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The Fontan Outcomes Network was created to improve outcomes for children and adults with single ventricle CHD living with Fontan circulation. The network mission is to optimise longevity and quality of life by improving physical health, neurodevelopmental outcomes, resilience, and emotional health for these individuals and their families. This manuscript describes the systematic design of this new learning health network, including the initial steps in development of a national, lifespan registry, and pilot testing of data collection forms at 10 congenital heart centres.
This paper maps key regulatory, governance and legal challenges associated with the UK's withdrawal from the European Union (EU) in terms of convergent and divergent pressures within the global pharmaceutical sector. These include (i) convergent regulatory pressures associated with the European framework for pre-market licensing; (ii) convergent and divergent industry pressures with regard to drug discovery and manufacturing; and (iii) divergent and convergent market pressures associated with the supply, pricing and assessment of medicines. The UK's sovereign ambitions risk a loss of influence over the licensing and surveillance of pharmaceuticals under convergent regulatory and industry pressures to engage in unilateral participation in the European regime. Further, they also risk a loss of influence over processes for pricing and assessing the effectiveness of new treatment regimens under divergent market pressures from larger pharmaceutical markets outside the EU, notably the United States.
To test the psychometric properties of the Quality Indicator for Rehabilitative Care (QuIRC), refine the toolkit and compare results with service user experiences.
Following the initial development of the toolkit, it was translated into the languages of the partner countries and piloted. It was then refined to maximize a) its inter-rater reliability, b) its usability and c) its ability to deliver assessments relevant to each country's established systems of change at local, regional and national level. Managers of participating units were re-interviewed using the refined tool. QuIRC scores were compared against service users’ quality of life, autonomy, experiences of care and markers of recovery to assess whether the QuIRc could provide a proxy-assessment of the unit's promotion of service users’ autonomy and Recovery.
The tool was piloted in 20 units in each country (a total of 200 units). Inter-rater reliability was assessed using intra-class correlations and Cohen's Kappa coefficients. Factors with low reliability or extreme response biases were dropped. Remaining items were subjected to an exploratory factor analysis to test domain allocation and improve internal consistency. QuIRC domain ratings were compared by country and facility type and with service user assessments. The QuIRC was found to have high reliability, to be easy to use and there was high correlation between domain ratings and service users’ ratings.
To identify the specific components of care that key stakeholders in ten European countries at different stages of de-institutionalization regard as most important in promoting recovery in this group; to measure consensus between and across stakeholder groups and countries; and to develop a conceptual framework of ‘domains’ of care.
Each participating country completed a series of conventional three-round Delphi exercises with four separate panels of experts; service users, mental health professionals, carers and advocates. In Round 1 an initial open question asked respondents to identify up to 10 components of care they considered most important in promoting recovery. In Round 2 these ideas were fed back to the group and rated on a 5-point scale. In Round 3 the group re-rated the components in the light of information about the whole group's response. Components achieving high importance rankings and high consensus were grouped into domains.
The 40 participating panels generated around 4,000 separate items of care. From these, eleven broad domains of recovery practice were identified. Results will be presented descriptively to show the domains and components of care considered to be most important to recovery, and to show consensus within and across countries, and between stakeholder groups. It will be seen that there was generally high consensus between groups and countries but some modest differences in priorities.
Delphi methodology is useful in eliciting and evaluating different perspectives on recovery-based practice. Strengths and weaknesses of the approach will be discussed.
To assess the social disability of people with different psychiatric disorders.
Cross-site survey in five psychiatric hospitals (Dresden, Wrocław, London, Michalovce and Prague). Working-aged patients diagnosed (ICD-10) with schizophrenia and related disorders (F2), affective disorders (F3), anxiety disorders (F4), eating disorders (F5) and personality disorders (F6), were assessed at admission (n = 969) and 3 months after discharge (n = 753) using the Brief Psychiatric Rating Scale and the Groningen Social Disability Schedule. The main outcome measure was Interviewer-rated social disability.
During acute episodes patients with personality, eating and schizophrenic disorders functioned less effectively than those with affective or anxiety disorders. After controlling for age and severity of psychopathology, there was no significant effect of the diagnosis (during remission), sex, education and history of disorder on disability. Site, employment and partnership were significant factors for the level of social disability in both measure points.
