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OBJECTIVE: Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT. METHODS: To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases. RESULTS: The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health. CONCLUSIONS: This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

Background: Psychiatric traits are heritable, highly comorbid and genetically correlated, suggesting that genetic effects that are shared across disorders are at play. The aim of the present study is to quantify the predictive capacity of common genetic variation of a variety of traits, as captured by their PRS, to predict case-control status in a child and adolescent psychiatric sample including controls to reveal which traits contribute to the shared genetic risk across disorders. Method: Polygenic risk scores (PRS) of 14 traits were used as predictor phenotypes to predict case-control status in a clinical sample. Clinical cases (N = 1,402), age 1–21, diagnostic categories: Autism spectrum disorders (N = 492), Attention-deficit/ hyperactivity disorders (N = 471), Anxiety (N = 293), disruptive behaviors (N = 101), eating disorders (N = 97), OCD (N = 43), Tic disorder (N = 50), Disorder of infancy, childhood or adolescence NOS (N = 65), depression (N = 64), motor, learning and communication disorders (N = 59), Anorexia Nervosa (N = 48), somatoform disorders (N = 47), Trauma/stress (N = 39) and controls (N = 1,448, age 17–84) of European ancestry. First, these 14 PRS were tested in univariate regression analyses. The traits that significantly predicted case-control status were included in a multivariable regression model to investigate the gain in explained variance when leveraging the genetic effects of multiple traits simultaneously. Results: In the univariate analyses, we observed significant associations between clinical status and the PRS of educational attainment (EA), smoking initiation (SI), intelligence, neuroticism, alcohol dependence, ADHD, major depression and anti-social behavior. EA (p-value: 3.53E-20, explained variance: 3.99%, OR: 0.66), and SI (p-value: 4.77E-10, explained variance: 1.91%, OR: 1.33) were the most predictive traits. In the multivariable analysis with these eight significant traits, EA and SI, remained significant predictors. The explained variance of the PRS in the model with these eight traits combined was 5.9%. Conclusion: Our study provides more insights into the genetic signal that is shared between childhood and adolescent psychiatric disorders. As such, our findings might guide future studies on psychiatric comorbidity and offer insights into shared etiology between psychiatric disorders. The increase in explained variance when leveraging the genetic signal of different predictor traits supports a multivariable approach to optimize precision accuracy for general psychopathology.

Background Compensatory mechanisms in patients with adult spinal deformity (ASD) that lead to poor quality of life include positive sagittal balance and pelvic retroversion. The objective of this retrospective review was to identify demographic and radiographic parameters of sagittal alignment that are correlated with thoracic kyphosis (TK), PJK, and reoperation in patients undergoing surgical correction for ASD. Methods A single-center database of 155 patients with ASD undergoing surgery from 2008 to 2015 was reviewed. Patients >18 years old who underwent multilevel thoracolumbar fusion or fusion of thoracic vertebrae to the pelvis were included. Demographics and radiographic measurements of sagittal alignment were collected preoperatively, 6 weeks postoperatively, and 1 year postoperatively. Statistical analysis was performed to compare groups that did or did not develop change in thoracic kyphosis or PJK at early or late follow-up. Additionally, patients requiring reoperation were evaluated. Results Increased thoracic kyphosis was associated with older age, hypolordosis, and comorbid PJK. Early PJK was associated with older age, hypolordosis, and increased T1 pelvic angle. Reoperation was associated with older age, higher positive sagittal balance, hypolordosis, and pelvic retroversion; PJK and thoracic kyphosis did not increase risk for reoperation. Conclusions Thoracic reciprocal change following surgical correction of ASD is highly associated with PJK, although neither increased risk of reoperation. PJK may be predicted by older age, hypolordosis, and increased T1 pelvic angle. Reoperation in patients with ASD is more likely in older patients with positive sagittal balance, a compensatory flat lower back, and compensatory pelvic retroversion.

