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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.
The Saks Institute for Mental Health Law, Policy, and Ethics at USC Gould School of Law is engaged in an innovation planning project in California to pilot programs and test the feasibility of using psychiatric advance directives (PADs) within the supported decision-making (SDM) paradigm. The project is supported by California’s Mental Health Services Oversight and Accountability Commission. This chapter provides an overview of the preliminary developments and pilot studies in the California PADs/SDM project. The project is a first-of-its-kind effort to explore the efficacy of the PADs/SDM paradigm across behavioral health county systems in the State of California. This chapter presents an overview of the pilot project and describes its research questions and implications, and ways in which the project and SDM paradigm embodies the principles of the United Nations Convention on the Rights of Persons with Disabilities.
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.
In addition to the development and research of battery-driven vehicles, a high research effort in the field of hydrogen technology can currently be observed. Various research and strategy initiatives relating to hydrogen are being initiated and pursued with considerable commitment worldwide. A significant expansion of the hydrogen filling station network is also being sought in Germany. In the course of designing a hydrogen refuelling station, the paradigms of thermal management must be taken into account in addition to a large number of different environmental and life phase-induced influencing factors. The interactions between influencing factors, requirements and the system architecture result in a multitude of possible refuelling station concepts, which can hardly be surveyed or managed from an organisational point of view. This publication introduces a method for the development of descriptive requirement collectives, which is applied to hydrogen refuelling stations in the framework of THEWA, but can also be adapted for other technical systems. The requirement collective is the first core element of the THEWA tool chain that enables a requirement-oriented and fast design of hydrogen refuelling stations.
Scanning transmission electron microscopy (STEM) allows for imaging, diffraction, and spectroscopy of materials on length scales ranging from microns to atoms. By using a high-speed, direct electron detector, it is now possible to record a full two-dimensional (2D) image of the diffracted electron beam at each probe position, typically a 2D grid of probe positions. These 4D-STEM datasets are rich in information, including signatures of the local structure, orientation, deformation, electromagnetic fields, and other sample-dependent properties. However, extracting this information requires complex analysis pipelines that include data wrangling, calibration, analysis, and visualization, all while maintaining robustness against imaging distortions and artifacts. In this paper, we present py4DSTEM, an analysis toolkit for measuring material properties from 4D-STEM datasets, written in the Python language and released with an open-source license. We describe the algorithmic steps for dataset calibration and various 4D-STEM property measurements in detail and present results from several experimental datasets. We also implement a simple and universal file format appropriate for electron microscopy data in py4DSTEM, which uses the open-source HDF5 standard. We hope this tool will benefit the research community and help improve the standards for data and computational methods in electron microscopy, and we invite the community to contribute to this ongoing project.
R-MAT (for Recursive MATrix) is a simple, widely used model for generating graphs with a power law degree distribution, a small diameter, and communitys structure. It is particularly attractive for generating very large graphs because edges can be generated independently by an arbitrary number of processors. However, current R-MAT generators need time logarithmic in the number of nodes for generating an edge— constant time for generating one bit at a time for node IDs of the connected nodes. We achieve constant time per edge by precomputing pieces of node IDs of logarithmic length. Using an alias table data structure, these pieces can then be sampled in constant time. This simple technique leads to practical improvements by an order of magnitude. This further pushes the limits of attainable graph size and makes generation overhead negligible in most situations.
Post-operative severe vascular stenosis and proliferating endothelial tissue lead to severe circulatory disorders and impair organ perfusion. Bioabsorbable magnesium scaffolds may help to overcome these obstructions without leaving obstructing stent material. We analyse their role in the treatment of vascular stenosis in infants.
Methods:
Since 2016, 15 magnesium scaffolds with a diameter of 3.5 mm were implanted in 9 patients aged 15 days to 7.6 years. Eight scaffolds were implanted in pulmonary venous restenoses, five in pulmonary arterial stenosis including one in-stent stenosis, one into a stenotic brachiocephalic artery, and one in a recurrent innominate vein thrombosis.
