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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.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
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.
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.
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.
Karin de Boer has given the best account so far of the reform of Wolffian metaphysics that Kant promised. But does such a reform cohere with the revolutionary goal that Kant also affirmed? Standpoint is singled out as the central meta-concept of Kant’s revolutionary goal, and it is argued that, in the second and third critiques, Kant himself developed his revolutionary insight into the perspectival character of both concept and judgement in ways that he did not anticipate at the time of the first critique, when his promise to reform metaphysics was made. The question is raised what room Kant’s revolution leaves for doctrinal and not merely disciplinary judgements in both general and special metaphysics, and also whether the opening of new vistas may have drained metaphysical reform of its interest.
This chapter synthesises insights from the Deep Decarbonisation Pathways Project (DDPP), which provided detailed analysis of how 16 countries representing three-quarters of global emissions can transition to very low-carbon economies. The four ‘pillars’ of decarbonisation are identified as: achieving low or zero-carbon electricity supply; electrification and fuel switching in transport, industry and housing; ambitious energy efficiency improvements; and reducing non-energy emissions. The chapter focuses on decarbonisation scenarios for Australia. It shows that electricity supply can be readily decarbonised and greatly expanded to cater for electrification of transport, industry and buildings. There would be remaining emissions principally from industry and agriculture, these could be fully compensated through land-based carbon sequestration. The analysis shows that such decarbonisation would be consistent with continued growth in GDP and trade, and would require very little change in economic structure of Australia’s economy. Australia is rich in renewable energy potential, which could re-enable new industries such as energy-intensive manufacturing for export
The intent of the review was to identify different methodological approaches used to calculate the planning target volume (PTV) margin for head and neck patients treated with volumetric arc therapy (VMAT), and whether the necessary factors to calculate the margin size with the selected formula were used.
Materials and Methods:
A comprehensive, systematic search of related studies was done using the Hydi search engine and different databases: MEDLINE, PubMed, CINAHL, ProQuest (Nursing and Allied Health), Scopus, ScienceDirect and tipsRO. The literature search included studies published between January 2007 and December 2020. Eligibility screening was performed by two reviewers.
A total of seven studies were found. All the reviewed studies used the Van Herk formula to measure the PTV margin. None of the studies incorporated the systematic errors of target volume delineation in the PTV equation. Inter-fraction translational errors were assessed in all the studies, whilst intra-fraction errors were only included in the margin equation for two studies. The studies showed great heterogeneity in the key characteristics, aims and methods.
Since systemic errors from target volume delineation were not considered and not all studies assess intra-fraction errors, PTV margins may be underestimated. The recommendations are that studies need to determine the effect of target volume variance on PTV margins. It is also recommended to compare PTV margin results using various formulas.
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.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
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.
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.
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 view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients.
Combining agility and convergence in the development of physical products is a major challenge. Rooted in a design thinking approach, Stanford's ME310 process model attempts to resolve the conflicting priorities of these two design principles. To investigate how successful Stanford's hybrid process model is in doing so, we have used a qualitative case study approach. Our paper begins by outlining this process model's fundamental principles in terms of engineering design methodology. Subsequently, we present the results of our empirical analysis, which tracks the coevolution of problem and solution space by meticulously examining all prototype paths in ten of Stanford's ME310 student projects. We have discovered that convergence during solution finding does not correspond to the process model's theoretical specifications. Even in the phase of the final prototype, both the technical concept and the underlying problem formulation changed frequently. Further research should focus on combining the prototype-based ME310 approach with methods from systems engineering which allow for a more comprehensive theoretical exploration of the solution space. This could lead to improved convergence during solution development.
Wavelength-dispersive X-ray (WDX) spectroscopy was used to measure silicon atom concentrations in the range 35–100 ppm [corresponding to (3–9) × 1018 cm−3] in doped AlxGa1–xN films using an electron probe microanalyser also equipped with a cathodoluminescence (CL) spectrometer. Doping with Si is the usual way to produce the n-type conducting layers that are critical in GaN- and AlxGa1–xN-based devices such as LEDs and laser diodes. Previously, we have shown excellent agreement for Mg dopant concentrations in p-GaN measured by WDX with values from the more widely used technique of secondary ion mass spectrometry (SIMS). However, a discrepancy between these methods has been reported when quantifying the n-type dopant, silicon. We identify the cause of discrepancy as inherent sample contamination and propose a way to correct this using a calibration relation. This new approach, using a method combining data derived from SIMS measurements on both GaN and AlxGa1–xN samples, provides the means to measure the Si content in these samples with account taken of variations in the ZAF corrections. This method presents a cost-effective and time-saving way to measure the Si doping and can also benefit from simultaneously measuring other signals, such as CL and electron channeling contrast imaging.
Several studies have signaled grammatical difficulties in individuals with developmental dyslexia. These difficulties may stem from a phonological deficit, but may alternatively be explained through a domain-general deficit in statistical learning. This study investigates grammar in children with and without dyslexia, and whether phonological memory and/or statistical learning ability contribute to individual differences in grammatical performance. We administered the CELF “word structure” and “recalling sentences” subtests and measures of phonological memory (digit span, nonword repetition) and statistical learning (serial reaction time, nonadjacent dependency learning) among 8- to 11-year-old children with and without dyslexia (N = 50 per group). Consistent with previous findings, our results show subtle difficulties in grammar, as children with dyslexia achieved lower scores on the CELF (word structure: p = .0027, recalling sentences: p = .053). While the two phonological memory measures were found to contribute to individual differences in grammatical performance, no evidence for a relationship with statistical learning was found. An error analysis revealed errors in irregular morphology (e.g., plural and past tense), suggesting problems with lexical retrieval. These findings are discussed in light of theoretical accounts of the underlying deficit in dyslexia.