The disease chytridiomycosis caused by the fungus Bd has devastated amphibian populations worldwide. Functional genomic contributions to host susceptibility remain enigmatic and vary between species and populations. We conducted experimental Bd infections in Rana yavapaiensis, a species with intraspecific variation in chytridiomycosis susceptibility, to assess the skin and spleen transcriptomic response to infection over time. We predicted that increased immune gene expression would be associated with a positive disease outcome, but we instead found that surviving frogs had significantly reduced immune gene expression compared to susceptible frogs and to uninfected controls. MHC class IIβ gene expression was also significantly higher in susceptible frogs compared to surviving frogs. Furthermore, susceptible frogs expressed a significantly larger number of distinct class IIβ alleles, demonstrating a negative correlation between class IIβ expression, functional diversity, and survival. Expression of the MHC class IIβ locus previously associated with Bd disease outcomes was a significant predictor of Bd infection intensity at early infection stages but not at late infection stages, suggesting initial MHC-linked immune processes are important for ultimate disease outcomes. We infer through disease association and phylogenetic analysis that certain MHC variants are linked to the immune expression that was negatively associated with survival, and we hypothesize that frogs that did not express these alleles could better survive infections. Our study finds that MHC expression at early and late infection stages predicts Bd infection intensity, and suggests that generating a sustained immune response against Bd may be counterproductive for surviving chytridiomycosis in this partially susceptible species.

Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders associated with cognitive impairment, which is considered a major determinant of functional outcome. Despite this, the etiology of the cognitive impairment is poorly understood, and no satisfactory cognitive treatments exist. Increasing evidence indicates that genetic risk for SCZ may contribute to cognitive impairment, whereas the genetic relationship between BD and cognitive function remains unclear. Here, we combined large genome-wide association study data on SCZ (n = 82,315), BD (n = 51,710), and general intelligence (n = 269,867) to investigate overlap in common genetic variants using conditional false discovery rate (condFDR) analysis. We observed substantial genetic enrichment in both SCZ and BD conditional on associations with intelligence indicating polygenic overlap. Using condFDR analysis, we leveraged this enrichment to increase statistical power and identified 75 distinct genomic loci associated with both SCZ and intelligence, and 12 loci associated with both BD and intelligence at conjunctional FDR

Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

Background The UK government has prioritized reducing the harmful effects of excessive alcohol consumption on mental and physical well-being. Aims To assess self-reported alcohol consumption amongst doctors at an acute London Trust. Methods An opportunistic, anonymous, survey was conducted by Postgraduate Education Fellows over 2 weeks in December 2018. This included all grades of doctors from Foundation Year One to Consultant. The survey consisted of nine questions, modified from the alcohol use disorders identification test (AUDIT) and CAGE questionnaire. Results Of 446 doctors within our institution, 109 completed the survey (24%). Fourteen per cent of those surveyed abstained from alcohol, 21% drank monthly or less, 31% drank between two to four times per month, 25% drank two to three times per week and 9% drank greater than four times per week. In the preceding 2 years, 9% reported being unable to do what was expected of them on at least one occasion due to alcohol. Five per cent were concerned about alcohol affecting their performance. Two per cent were annoyed by criticism of their drinking, 9% felt guilty about drinking and 4% needed an eye-opener. Eighteen per cent wanted to reduce their alcohol consumption; however, 43% of the 109 doctors surveyed were uncertain where to seek help. Conclusions Twenty per cent of surveyed doctors reported consuming potentially hazardous levels of alcohol and 18% of respondents wanted to cut down. Forty-three per cent were unaware of sources of support. Our findings suggest a role for collaboration between Occupational Health departments and Postgraduate Education teams to support doctors misusing alcohol.

Over the past few years, the rate of journal article publication has increased in most academic disciplines - in some cases more than doubling in the past decade. While journal articles are the de facto currency of knowledge production in many science disciplines, social science scholars routinely publish books as well as journal articles. The social sciences have also undergone a rapid transformation towards more quantitative methodologies, thus representing a unique opportunity to study the increased rate of journal article publication in an area where books are also an important mode of dissemination. We studied the publishing activity of social sciences faculty members in 12 disciplines at 290 Ph.D. granting institutions in the United States between 2011 and 2019. In all disciplines, journal articles per person increased between 2011 and 2019 by between 3% and 64%, while books per person decreased by at least 31% and as much as 54%. Overall, early career researchers show the largest increase in rates of journal article production, while senior scholars show the greatest increase in participation in journal article production. Younger scholars appear to have greater publication output, while growing numbers of older scholars turn towards journal articles as a means of disseminating their work in the social sciences. We observe growing uniformity in the disciplinary literatures of the social sciences, which increasingly resemble the physical and biological sciences in terms of publication practices.

