Search

Abstract In the past two decades, significant progress has been made in the development of polygenic scores (PGSs). One specific application of PGSs is the development and potential use of pharmacogenomic- scores (PGx-scores) to identify patients who can benefit from a specific medication or are likely to experience side effects. This systematic review comprehensively evaluates published PGx-score studies in psychiatry and provides insights into their potential clinical use and avenues for future development. A systematic literature search was conducted across PubMed, EMBASE, and Web of Science databases until 22 August 2023. This review included fifty-three primary studies, of which the majority (69.8%) were conducted using samples of European ancestry. We found that over 90% of PGx-scores in psychiatry have been developed based on psychiatric and medical diagnoses or trait variants, rather than pharmacogenomic variants. Among these PGx-scores, the polygenic score for schizophrenia (PGSSCZ) has been most extensively studied in relation to its impact on treatment outcomes (32 publications). Twenty (62.5%) of these studies suggest that individuals with higher PGSSCZ have negative outcomes from psychotropic treatment — poorer treatment response, higher rates of treatment resistance, more antipsychotic-induced side effects, or more psychiatric hospitalizations, while the remaining studies did not find significant associations. Although PGx-scores alone accounted for at best 5.6% of the variance in treatment outcomes (in schizophrenia treatment resistance), together with clinical variables they explained up to 13.7% (in bipolar lithium response), suggesting that clinical translation might be achieved by including PGx-scores in multivariable models. In conclusion, our literature review found that there are still very few studies developing PGx-scores using pharmacogenomic variants. Research with larger and diverse populations is required to develop clinically relevant PGx-scores, using biology-informed and multi-phenotypic polygenic scoring approaches, as well as by integrating clinical variables with these scores to facilitate their translation to psychiatric practice.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

This study investigates the effect of the particle size and solid-to-liquid ratio on the dissolution rate of magnesium (Mg) and silicon (Si) in heat-activated lizardite. The investigation was conducted under specific conditions: without the presence of sodium bicarbonate (NaHCO3), at a moderate temperature (40 °C), and under elevated CO2 pressure (100 bar). The aim was to isolate the dissolution reactions and enhance comprehension of the factors constraining the overall yields in the Albany Research Center (ARC) mineral carbonation process. Our study disclosed two distinct dissolution regimes: an initial stage with a rapid initial rate of Mg extraction, resulting in the fraction of Mg extracted ranging from 30 to 65% during the first 20 min of the experiment, following which the dissolution rate decreases dramatically. The initial rapid dissolution stage is primarily driven by the low pH of the supernatant solution, resulting from CO2 dissolution, leading to a higher concentration of protons that extract Mg2+ cations. However, as the heat-activated lizardite dissolution progresses, the pH increases due to the high level of leached Mg2+, and a diffusion barrier forms due to the precipitation of amorphous silica. This phenomenon ultimately slows down the mineral’s dissolution rate during the latter stages of particle dissolution.

Despite their small spatial extent, fluvial ecosystems play a significant role in processing and transporting carbon in aquatic networks, which results in substantial emission of methane (CH4) into the atmosphere. For this reason, considerable effort has been put into identifying patterns and drivers of CH4 concentrations in streams and rivers and estimating fluxes to the atmosphere across broad spatial scales. However, progress toward these ends has been slow because of pronounced spatial and temporal variability of lotic CH4 concentrations and fluxes and by limited data availability across diverse habitats and physicochemical conditions. To address these challenges, we present a comprehensive database of CH4 concentrations and fluxes for fluvial ecosystems along with broadly relevant and concurrent physical and chemical data. The Global River Methane Database (GriMeDB; https://doi.org/10.6073/pasta/f48cdb77282598052349e969920356ef, Stanley et al., 2023) includes 24 024 records of CH4 concentration and 8205 flux measurements from 5029 unique sites derived from publications, reports, data repositories, unpublished data sets, and other outlets that became available between 1973 and 2021. Flux observations are reported as diffusive, ebullitive, and total CH4 fluxes, and GriMeDB also includes 17 655 and 8409 concurrent measurements of concentrations and 4444 and 1521 fluxes for carbon dioxide (CO2) and nitrous oxide (N2O), respectively. Most observations are date-specific (i.e., not site averages), and many are supported by data for 1 or more of 12 physicochemical variables and 6 site variables. Site variables include codes to characterize marginal channel types (e.g., springs, ditches) and/or the presence of human disturbance (e.g., point source inputs, upstream dams). Overall, observations in GRiMeDB encompass the broad range of the climatic, biological, and physical conditions that occur among world river basins, although some geographic gaps remain (arid regions, tropical regions, high-latitude and high-altitude systems). The global median CH4 concentration (0.20 µmol L−1) and diffusive flux (0.44 mmolm-2d-1) in GRiMeDB are lower than estimates from prior site-averaged compilations, although ranges (0 to 456 µmol L−1 and −136 to 4057 mmolm-2d-1) and standard deviations (10.69 and 86.4) are greater for this larger and more temporally resolved database. Available flux data are dominated by diffusive measurements despite the recognized importance of ebullitive and plant-mediated CH4 fluxes. Nonetheless, GriMeDB provides a comprehensive and cohesive resource for examining relationships between CH4 and environmental drivers, estimating the contribution of fluvial ecosystems to CH4 emissions, and contextualizing site-based investigations.

