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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.
Carbon-rich dust is known to form in the atmosphere of the semiregular variable star R Sculptoris. Such stardust, as well as the molecules and gas produced during the lifetime of the star, will be spread into the Galaxy via the mass-loss process. Probing this process is crucial to understand the chemical enrichment of the Galaxy. R Scl was observed using the ESO/VLTI MATISSE instrument in December 2018. Here we show the first images of the star between 3 and 10 R*. Using the complementary MIRA 3D image reconstruction and the RHAPSODY 1D intensity profile reconstruction code, we reveal the location of molecules and dust in the close environment of the star. Indeed, the C2H2 and HCN molecules are spatially located between 1 and 3.4 R* which is much closer to the star than the location of the dust. The R Scl spectrum is fitted by molecules and a dust mixture of 90% of amorphous carbon and 10% of silicone carbide. The inner boundary of the dust envelope is estimated by DUSTY at about 4.6 R*. We derive a mass-loss rate of 1.2 ± 0.4 × 10−6M⊙ yr−1however no clear SiC forming region has been detected in the MATISSE data.
Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence.
Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence.
No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value = 6.63 × 10−3); 5′-adenosine monophosphate-activated protein kinase signalling (P-value = 9.57 × 10−3); and apoptosis (P-value = 1.75 × 10−2) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status.
The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.
The literature contains considerable disagreements on the relative stabilities of the members of the copper hydroxyl sulphate family. Titration of copper sulphate with sodium hydroxide is claimed by some to produce only brochantite, while other reports indicate that antlerite and a dihydrate of antlerite are produced in the titration. Most stability field diagrams show that antlerite is the more stable stoichiomer at pH 4 and sulphate activity of 0.05–1. We have reexamined this stoichiometric family by titration of aqueous copper sulphate with sodiumhydroxide and sodium carbonate, reverse titration of sodiumhydroxide with copper sulphate and simultaneous addition of copper sulphate and sodium hydroxide at a variety of mole ratios, concentrations, temperatures and reaction times. We have also explored the reaction of copper hydroxide with copper sulphate and the reaction of weak bases, such as sodiumacetate, sodiumcarbonate and urea, with copper sulphate. Our work indicates that: (1) antlerite is not formed in reactions of 0.05 to 1.2 M CuSO4 with 0.05–1.0 M NaOH or Na2CO3 at room temperature; (2) antlerite is formed in the addition of small concentrations of base (≤0.01 M) to 1 M CuSO4 at 80°C, but not at roomtem perature or with 0.01 M CuSO4 at 80°C; (3) the formation of Cu5(SO4)2(OH)6·4H2O occurs at large Cu2+ to base mole ratios; (4) the compound described in the literature as antlerite dihydrate is actually Cu5(SO4)2(OH)6.4H2O; (5) at mole ratios of Cu2+ to OH– ranging from 2:1 to 1:2 the predominant product is brochantite; and (6) brochantite and Cu5(SO4)2(OH)6.4H2O are converted to antlerite in the presence of 1 M CuSO4 (the latter requires temperatures of 80°C or greater).
The Ksp (ion activity product) values of antlerite and brochantite were determined to be 2.53 (0.01)⨯10−48 and 1.01 (0.01)⨯10−69, respectively, using atomic absorption spectroscopy and Visual MINTEQ after equilibration in solutions of varying ionic strength and pH for six days. These values are in good agreement with those from the literature. However, after 6 months, antlerite in contact with solution is partially converted to brochantite and hence is metastable with a relatively low conversion rate. The Ksp value for antlerite must therefore be considered approximate. The relative stabilities of the copper hydroxyl sulphates are rationalized using appropriate equations and Gibbs energy calculations. A Gibbs free energy of formation for Cu5(SO4)2(OH)6.4H2O of –3442 kJ/mol was obtained from the simple salt approximation.
Elemental, chemical, and structural analysis of polycrystalline materials at the micron scale is frequently carried out using microfocused synchrotron X-ray beams, sometimes on multiple instruments. The Maia pixelated energy-dispersive X-ray area detector enables the simultaneous collection of X-ray fluorescence (XRF) and diffraction because of the relatively large solid angle and number of pixels when compared with other systems. The large solid angle also permits extraction of surface topography because of changes in self-absorption. This work demonstrates the capability of the Maia detector for simultaneous measurement of XRF and diffraction for mapping the short- and long-range order across the grain structure in a Ni polycrystalline foil.
