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Group cognitive stimulation therapy (CST) has been shown to improve cognition and quality of life of people with dementia in multiple trials, but there has been scant research involving people with intellectual disability and dementia. This study aimed to assess the feasibility of conducting a randomised controlled trial of group CST for this population.
Aims
To assess the feasibility of participant recruitment and retention, the appropriateness of outcome measures, and the feasibility of group CST (adherence, fidelity, acceptability), as well as the feasibility of collecting data for an economic evaluation.
Method
Participants were recruited from six National Health Service trusts in England and randomised to group CST plus treatment as usual (TAU) or TAU only. Cognition, quality of life, depression, and use of health and social care services were measured at baseline and at 8–9 weeks. Qualitative interviews with participants, carers and facilitators were used to explore facilitators of and barriers to delivery of CST. Trial registration number: ISRCTN88614460.
Results
We obtained consent from 46 participants, and 34 (73.9%) were randomised: 18 to CST and 16 to TAU. All randomised participants completed follow-up. Completion rates of outcome measures (including health economic measures) were adequate; 75.7% of sessions were delivered, and 56% of participants attended ten or more. Fidelity of delivery was of moderate quality. CST was acceptable to all stakeholders; barriers included travel distance, carer availability and sessions needing further adaptations. The estimated cost per participant of delivering CST was £602.
Conclusions
There were multiple challenges including recruitment issues, a large dropout rate before randomisation and practical issues affecting attendance. These issues would need to be addressed before conducting a larger trial.
OBJECTIVES/GOALS: Determine how a history of unpredictable foot shock in mice affects brain wide patterns of neural activation to future stressors. Additionally, we aimed to characterize how the paraventricular nucleus of the thalamus (PVT) is involved in the fear sensitization process. METHODS/STUDY POPULATION: We used a mouse model of stress enhanced fear learning, where stressed mice are first subjected to a series of unpredictable foot shocks in a novel context while control mice undergo exposure to the novel context without experiencing foot shock. Mice are then left undisturbed for 28 days, following which they are exposed to a single foot shock in a novel context. Mice are tested in the second context 24 hours after single shock, and the amount of time spent frozen in the context provides a measure of fear sensitization. Whole brain patterns of activation during the second context test will be assessed via whole brain optical clearing with antibody staining of immediate early genes. The role of the PVT in fear sensitization will be characterized using chemogenetic approaches. RESULTS/ANTICIPATED RESULTS: Our preliminary results demonstrate that mice display enhanced fear acquisition long after the initial experience of unpredictable shocks. We anticipate to identify regions previously implicated in fear learning and novel regions not previously described through our brain clearing approach. In addition, we anticipate chemogenetic inhibition of the PVT will reduce freezing to an auditory cue associated with the shock in the second context but not to the context itself. DISCUSSION/SIGNIFICANCE: Our findings will provide a comprehensive view of how a history of unpredictable stress affects whole brain processing of subsequent stressful experiences, and describe the role of the PVT in cued fear sensitization.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
This paper reviews recent developments in the production and use of unconventional natural gas in the United States with a focus on water and greenhouse gas emission implications. If unconventional natural gas in the U.S. is produced responsibly, transported and distributed with little leakage, and incorporated into integrated energy systems that are designed for future resiliency, it could play a significant role in realizing a more sustainable energy future; however, the increased use of natural gas as a substitute for more carbon intensive fuels will alone not substantially alter world carbon dioxide concentration projections.
This paper reviews recent developments in the production and use of unconventional natural gas in the United States with a focus on environmental impacts. Specifically, we focus on water management and greenhouse gas emission implications. If unconventional natural gas in the United States is produced responsibly, transported and distributed with little leakage, and incorporated into integrated energy systems that are designed for future resiliency, it could play a significant role in realizing a more sustainable energy future. The cutting-edge of industry water management practices gives a picture of how this transition is unfolding, although much opportunity remains to minimize water use and related environmental impacts. The role of natural gas to mitigate climate forcing is less clear. While natural gas has low CO2 emissions upon direct use, methane leakage and long term climate effects lead to the conclusion that increased use of natural gas as a substitute for more carbon intensive fuels will not substantially alter world carbon dioxide concentration projections, and that other zero or low carbon energy sources will be needed to limit GHG concentrations. We conclude with some possible avenues for further work.
