control and learning as a potential acquired mediator for the pathway between cumulative early childhood adversity from birth to age 7 and later antisocial behavior through age 18, using prospective longitudinal data from 585 participants. Path analyses showed that cumulative early childhood adversity predicted impaired passive avoidance during adolescence and increased antisocial behavior during late adolescence. Furthermore, poor neurocognition, namely, passive avoidance, predicted later antisocial behavior and significantly mediated the relation between cumulative early childhood adversity and later antisocial behavior. This research has implications for understanding the development of later antisocial behavior and points to a potential target for neurocognitive intervention within the pathway from cumulative early childhood adversity to later antisocial behavior.
Interstage mortality causes are often unknown in infants with shunt-dependent univentricular defects. For 2 years, screening catheterisation was encouraged before neonatal discharge to determine if routine evaluation improved interstage outcomes.
Retrospective single-centre review of home monitoring programme from December, 2010 to June, 2012. Composite scores were created for physical examination/echocardiography risk factors; catheterisation risk factors; and interstage adverse events. Composite scores were compared between usual care and screening catheterisation groups. The ability of each risk factor composite to predict interstage adverse events, individually and in combination, was assessed with sensitivity, specificity, and receiver operating characteristic curves.
There were 27 usual care and 32 screening catheterisation patients. There were no significant differences between groups except rates of catheterisation before discharge (29.6 versus 100%, p < 0.001). Usual care patients who underwent catheterisation for clinical indications had higher intervention rates (37.5 versus 3.1%, p = 0.004). Physical examination/echocardiography risk factor frequency was similar, but usual care patients with catheterisation had a higher catheterisation risk factor frequency. Interstage adverse event frequency was similar (48.2 versus 53.1%, p = 0.7). For interstage adverse event prediction, sensitivity for the physical examination/echocardiography, catheterisation, and either risk factor composites was 53.3, 72, and 80%, respectively; specificity was 59, 60, and 48%. The area under the receiver operating characteristic curve was 0.56, 0.66, and 0.64.
Screening catheterisation evaluation offered slightly increased sensitivity and specificity, but no difference in interstage adverse event frequency. Given this small advantage versus known risks, screening catheterisations are no longer encouraged.
Chondritic meteorites, and especially the most volatile-rich chondrites, the carbonaceous chondrites, preserve a record of the solar protoplanetary disk dust component and how it has been changed both in the disk environment itself and in its asteroidal parent body. Here we review some of the key features of carbonaceous chondrites and report some new data on their organics component. These show that the nebula reached temperature of >10000C, but only very locally, to produce chondrules. Most meteoritic material underwent thermal and/or aqueous processing, but some retain delicate nebular components such as complex organic molecules and amorphous silicates.
We recently reported an association of offspring educational attainment with polygenic risk scores (PRS) computed on parent’s non-transmitted alleles for educational attainment using the second GWAS meta-analysis article on educational attainment published by the Social Science Genetic Association Consortium. Here we test the replication of these findings using a more powerful PRS from the third GWAS meta-analysis article by the Consortium. Each of the key findings of our previous paper is replicated using this improved PRS (N = 2335 adolescent twins and their genotyped parents). The association of children’s attainment with their own PRS increased substantially with the standardized effect size, moving from β = 0.134, 95% CI = 0.079, 0.188 for EA2, to β = 0.223, 95% CI = 0.169, 0.278, p < .001, for EA3. Parent’s PRS again predicted the socioeconomic status (SES) they provided to their offspring and increased from β = 0.201, 95% CI = 0.147, 0.256 to β = 0.286, 95% CI = 0.239, 0.333. Importantly, the PRS for alleles not transmitted to their offspring — therefore acting via the parenting environment — was increased in effect size from β = 0.058, 95% CI = 0.003, 0.114 to β = 0.067, 95% CI = 0.012, 0.122, p = .016. As previously found, this non-transmitted genetic effect was fully accounted for by parental SES. The findings reinforce the conclusion that genetic effects of parenting are substantial, explain approximately one-third the magnitude of an individual’s own genetic inheritance and are mediated by parental socioeconomic competence.
Recovery Colleges are opening internationally. The evaluation focus has been on outcomes for Recovery College students who use mental health services. However, benefits may also arise for: staff who attend or co-deliver courses; the mental health and social care service hosting the Recovery College; and wider society. A theory-based change model characterising how Recovery Colleges impact at these higher levels is needed for formal evaluation of their impact, and to inform future Recovery College development. The aim of this study was to develop a stratified theory identifying candidate mechanisms of action and outcomes (impact) for Recovery Colleges at staff, services and societal levels.