Abstract Background The COVID-19 pandemic constitutes a social crisis that will have long-term health consequences for much of the global population, especially for adolescents. Adolescents are triply affected as they: 1) are experiencing its immediate, direct effects, 2) will carry forward health habits they develop now into adulthood, and 3) as future parents, will shape the early life health of the next generation. It is therefore imperative to assess how the pandemic is influencing adolescent wellbeing, identify sources of resilience, and outline strategies for attenuating its negative impacts. Methods We report the results of longitudinal analyses of qualitative data from 28 focus group discussions (FGDs) with 39 Canadian adolescents and of cross-sectional analyses of survey data from 482 Canadian adolescents gathered between September 2020 and August 2021. FGD participants and survey respondents reported on their: socio-demographic characteristics; mental health and wellbeing before and during the pandemic; pre- and during-pandemic health behaviours; experiences living through a crisis; current perceptions of their school, work, social, media, and governmental environments; and ideas about pandemic coping and mutual aid. We plotted themes emerging from FGDs along a pandemic timeline, noting socio-demographic variations. Following assessment for internal reliability and dimension reduction, quantitative health/wellbeing indicators were analyzed as functions of composite socio-demographic, health-behavioural, and health-environmental indicators. Results Our mixed methods analyses indicate that adolescents faced considerable mental and physical health challenges due to the pandemic, and were generally in poorer health than expected in non-crisis times. Nevertheless, some participants showed significantly better outcomes than others, specifically those who: got more exercise; slept better; were food secure; had clearer routines; spent more time in nature, deep in-person social relationships, and leisure; and spent less time on social media. Conclusions Support for youth during times of crisis is essential to future population health because adolescence is a period in the life course which shapes the health behaviours, socio-economic capacities, and neurophysiology of these future parents/carers and leaders. Efforts to promote resilience in adolescents should leverage the factors identified above: helping them find structure and senses of purpose through strong social connections, well-supported work and leisure environments, and opportunities to engage with nature.

Abstract Purpose Pregnancy complications affect over one quarter of Australian pregnancies, and this group of mothers is vulnerable and more likely to experience adverse cardiometabolic health outcomes in the postpartum period. Metabolic syndrome is common in this population and may be associated with postpartum mental health issues. However, this relationship remains poorly understood. To compare the differences in psychosocial parameters and mental health outcomes between women with metabolic syndrome and women without metabolic syndrome 6 months after a complicated pregnancy. Methods This study is prospective registry analysis of women attending a postpartum healthy lifestyle clinic 6 months following a complicated pregnancy. Mental health measures included 9-item Patient Health Questionnaire (PHQ-9), 7-item Generalised Anxiety Disorder questionnaire (GAD-7), self-reported diagnosed history of depression, anxiety and/or other psychiatric condition, and current psychotropic medication use. Results Women with metabolic syndrome reported significantly more subjective mental health concerns, were more likely to have a history of depression and other psychiatric diagnoses and were more likely prescribed psychotropic medications. However, there were no significant differences in PHQ-9 and GAD-7 scores. Conclusion Amongst new mothers who experienced complications of pregnancy, those with metabolic syndrome represent a particularly vulnerable group with regards to psychosocial disadvantage and mental health outcomes. These vulnerabilities may not be apparent when using common standardised cross-sectional mental health screening tools such as PHQ-9 and GAD-7.