Organic-walled microfossils are reported from the Borden Rift Basin of northern Baffin Island and Bylot Island. The diverse assemblage, obtained by palynological acid maceration, comprises 39 taxa and occurs in fine-grained siliciclastic and carbonate units from all but the two lowermost formations of the Bylot Supergroup; their age is bracketed between 1,270 and 750 Ma. Of 307 samples analyzed from all parts of the basin, 133 yielded identifiable remains. The microbiota comprises the following taxa: Siphonophycus septatum, S. robustum, S. rugosum n. comb., S. kestron, S. capitaneum, Pellicularia tenera, Polythrichoides lineatus, Obruchevella valdaica, Karamia? sp., opaque filaments, Oscillatoriopsis spp., Palaeolyngbya sp., Arctacellularia tetragonala n. comb., A. ellipsoidea, Chlorogloeaopsis contexta n. comb., C. kanshiensis n. comb., Navifusa bacillaris n. comb., N. majensis, N. actinomorpha n. comb., Leiosphaeridia minutissima, L. tenuissima, L. crassa, L. jacutica, L. ternata, Lophosphaeridium granulatum, Valeria lophostriata, Pterospermopsimorpha insolita, Eomicrocystis elegans, E. malgica, Symplassosphaeridium spp., Synsphaeridium spp., Satka squamifera, Satka spp., Coneosphaera arctica n. sp., Coneosphaera sp., Spumosina rubiginosa, and Fabiformis baffinensis n. sp. The taxon Palaeocalothrix divaricatus, present in some macerates, is possibly a modern fungal contaminant. Abundance and taxonomic diversity varies considerably between formations and environments, with the Arctic Bay Formation exhibiting the greatest productivity and species diversity of the seven formations studied, and the transgressive muddy shelf deposits being the most productive of the 11 environments recognized. This microfossil assemblage of predominantly planktonic species has distinctive taxa in common with Middle to Late Riphean sequences in Siberia (Lakhanda and Miroedikha Groups, ca. 950 to 850 Ma), the lower part of the Thule Group (< 1,270 Ma) in northwest Greenland, the Fury and Hecla Group in western Baffin Island, and taxa reported from the upper part of the Bushimay Supergroup in Zaire. On the other hand, some elements in the Bylot Supergroup are more characteristic of Vendian beds on the Russian Platform, indicating longer stratigraphic ranges for such taxa than previously thought. The compositional similarity between the Borden Basin and Siberian sequences supports palinspastic reconstructions juxtaposing Siberia and Laurentia during the middle to late Proterozoic, and the opening of the Poseidon Ocean.
The influence of baseline severity has been examined for antidepressant
medications but has not been studied properly for cognitive–behavioural
therapy (CBT) in comparison with pill placebo.
To synthesise evidence regarding the influence of initial severity on
efficacy of CBT from all randomised controlled trials (RCTs) in which
CBT, in face-to-face individual or group format, was compared with
pill-placebo control in adults with major depression.
A systematic review and an individual-participant data meta-analysis
using mixed models that included trial effects as random effects. We used
multiple imputation to handle missing data.
We identified five RCTs, and we were given access to individual-level
data (n = 509) for all five. The analyses revealed that
the difference in changes in Hamilton Rating Scale for Depression between
CBT and pill placebo was not influenced by baseline severity (interaction
P = 0.43). Removing the non-significant interaction
term from the model, the difference between CBT and pill placebo was a
standardised mean difference of –0.22 (95% CI –0.42 to –0.02,
P = 0.03, I2 = 0%).
