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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.
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.
The use of Alzheimer disease medication for the treatment of dementia symptoms has shown significant benefits with regards to functional and cognitive outcomes as well as nursing home placement (NHP) and mortality. Hospitalisations in these patient groups are characterised by extended length of stays (LOS), frequent readmissions, frequent NHP and high-mortality rates. The impact of Alzheimer disease medication on the aforementioned outcomes remains still unknown. This study assessed the association of Alzheimer disease medication with outcomes of hospitalisation among patients with Alzheimer disease and other forms of dementia.
Methods
A dynamic retrospective cohort study from 2004 to 2015 was conducted which claims data from a German health insurance company. People with dementia (PWD) were identified using ICD-10 codes and diagnostic measures. The main predictor of interest was the use of Alzheimer disease medication. Hospitalisation outcomes included LOS, readmissions, NHP and mortality during and after hospitalisation across four hospitalisations. Confounding was addressed using a propensity score throughout all analyses.
Results
A total of 1380 users of Alzheimer disease medication and 6730 non-users were identified. The use of Alzheimer disease medication was associated with significantly shorter LOS during the first hospitalisations with estimates for the second, third and fourth showed a tendency towards shorter hospital stays. In addition, current users of Alzheimer disease medication had a lower risk of hospital readmission after the first two hospitalisations. These associations were not significant for the third and fourth hospitalisations. Post-hospitalisation NHP and mortality rates also tended to be lower among current users than among non-users but differences did not reach statistical significance.
Conclusions
Our results indicate that Alzheimer disease medication might contribute to a reduction of the LOS and the number of readmissions in PWD.
As evidence for the second process of the Embracing factor, the target article characterizes being moved as a mixed emotion linked to sadness through metonymy. We question these characterizations and argue that emotions should not be equated with their vernacular labels.
New records of Jefferson's ground sloth (Megalonyx jeffersonii) and elk-moose (Cervalces scotti) from Lang Farm provide the first precise temporal correlation of these taxa with the specific environments inhabited by them near the time of their extinction. Six AMS 14C measurements establish an age of 11,405 ± 50 14C yr B.P. for Lang Farm Cervalces and an age of 11,430 ± 60 or 11,485 ± 40 14C yr B.P. for the Megalonyx. These measurements represent the youngest 14C dates for these two genera based on direct dating. Comparison of the dates with pollen data from northern Illinois indicates that these species inhabited a nonanalog environment that was transitional from mid-latitude tundra to mixed conifer and deciduous woodland. Although spruce (Picea sp.) was dominant, it was less abundant than prior to 12,500 14C yr B.P. The presence of black ash (Fraxinus nigra) and fir (Abies sp.) indicates a wet climate and heavy winter precipitation. This may have been the preferred habitat for Cervalces because of its narrow geographic range. However, this habitat type was only one of many occupied by Megalonyx as indicated by its broad geographic distribution.
The South American giant short-faced bear (Arctotherium angustidens Gervais and Ameghino, 1880) is one of five described Arctotherium species endemic to South America and it is known for being the earliest, largest, and most carnivorous member of the genus. Here we report an extraordinarily large A. angustidens individual exhumed from Ensenadan sediments (early to middle Pleistocene) at Buenos Aires Province, Argentina. Based on overall size, degree of epiphyseal fusion, and pathologies, this bear was an old-aged male that sustained serious injuries during life. Body mass of the bear is estimated and compared to other ursid species based on a series of allometric equations. To our knowledge, this specimen now represents the largest bear ever recorded. In light of this discovery, we discuss the evolution of body size in Arctotherium (from large-to-small) and compare this to bears that exhibited different evolutionary trajectories. We suggest that the larger size and more carnivorous nature of A. angustidens, compared to later members of the genus, may reflect the relative lack of other large carnivores and abundance of herbivores in South America just after the Great American Biotic Interchange.
In view of the complexity of thin-film solar cells, which are comprised of a multitude of layers, interfaces, surfaces, elements, impurities, etc., it is crucial to characterize and understand the chemical and electronic structure of these components. Because of the high complexity of the Cu2ZnSn(S,Se)4 compound semiconductor absorber material alone, this is particularly true for kesterite-based devices. Hence, this paper reviews our recent progress in the characterization of Cu2ZnSnS4 (CZTS) thin films. It is demonstrated that a combination of different soft x-ray spectroscopies is an extraordinarily powerful method for illuminating the chemical and electronic material characteristics from many different perspectives, ultimately resulting in a comprehensive picture of these properties. The focus of the article will be on secondary impurity phases, electronic structure, native oxidation, and the CZTS surface composition.