Low‐grade inflammation is considered as a pathophysiological mechanism in a subtype of patients with major depressive disorder (MDD). Anti‐inflammatory drugs have shown efficacy in treating MDD. However, it remains unclear how to identify suitable patients for anti‐inflammatory treatment of depression. This study investigates the predictive value of pre‐treatment high‐sensitivity C‐Reactive Protein (hsCRP) stratification on the outcome of celecoxib augmentation of vortioxetine. The PREDDICT study was conducted as a randomized, double‐blind, placebo‐controlled 6‐week trial on augmentation of vortioxetine with celecoxib between December 2017 and April 2020 at the University of Adelaide (Australia). The present analysis focusses on the question of whether the pre‐treatment hsCRP measurement and stratification of patients to depression with inflammation (hsCRP >3 mg/L) or without inflammation (hsCRP ≤3 mg/L) has an impact on the outcome of anti‐inflammatory treatment with celecoxib. A total of n = 119 mostly treatment‐resistant MDD patients with moderate to severe symptomatology were recruited in the trial. There was no effect of treatment group (celecoxib or placebo), pre‐treatment hsCRP strata (with/without inflammation), or interaction between the two terms on treatment outcome. The results of the current analysis do not support the hypothesis that pre‐treatment hsCRP level is predictive for response to anti‐inflammatory treatment with celecoxib in MDD patients. Further research is needed to identify appropriate biomarkers for the prediction of anti‐inflammatory treatment outcome in depression. Clinical Trials Registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Abstract Autoimmune processes are suspected to play a role in the pathophysiology of psychotic disorders. Better understanding of the associations between auto-immunoglobulin G (IgG) repertoires and clinical features of mental illness could yield novel models of the pathophysiology of psychosis, and markers for biological patient stratification. We undertook cross-sectional detection and quantification of auto-IgGs in peripheral blood plasma of 461 people (39% females) with established psychotic disorder diagnoses. Broad screening of 24 individuals was carried out on group level in eight clinically defined groups using planar protein microarrays containing 42,100 human antigens representing 18,914 proteins. Autoantibodies indicated by broad screening and in the previous literature were measured using a 380-plex bead-based array for autoantibody profiling of all 461 individuals. Associations between autoantibody profiles and dichotomized clinical characteristics were assessed using a stepwise selection procedure. Broad screening and follow-up targeted analyses revealed highly individual autoantibody profiles. Females, and people with family histories of obesity or of psychiatric disorders other than schizophrenia had the highest overall autoantibody counts. People who had experienced subjective thought disorder and/or were treated with clozapine (trend) had the lowest overall counts. Furthermore, six autoantibodies were associated with specific psychopathology symptoms: anti-AP3B2 (persecutory delusions), anti-TDO2 (hallucinations), anti-CRYGN (initial insomnia); anti-APMAP (poor appetite), anti-OLFM1 (above-median cognitive function), and anti-WHAMMP3 (anhedonia and dysphoria). Future studies should clarify whether there are causal biological relationships, and whether autoantibodies could be used as clinical markers to inform diagnostic patient stratification and choice of treatment.

The concept of anomalous self-experience, also termed Self-Disorder, has attracted both clinical and research interest, as empirical studies suggest such experiences specifically aggregate in and are a core feature of schizophrenia spectrum disorders. A comprehensive neurophenomenological understanding of Self-Disorder may improve diagnostic and therapeutic practice. This systematic review aims to evaluate anatomical, physiological, and neurocognitive correlates of Self-Disorder (SD), considered a core feature of Schizophrenia Spectrum Disorders (SSDs), towards developing a neurophenomenological understanding. A search of the PubMed database retrieved 285 articles, which were evaluated for inclusion using PRISMA guidelines. Non-experimental studies, studies with no validated measure of Self-Disorder, or those with no physiological variable were excluded. In total, 21 articles were included in the review. Findings may be interpreted in the context of triple-network theory and support a core dysfunction of signal integration within two anatomical components of the Salience Network (SN), the anterior insula and dorsal anterior cingulate cortex, which may mediate connectivity across both the Default Mode Network (DMN) and Fronto-Parietal Network (FPN). We propose a theoretical Triple-Network Model of Self-Disorder characterized by increased connectivity between the Salience Network (SN) and the DMN, increased connectivity between the SN and FPN, decreased connectivity between the DMN and FPN, and increased connectivity within both the DMN and FPN. We go on to describe translational opportunities for clinical practice and provide suggestions for future research.

BackgroundLithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.MethodsHere, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.FindingsA single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).InterpretationThe response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.FundingDeutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Understanding the genomic architecture and molecular mechanisms of cognitive functioning in healthy individuals is critical for developing tailored interventions to enhance cognitive functioning, as well as for identifying targets for treating impaired cognition. There has been substantial progress in uncovering the genetic composition of the general cognitive ability (g). However, there is an ongoing debate whether executive functioning (EF)-another key predictor of cognitive health and performance, is separable from general g. To provide an analytical review on existing findings on genetic influences on the relationship between g and EF, we re-analysed a subset of genome-wide association studies (GWAS) from the GWAS catalogue that used measures of g and EF as outcomes in non-clinical populations. We identified two sets of single nucleotide polymorphisms (SNPs) associated with g (1,372 SNPs across 12 studies), and EF (300 SNPs across 5 studies) at p