Severity of psychopathological symptoms, not the diagnosis of a mental disorder, was the most significant factor in determining the level of social functioning, particularly during the remission period. Site, employment and partnership appeared as significant factors influencing the level of social disability.
Schizophrenia often presents in adolescence (13–18 years), is more likely to have a poor prognosis and young people are also more prone to adverse effects. Clearer guidance is needed in order to plan treatment for early onset cases more effectively.
We aimed to evaluate effects of atypical antipsychotic medications for psychosis in adolescents.
We searched the Cochrane Schizophrenia Group's Register. References of all identified studies were inspected for further trials.
All relevant RCTs that compared atypical antipsychotic medication with pharmacological or non-pharmacological interventions in adolescents with psychosis were included. We reliably selected, quality assessed and extracted data from trials.
There were 13 RCTs with a total of 1112 participants. Adolescents improved more on standard dose of risperidone (1.5 – 6.0 mg) against low dose of risperidone (0.15 – 0.6 mg) (1 RCT, n = 255, RR 0.54 CI 0.38 to 0.75). Participants on clozapine were three times more likely to have drowsiness as compared to haloperidol (1 RCT, n = 21, RR 3.30 CI 1.23 to 8.85, NNH 2 CI 2 to 17). Lesser number of adolescents on atypical antipsychotics left the study due to adverse effects (3 RCTs, n = 187, RR 0.65 CI 0.36 to 1.15) than on typical antipsychotics.
There is no convincing evidence that atypical-antipsychotic medications are superior over typical antipsychotic medications. There is some evidence to show that adolescents respond better to standard-dose as opposed to lower dose of medications. Larger, more robust, trials are required.
Despite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia.
We analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb2+), manganese (Mn2+), cadmium (Cd2+), copper (Cu2+), magnesium (Mg2+), and zinc (Zn2+), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry.
We found higher early-life Pb2+ exposure among patients with schizophrenia than controls. The differences in log Mn2+ and log Cu2+ changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb2+ levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb2+ levels and adult IQ.
In our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis.
In 2001, the World Health Organization (WHO) created the International Classification of Functioning, Disability and Health (ICF) to offer a comprehensive and universally accepted framework to describe functioning, disability and health. The ICF Core Sets (ICF-CS) are a selection of categories that serve as a minimal standard for the assessment of functioning and disability in a specific health condition. The ICF-CS for schizophrenia was created in 2015 based on four preliminary studies that intend to capture different perspectives.
The aim of this study is to describe the similarities (i.e. overlap) and discrepancies (i.e. unique contribution) between the clinical, patient and expert perspectives on the most relevant problems in functioning of individuals with schizophrenia, being focused on the European WHO region.
Forty-four experts from 14 European countries participated in an expert survey, patients with schizophrenia were involved in four focus groups, and health professionals assessed 127 patients in relation to daily life functioning. Information gathered from these three preliminary studies was linked to the ICF.
Data showed that although a considerable number of second-level ICF categories agreed on the three preparatory studies (n = 54, 27.7%), each perspective provided a unique set of ICF categories. Specifically, experts reported 65 unique ICF categories, patients 23 and health professionals 11.
Even though there were similarities between perspectives, each one underlined different areas of functioning, showing the importance of including different perspectives in order to get a complete view of functioning and disability in individuals with schizophrenia.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Incidence of human yersiniosis in New Zealand has increased between 2013 and 2017. For surveillance and outbreak investigations it is essential that an appropriate level of discrimination between pathogenic Yersinia enterocolitica isolates is provided, in order to support epidemiological linking of connected cases. Subtyping of 227 Y. enterocolitica isolates was performed using a range of different typing methods, including biotyping, serotyping and seven loci multiple-locus variable-number tandem-repeat analysis (MLVA). In addition, core genome single-nucleotide polymorphism (core SNP) analysis and multi-locus sequence typing were performed on a subset of 69 isolates. Sixty-seven different MLVA types were identified. One MLVA profile was associated with an outbreak in the Bay of Plenty region, supported by epidemiological data. Core SNP analysis showed that all the outbreak-related isolates clustered together. The subtyping and epidemiological evidence suggests that the outbreak of yersiniosis in the Bay of Plenty region between October and December 2016 could be attributed to a point source. However, subtyping results further suggest that the same clone was isolated from several regions between August 2016 and March 2017. Core SNP analysis and MLVA typing failed to differentiate between Y. enterocolitica biotype 2 and biotype 3. For this reason, we propose that these biotypes should be reported as a single type namely: Y. enterocolitica biotype 2/3 and that the serotype should be prioritised as an indicator of prevalence.
