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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.
SCN2A encodes a voltage-gated sodium channel (designated NaV1.2) vital for generating neuronal action potentials. Pathogenic SCN2A variants are associated with a diverse array of neurodevelopmental disorders featuring neonatal or infantile onset epilepsy, developmental delay, autism, intellectual disability and movement disorders. SCN2A is a high confidence risk gene for autism spectrum disorder and a commonly discovered cause of neonatal onset epilepsy. This remarkable clinical heterogeneity is mirrored by extensive allelic heterogeneity and complex genotype-phenotype relationships partially explained by divergent functional consequences of pathogenic variants. Emerging therapeutic strategies targeted to specific patterns of NaV1.2 dysfunction offer hope to improving the lives of individuals affected by SCN2A-related disorders. This Element provides a review of the clinical features, genetic basis, pathophysiology, pharmacology and treatment of these genetic conditions authored by leading experts in the field and accompanied by perspectives shared by affected families. This title is also available as Open Access on Cambridge Core.
We report on Lagrangian statistics of turbulent Rayleigh–Bénard convection under very different conditions. For this, we conducted particle tracking experiments in a $H=1.1$-m-high cylinder of aspect ratio $\varGamma =1$ filled with air (Pr = 0.7), as well as in two rectangular cells of heights $H=0.02$ m ($\varGamma =16$) and $H=0.04$ m ($\varGamma =8$) filled with water (Pr = 7.0), covering Rayleigh numbers in the range $10^6\le {\textit {Ra}}\le 1.6\times 10^9$. Using the Shake-The-Box algorithm, we have tracked up to 500 000 neutrally buoyant particles over several hundred free-fall times for each set of control parameters. We find the Reynolds number to scale at small Ra (large Pr) as $ {\textit{Re}} \propto {\textit{Ra}}^{0.6}$. Further, the averaged horizontal particle displacement is found to be universal and exhibits a ballistic regime at small times and a diffusive regime at larger times, for sufficiently large $\varGamma$. The diffusive regime occurs for time lags larger than $\tau _{co}$, which is the time scale related to the decay of the velocity autocorrelation. Compensated as $\tau _{co} {\textit {Pr}}^{-0.3}$, this time scale is universal and rather independent of $ {\textit {Ra}}$ and $\varGamma$. We have also investigated the Lagrangian velocity structure function $S^2_i(\tau )$, which is dominated by viscous effects for times smaller than the Kolmogorov time $\tau _\eta$ and hence $S^2_i\propto \tau ^2$. For larger times we find a novel scaling for the different components with exponents smaller than what is expected in the inertial range of homogeneous isotropic turbulence without buoyancy. Studying particle-pair dispersion, we find a Batchelor scaling (${\propto }\,t^2$) on small time scales, diffusive scaling (${\propto }\,t$) on large time scales and Richardson-like scaling (${\propto }\,t^3$) for intermediate time scales.
Physician-assisted suicide (PAS) is typically associated with serious physical illnesses that are prevalent in palliative care. However, individuals with mental illnesses may also experience such severity that life becomes intolerable. In February 2020, the previous German law prohibiting PAS was repealed. Patients with severe mental illnesses are increasingly likely to approach physicians with requests for PAS.
Aims
To explore the ethical and moral perspectives of medical students and physicians when making individual decisions regarding PAS.
Method
An anonymised digital survey was conducted among medical students and physicians in Germany. Participants were presented with a case vignette of a chronically depressed patient requesting PAS. Participants decided on PAS provision and assessed theoretical arguments. We employed generalised ordinal regression and qualitative analysis for data interpretation.
Results
A total of N = 1478 participants completed the survey. Of these, n = 470 (32%) stated that they would refuse the request, whereas n = 582 (39%) would probably refuse, n = 375 (25%) would probably agree and n = 57 (4%) would definitely agree. Patient-centred arguments such as the right to self-determination increased the likelihood of consent. Concerns that PAS for chronically depressed patients might erode trust in the medical profession resulted in a decreased willingness to provide PAS.
Conclusions
Participants displayed relatively low willingness to consider PAS in the case of a chronically depressed patient. This study highlights the substantial influence of theoretical medical-ethical arguments and the broader public discourse, underscoring the necessity of an ethical discussion on PAS for mental illnesses.