Patients suffering from major depression can expect as much benefit from
CBT across the wide range of baseline severity. This finding can help
inform individualised treatment decisions by patients and their
A new generation of solar instruments provides improved spectral, spatial, and temporal resolution, thus facilitating a better understanding of dynamic processes on the Sun. High-resolution observations often reveal multiple-component spectral line profiles, e.g., in the near-infrared He i 10830 Å triplet, which provides information about the chromospheric velocity and magnetic fine structure. We observed an emerging flux region, including two small pores and an arch filament system, on 2015 April 17 with the ‘very fast spectroscopic mode’ of the GREGOR Infrared Spectrograph (GRIS) situated at the 1.5-meter GREGOR solar telescope at Observatorio del Teide, Tenerife, Spain. We discuss this method of obtaining fast (one per minute) spectral scans of the solar surface and its potential to follow dynamic processes on the Sun. We demonstrate the performance of the ‘very fast spectroscopic mode’ by tracking chromospheric high-velocity features in the arch filament system.
Coccoid and filamentous microfossils in the Borden Rift Basin on northwestern Baffin Island and western Bylot Island are reported from 14 localities at six general stratigraphic levels in the Society Cliffs Formation, and one in the Victor Bay Formation. At least seven of 12 fossiliferous Society Cliffs samples, and one of two Victor Bay samples, are from cherty dolostones formed in shallow restricted, peritidal evaporitic environments. The remaining six fossiliferous samples accumulated in somewhat deeper, less restricted waters. The assemblage is preserved in black chert nodules and layers and comprises 30 taxa, including the filamentous forms Archaeotrichion? sp., Tenuofilum septatum, Eomycetopsis robusta, Siphonophycus inornatum, S. kestron, Rhicnonema antiquum, Brachypleganon sp., Eomicrocoleus sp., Uluksanella baffinensis n. gen. and sp., Talakania? sp., the coccoid taxa Eosynechococcus medius, E. grandis, Archaeoellipsoides obesus, Sphaerophycus parvum, S. medium, Myxococcoides minor, M. grandis, Melasmatosphaera spp., Phanerosphaerops capitaneus, Palaeoanacystis sp., Tetraphycus hebeiensis, Eogloeocapsa bella, Gloeodiniopsis magna, G. sp. 1, G. mikros, Polybessurus bipartitus, Cymatiosphaera? sp., the fusiform Eupoikilofusa? sp., and rare specimens of two unidentified and problematic taxa.
The effects of antidepressants for treating depressive disorders have been overestimated because of selective publication of positive trials. Reanalyses that include unpublished trials have yielded reduced effect sizes. This in turn has led to claims that antidepressants have clinically insignificant advantages over placebo and that psychotherapy is therefore a better alternative. To test this, we conducted a meta-analysis of studies comparing psychotherapy with pill placebo.
Ten 10 studies comparing psychotherapies with pill placebo were identified. In total, 1240 patients were included in these studies. For each study, Hedges’ g was calculated. Characteristics of the studies were extracted for subgroup and meta-regression analyses.
The effect of psychotherapy compared to pill placebo at post-test was g = 0.25 [95% confidence interval (CI) 0.14–0.36, I2 = 0%, 95% CI 0–58]. This effect size corresponds to a number needed to treat (NNT) of 7.14 (95% CI 5.00–12.82). The psychotherapy conditions scored 2.66 points lower on the Hamilton Depression Rating Scale (HAMD) than the placebo conditions, and 3.20 points lower on the Beck Depression Inventory (BDI). Some indications for publication bias were found (two missing studies). We found no significant differences between subgroups of the studies and in meta-regression analyses we found no significant association between baseline severity and effect size.
Although there are differences between the role of placebo in psychotherapy and pharmacotherapy research, psychotherapy has an effect size that is comparable to that of antidepressant medications. Whether these effects should be deemed clinically relevant remains open to debate.
We demonstrate that the anisotropic optical response of metal (cobalt) slanted columnar thin films (STF) at THz frequencies strongly depends on the dielectric properties of the dielectric ambient surrounding the slanted columnar thin films. An effective medium dielectric function approach is used to describe the combined optical response of metal slanted columnar thin film and dielectric ambient. Our observations indicate that metal (cobalt) slanted columnar thin films can be used as sensors which will enable detection and characterization of minute amounts of dielectrics at THz frequencies, such as for flow-based detection of liquid chemical constituents.
The early Neolithic in northern Central Europe ought to be the theatre in which incoming farmers meet local hunter-gatherers, with greater or lesser impact. By way of contrast, the authors use isotope analysis in a cemetery beside the Danube to describe a peaceful, well-integrated community with a common diet and largely indigenous inhabitants. Men and women may have had different mobility strategies, but the isotopes did not signal special origins or diverse food-producing roles. Other explanations attend the variations in the burial rites of individuals and their distribution into cemetery plots.