Inductive thematic analysis of 44 publications identified in a systematised review was supplemented by collaborative analysis involving a lived experience advisory panel to develop a preliminary theoretical framework. This was refined through semi-structured interviews with 33 Recovery College stakeholders (service user students, peer/non-peer trainers, managers, community partners, clinicians) in three sites in England.
Candidate mechanisms of action and outcomes were identified at staff, services and societal levels. At the staff level, experiencing new relationships may change attitudes and associated professional practice. Identified outcomes for staff included: experiencing and valuing co-production; changed perceptions of service users; and increased passion and job motivation. At the services level, Recovery Colleges often develop somewhat separately from their host system, reducing the reach of the college into the host organisation but allowing development of an alternative culture giving experiential learning opportunities to staff around co-production and the role of a peer workforce. At the societal level, partnering with community-based agencies gave other members of the public opportunities for learning alongside people with mental health problems and enabled community agencies to work with people they might not have otherwise. Recovery Colleges also gave opportunities to beneficially impact on community attitudes.
This study is the first to characterise the mechanisms of action and impact of Recovery Colleges on mental health staff, mental health and social care services, and wider society. The findings suggest that a certain distance is needed in the relationship between the Recovery College and its host organisation if a genuine cultural alternative is to be created. Different strategies are needed depending on what level of impact is intended, and this study can inform decision-making about mechanisms to prioritise. Future research into Recovery Colleges should include contextual evaluation of these higher level impacts, and investigate effectiveness and harms.
This study investigated the characteristics of subjective memory complaints (SMCs) and their association with current and future cognitive functions.
A cohort of 209 community-dwelling individuals without dementia aged 47–90 years old was recruited for this 3-year study. Participants underwent neuropsychological and clinical assessments annually. Participants were divided into SMCs and non-memory complainers (NMCs) using a single question at baseline and a memory complaints questionnaire following baseline, to evaluate differential patterns of complaints. In addition, comprehensive assessment of memory complaints was undertaken to evaluate whether severity and consistency of complaints differentially predicted cognitive function.
SMC and NMC individuals were significantly different on various features of SMCs. Greater overall severity (but not consistency) of complaints was significantly associated with current and future cognitive functioning.
SMC individuals present distinctive features of memory complaints as compared to NMCs. Further, the severity of complaints was a significant predictor of future cognition. However, SMC did not significantly predict change over time in this sample. These findings warrant further research into the specific features of SMCs that may portend subsequent neuropathological and cognitive changes when screening individuals at increased future risk of dementia.
Collaborative quality improvement and learning networks have amended healthcare quality and value across specialities. Motivated by these successes, the Pediatric Acute Care Cardiology Collaborative (PAC3) was founded in late 2014 with an emphasis on improving outcomes of paediatric cardiology patients within cardiac acute care units; acute care encompasses all hospital-based inpatient non-intensive care. PAC3 aims to deliver higher quality and greater value care by facilitating the sharing of ideas and building alignment among its member institutions. These aims are intentionally aligned with the work of other national clinical collaborations, registries, and parent advocacy organisations. The mission and early work of PAC3 is exemplified by the formal partnership with the Pediatric Cardiac Critical Care Consortium (PC4), as well as the creation of a clinical registry, which links with the PC4 registry to track practices and outcomes across the entire inpatient encounter from admission to discharge. Capturing the full inpatient experience allows detection of outcome differences related to variation in care delivered outside the cardiac ICU and development of benchmarks for cardiac acute care. We aspire to improve patient outcomes such as morbidity, hospital length of stay, and re-admission rates, while working to advance patient and family satisfaction. We will use quality improvement methodologies consistent with the Model for Improvement to achieve these aims. Membership currently includes 36 centres across North America, out of which 26 are also members of PC4. In this report, we describe the development of PAC3, including the philosophical, organisational, and infrastructural elements that will enable a paediatric acute care cardiology learning network.
There are no available medications for the management of alcohol dependence for patients with alcoholic liver disease (ALD).
To conduct a multisite, double blind, placebo-controlled, randomised clinical trial of baclofen in the treatment of alcohol dependence, with or without liver disease (trial registration: ClinicalTrials.gov, NCT01711125).
Patients (n = 104) were randomised to placebo, baclofen 30 mg/day or 75 mg/day for 12 weeks. Primary outcomes included survival time to lapse (any drinking), relapse (≥5 drinks per day in men and ≥4 in women), and the composite outcome of drinks per drinking day, number of heavy drinking days, and percentage days abstinent.
There was a significant effect of baclofen (composite groups) on time to lapse (χ2 = 6.44, P<0.05, Cohen's d = 0.56) and relapse (χ2 = 4.62, P<0.05, d = 0.52). A significant treatment effect of baclofen was observed for percentage days abstinent (placebo 43%, baclofen 30 mg 69%, baclofen 75 mg 65%; P<0.05). There was one serious adverse event (overdose) directly related to medication (75 mg).