We conducted Hydrothermal carbonization (HTC) of simulated food waste under different reaction conditions (180 to 220 °C, 15 and 30 min), with the aim of recovering both fatty acids from the hydrochar and nutrients from the aqueous-phase products. HTC of the simulated food waste produced hydrochar that retained up to 78% of the original fatty acids. These retained fatty acids were extracted from the hydrochar using ethanol, a food-grade solvent, and gave a net recovery of fatty acid of ∼ 50%. The HTC process partitioned more than 50 wt% of the phosphorus and around 38 wt% of the nitrogen into the aqueous-phase products. A reaction path consistent with decarboxylation predominated during HTC under all of the reaction conditions investigated. A path consistent with dehydration was also observed, but only for the more severe reaction conditions. This work illustrates the potential that HTC has for valorization of food waste.

Cerebellar volume is highly heritable and associated with neurodevelopmental and neurodegenerative disorders. Understanding the genetic architecture of cerebellar volume may improve our insight into these disorders. This study aims to investigate the convergence of cerebellar volume genetic associations in close detail. A genome-wide associations study for cerebellar volume was performed in a sample of 27,486 individuals from UK Biobank, resulting in 29 genome-wide significant loci and a SNP heritability of 39.82%. We pinpoint variants that have effects on amino acid sequence or cerebellar gene-expression. Additionally, 85 genome-wide significant genes were detected and tested for convergence onto biological pathways, cerebellar cell types or developmental stages. Local genetic correlations between cerebellar volume and neurodevelopmental and neurodegenerative disorders reveal shared loci with Parkinson’s disease, Alzheimer’s disease and schizophrenia. These results provide insights into the heritable mechanisms that contribute to developing a brain structure important for cognitive functioning and mental health.

SummaryLate-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.

Genome-wide association studies (GWASs) of the Alcohol Use Disorder Identification Test (AUDIT), a ten-item screener for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders/medical conditions. To explore these unexpected differences in genetic correlations, we conducted the first item-level and largest GWAS of AUDIT items (N=160,824), and applied a multivariate framework to mitigate previous biases. In doing so, we identified novel patterns of similarity (and dissimilarity) among the AUDIT items, and found evidence of a correlated two-factor structure at the genetic level (Consumption and Problems, rg=.80). Moreover, by applying empirically-derived weights to each of the AUDIT items, we constructed an aggregate measure of alcohol consumption that is strongly associated with alcohol dependence (rg=.67) and several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by performing polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, we identified novel genetic associations between alcohol consumption, alcohol misuse, and human health. Our work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD, and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

Purpose To describe the corneal findings and management of a 61-year-old female with vortex keratopathy following short term, high dose hydroxychloroquine used in the setting of a clinical trial for recurrent breast cancer. Observations The patient was found to have significant corneal vortex keratopathy without retinal pathology within 3 months of 1200 mg daily hydroxychloroquine treatment as an adjuvant medication for cancer therapy. Cessation of the medication led to the resolution of the corneal verticillata within 1 month yet the vision did not return to baseline. Ultimately, remaining irregular astigmatism and ocular surface disease required a scleral contact lens to achieve a BSCVA of 20/25 OU. Conclusions and Importance Hydroxychloroquine-induced vortex keratopathy is largely considered dose and duration dependent and is uncommon with most standard treatment algorithms. However, with increasing use of high-dose hydroxychloroquine in adjunct cancer therapy, corneal findings are likely to become more frequent. Persistent visual impairment may occur, thus increased understanding of this pathology can aid in counseling patients and guiding treatment recommendations.

