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Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently unable to predict which patients are at higher risk of treatment resistance.
To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP).
In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP.
Younger age at onset (odds ratio 0.94, P = 7.79 × 10−13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10−4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10−3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP.
People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.
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.
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.
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.
The resonance lines of Mgii occur at wavelengths (2802.7 Å, 2795.5 Å) just beyond the extinction limit of the Earth's atmosphere. At such wavelengths sophisticated optical techniques can now be employed and this fact, together with the high cosmic abundance of magnesium, makes these lines particularly important for study in UV Astronomy. In the case of the Sun, the lines consist of a broad absorption with a pronounced emission core.
A suite of woody plants inhabiting the seasonally dry tropics flower while leafless during the dry season, raising intriguing questions about the role of moisture limitation in shaping their phenology. Brachychiton megaphyllus is one such species, a shrub of open forests and savannas in northern Australia. We documented leaf and reproductive phenology of 14 shrubs, and irrigated a further 15, to determine if soil moisture affected leafiness and reproductive activity. Brachychiton megaphyllus showed first flower buds shortly after the cessation of wet-season rains, and budded and flowered throughout the dry season. In some plants, leaf flush occurred prior to the first rains. Rates of fruit set and maturity were very low. Irrigation did not significantly influence leaf shoot or subsequent canopy development. Contrary to expectation, irrigation decreased the production of buds and flowers though it had no impact on the production of fruit, a response for which we suggest a number of hypotheses. Phenological responses to irrigation may have been limited because B. megaphyllus responds primarily to cues other than soil moisture and is buffered against seasonal drought by a large tap root. This suggests mechanisms by which flowering while leafless may occur in a range of species.
The acheulian site at Boxgrove contains one of the most extensive areas of in situ fauna and flintwork yet discovered in Britain. This material is found in a complex sequence of sediments which represent depositional conditions from a 42 m sea level rise to the onset of a full periglacial climate. Excavation of the archaeological horizon has been accompanied by a programme of multidisciplinary research examining site formation processes, palaeolandscape and palaeoecological development, using sedimentological and environmental reconstruction techniques. Dating of the site is tentative as no absolute dates are available at present. However, comparative analysis with other British sites would suggest a position for the Boxgrove sequence within the Middle Pleistocene. The archaeological horizon is interpreted as being deposited towards the latter part of an interglacial or an interstadial period.
The release fractions of the five elements in the ε-phase (99Tc,
97Mo, Ru, Rh, and Pd) as well as that of 238U are
reported for the reaction of two oxide fuels (ATM-103 and ATM-106) in
unsaturated tests under oxidizing conditions. The 99Tc release
fractions provide a lower limit for the magnitude of the spent fuel
reaction. The 99Tc release fractions indicate that a surface
reaction might be the rate controlling mechanism for fuel reaction under
unsaturated conditions and the oxidant is possibly
H2O2, a product of alpha radiolysis of water.
The alteration behavior of UO2 pellets following their reaction
under unsaturated drip-test conditions, at 90°C, for time periods of up to
10 years has been examined by solid phase and leachate analyses. Sample
reactions were characterized by preferential dissolution of grain boundaries
between the original press-sintered UO2 granules comprising the
samples, development of a polygonal network of open channels along the
intergrain boundaries, and spallation of surface granules that had undergone
severe grain boundary corrosion. The development of a dense mat of
alteration phases after two years of reaction trapped loose granules,
resulting in reduced rates of particulate uranium release. The paragenetic
sequence of alteration phases that formed on the present samples was similar
to that observed in surficial weathering zones of natural uraninite
(UO2) deposits, with alkali and alkaline earth uranyl
silicates representing the long-term solubility-limiting phases for uranium
in both systems.
Two alkali-tin-silicate (ATS) glasses have been prepared at Argonne National
Laboratory (ANL) as part of our ongoing research in radioactive waste glass
development. These glasses dissolved 5% and approximately 7% Pu. Early
corrosion test results indicate that Pu-bearing ATS glass is extremely
durable. The initial goal in this project concerned equally both the
solubility of Pu and the durability of the ATS glasses; however, our primary
emphasis has changed recently to maximizing the loading of Pu in the glass.
ATS-based glasses, using Th(VI) and Ce(III) as surrogates for Pu(IV), are
now being investigated to increase the solubility of Pu without
substantially sacrificing the durability of the current ATS formulations.
The solution data from various corrosion tests on the original Pu-containing
ATS glasses are also presented.