Baclofen may be an effective treatment option for patients with ALD. However, given the profile of adverse events, the role for this medication might be best limited to specialist services.
Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.
Research shows that childhood dysregulation is associated with later psychiatric disorders. It does not yet resolve discrepancies in the operationalization of dysregulation. It is also far from settled on the origins and implications of individual differences in dysregulation. This study tested several operational definitions of dysregulation using Achenbach attention, anxious/depressed, and aggression subscales. Individual growth curves of dysregulation were computed, and predictors of growth differences were considered. The study also compared the predictive utility of the dysregulation indexes to standard externalizing and internalizing indexes. Dysregulation was indexed annually for 24 years in a community sample (n = 585). Hierarchical linear models considered changes in dysregulation in relation to possible influences from parenting, family stress, child temperament, language, and peer relations. In a test of the meaning of dysregulation, it was related to functional and psychiatric outcomes in adulthood. Dysregulation predictions were further compared to those of the more standard internalizing and externalizing indexes. Growth curve analyses showed strong stability of dysregulation. Initial levels of dysregulation were predicted by temperamental resistance to control, and change in dysregulation was predicted by poor language ability and peer relations. Dysregulation and externalizing problems were associated with negative adult outcomes to a similar extent.
The current study used data from two longitudinal samples to test whether self-regulation, depressive symptoms, and aggression/antisociality were mediators in the relation between a polygenic score indexing serotonin (5-HT) functioning and alcohol use in adolescence. The results from an independent genome-wide association study of 5-hydroxyindoleacetic acid in the cerebrospinal fluid were used to create 5-HT polygenic risk scores. Adolescents and/or parents reported on adolescents’ self-regulation (Time 1), depressive symptoms (Time 2), aggression/antisociality (Time 2), and alcohol use (Time 3). The results showed that 5-HT polygenic risk did not predict self-regulation. However, adolescents with higher levels of 5-HT polygenic risk showed greater depression and aggression/antisociality. Adolescents’ aggression/antisociality mediated the relation between 5-HT polygenic risk and later alcohol use. Deficits in self-regulation also predicted depression and aggression/antisociality, and indirectly predicted alcohol use through aggression/antisociality. Pathways to alcohol use were especially salient for males from families with low parental education in one of the two samples. The results provide insights into the longitudinal mechanisms underlying the relation between 5-HT functioning and alcohol use (i.e., earlier aggression/antisociality). There was no evidence that genetically based variation in 5-HT functioning predisposed individuals to deficits in self-regulation. Genetically based variation in 5-HT functioning and self-regulation might be separate, transdiagnostic risk factors for several types of psychopathology.
This study considers the developmental origins of alcohol use in young adulthood. Despite substantial evidence linking committed romantic relationships to less problematic alcohol use in adulthood, the uniformity of these protective benefits across different romantic relationships is unclear. Further, the extent to which the establishment and maintenance of these romantic relationships is preceded by earlier adolescence alcohol use remains unknown. To address these gaps in the literature, the current study utilized multitiple-dimensional, multiple-informant data spanning 20 years on 585 individuals in the Child Development Project. Findings from both variable- and person-centered analyses support a progression of associations predicting adolescent alcohol use (ages 15–16), drinking, and romantic relationships in early adulthood (ages 18–25), and then problematic young adult alcohol use (age 27). Although adolescent alcohol use predicted greater romantic involvement and turnover in early adulthood, romantic involvement, but not turnover, appeared to reduce the likelihood of later problematic drinking. These findings remained robust even after accounting for a wide array of selection and socialization factors. Moreover, characteristics of the individuals (e.g., gender) and of their romantic relationships (e.g., partner substance use problems and romantic relationship satisfaction) did not moderate these findings. Findings underscore the importance of using a developmental–relational perspective to consider the antecedents and consequences of alcohol use early in the life span.
National organisations in several countries have recently released more restrictive guidelines for infective endocarditis prophylaxis, including the American Heart Association 2007 guidelines. Initial studies demonstrated no change in infective endocarditis rates over time; however, a recent United Kingdom study suggested an increase; current paediatric trends are unknown.
Children (<18 years) hospitalised with infective endocarditis at 29 centres participating in the Pediatric Health Information Systems Database from 2003 to 2014 were eligible for inclusion. Our primary analysis focussed on infective endocarditis most directly related to the change in guidelines and included community-acquired cases in those >5 years of age. Interrupted time series analysis was used to evaluate rates over time indexed to total hospitalisations.