Introduction: With the expansion of palliative care into non-malignant conditions, there is an increasing emphasis on inter-disciplinary working between geriatric and palliative care teams. This inter-disciplinary working has evolved organically and more needs to be known about current working practices. This is of policy and clinical interest as the elderly patient population continues to grow. Methods: An exploratory qualitative interview study was undertaken of end-of-life care for older in-patients in a large London NHS Trust. Staff from palliative care and geriatric medical and nursing teams and patients and carers were contacted for interview. 30 semi-structured qualitative interviews were conducted with staff, two with patients and five with carers. Questions covered: recent examples where teams worked together; staff perceptions of collaboration and issues; patient and carer perceptions of clarity as to who was providing care. Interviews were transcribed and thematically analysed focusing on: examples of successful collaboration; areas of tension, duplication or confusion about responsibilities; suggestions for future practice. Results: Participants were overwhelmingly positive about collaboration between the teams. Examples of what currently works well were: the referral process to the palliative care team; inter-team communication and use of face-to-face handovers; unity between the teams when communicating with patients and families. Areas of concern and for future development were: embedding palliative care within multidisciplinary team meetings within the ward; the need for continual on-ward education given rotation of junior medical staff; improving collaboration between palliative care, physiotherapy and occupational therapy; patients’ and carers’ lack of awareness of the different teams and whether this has a detrimental effect on their care. Conclusions: There is evidence of strong collaborative working between the teams however this study provides insights into where things could be improved. The study has shown the feasibility of the methodology, particularly when interviewing patients and carers during a difficult time in their care. An exploration of these relationships in other settings is required to determine if the same themes arise with a view to inform national guidelines and policy to improve care towards the end of life.

This study uses novel approaches to examine genetic and environmental influences shared between childhood behavioral inhibition (BI) and symptoms of preadolescent anxiety disorders. Three hundred and fifty-two twin pairs aged 9–13 and their mothers completed questionnaires about BI and anxiety symptoms. Biometrical twin modeling, including a direction-of-causation design, investigated genetic and environmental risk factors shared between BI and social, generalized, panic and separation anxiety. Social anxiety shared the greatest proportion of genetic (20%) and environmental (16%) variance with BI with tentative evidence for causality. Etiological factors underlying BI explained little of the risk associated with the other anxiety domains. Findings further clarify etiologic pathways between BI and anxiety disorder domains in children.

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

Introduction With the expansion of palliative care into non-malignant conditions, there is an increasing emphasis on inter-disciplinary working between extended geriatric teams and palliative care. This inter-disciplinary working has evolved organically and more needs to be known about current working practices. This is of policy and clinical interest as the elderly patient population continues to grow. Methods An exploratory case study was undertaken of end-of-life care for older in-patients in a London hospital. Staff from all grades and roles within palliative care and geriatric medical/nursing teams, patients and carers were invited to be interviewed, according to a protocol approved by HRA. 30 semi-structured qualitative interviews were conducted with staff, two with patients and five with carers. Questions covered: recent examples where teams worked together; staff perceptions of collaboration, working practices and issues; patient and carer perceptions of clarity as to who was providing care. Interviews were transcribed and thematically analysed focusing on: examples of successful collaboration; areas of tension, duplication or confusion about responsibilities; suggestions for future practice. Results Participants were overwhelmingly positive about collaboration between the teams. Examples of what currently works well were: the referral process to the palliative care team; inter-team communication and use of face-to-face handovers; unity between the teams when communicating with patients and families. Areas of concern and for future development were: improving collaboration between palliative care and physiotherapy and occupation health; the need for continual on-ward education given rotation of junior medical staff; embedding palliative care within multidisciplinary team meetings within the ward. Patients and carers did not generally distinguish between the teams and presumed collaborative working practices. Conclusions A commitment to working together was important. The findings are also relevant to understanding good practice between older persons ward teams and other specialisms.

Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370. These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Background: Alcohol use on college campuses is prevalent and contributes to problems that affect the health, emotional wellbeing, and academic success of college students. Risk factors, such as family history of alcohol problems, predict future alcohol problems, but less is known about their potential impact on intervention effectiveness. The purpose of this study was to examine the effect of an intervention implemented in a non-randomized sample of drinking and non-drinking college freshmen. Methods: Freshmen college students recruited for the intervention study (n = 153) completed a web-adaptation of the Brief Alcohol Screening and Intervention for College Students (BASICS) at the start of spring semester. We compared their 30-days post-intervention alcohol initiation, number of drinking days (DAYS), drinks per occasion (DRINKS), maximum drinks in 24 h (MAX24) and alcohol use disorder symptoms (AUDsx) to 151 comparison participants retrospectively matched on demographics and baseline alcohol use behaviors. We also tested baseline DRINKS, DAYS, AUDsx, MAX24, and parental family history (PFH) of alcohol problems as moderators of the effect of the intervention. Results: At follow-up, intervention participants had lower rates of AUDsx than comparison participants, especially among baseline drinkers. Among participants drinking 3+ days/month at baseline, intervention participants showed fewer DAYS at follow-up than the comparison group participants. BASICS was also associated with a decreased likelihood of initiation among baseline non-drinkers. PFH significantly interacted with treatment group, with positive PFH intervention participants reporting significantly fewer AUDsx at follow-up compared to positive PFH comparison participants. We found no evidence for an effect of the intervention on DRINKS or MAX24 in our analyses. Conclusions: Results suggest some indication that novel groups, such as non-drinkers, regular drinkers, and PFH positive students may experience benefits from BASICS. Although conclusions were limited by lack of randomization and short follow-up period, PFH positive and low to moderate drinking groups represent viable targets for future randomized studies.