Conventional superplasticizers based on polycarboxylate ether (PCE) show an intolerance to clay minerals due to intercalation of their polyethylene glycol (PEG) side chains into the interlayers of the clay mineral. An intolerance to very basic media is also known. This makes PCE an unsuitable choice as a superplasticizer for geopolymers. Bio-based superplasticizers derived from starch showed comparable effects to PCE in a cementitious system. The aim of the present study was to determine if starch superplasticizers (SSPs) could be a suitable additive for geopolymers by carrying out basic investigations with respect to slump, hardening, compressive and flexural strength, shrinkage, and porosity. Four SSPs were synthesized, differing in charge polarity and specific charge density. Two conventional PCE superplasticizers, differing in terms of molecular structure, were also included in this study. The results revealed that SSPs improved the slump of a metakaolin-based geopolymer (MK-geopolymer) mortar while the PCE investigated showed no improvement. The impact of superplasticizers on early hardening (up to 72 h) was negligible. Less linear shrinkage over the course of 56 days was seen for all samples in comparison with the reference. Compressive strengths of SSP specimens tested after 7 and 28 days of curing were comparable to the reference, while PCE led to a decline. The SSPs had a small impact on porosity with a shift to the formation of more gel pores while PCE caused an increase in porosity. Throughout this research, SSPs were identified as promising superplasticizers for MK-geopolymer mortar and concrete.
We study experimentally the dynamics of a water droplet on a tilted and vertically oscillating rigid fibre. As we vary the frequency and amplitude of the oscillations the droplet transitions between different modes: harmonic pumping, subharmonic pumping, a combination of rocking and pumping modes, and a combination of pumping and swinging modes. We characterize these responses and report how they affect the sliding speed of the droplet along the fibre. The swinging mode is explained by a minimal model making an analogy between the droplet and a forced elastic pendulum.
Against the background of missing culturally sensitive mental health care services for refugees, we developed a group intervention (Empowerment) for refugees at level 3 within the stratified Stepped and Collaborative Care Model of the project Mental Health in Refugees and Asylum Seekers (MEHIRA). We aim to evaluate the effectiveness of the Empowerment group intervention with its focus on psychoeducation, stress management, and emotion regulation strategies in a culturally sensitive context for refugees with affective disorders compared to treatment-as-usual (TAU).
Method
At level 3 of the MEHIRA project, 149 refugees and asylum seekers with clinically relevant depressive symptoms were randomized to the Empowerment group intervention or TAU. Treatment comprised 16 therapy sessions conducted over 12 weeks. Effects were measured with the Patient Health Questionnaire-9 (PHQ-9) and the Montgomery–Åsberg Depression Rating Scale (MÅDRS). Further scales included assessed emotional distress, self-efficacy, resilience, and quality of life.
Results
Intention-to-treat analyses show significant cross-level interactions on both self-rated depressive symptoms (PHQ-9; F(1,147) = 13.32, p < 0.001) and clinician-rated depressive symptoms (MÅDRS; F(1,147) = 6.91, p = 0.01), indicating an improvement in depressive symptoms from baseline to post-intervention in the treatment group compared to the control group. The effect sizes for both scales were moderate (d = 0.68, 95% CI 0.21–1.15 for PHQ-9 and d = 0.51, 95% CI 0.04–0.99 for MÅDRS).
Conclusion
In the MEHIRA project comparing an SCCM approach versus TAU, the Empowerment group intervention at level 3 showed effectiveness for refugees with moderately severe depressive symptoms.
The endowment effect has been debated for over 30 years. Recent research suggests that differential focus of attention might play a role in shaping preferences. In two studies we investigated the role of biased attention in the emergence of endowment effects. We thereby derive predictions from an extended version of evidence accumulation models by additionally assuming a bias in attentional allocation based on one’s endowment status. We test these predictions against an alternative account in which the endowment effect is the result of initial anchoring and adjustment differences (Sequential Value Matching model; Johnson & Busemeyer, 2005). In both studies we add deliberation time constraints to a standard Willingness-to-Accept/Willingness-to-Pay paradigm and consistently find that the endowment effect grows as deliberation time increases. In Study 2 we additionally use eye tracking and find that buyers focus more on value decreasing attributes than sellers (and vice versa for value increasing attributes). This shift in attention plays a pivotal role in the construction of value and partially mediates the endowment effect.