Results:
All patients clinically improved after the implantation of a scaffold. The magnesium scaffolds lost integrity after 30–48 days (mean 42 days). The innominate vein thrombosed early, while all other vessels remained open. Two patients died after 1.3 and 14 weeks not related to the scaffolds. Five patients needed further balloon dilations or stent implantations after the scaffold had fractured. At first recatheterisation after in mean 2.5 months, the mean minimum/maximum diameter in relation to the scaffold’s original diameter was 89%/99% in the arterial implantations (n = 6) and 66%/77% in the pulmonary venous implantations.
Conclusions:
The magnesium scaffolds can be used as a bridging solution to treat severe vascular stenosis in different locations. Restenosis can occur after degradation and make further interventions necessary, but neither vessel growth nor further interventions are hindered by stent material. Larger diameters may improve therapeutic options.
This research communication addresses the hypothesis that Southeast dairy producers' self-reported bulk tank somatic cell count (BTSCC) was associated with producers' response to three statements (1) ‘a troublesome thing about mastitis is the worries it causes me,’ (2) ‘a troublesome thing about mastitis is that cows suffer,’ and (3) ‘my broad goals include taking good care of my cows and heifers.’ Surveys were mailed to producers in Georgia, Kentucky, Mississippi, North Carolina, South Carolina, Tennessee, and Virginia (29% response rate, N = 596; final analysis N = 574), as part of a larger survey to assess Southeastern dairy producers' opinions related to BTSCC. Surveys contained 34 binomial (n = 9), Likert scale (n = 7), and descriptive (n = 18) statements targeted at producer self-assessment of herd records, management practices, and BTSCC. Statements 1 and 2 were assessed on a 5-point Likert scale from ‘strongly disagree’ to ‘strongly agree.’ Statement 3 was assessed on a 5-point Likert scale from ‘very unimportant’ to ‘very important.’ Reported mean BTSCC for all participants was 254 500 cells/ml. Separate univariable logistic regressions using generalized linear mixed models (SAS 9.4, Cary, NC, USA) with a random effect of farm, were performed to determine if BTSCC was associated with probability for a producer's response to statements. If BTSCC was significant, forward manual addition was performed until no additional variables were significant (P ≤ 0.05), but included BTSCC, regardless of significance. Bulk tank somatic cell count was associated with ‘a troublesome thing about mastitis is the worries it causes me,’ but not with Statements 2 or 3. This demonstrates that >75% of Southeastern dairy producers are concerned with animal care and cow suffering, regardless of BTSCC. Understanding Southeast producers' emphasis on cow care is necessary to create targeted management tools for herds with elevated BTSCC.
The Upper Cretaceous Kanguk Formation of the Sverdrup Basin, Canadian Arctic Islands, contains numerous diagenetically altered volcanic ash layers (bentonites). Eleven bentonites were sampled from an outcrop section on Ellesmere Island for U–Pb zircon secondary ion mass spectrometry dating and whole-rock geochemical analysis. Two distinct types of bentonite are identified from the geochemical data. Relatively thick (0.1 to 5 m) peralkaline rhyolitic to trachytic bentonites erupted in an intraplate tectonic setting. These occur throughout the upper Turonian to lower Campanian (c. 92–83 Ma) outcrop section and are likely associated with the alkaline phase of the High Arctic Large Igneous Province. Two thinner (<5 cm) subalkaline dacitic to rhyolitic bentonites of late Turonian to early Coniacian age (c. 90–88 Ma) are also identified. The geochemistry of these bentonites is consistent with derivation from volcanoes within an active continental margin tectonic setting. The lack of nearby potential sources of subalkaline magmatism, together with the thinner bed thickness of the subalkaline bentonites and the small size of zircon phenocrysts therein (typically 50–80 μm in length) are consistent with a more distal source area. The zircon U–Pb age and whole-rock geochemistry of these two subalkaline bentonites correlate with an interval of intense volcanism in the Okhotsk–Chukotka Volcanic Belt, Russia. It is proposed that during late Turonian to early Coniacian times intense volcanism within the Okhotsk–Chukotka Volcanic Belt resulted in widespread volcanic ash dispersal across Arctic Alaska and Canada, reaching as far east as the Sverdrup Basin, more than 3000 km away.
