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Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
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.
Evaluate the effects of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD) according to disease severity.
Methods
Pooled data (quetiapine XR 50, 150 and 300mg/day doses combined) from four 6- or 8-week placebo-controlled quetiapine XR monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00004) were analysed. Key inclusion criterion for all 4 studies: HAM-D total score ≥22. Primary endpoint: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. A post-hoc analysis assessed change from randomisation in MADRS total score and MADRS response (≥ 50% reduction in MADRS total score) at endpoint (Week 6 or Week 8) in 6 severity cohorts (defined by a MADRS total score at randomisation ≥24, ≥26, ≥28, ≥30, ≥32 or ≥34).
Results
1752 patients (comprising the l’ all patients’ group) were evaluated (MADRS score ≥24 at randomisation, n=1601; ≥26, n=1467; ≥28, n=1269; ≥30, n=1038; ≥32, n=745; ≥34, n=500). Quetiapine XR significantly reduced mean MADRS total score at endpoint in lrsquo;all patients’ (p< 0.001 vs placebo) and in all 6 severity cohorts (≥24, ≥26, ≥28, ≥30 and ≥32, p< 0.001 vs placebo; ≥34, p< 0.01 vs placebo). MADRS response rates were significantly higher in the quetiapine XR group vs placebo in the ‘all patients’ group (p< 0.001 vs placebo) and in all 6 severity cohorts (≥24, ≥26, ≥28, ≥30 and ≥32, p< 0.001 vs placebo; ≥34, p=0.001 vs placebo).
Conclusions
Quetiapine XR monotherapy significantly improved depressive symptoms in patients with MDD irrespective of disease severity, including the most severe levels of depression.
Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.
Methods:
The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.
Results:
There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.
Conclusion:
These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.
Self-ratings of psychotic experiences might be biased by depressive symptoms.
Method
Data from a large naturalistic multicentre trial on depressed inpatients (n = 488) who were assessed on a biweekly basis until discharge were analyzed. Self-rated psychotic symptoms as assessed with the 90-Item Symptom Checklist (SCL-90) were correlated with the SCL-90 total score, the SCL-90 depression score, the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale 21 item (HAMD-21) total score, the Montgomery Åsberg Depression Rating Scale (MADRS) total score and the clinician-rated paranoid-hallucinatory score of the Association for Methodology and Documentation in Psychiatry (AMDP) scale.
Results
At discharge the SCL-90 psychosis score correlated highest with the SCL-90 depression score (0.78, P<0.001) and with the BDI total score (0.64, P<0.001). Moderate correlations were found for the MADRS (0.34, P<0.001), HAMD (0.37, P<0.001) and AMDP depression score (0.33, P<0.001). Only a weak correlation was found between the SCL-90 psychosis score and the AMDP paranoid-hallucinatory syndrome score (0.15, P<0.001). Linear regression showed that change in self-rated psychotic symptoms over the treatment course was best explained by a change in the SCL-90 depression score (P<0.001). The change in clinician-rated AMDP paranoid-hallucinatory score had lesser influence (P = 0.02).
Conclusions
In depressed patients self-rated psychotic symptoms correlate poorly with clinician-rated psychotic symptoms. Caution is warranted when interpreting results from epidemiological surveys using self-rated psychotic symptom questionnaires as indicators of psychotic symptoms. Depressive symptoms which are highly prevalent in the general population might influence such self-ratings.
We derive zphot for sources in the entire (~0.4 deg2) H-HDF-N field with the EAzY code, based on PSF-matched broad-band (U band to IRAC 4.5 μm) photometry. Our catalog consists of a total of 131,678 sources. We find σNMAD = 0.029 for non-X-ray sources. We also classify each object as a star or galaxy through SED fitting. Furthermore, we match our catalog with the 2 Ms CDF-N main X-ray catalog. For the 462 matched non-stellar X-ray sources, we improve their zphot quality (σNMAD = 0.035) by adding three additional AGN templates. We make our photometry and zphot catalog publicly available.
The X-ray powder diffraction data for δ-Na2Si2O5 are reported. The sample was prepared from water glass solution applied to pressed powder tablets of finely ground quartz using a heating program with a maximal temperature of 700 °C. The crystallographic data for δ-disilicate obtained from a Rietveld analysis are: space group P21/n, a=8.3818(4) Å, b=12.0726(5) Å, c=4.8455(2) Å, β=90.303(5)°, V=490.31 Å3, Z=4, and Dcalc.=2.468 g/cm3.
1. Growing young sugar-beet plants under continuous illumination before transplanting into the field induced stem elongation and anthesis in considerably greater proportions than in plants not exposed to continuous light exposure.
2. The technique of growing young plants under continuous light exposure during the winter offers a means of rapid multiplication of small seed stocks, and also of isolating the various physiological types comprising the population. In particular, the technique should make it possible to select types resistant to bolting.
3. Analysis of the glomerule populations obtained from the plants showing anthesis at definite dates indicates that there is a definite trend in the proportions of large, medium and small glomerules as the season progresses.
1. Experiments are described demonstrating a technique for raising sugar beet seedlings under glass during the winter to provide plants for seed production after transplanting into the field.
2. The use of 24 hr. illumination for this purpose is discussed, and the effect of this illumination in resolving a heterogeneous population is described.
3. The association between the growth habit of the seeding plant and root characters, glomerule yield, weight and size, and the time of anthesis is considered in relation to the recognition of types showing B. maritima and B. vulgaris characteristics.