Antarctic and Southern Ocean science is vital to understanding natural variability, the processes that govern global change and the role of humans in the Earth and climate system. The potential for new knowledge to be gained from future Antarctic science is substantial. Therefore, the international Antarctic community came together to ‘scan the horizon’ to identify the highest priority scientific questions that researchers should aspire to answer in the next two decades and beyond. Wide consultation was a fundamental principle for the development of a collective, international view of the most important future directions in Antarctic science. From the many possibilities, the horizon scan identified 80 key scientific questions through structured debate, discussion, revision and voting. Questions were clustered into seven topics: i) Antarctic atmosphere and global connections, ii) Southern Ocean and sea ice in a warming world, iii) ice sheet and sea level, iv) the dynamic Earth, v) life on the precipice, vi) near-Earth space and beyond, and vii) human presence in Antarctica. Answering the questions identified by the horizon scan will require innovative experimental designs, novel applications of technology, invention of next-generation field and laboratory approaches, and expanded observing systems and networks. Unbiased, non-contaminating procedures will be required to retrieve the requisite air, biota, sediment, rock, ice and water samples. Sustained year-round access to Antarctica and the Southern Ocean will be essential to increase winter-time measurements. Improved models are needed that represent Antarctica and the Southern Ocean in the Earth System, and provide predictions at spatial and temporal resolutions useful for decision making. A co-ordinated portfolio of cross-disciplinary science, based on new models of international collaboration, will be essential as no scientist, programme or nation can realize these aspirations alone.
Over 5 years (1987–91), the progeny of rams selected for fast (Low T-half) or slow (High T-half) glucose clearance after an intravenous glucose tolerance test, differed significantly in glucose tolerance. In comparison with an unselected control, the line differences were mainly in the direction of Low T-half. They appear to have arisen during the establishment period, with little evidence of enhanced divergence over the four subsequent years of continued selection (heritability 0·10±0·03). The Low line had higher plasma insulin concentrations during the glucose tolerance test than the High line. Basal plasma concentrations of glucose were lower, and urea higher in the Low than the High line. In addition, carcasses of Low line ram progeny had more subcutaneous fat at the same carcass weight than High line carcasses (11% higher GR in the final year of the experiment). Selection of sheep for glucose clearance appeared to be associated with differential partitioning of nutrients into adipose tissue, the pooled genetic correlation between T-half and GR being −0·28±0·13.
This paper gives a direct and elementary proof of the fact that under hypotheses of Tonelli type, solutions to the basic problem in the calculus of variations are Lipschitz when the Lagrangian is autonomous. This fact was first proved by Clarke and Vinter in 1985, using other methods.
Roseomonas species have been increasingly noted as causes of human infection. We present what we believe is the first case of left ventricular assist device (LVAD) infection secondary to Roseomonas. The clinical characteristics of Roseomonas infection and the pertinent features of LVAD infection are reviewed.
An optimal control problem is studied, in which the state is requiredto remain in acompact set S. A control feedback law is constructed which, forgiven ε > 0, produces ε-optimal trajectories that satisfy thestate constraint universally with respect to all initial conditionsin S.The construction relies upon a constraint removal technique whichutilizes geometric properties of inner approximations of S and arelated trajectory tracking result.The control feedback is shown to possess a robustness property withrespect to state measurement error.
In [1] Almkvist and Meurman proved a result on the values of the Bernoulli polynomials (Theorem 5 below). Subsequently, Sury [5] and Bartz and Rutkowski [2] have given simpler proofs.
In this paper we show how this theorem can be obtained from classical results on the arithmetic of the Bernoulli numbers. The other ingredient is the remark that a polynomial with rational coefficients which is integer-valued on the integers is ℤ(p)-valued on ℤ(p). Here ℤ(p) denotes the ring of rational numbers whose denominator is not divisible by the prime p. An application is given in Section 3 to the arithmetic of generalised Bernoulli numbers.