Young people who are born very preterm exhibit a narrower arterial tree as compared with people born at term. We hypothesized that such arterial narrowing occurs as a direct result of premature birth. The aim of this study was to compare aortic and carotid artery growth in infants born preterm and at term. Observational and longitudinal cohort study of 50 infants (21 born very preterm, all appropriate for gestational age, 29 controls born at term) was conducted. Diameters of the upper abdominal aorta and common carotid artery were measured with ultrasonography at three months before term, at term and three months after term-equivalent age. At the first assessment, the aortic end-diastolic diameter (aEDD) was slightly larger in very preterm infants as compared with fetal dimensions. Fetal aortic EDD increased by 2.6 mm during the third trimester, whereas very preterm infants exhibited 0.9 mm increase in aEDD during the same developmental period (P < 0.001 for group difference). During the following 3-month period, aortic growth continued unchanged (+0.9 mm) in very preterm infants, whereas postnatal growth in term controls slowed down to +1.3 mm (P < 0.001 v. fetal aortic growth). At the final examination, aEDD was 22% and carotid artery EDD was 14% narrower in infants born preterm compared with controls, also after adjusting for current weight (P < 0.01). Aortic and carotid artery growth is impaired after very preterm birth, resulting in arterial narrowing. Arterial growth failure may be a generalized vascular phenomenon after preterm birth, with implications for cardiovascular morbidity in later life.
Wire shading during thin film deposition is a promising approach to low-cost, high volume manufacturing of flexible thin film photovoltaic modules. This contribution demonstrates successful patterning of a transparent conducting oxide layer by wire shading during dynamic web coating. Continuous sputter deposition of Al-doped ZnO on a 30 cm wide polymer foil and simultaneous wire shading form 1 cm wide and 300 cm long front contact stripes for thin film photovoltaic modules. Analysing the distribution of lateral shunt resistances after separating the initial 28 stripes into 1323 pieces, yields a patterning success of 97.3 %. Thus the technique seems well suited for flexible modules from organic solar cells.
The composition of Cu2ZnSnS4 thin-film solar cell absorbers was varied to induce the.formation of secondary impurity phases. For their identification, the samples have been investigated by Cu L3 and S L2,3 soft x-ray absorption (XAS) spectroscopy. We find that Cu L3 XAS is especially sensitive to the presence of copper sulfides as well as copper oxides and/or changes in the electron configuration, suggesting a basis for future studies of the surface, defect, and interface characterization of similar samples. Additionally, it is shown that the S L2,3 absorption data can be used as a very sensitive probe of the variations in the prevalence of S-Zn bonds in the near-surface region of the investigated samples.
We present an attempt to clarify the valence band order of ZnO and MgxZn1−xO films grown by pulsed laser deposition (PLD) on sapphire substrates. We derive the dependence of spin orbit interaction (Δso) and crystal field interaction (Δcf) on the temperature, strain and cation replacement (Zn with Mg) and compared this with theoretical predictions. The strain was varied by using different orientated sapphire substrates (c-, r-, and m-plane orientations) and by varying the film thicknesses. All these investigations support the conclusion that the symmetry order of the valence band is Γ7-Γ9-Γ7 for ZnO and MgxZn1−xO for x ≤ 0.55.
A Galerkin method is used to study the two-dimensional modes of oscillatory convection in a gravitationally modulated fluid layer with rigid, isothermal boundaries heated either from below or from above. Nonlinear solutions are obtained for dimensionless frequencies ω (frequency is made non-dimensional with the timescale d2/κ where d is the depth of the fluid layer and κ is the thermal diffusivity) in the range 100–3000, dimensionless accelerations ε (εg is the amplitude of the externally imposed oscillatory vertical acceleration and g is the constant vertical acceleration of gravity) in the range of 1–104, and Prandtl numbers P in the range 0.71 (air) to 7 (water). The problem of convective onset is explored for a broader range of parameters than heretofore considered, including Prandtl numbers between 0.71 and 50. Both synchronous and subharmonic modes of convection are identified and it is found that finite-amplitude synchronous convection can be unstable to subharmonic modes.
The gravitational instability of a horizontal fluid layer with a univariant phase transition is considered. It is found that the layer can be unstable even when the less dense phase lies above the dense phase and can be stable in the opposite case. Applications of the theory to convection with phase transitions in astrophysical and geophysical problems are briefly discussed.
Nanoparticle-loaded encapsulants provide unique optical and material properties for the enhancement of light extraction efficiency in light-emitting diodes (LEDs). We report on the uniform dispersion of TiO2 nanoparticles with average diameter of 40 nm in epoxy, and the demonstration of a refractive index (n)of 1.68 at 400 nm wavelength, higher than that of pure epoxy (n = 1.53). It is found that proper chemical surfactants and nanoparticle preparation are critical to eliminate agglomeration of nanoparticles. Theoretical analysis of optical scattering in nanoparticle-loaded encapsulation materials reveals that although the size and loading factor of nanoparticles greatly influence scattering, specular transparency of the encapsulant film occurs if the thicknesses of the films are kept below the optical scattering length. Furthermore, the encapsulants benefit from an optimized scattering coefficient as demonstrated by three-dimensional ray-tracing simulations showing light extraction efficiency enhancements greater than 50%.