Adhesive contact between a thin elastic sheet and a substrate arises in a range of biological, physical and technological applications. By considering the dynamics of this process that naturally couples fluid flow, long-wavelength elastic deformations and microscopic adhesion, we analyse a sixth-order thin-film equation for the short-time dynamics of the onset of adhesion and the long-time dynamics of a steadily propagating adhesion front. Numerical solutions corroborate scaling laws and asymptotic analyses for the characteristic waiting time for adhesive contact and for the speed of the adhesion front. A similarity analysis of the governing partial differential equation further allows us to determine the shape of a fluid-filled blister ahead of the adhesion front. Finally, our analysis reveals a near-singular behaviour at the moving elastohydrodynamic contact line with an effective boundary condition that might be useful in other related problems.
This chapter gives an overview of UK competition law sanctions and their objectives, and provides a critical analysis of: the method for calculating fines; the Competition and Markets Authority (CMA)’s leniency and settlement policies; review by the appropriate court; private enforcement; the level of enforcement and compliance with UK competition law; and other sanctions against undertakings and individuals. The major issues in the UK centre on the comparatively low number of cases completed by the CMA and the potential chilling effect of its criminal cartel offence. Brexit creates new opportunities for the UK to design and apply its sanctions in a more effective way and outside of the constraints of EU Competition Law, but it also creates significant challenges – in particular in requiring the scaling-up of the CMA’s enforcement to include cases that were previously investigated by the European Commission on the UK’s behalf.
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.
Gravitational settling of a droplet in air onto a soft substrate is a ubiquitous event relevant to many natural processes and engineering applications. We study this phenomenon by developing a three-phase lubrication model of droplet settling onto a solid substrate coated by a thin soft layer represented by a viscous film, an elastic compressible layer and an elastic sheet supported by a viscous film. By combining scaling analysis, analytical methods and numerical simulations we elucidate how the resulting droplet dynamics is affected by the nature of the soft layer. We show that these soft layers can significantly affect the droplet shape during gravitational settling. When there is a linear response of the deformations of the soft layer, the air layer takes longer to drain as compared with the case of a droplet settling onto a rigid substrate. Our results provide new insight into the coupled interactions between droplets and solids coated by a thin film of a soft material.
Despite multiple ethical issues and little evidence of their efficacy, compulsory admission and treatment are still common psychiatric practice. Therefore, we aimed to assess potential differences in treatment and outcome between voluntarily and compulsorily admitted patients.
Methods
We extracted clinical data from inpatients treated in an academic hospital in Zurich, Switzerland between January 1, 2013 and December 31, 2019. Observation time started upon the first admission and ended after a one-year follow-up after the last discharge. Several sociodemographic and clinical characteristics, including Health of the Nation Outcome Scales (HoNOS) scores, were retrospectively obtained. We then identified risk factors of compulsory admission using logistic regression in order to perform a widely balanced propensity score matching. Altogether, we compared 4,570 compulsorily and 4,570 voluntarily admitted propensity score-matched patients. Multiple differences between these groups concerning received treatment, coercive measures, clinical parameters, and service use outcomes were detected.
Results
Upon discharge, compulsorily admitted patients reached a similar HoNOS sum score in a significantly shorter duration of treatment. They were more often admitted for crisis interventions, were prescribed less pharmacologic treatment, and received fewer therapies. During the follow-up, voluntarily admitted patients were readmitted more often, while the time to readmission did not differ.
Conclusions
Under narrowly set circumstances, compulsory admissions might be helpful to avert and relieve exacerbations of severe psychiatric disorders.
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 studies of Holocaust representation and memory, scholars of literature and culture traditionally have focused on particular national contexts. At the same time, recent work has brought the Holocaust into the arena of the transnational, leading to a crossroads between localized and global understandings of Holocaust memory. Further complicating the issue are generational shifts that occur with the passage of time, and which render memory and representations of the Holocaust ever more mediated, commodified, and departicularized. Nowhere is the inquiry into Holocaust memory more fraught or potentially more productive than in German Studies, where scholars have struggled to address German guilt and responsibility while doing justice to the global impact of the Holocaust, and are increasingly facing the challenge of engaging with the broader, interdisciplinary, transnational field. Persistent Legacy connects the present, critical scholarly moment with this long disciplinary tradition, probing the relationship between German Studies and Holocaust Studies today. Fifteen prominent scholars explore how German Studies engages with Holocaust memory and representation, pursuingcritical questions concerning the borders between the two fields and how they are impacted by emerging scholarly methods, new areas of inquiry, and the changing place of Holocaust memory in contemporary Germany.