The Pseudospark is an axially symmetric, high-voltage gas discharge operating at pressures below 100 Pa. It is capable of producing pinched high current ion beams. Streak camera photographs of the operation of this discharge reveal that a pinch with a diameter of ∼1 mm occurs in the diode. The beam then expands to about 1 to 10 mm in a distance of 12 cm. The beam-target interaction shows a UV-emitting plasma corresponding to protons with a main energy of 100 keV and a current density of about 16 kA/cm2. Initial theoretical results for the pseudospark are given.
The CRESST-II direct Dark Matter search is located in the Gran Sasso underground laboratories, Italy. CaWO4 crystals are used as scintillating targets for WIMP (weakly interacting massive particle) interactions. They are operated as cryogenic calorimeters in combination with a second cryogenic detector used to measure the scintillation light produced in the target crystal. For each particle interaction, the combination of phonon and light signals provides an event by event discrimination which allows to distinguish known particles (alphas, betas, gammas, neutrons) from the expected signal of WIMPs. A major upgrade of the setup comprises modifications of the shielding, installation of a muon-veto, and new read out electronics, as well as a new detector-support structure to accommodate up to 33 detector modules, i.e. 10 kg of target mass. The experiment was thereafter successfully commissioned in 2007. Data obtained during this commissioning phase from 2 detector modules are presented here. Combining the data collected with these two detector modules with data from one single module obtained during the CRESST-I phase, the experiment could already place a limit of ~6 × 10-7 pb for the spin independent WIMP-nucleon scattering cross section at a WIMP mass of ~60 GeV/c2.
EURECA (European Underground Rare Event Calorimeter Array) is an astro-particle physics facility aiming to directly detect galactic dark matter. The Laboratoire Souterrain de Modane has been selected as host laboratory. The EURECA collaboration unites CRESST, EDELWEISS and the Spanish-French experiment ROSEBUD, thus concentrating and focussing effort on cryogenic detector research in Europe into a single facility. EURECA will use a target mass of up to one ton, enough to explore WIMP – nucleon scalar scattering cross sections in the region of 10-9 – 10-10 picobarn. A major advantage of EURECA is the planned use of more than just one target material (multi target experiment for WIMP identification).
Electron mobilities were studied as a function of thin-film growth conditions in hot wall epitaxially grown C60 based field-effect transistors. Mobilities in the range of ∼ 0.5 to 6 cm2/Vs are obtained depending on the thin-film morphology arising from the initial growth conditions. Moreover, the field-effect transistor current is determined by the morphology of the film at the interface with the dielectric, while the upper layers are less relevant to the transport. At high electric fields, a non-linear transport has been observed. This effect is assigned to be either because of the dominance of the contact resistance over the channel resistance or because of the gradual move of the Fermi level towards the band edge as more and more empty traps are filled due to charge injection.
First 405 GHz and 212 GHz solar flare observations were obtained during short campaigns while the new solar submillimeter-wave telescope (SST) was still undergoing adjustments at the CASLEO El Leoncito observatory in the Argentina Andes. We show here preliminary results for a large X1.1 class X-ray event occurred on 2000 March 22, which exhibited a small submm-w continuum response to the slow (minutes) bulk flare emission, and numerous subsecond spikes (100-300 ms), the brightest spikes reaching about 180 and 50 s.f.u. at 405 and 212 GHz, respectively.
The study of the morphology, lateral and vertical correlation of self-organized PbSe quantum dots in Pb1−xEux Te is presented. The samples consist of quantum dot superlattices of n periods of (PbSe/Pb1−xEux Te) grown on PbTe/(111) BaF2 by the S-K mode using MBE. The Pb1−xEux Te spacer thickness was varied from 34.3nm to 312nm and the growth temperature was varied between 335°C and 380°C. Our TEM results show very good lateral and vertical correlation of the dots. The dots form an array with either a/b/c/a/b/c/... or a/a/a/... vertical stacking sequence along the [111] growth direction. The stacking sequence is accurately controlled by the thickness of the Pb1−xEux Te spacer layer thickness and the growth temperature. The best a/b/c/... spatial correlation was obtained for temperatures around 380°C and spacer thickness of ˜40nm. The dots are highly strained and form triangular pyramids with (111) bases and (100) facets as observed by AFM. The shape of the dots also varied with the Pb1−xEux Te spacer thickness. An analysis of the spatial correlation of the dots' size and shape with respect to spacer thickness and growth temperature is presented.
In this paper, the interrelation between structural and magnetic properties of ultra-thin Mn films epitaxially grown on (001) bcc Fe is studied. The Mn growth and in-plane structure were controlled by electron diffraction (RHEED). The structures of the Mn films were determined by using X-Ray absorption spectroscopy (SEXAFS). Finally, the magnetic properties were studied by using X-Ray magnetic circular dichroïsm (XMCD). All the experiments were performed under ultra-high vacuum. As shown by XMCD experiments, a magnetic transition is observed at 2 Mn monolayers. The analysis of RHEED and SEXAFS experimental results clearly demonstrates that a structural transition comes with this magnetic transition.
Charge collection, transient photocurrents and collection efficiency under additional bias illumination were used to characterize 3–4 micron thick a-Si:H pin-diodes. The wavelength dependent decrease or increase in the spectral response, depending on the bias flux and absorption depth, is related to the distribution of the electric field, recombination and majority carrier diffusion. At higher photon flux an overshoot in the transient photocurrent after switch-on of steady illumination indicates the time scale for the changes in internal variables. Collection efficiencies under large bias monochromatic photon flux well in excess of the maximum value of 100 % for probe beam generated carriers are observed with a large amplification ratio. These efficiencies sensitively depend both on the applied voltage and the defect density. Numerical modelling reveals the influence of internal variables on the transient and steady state photocurrents under the different illumination conditions.