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.
Birth weight and early growth have been associated with later blood pressure. However, not all studies consistently find a significant reduction in blood pressure with an increase in birth weight. In addition, the relative importance of birth weight and of other lifestyle and environmental factors is often overlooked and the association is rarely studied in adolescents. We investigated early life predictors, including birth weight, of adolescent blood pressure in the Gateshead Millennium Study (GMS). The GMS is a cohort of 1029 individuals born in 1999–2000 in Gateshead in Northern England. Throughout infancy and early childhood, detailed information were collected, including birth weight and measures of height and weight. Assessments of 491 returning participants at age 12 years included measures of body mass and blood pressure. Linear regression and path analysis were used to determine predictors and their relative importance on blood pressure. Birth weight was not directly associated with blood pressure at the age of 12. However, after adjustment for contemporaneous body mass index (BMI), an inverse association of standardized birth weight on systolic blood pressure was significant. The relative importance of birth weight on later systolic blood pressure was smaller than other contemporaneous body measures (height and BMI). There was no independent association of birth weight on blood pressure seen in this adolescent population. Contemporaneous body measures have an important role to play. Lifestyle factors that influence body mass or size, such as diet and physical activity, where interventions are directed at early prevention of hypertension should be targeted.
The trial-to-trial response variability in sensory cortices and the extent to which this variability can be coordinated among cortical units have strong implications for cortical signal processing. Yet, little is known about the relative contributions and dynamics of defined sources to the cortical response variability and their correlations across cortical units. To fill this knowledge gap, here we obtained and analyzed multisite local field potential (LFP) recordings from visual cortex of turtles in response to repeated naturalistic movie clips and decomposed cortical across-trial LFP response variability into three defined sources, namely, input, network, and local fluctuations. We found that input fluctuations dominate cortical response variability immediately following stimulus onset, whereas network fluctuations dominate the response variability in the steady state during continued visual stimulation. Concurrently, we found that the network fluctuations dominate the correlations of the variability during the ongoing and steady-state epochs, but not immediately following stimulus onset. Furthermore, simulations of various model networks indicated that (i) synaptic time constants, leading to oscillatory activity, and (ii) synaptic clustering and synaptic depression, leading to spatially constrained pockets of coherent activity, are both essential features of cortical circuits to mediate the observed relative contributions and dynamics of input, network, and local fluctuations to the cortical LFP response variability and their correlations across recording sites. In conclusion, these results show how a mélange of multiscale thalamocortical circuit features mediate a complex stimulus-modulated cortical activity that, when naively related to the visual stimulus alone, appears disguised as high and coordinated across-trial response variability.
Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in the sod1 gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.
We implemented a cross-sectional study in Tana River County, Kenya, a Rift Valley fever (RVF)-endemic area, to quantify the strength of association between RVF virus (RVFv) seroprevalences in livestock and humans, and their respective intra-cluster correlation coefficients (ICCs). The study involved 1932 livestock from 152 households and 552 humans from 170 households. Serum samples were collected and screened for anti-RVFv immunoglobulin G (IgG) antibodies using inhibition IgG enzyme-linked immunosorbent assay (ELISA). Data collected were analysed using generalised linear mixed effects models, with herd/household and village being fitted as random variables. The overall RVFv seroprevalences in livestock and humans were 25.41% (95% confidence interval (CI) 23.49–27.42%) and 21.20% (17.86–24.85%), respectively. The presence of at least one seropositive animal in a household was associated with an increased odds of exposure in people of 2.23 (95% CI 1.03–4.84). The ICCs associated with RVF virus seroprevalence in livestock were 0.30 (95% CI 0.19–0.44) and 0.22 (95% CI 0.12–0.38) within and between herds, respectively. These findings suggest that there is a greater variability of RVF virus exposure between than within herds. We discuss ways of using these ICC estimates in observational surveys for RVF in endemic areas and postulate that the design of the sentinel herd surveillance should consider patterns of RVF clustering to enhance its effectiveness as an early warning system for RVF epidemics.