In most of the world Toxoplasma gondii is comprised of archetypal types (types I, II and III); however, South America displays several non-archetypal strains. This study used an experimental mouse model to characterize the immune response and parasite kinetics following infection with different parasite genotypes. An oral inoculation of 50 oocysts per mouse from T. gondii M4 type II (archetypal, avirulent), BrI or BrIII (non-archetypal, virulent and intermediate virulent, respectively) for groups (G)2, G3 and G4, respectively was used. The levels of mRNA expression of cytokines, immune compounds, cell surface markers and receptor adapters [interferon gamma (IFNγ), interleukin (IL)-12, CD8, CD4, CD25, CXCR3 and MyD88] were quantified by SYBR green reverse transcription-quantitative polymerase chain reaction. Lesions were characterized by histology and detection by immunohistochemistry established distribution of parasites. Infection in G2 mice was mild and characterized by an early MyD88-dependent pathway. In G3, there were high levels of expression of pro-inflammatory cytokines IFNγ and IL-12 in the mice showing severe clinical symptoms at 8–11 days post infection (dpi), combined with the upregulation of CD25, abundant tachyzoites and tissue lesions in livers, lungs and intestines. Significant longer expression of IFNγ and IL-12 genes, with other Th1-balanced immune responses, such as increased levels of CXCR3 and MyD88 in G4, resulted in survival of mice and chronic toxoplasmosis, with the occurrence of tissue cysts in brain and lungs, at 14 and 21 dpi. Different immune responses and kinetics of gene expression appear to be elicited by the different strains and non-archetypal parasites demonstrated higher virulence.
A prior systematic review on the efficacy of halofuginone (HFG) treatment to prevent or treat cryptosporidiosis in bovine calves was inconclusive. We undertook an updated synthesis and meta-analyses on key outcomes for the treatment of calves with HFG. Evaluated outcomes were oocyst shedding, diarrhoea, mortality and weight gain. Experiments had to describe results for same age animals in contemporary arms. Most doses were 100–150 mcg kg−1 day−1. Results were subgrouped by study design, experiments with the lowest risk of bias and lack of industry funding. Eighteen articles were found that described 25 experiments. Most evidence came from randomized controlled trials in Europe. Significantly lower incidence of oocyst shedding, diarrhoea burden and mortality was reported when treatment started before calves were 5 days old. Most studies reported on outcomes for animals up to at least 28 days old. Publication bias was possible in all outcomes and seemed especially likely for diarrhoea outcomes. Beneficial results when HFG treatment was initiated in calves older than 5 days were also found. Prophylactic treatment to prevent cryptosporidiosis is effective in preventing multiple negative outcomes and is beneficial to calf health and will result in a reduction of environmental contamination by Cryptosporidium oocysts.
Ever since the first deep ice cores were drilled, it has been a challenge to determine their original, in-situ orientation. In general, the orientation of an ice core is lost as the drill is free to rotate during transport to the surface. For shallow ice cores, it is usually possible to match the adjacent core breaks, which preserves the orientation of the ice column. However, this method fails for deep ice cores, such as the EastGRIP ice core in Northeast Greenland. We provide a method to reconstruct ice core orientation using visual stratigraphy and borehole geometry. As the EastGRIP ice core is drilled through the Northeast Greenland Ice Stream, we use information about the directional structures to perform a full geographical re-orientation. We compared the core orientation with logging data from core break matching and the pattern of the stereographic projections of the crystals’ c-axis orientations. Both comparisons agree very well with the proposed orientation method. The method works well for 441 out of 451 samples from a depth of 1375–2120 m in the EastGRIP ice core. It can also be applied to other ice cores, providing a better foundation for interpreting physical properties and understanding the flow of ice.
This article reports on the early results of using behavioural and educational data to evaluate a residential education programme. The programme serves male and female students between 12 and 16 years of age who have been suspended or expelled from school due to behavioural issues or who refused to attend school. Using measures of behavioural and educational progress during care and reporting these changes over time provided empirical evidence that the programme was achieving its primary aims of ‘behaviour change and educational gains.’ Collecting and reporting this data has empowered the programme to increase programme effectiveness through both data-informed decision-making and ongoing programme evaluation.
Glaciers in the Alps and several other regions in the world have experienced strong negative mass balances over the past few decades. Some of them are disappearing, undergoing exceptionally negative mass balances that impact the mean regional value, and require replacement. In this study, we analyse the geomorphometric characteristics of 46 mass-balance glaciers in the Alps and the long-term mass-balance time series for a subset of nine reference glaciers. We identify regime shifts in the mass-balance time series (when non-climatic controls started impacting) and develop a glacier vulnerability index (GVI) as a proxy for their possible future development, based on criteria such as hypsometric index, breaks in slope, thickness distribution and elevation change pattern. We found that the subset of 46 mass-balance glaciers reflects the characteristics of the total glacier sample very well and identified a region-specific variability of the mass balance. As the GVI is strongly related to cumulative glacier mass balances, it can be used as a pre-selector of future mass-balance glaciers. We conclude that measurements on rapidly shrinking glaciers should be continued as long as possible to identify regime shifts in hind-cast and better understand the impacts of climatic variability on such glaciers.