In this study, compact Charpy impact testing was used to investigate the effect of processing history and dendrite morphology of bulk metallic glass matrix composites (BMGMCs) on impact toughness. Composite samples were fabricated via suction casting and semisolid forging, and the results were compared with crystalline alloys in the same geometry. A strong dependence on processing was observed, with samples exhibiting up to a 30-fold increase in impact toughness depending on processing and microstructure. Provided that attention is paid to processing techniques, BMGMCs are shown to have properties that equal or surpass some conventionally used crystalline alloys. These properties invite further exploration of these materials in structural applications.
We have used monolayer cultures prepared from early postnatal rabbit retinae (days 2–5) by the sandwich technique to study the capacity of immature neurons to express specific neuronal phenotypes in a homogeneous in vitro environment. Applying morphological, immunocytochemical, and autoradiographic criteria, we demonstrate that a variety of phenotypes could be distinguished after 7–14 days in vitro, and correlated with known retinal cell types. Bipolar cell-like neurons (approximately 4% of total cell number) were identified by cell type-specific monoclonal antibodies (115A10) and their characteristic bipolar morphology. Small subpopulations (about 1%) of GABA-immunoreactive neurons acquired elaborate morphologies strikingly similar to those of A- and B-type horizontal cells. Amongst putative amacrine cells several different subpopulations could be classified. GABA-immunoreactive amacrine-like neurons (6.5%), which also showed high affinity [3H]-GABA uptake, comprised cells of varying size and shape and could be subdivided into subpopulations with respect to their response to different glutamate receptor agonists (NMDA, kainic acid, quisqualic acid). In addition, a small percentage of [3H]-GABA accumulating cells with large dendritic fields showed tyrosine-hydroxylase immunoreactivity. Presumptive glycinergic amacrine cells (18.5%) were rather uniform in shape and had small dendritic fields. Release of [3H]-glycine from these neurons was evoked by kainic and quisqualic acid but not by NMDA. Small [3H]-glutamate accumulating neurons with few short processes were the most frequent cell type (73%). This cell type also exhibited opsin immunoreactivity and probably represented incompletely differentiated photoreceptor cells. Summing the numbers of characterized cells indicated that we were able to attribute a defined retinal phenotype to most, if not all of the cultured neurons. Thus, we have demonstrated that immature neuronal cells growing in monolayer cultures, in the absence of a structured environment, are capable of maintaining or producing specific morphological and functional properties corresponding to those expressed in vivo. These results stress the importance of intrinsic factors for the regulation of neuronal differentiation. On the other hand, morphological differentiation was far from perfect indicating the requirement for regulatory factors.
Previous studies investigating attentional biases in social anxiety disorder (SAD) have yielded mixed results. Recent event-related potential (ERP) studies using the dot-probe paradigm in non-anxious participants have shown that the P1 component is sensitive to visuospatial attention towards emotional faces. We used a dot-probe task in conjunction with high-density ERPs and source localization to investigate attentional biases in SAD.
Twelve SAD and 15 control participants performed a modified dot-probe task using angry–neutral and happy–neutral face pairs. The P1 component elicited by face pairs was analyzed to test the hypothesis that SAD participants would display early hypervigilance to threat-related cues. The P1 component to probes replacing angry, happy or neutral faces was used to evaluate whether SAD participants show either sustained hypervigilance or decreased visual processing of threat-related cues at later processing stages.
Compared to controls, SAD participants showed relatively (a) potentiated P1 amplitudes and fusiform gyrus (FG) activation to angry–neutral versus happy–neutral face pairs; (b) decreased P1 amplitudes to probes replacing emotional (angry and happy) versus neutral faces; and (c) higher sensitivity (d′) to probes following angry–neutral versus happy–neutral face pairs. SAD participants also showed significantly shorter reaction times (RTs) to probes replacing angry versus happy faces, but no group differences emerged for RT.
The results provide electrophysiological support for early hypervigilance to angry faces in SAD with involvement of the FG, and reduced visual processing of emotionally salient locations at later stages of information processing, which might be a manifestation of attentional avoidance.