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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.
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.
A pandemic arises when biology meets politics. The biology may be universal, but politics are local. Some nations suffer many thousands of deaths; some hundreds. Same virus; different politics. Economic development accounts for some of the differences, but even nations at the same level of development can have radically different pandemics. If politics is destiny, then our fate is in our hands.
The threat of the coronavirus to a community raises a political question: What is the nation prepared to do? In the United States and the United Kingdom, the initial answer was “very little.” Other places – for example, China, Israel, or South Korea – were prepared to do quite a lot. The statistics show the consequences.
The best apocalyptic movies (from Mad Max to The Stalker) are less about the apocalypse than what follows it. They focus on the systemic changes triggered by the apocalypse. About the apocalypse itself, little can be said. Speech begins again with survival. Likewise, in the middle of the current pandemic, we operate under the law of necessity. For this reason, nations with very different political systems have converged on the same practices of lockdown, social distancing, testing, and tracing. Nations that refuse to accept the law of necessity demonstrate not political strength, but weakness. They suffer the consequences, for the virus recognizes no excuses. Consider the ravages of the pandemic in Brazil and the United States.
The COVID-19 pandemic has presented an important case study, on a global scale, of how democracy works - and fails to work - today. From leadership to citizenship, from due process to checks and balances, from globalization to misinformation, from solidarity within and across borders to the role of expertise, key democratic concepts both old and new are now being put to the test. The future of democracy around the world is at issue as today's governments manage their responses to the pandemic. Bringing together some of today's most creative thinkers, these essays offer a variety of inquiries into democracy during the global pandemic with a view to imagining post-crisis political conditions. Representing different regions and disciplines, including law, politics, philosophy, religion, and sociology, eighteen voices offer different outlooks - optimistic and pessimistic - on the future.
Migration has been reported to be associated with higher prevalence of mental disorders and suicidal behaviour.
To examine the prevalence of emotional and behavioural difficulties, suicidal ideation and suicide attempts among migrant adolescents and their non-migrant peers.
A school-based survey was completed by 11 057 European adolescents as part of the Saving and Empowering Young Lives in Europe (SEYLE) study.
A previous suicide attempt was reported by 386 (3.6%) adolescents. Compared with non-migrants, first-generation migrants had an elevated prevalence of suicide attempts (odds ratio (OR) 2.08; 95% CI 1.32–3.26; P=0.001 for European migrants and OR 1.86; 95% CI 1.06–3.27; P=0.031 for non-European migrants) and significantly higher levels of peer difficulties. Highest levels of conduct and hyperactivity problems were found among migrants of non-European origin.
Appropriate mental health services and school-based supports are required to meet the complex needs of migrant adolescents.
No study outside the UK has examined the diagnostic stability of psychotic disorders in a population-based sample.
To determine diagnostic stability in a Dutch population-based psychosis incidence cohort, to examine the frequencies of diagnostic shifts to and from schizophrenic disorders and to report the revised relative risks of schizophrenic disorders for immigrants.
A 30-month follow-up study assessed the cohort (n=181) by means of face-to-face diagnostic interviews.
Diagnostic stability of schizophrenic disorders was high (91%), but lower for other psychotic disorders. At follow-up, the initial diagnosis was adjusted to schizophrenic disorder more often than that the reverse occurred. Almost half (49%) of the patients who were not initially diagnosed as having a schizophrenic disorder received this diagnosis at follow-up. The relative risks for most immigrant groups were stable.
Schizophrenic disorders are underdiagnosed, rather than overdiagnosed, at first presentation.
To assess the resource utilization associated with sepsis syndrome in academic medical centers.
Prospective cohort study.
Eight academic, tertiary-care centers.
Stratified random sample of 1,028 adult admissions with sepsis syndrome and all 248,761 other adult admissions between January 1993 and April 1994. The main outcome measures were length of stay (LOS) in total and after onset of sepsis syndrome (post-onset LOS) and total hospital charges.
The mean LOS for patients with sepsis was 27.7 ± 0.9 days (median, 20 days), with sepsis onset occurring after a mean of 8.1 ± 0.4 days (median, 3 days). For all patients without sepsis, the LOS was 7.2 ± 0.03 days (median, 4 days). In multiple linear regression models, the mean for patients with sepsis syndrome was 18.2 days, which was 11.0 days longer than the mean for all other patients (P < .0001), whereas the mean difference in total charges was $43,000 (both P < .0001). These differences were greater for patients with nosocomial as compared with community-acquired sepsis, although the groups were similar after adjusting for pre-onset LOS. Eight independent correlates of increased post-onset LOS and 12 correlates of total charges were identified.
These data quantify the resource utilization associated with sepsis syndrome, and demonstrate that resource utilization is high in this group. Additional investigation is required to determine how much of the excess post-onset LOS and charges are attributable to sepsis syndrome rather than the underlying medical conditions.