Edited by
Evgeni Fedorovich, University of Oklahoma,Richard Rotunno, National Center for Atmospheric Research, Boulder, Colorado,Bjorn Stevens, University of California, Los Angeles
When we were students at UCLA in the early 1970s, the California stratus deck frequently floated over our heads. There on the beautiful campus under the clouds, we studied Doug Lilly's (1968; hereafter L68) paper about cloud-topped mixed layers under strong inversions. The paper was recommended to us by our mentor, Professor Akio Arakawa, who recognized the relevance of Lilly's insights to climate dynamics. Whereas spectacular supercells leap from the boundary layer to the tropopause in a single bound, L68 analyzed “wimpy” stratus and stratocumulus clouds that are only a few hundred meters thick and barely manage to precipitate. L68 was a “sleeper.” It received little attention at first, but over the decades since then it has picked up many citations (417 as of June 2003), and it forms the groundwork for several currently thriving lines of research. L68's emergence as a classic research paper stems in part from the climatic importance of the cloud regimes it dealt with, but more importantly from the amazing prescience of Lilly's ideas and the clarity with which he expressed them.
Several ingredients, acquired over a number of years, came together in a two-week period during the summer of 1965 to produce the remarkable L68 paper. The first was personal experience and interest. Lilly's high-school physics teacher, at Sequoia Union High School in Redwood City, California, ran a weather club, which Lilly joined with enthusiasm. After becoming the club's student leader, Lilly began to evolve, by his own description, into a
weather junkie, keeping daily weather records, making forecasts, and testing their accuracy. When I learned to drive, I did something akin to tornado chasing, within the limits of California weather.[…]
The effect of the density and in-plane distribution of interfacial interactions on crack initiation in an epoxy-silicon joint was studied in nominally pure shear loading. Well-defined combinations of strong (specific) and weak (nonspecific) interactions were created using self-assembling monolayers. The in-plane distribution of strong and weak interactions was varied by employing two deposition methods: depositing mixtures of molecules with different terminal groups resulting in a nominally random distribution, and depositing methyl-terminated molecules in domains defined lithographically with the remaining area interacting through strong acid-base interactions. The two distributions lead to very different fracture behavior. For the case of the methyl-terminated domains (50 μm on a side) fabricated lithographically, the joint shear strength varies almost linearly with the area fraction of strongly interacting sites. From this we infer that cracks nucleate on or near the interface over nearly the entire range of bonded area fraction and do so at nearly the same value of local stress (load/bonded area). We postulate that the imposed heterogeneity in interfacial interactions results in heterogeneous stress and strain fields within the epoxy in close proximity to the interface. Simply, the bonded areas carry load while the methyl terminated domains carry negligible load. Stress is amplified adjacent to the well-bonded regions (and reduced adjacent to the poorly bonded regions), and this leads to crack initiation by plastic deformation and chain scission within the epoxy near the interface. For the case of mixed monolayers, the dependence is entirely different. At low areal density of strongly interacting sites, the joint shear strength is below the detection limit of our transducer for a significant range of mixed monolayer composition. With increasing density of strongly interacting sites, a sharp increase in joint shear strength occurs at a methyl terminated area fraction of roughly 0.90. We postulate that this coincides with the onset of yielding in the epoxy. For methyl-terminated area fractions less than 0.85, the joint shear strength becomes independent of the interfacial interactions. This indicates that fracture no longer initiates on the interface but away from the interface by a competing mechanism, likely plastic deformation and chain scission within the bulk epoxy. The data demonstrate that the in-plane distribution of interaction sites alone can affect the location of crack nucleation and the far-field stress required.
The junction temperature of AlGaN/GaN ultraviolet (UV) Light-Emitting Diodes (LEDs) emitting at 295 nm is measured by using the temperature coefficients of the diode forward voltage and emission peak energy. The high-energy slope of the spectrum is explored to measure the carrier temperature. A linear relation between junction temperature and current is found. Analysis of the experimental methods reveals that the diode-forward voltage is the most accurate method (± 3 °C). A theoretical model for the dependence of the diode junction voltage (Vj) on junction temperature (T) is developed that takes into account the temperature dependence of the energy gap. A thermal resistance of 87.6 K/W is obtained with the AlGaN/GaN LED sample mounted with thermal paste on a heat sink.
Transfer of monocrystalline silicon films to arbitrary foreign substrates is a promising way for the fabrication of high quality silicon films on foreign substrates, demonstrated by solar cell efficiencies on glass as high as 16.6 % in the past. Transfer technologies also enable the use of flexible substrates. This paper investigates the mechanical stability of the separation layer for two different morphologies. First measurements on the minimum bending radius of unsupported silicon films are presented that allow us to estimate minimum curvatures for flexible monocrystalline devices. Finally, we report the first flexible monocrystalline thin film silicon solar cell of 4 cm2 with an independently confirmed efficiency of 14.6 %.