The Genetic and Environmental Contributions of Negative Valence Systems to Internalizing Pathways study (also referred to as the Adolescent and Young Adult Twin Study) was designed to examine varying constructs of the negative valence systems as they relate to the development of internalizing disorders from a genetically informed perspective. The goal of this study was to evaluate genetic and environmental contributions to potential psychiatric endophenotypes that contribute to internalizing psychopathology by studying adolescent and young adult twins longitudinally over a two-year period. This report details the sample characteristics, study design, and methodology of this study. The first wave of data collection (i.e., time 1) is complete; the 2-year follow-up (i.e., time 2) is currently underway. A total of 430 twin pairs (N=860 individual twins; 166 monozygotic pairs; 57.2% female) and 422 parents or legal guardians participated at time 1. Twin participants completed self-report surveys and participated in experimental paradigms to assess processes within the negative valence systems. Additionally, parents completed surveys to report on themselves and their twin children. Findings from this study will help clarify the genetic and environmental influences of the negative valence systems and their association with internalizing risk. The goal of this line of research is to develop methods for early internalizing disorder risk detection.

Background: ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D). Methods: Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement. Results: 80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-value

Cognitive brain networks such as the default-mode network (DMN), frontoparietal network, and salience network, are key functional networks of the human brain. Here we show that the rapid evolutionary cortical expansion of cognitive networks in the human brain, and most pronounced the DMN, runs parallel with high expression of human-accelerated genes (HAR genes). Using comparative transcriptomics analysis, we present that HAR genes are differentially more expressed in higher-order cognitive networks in humans compared to chimpanzees and macaques and that genes with high expression in the DMN are involved in synapse and dendrite formation. Moreover, HAR and DMN genes show significant associations with individual variations in DMN functional activity, intelligence, sociability, and mental conditions such as schizophrenia and autism. Our results suggest that the expansion of higher-order functional networks subserving increasing cognitive properties has been an important locus of genetic changes in recent human brain evolution., Several cortical association areas have rapidly expanded in size during human evolution, including elements of the central cognitive default mode network (DMN). Here, the authors show that genes highly divergent between humans and other primates (HAR genes) are particularly expressed in these brain regions.

Importance Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance.Objectives To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences.Design, Setting and Participants Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses.Main Outcomes and Measures Genetic associations with psychotic experience phenotypes.Results The study included a total of 127 966 participants (56.0% women and 44.0% men; mean [SD] age, 64.0 [7.6] years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio [OR], 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10−4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10−3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 [GenBank NM_020987]) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10−8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 [GenBank NM_001841]) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10−8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism–based heritability estimate (h2 = 1.71%; 95% CI, 1.02%-2.40%).Conclusions and Relevance A large genetic association study of psychotic experiences from the population-based UK Biobank sample found support for a shared genetic liability between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders.