There is no established methodology to assess the feasibility of medicine price data sources. Against this backdrop, a framework to guide the selection of most appropriate price data sources for pharmacoeconomic research has been developed.
Methods
A targeted literature review was carried out. Dimensions discussed in literature as relevant for medicine price comparisons and practical experience of the authors in medicine price studies informed the conceptional work of the framework development. A draft version of the framework was reviewed by peer pricing experts. The feasibility of the framework was tested in case studies.
Results
According to the developed framework (called Re-ADAPT), a medicine price data source should meet the following criteria: reliability and sustainability; accessibility at a cost that users can afford; provision of medicine price information at the date(s) required; information for the defined geographic area, or at least in a representative way; coverage of the pharmaceuticals and at the price type(s) required. Easy handling and provision of additional information were defined as supportive assets of candidate data sources (secondary criteria). The case studies confirmed the feasibility of the Re-ADAPT framework. In some cases, however, it can be difficult to disentangle assessment criteria (particularly geographic area, scope of pharmaceuticals and price types) for separate consideration, given their interlinkage.
Conclusions
While selection of the most appropriate data sources will remain a challenge, the Re-ADAPT framework aims to provide practical guidance and thus contribute to a more careful, balanced, and evidence-based selection of data sources for medicine price studies.
Physical activity (PA) may be therapeutic for people with severe mental illness (SMI) who generally have low PA and experience numerous life style-related medical complications. We conducted a meta-review of PA interventions and their impact on health outcomes for people with SMI, including schizophrenia-spectrum disorders, major depressive disorder (MDD) and bipolar disorder. We searched major electronic databases until January 2018 for systematic reviews with/without meta-analysis that investigated PA for any SMI. We rated the quality of studies with the AMSTAR tool, grading the quality of evidence, and identifying gaps, future research needs and clinical practice recommendations. For MDD, consistent evidence indicated that PA can improve depressive symptoms versus control conditions, with effects comparable to those of antidepressants and psychotherapy. PA can also improve cardiorespiratory fitness and quality of life in people with MDD, although the impact on physical health outcomes was limited. There were no differences in adverse events versus control conditions. For MDD, larger effect sizes were seen when PA was delivered at moderate-vigorous intensity and supervised by an exercise specialist. For schizophrenia-spectrum disorders, evidence indicates that aerobic PA can reduce psychiatric symptoms, improves cognition and various subdomains, cardiorespiratory fitness, whilst evidence for the impact on anthropometric measures was inconsistent. There was a paucity of studies investigating PA in bipolar disorder, precluding any definitive recommendations. No cost effectiveness analyses in any SMI condition were identified. We make multiple recommendations to fill existing research gaps and increase the use of PA in routine clinical care aimed at improving psychiatric and medical outcomes.
Chip-package interaction (CPI) and the related thermomechanical stress in microchips increase the risk of failure in on-chip interconnect stacks, caused by delamination along Cu/dielectrics interfaces (adhesive failure) and fracture in dielectrics (cohesive failure). High-resolution transmission X-ray microscopy (TXM) is a unique technique to image crack propagation in on-chip interconnect stacks. The visualization of crack evolution in Cu/low-k Backend-of-Line (BEoL) structures is demonstrated using an experimental setup which combines high-resolution X-ray imaging with mechanical loading. The application of an indenter manipulator at the TXM beamline of the synchrotron radiation source BESSY II provides an unprecedented level of details on the fracture behavior of microchips. This in-situ experiment allows to identify the weakest layers and interfaces and to evaluate the robustness of the BEoL stack against CPI.