Contributors: David Bathrick, Stephan Braese, William Collins Donahue, Tobias Ebbrecht-Hartmann, Katja Garloff, Andreas Huyssen, Irene Kacandes, Jennifer M. Kapczynski, Sven Kramer, Erin McGlothlin, Leslie Morris, Brad Prager, Karen Remmler, Michael D. Richardson, Liliane Weissberg.
Erin McGlothlin and Jennifer M. Kapczynski are both Associate Professors in the Department of Germanic Languages and Literatures at Washington University in St. Louis.
This paper links banking system development to the colonial and legal history of African countries. Based on a sample of 40 African countries from 2000 to 2018, our empirical findings show a significant dependence of current financial institutions on the inherited legal origin and the colonization type. Findings also reveal that current financial legal institutions are not major determinants of banking system development, and that institutional development and governance quality are more important. A high share of government spending relative to GDP also positively affects banking system development in African countries.
Older adults exhibit heightened vulnerability for alcohol-related health impairments. Increases in the proportion of older adults within the European Union’s total population and prevalence rates of alcohol use disorders in this age group are being observed. This large scale international study was conducted to identify those older adults with an increased risk to engage in hazardous drinking behaviour.
Methods
Socio-demographic, socio-economic, personality characteristics (Big Five Inventory, BFI-10), and alcohol consumption patterns of 13,351 individuals from 12 different European countries, collected by the Survey of Health, Aging, and Retirement in Europe, were analyzed using regression models.
Results
Age, nationality, years of education, as well as personality traits, were significantly associated with alcohol intake. For males, extraversion predicted increased alcohol intake (RR = 1.11, CI = 1.07–1.16), whereas conscientiousness (RR = 0.93, CI = 0.89–0.97), and agreeableness (RR = 0.94, CI = 0.90–0.99), were associated with a reduction. For females, openness to new experiences (RR = 1.11, CI = 1.04–1.18) predicted increased alcohol intake. Concerning excessive drinking, personality traits, nationality, and age-predicted consumption patterns for both sexes: Extraversion was identified as a risk factor for excessive drinking (OR = 1.15; CI = 1.09–1.21), whereas conscientiousness was identified as a protective factor (OR = 0.87; CI = 0.823–0.93).
Conclusion
Hazardous alcohol consumption in the elderly was associated with specific personality characteristics. Preventative measures, crucial in reducing deleterious health consequences, should focus on translating the knowledge of the association of certain personality traits and alcohol consumption into improved prevention and treatment.
Suicide risk in patients is markedly elevated during psychiatric inpatient care, as well as after discharge. However, it is unclear whether, and to what extent, this increased suicide risk varies between sex. Thus, the aim of this study was to analyze sex differences for suicides during and after psychiatric hospitalization in various countries.
Methods.
National suicide mortality rates and inpatient-related suicide rates (three intervals: during psychiatric inpatient treatment, 1 month, and 1 year after discharge) from 12 countries for 2000–2016 were analyzed, and a logistic model was used to quantify the effect of sex.
Results.
Persons admitted to or discharged from psychiatric inpatient care exhibited significantly increased rates of suicide compared to those in the general population. Furthermore, increase of suicide risk was significantly higher for females than for males for all investigated time intervals (inpatient suicide odds ratio [OR] 1.85; suicide within 1 month after discharge—OR 1.94; suicide within 1 year after discharge—OR 2.04).
Conclusion.
Analysis confirmed the time during and after psychiatric inpatient care to be significantly associated with an elevated risk for suicide. Further, a significant sex effect was observed, with females in this population being at a proportionally higher risk for suicide during psychiatric inpatient treatment as well as the year following discharge. Our study implicates that more effective suicide preventive measures during inpatient stay, focusing on female patients, are needed.
Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood.
Methods
We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors.
Results
We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy.
Conclusions
This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).