A total of 841 cases were identified. The median age was 13 years (interquartile range 9–15 years). In the pre-guideline period, there was a slight increase in the rate of infective endocarditis by 0.13 cases/10,000 hospitalisations per semi-annual period. In the post-guideline period, the rate of infective endocarditis increased by 0.12 cases/10,000 hospitalisations per semi-annual period. There was no significant difference in the rate of change in the pre- versus post-guidelines period (p=0.895). Secondary analyses in children >5 years of age with CHD and in children hospitalised with any type of infective endocarditis at any age revealed similar results.
We found no significant change in infective endocarditis hospitalisation rates associated with revised prophylaxis guidelines over 11 years across 29 United States children’s hospitals.
Dialysis is the process by which an artificial kidney device removes waste and excess water from a patient. An outstanding problem with dialysis is that the body has a remarkable immune function where proteins and antigens mark foreign objects as possible threats despite the biocompatibility of the material. Upon adhesion to polymeric materials used currently in dialysis, proteins are lost. In this study, polytetrafluoroethylene (PTFE) is investigated as a potential replacement material for dialysis tubing because of its unreactive nature. The focus is to determine if PTFE will prove a viable material in minimizing protein adhesion and further reducing antibody loss of the patient. Protein loss as a function of filtration time was measured. PVC and PTFE materials were investigated following the same battery of testing where the protein concentrations in the blood were characterized using UV Visible spectrophotometry. Results demonstrate a loss of nearly 12 percent of blood proteins to the PVC material over the course of a typical dialysis treatment. Conversely, the protein loss due to adhesion to PTFE was less than two percent.
We conducted a developmental analysis of genetic moderation of the effect of the Fast Track intervention on adult externalizing psychopathology. The Fast Track intervention enrolled 891 children at high risk to develop externalizing behavior problems when they were in kindergarten. Half of the enrolled children were randomly assigned to receive 10 years of treatment, with a range of services and resources provided to the children and their families, and the other half to usual care (controls). We previously showed that the effect of the Fast Track intervention on participants' risk of externalizing psychopathology at age 25 years was moderated by a variant in the glucocorticoid receptor gene. Children who carried copies of the A allele of the single nucleotide polymorphism rs10482672 had the highest risk of externalizing psychopathology if they were in the control arm of the trial and the lowest risk of externalizing psychopathology if they were in the treatment arm. In this study, we test a developmental hypothesis about the origins of this for better and for worse Gene × Intervention interaction (G × I): that the observed G × I effect on adult psychopathology is mediated by the proximal impact of intervention on childhood externalizing problems and adolescent substance use and delinquency. We analyzed longitudinal data tracking the 270 European American children in the Fast Track randomized control trial with available genetic information (129 intervention children, 141 control group peers, 69% male) from kindergarten through age 25 years. Results show that the same pattern of for better and for worse susceptibility to intervention observed at the age 25 follow-up was evident already during childhood. At the elementary school follow-ups and at the middle/high school follow-ups, rs10482672 predicted better adjustment among children receiving the Fast Track intervention and worse adjustment among children in the control condition. In turn, these proximal G × I effects early in development mediated the ultimate G × I effect on externalizing psychopathology at age 25 years. We discuss the contribution of these findings to the growing literature on genetic susceptibility to environmental intervention.
Molecular imprinting is the process by which molecules are imprinted into the matrix of a material through non-covalent bonding, including hydrogen bonding and van der Waals interactions. In this study hydrogels were imprinted with glaucoma medication with the purpose of creating a reusable ocular drug delivery device with reversible binding sites. The material was synthesized and tested with UV-Vis spectroscopy to determine the concentration of the released drug after twelve hours in distilled water. Modifications were made to the polymer to explore methods required for the proper delivery of the drug over an adequate period of time.
This longitudinal study considers externalizing behavior problems from ages 5 to 27 (N = 585). Externalizing problem ratings by mothers, fathers, teachers, peers, and self-report were modeled with growth curves. Risk and protective factors across many different domains and time frames were included as predictors of the trajectories. A major contribution of the study is in demonstrating how heterotypic continuity and changing measures can be handled in modeling changes in externalizing behavior over long developmental periods. On average, externalizing problems decreased from early childhood to preadolescence, increased during adolescence, and decreased from late adolescence to adulthood. There was strong nonlinear continuity in externalizing problems over time. Family process, peer process, stress, and individual characteristics predicted externalizing problems beyond the strong continuity of externalizing problems. The model accounted for 70% of the variability in the development of externalizing problems. The model's predicted values showed moderate sensitivity and specificity in prediction of arrests, illegal drug use, and drunk driving. Overall, the study showed that by using changing, developmentally relevant measures and simultaneously taking into account numerous characteristics of children and their living situations, research can model lengthy spans of development and improve predictions of the development of later, severe externalizing problems.