Abstract Multiple studies have reported widespread browning of Northern Hemisphere lakes. Most examples are from boreal lakes that have experienced limited human influence, and browning has alternatively been attributed to changes in atmospheric deposition, climate, and land use. To determine the extent and possible causes of browning across a more geographically diverse region, we examined watercolor and dissolved organic carbon (DOC) time series in hundreds of northeastern U.S. lakes. The majority of lakes have increased in both DOC and color, but there were neither coherent spatial patterns in trends nor relationships with previously reported drivers. Color trends were more variable than DOC trends, and DOC and color trends were not strongly correlated, indicating a cause other than or in addition to increased loading of terrestrial carbon. Browning may be pronounced in regions where climate and atmospheric deposition are dominant drivers but muted in more human‐dominated landscapes with a limited extent of organic soils where other disturbances predominate.

The objectives of this article are to describe the ASCO Resource-Stratified Guidelines and to provide background within the context of ASCO Guidelines and efforts to address the global cancer burden.

A 90-day repeated-dose oral toxicological evaluation was conducted according to GLP and OECD guidelines on lyophilized spores of the novel genetically modified strain B. subtilis ZB183. Lyophilized spores at doses of 109, 1010, and 1011 CFU/kg body weight/day were administered by oral gavage to Wistar rats for a period of 90 consecutive days. B. subtilis ZB183 had no effects on clinical signs, mortality, ophthalmological examinations, functional observational battery, body weights, body weight gains and food consumption in both sexes. There were no test item-related changes observed in haematology, coagulation, urinalysis, thyroid hormonal analysis, terminal fasting body weights, organ weights, gross pathology and histopathology. A minimal increase in the plasma albumin level was observed at 1010 and 1011 CFU/kg/day doses without an increase in total protein in males or females and was considered a nonadverse effect. The “No Observed Adverse Effect Level (NOAEL)” is defined at the highest dose of 1011 CFU/kg body weight/day for lyophilized B. subtilis ZB183 Spores under the test conditions employed.

Prediction of treatment response and illness trajectory in psychotic disorders including schizophrenia, bipolar affective disorder, schizoaffective disorder, and psychotic depression is difficult due to heterogeneity in presentation and outcome. Consequently, patients may receive prolonged ineffective treatments leading to functional decline, illness chronicity, and iatrogenic physical illness. One approach to addressing these problems is to stratify patients based on historical, clinical, and biological signatures. Such an approach has the potential to improve categorization resulting in better understanding of underlying mechanisms and earlier evidence-based treatment with reduced side effect burden. To investigate these multimodal signatures we developed the Cognitive and Functional Assessment of Psychosis Stratification Study (CoFAPSS) employing a prospective study design and a healthy control group comparison. The main aim of this study is to investigate cognitive, and biological “genomics” markers of psychotic illnesses that can be integrated with clinical data to improve prediction of risk and define functional trajectories. We also aim to identify biological “genomic” signatures underpinning variation in treatment response and adverse medical outcomes. The study commenced in June 2016, including patients with primary diagnosis of psychotic disorders including schizophrenia, bipolar affective disorder, schizoaffective disorder, and psychotic depression according to DSM-5 criteria. The assessment covers a wide range of participant history (life stressors, trauma, and family history), cognitive dimensions (social perception, memory and learning, attention, executive function, and general cognition), measures to assess psychosocial function and quality of life, psychotic symptom severity, clinical course of illness, and parameters for adverse medical outcome. Blood is collected for comprehensive genomic discovery analyses of biological (genomic, transcriptomic, proteomic, and cell-biologic) markers. The CoFAPSS is a novel approach that integrates clinical, cognitive and biological “genomic” markers to clarify clinico-pathological basis of risk, functional trajectories, disease stratification, treatment response, and adverse medical outcome. The CoFAPSS team welcomes collaborations with both national and international investigators.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Abstract Science is increasingly being conducted in large, interdisciplinary teams. As team size increases, challenges can arise during manuscript development, where achieving one team goal (e.g., inclusivity) may be in direct conflict with other goals (e.g., efficiency). Here, we present strategies for effective collaborative manuscript development that draw from our experiences in an interdisciplinary science team writing collaborative manuscripts for six years. These strategies are rooted in six guiding principles that were important to our team: to create a transparent, inclusive, and accountable research team that promotes and protects team members who have less power to influence decision‐making while fostering creativity and productivity. To help alleviate the conflicts that can arise in collaborative manuscript development, we present the following strategies: understand your team composition, create an authorship policy and discuss authorship early and often, openly announce manuscript ideas, identify and communicate the type of manuscript and lead author management style, and document and describe authorship contributions. These strategies can help reduce the probability of group conflict, uphold individual and team values, achieve fair authorship practices, and increase science productivity.