Background Metastatic cancer is incurable and understanding the molecular underpinnings is crucial to improving survival for our patients. The IGF-1/Akt signaling pathway is often impaired in cancer leading to its progression and metastases. Diet modification is known to alter the IGF-1/Akt pathway and affect the expression of microRNA involved in tumor initiation, growth and metastases. Liver metastases are one of the most common type of metastases in breast and colon cancer. In the present study, we looked at the effect of diet modification on the expression of microRNA in normal liver and liver with breast cancer metastases using in vivo model. Methodology 6-month-old C57BL/6 J mice were put on either an ad libitum (AL) diet, or 40% calorie restricted (CR) diet or were fasted for 24 h (FA) before sacrifice. MicroRNA array analysis, western blot and qRT-PCR were performed using liver tissue to compare the treatment groups. A breast cancer model was also used to study the changes in microRNA expression in liver of a group of BALB/c mice orthotopically injected with 4 T1 cells in the mammary fat pad, put on either an AL or 30% CR diet. Liver and primary tumor tissues were used to perform qRT-PCR to compare the treatment groups. Results MicroRNA array analysis showed significant changes in miRNA expression in both CR and FA conditions in normal liver. Expression of miR-29 and miR-30 family members was increased in both CR and FA. Western blot analysis of the normal liver tissue showed that CR and FA downregulated the IGF-1/Akt pathway and qRT-PCR showed that the expression of miR-29b, miR-29c, miR-30a and miR-30b were increased with CR and FA. Liver tissue collected from mice in the breast cancer model showed an increase in expression of miR-29b, miR-29c and miR-30b while tumor tissue showed increased expression of miR-29c, miR-30a and miR-30b. Discussion Members of the miR-29 family are known to target and suppress IGF-1, while members of the miR-30 family are known to target and suppress both IGF-1 and IGF-1R. In the present study, we observe that calorie restriction increased the expression of miR-29 and miR-30 in both the normal liver as well as the liver with breast cancer metastases. These findings suggest that dietary alterations may play a role in the treatment of liver metastasis, which should be evaluated further.

Objective To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB) as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels. Methods Data were examined retrospectively, in patients who either used CBD with concomitant CLB or without concomitant CLB after two months of treatment with CBD and at the point of best seizure control within the first year of treatment with CBD. Responder rates (percentage of subjects with a 50 % or greater reduction in weekly seizures from their baseline) and mean reduction in weekly seizure frequency were calculated and compared between those who concomitantly used CLB and those who did not. The relationship between the change in CLB and nCLB levels and change in mean weekly seizure frequency was also investigated within the group of subjects using concomitant CLB and CBD. Results We analyzed data from 47 subjects between the ages of 2.5–51 years. There was no significant difference between the concomitant CLB (n = 32) and no concomitant CLB (n = 15) groups in terms of demographics (age (p = 0.4344), race (p = 1.0000), sex (p = 0.7507)) or most epilepsy characteristics (underlying condition (all p > 0.05), mean baseline seizure frequency (p = 0.6483)). There was only one significant difference between groups regarding seizure types (more subjects with epileptic spasms in concomitant CLB group (p = 0.0413)). Concomitant AED usage was not significantly different in the two groups (all p > 0.05). Mean reduction in weekly seizure frequency was greater at the best point of seizure control within the first year than at two months of treatment with CBD, regardless of concomitant CLB usage (all p > 0.05). There was no significant difference in reduction of mean weekly seizure frequency between those who took concomitant CLB and those who did not at either time point (all p > 0.05). There was a significantly greater responder rate for subjects taking CBD and CLB than those taking CBD without CLB only at the point of best seizure control within the first year of CBD treatment (p = 0.0240). There was no strong, significant correlation between change in nCLB or CLB levels and change in seizure frequency at either time point (all |p| Significance With or without concomitant CLB, CBD can be effective in reducing seizure frequency. Changes in nCLB and CLB levels do not have a clinically significant correlation with changes in weekly seizure frequency for those taking CBD with CLB.

Cognitive functional networks such as the default-mode network (DMN), frontal-parietal network (FPN), and salience network (SN), are key networks of the human brain. Here, we show that the distinct rapid evolutionary cortical expansion of cognitive networks in the human brain, and most pronounced the DMN, runs parallel with high expression of genes important for human evolution (so-called HAR genes). Comparative gene expression examination then shows that HAR genes are more differentially expressed in cognitive networks in humans compared to the chimpanzee and macaque. Genes with distinct high expression in the DMN display broad involvement in the formation of synapses and dendrites. Next, we performed a genome-wide association analysis on functional MRI data, and show that HAR genes are associated with individual variations in DMN functional connectivity in today’s human population. Finally, gene-set analysis suggests associations of HAR genes with intelligence, social cognition, and mental conditions such as schizophrenia and autism. Taken together, our results indicate that the expansion of higher-order functional networks and their cognitive properties have been an important locus of change in recent human brain evolution.

Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD. © 2019. This is the authors' accepted and refereed manuscript to the chapter. The final authenticated version is available online at: http://dx.doi.org/10.1038/s41588-018-0311-9

Background and Purpose Diverse proteases cleave protease-activated receptor-2 (PAR2) on primary sensory neurons and epithelial cells to evoke pain and inflammation. Trypsin and tryptase activate PAR2 by a canonical mechanism that entails cleavage within the extracellular N-terminus revealing a tethered ligand that activates the cleaved receptor. Cathepsin-S and elastase are biased agonists that cleave PAR2 at different sites to activate distinct signalling pathways. Although PAR2 is a therapeutic target for inflammatory and painful diseases, the divergent mechanisms of proteolytic activation complicate the development of therapeutically useful antagonists. Experimental Approach We investigated whether the PAR2 antagonist GB88 inhibits protease-evoked activation of nociceptors and protease-stimulated oedema and hyperalgesia in rodents. Key Results Intraplantar injection of trypsin, cathespsin-S or elastase stimulated mechanical and thermal hyperalgesia and oedema in mice. Oral GB88 or par2 deletion inhibited the algesic and proinflammatory actions of all three proteases, but did not affect basal responses. GB88 also prevented pronociceptive and proinflammatory effects of the PAR2-selective agonists 2-furoyl-LIGRLO-NH2 and AC264613. GB88 did not affect capsaicin-evoked hyperalgesia or inflammation. Trypsin, cathepsin-S and elastase increased [Ca2+]i in rat nociceptors, which expressed PAR2. GB88 inhibited this activation of nociceptors by all three proteases, but did not affect capsaicin-evoked activation of nociceptors or inhibit the catalytic activity of the three proteases. Conclusions and Implications GB88 inhibits the capacity of canonical and biased protease agonists of PAR2 to cause nociception and inflammation.

Cholesterol reacted over 5 wt % Pt/C, 5 wt % Pd/C, and HZSM-5 in supercritical water at 400 °C. The major products with the Pt/C and Pd/C catalysts are cholesterol-derived steroids, polynuclear aromatic compounds, aliphatic hydrocarbons, and gases (H2, CH4, and C2H6), resulting from hydrogenation, dehydrogenation, and cracking reactions. HZSM-5 favored initial dehydration of cholesterol to form cholesta-3,5-diene and then catalyzed further isomerization and cracking reactions. The presence of H2 had little or no effect, except when the catalyst was absent, in which case added H2 led to higher cholestadiene yields and lower cholesterol conversion. Increasing the catalyst loading resulted in higher yields of lower molecular weight products but also significantly lower carbon recoveries. Characterization of the Pt/C and Pd/C catalysts showed carbon support gasification and particle growth after exposure to supercritical water.

Conflicting reports exist on the direction of the relationship between social anxiety (SA) and alcohol/cigarette use (AU/CU) and alcohol/nicotine dependence (AD/ND), with both positive and negative associations reported. A prospective, longitudinal sample of Finnish twins (n = 1,906) was used to test potential explanations for these discrepancies. Specifically, this study used peer, parent, and teacher ratings of SA, and a clinical interview screening item for social anxiety disorder (SAD-Sc) to examine associations between SA and AU/CU and AD/ND from early adolescence into young adulthood. Peer-rated SA was negatively associated with AU, CU, and AD from age 14 through age 22, implying a protective effect (β = −0.01 to −.03). Teacher- and parent-rated SA associations were in the same directions but weaker or nonsignificant, indicating that aspects of SA that are recognizable by peers may be most relevant to AU/CU. Self-reported SAD-Sc was also negatively associated with AU, but positively associated with AD symptoms in young adulthood (β = 0.38). Our findings partially support the existence of different associations between SA and AU versus AD, but only in the context of SAD-Sc rather than trait SA. Neither trait SA nor SAD-Sc significantly predicted ND symptoms, although SAD-Sc was associated with both cigarette abstinence and daily smoking. These findings suggest that adolescent SA is modestly associated with lower AU/CU, although there may be some individuals with more severe SA who develop alcohol problems later in life. There was little evidence of a common underlying liability contributing to both SA and alcohol/cigarette use. (PsycINFO Database Record (c) 2016 APA, all rights reserved) peerReviewed

When the Black Women's Health Study, a prospective cohort of over 59,000 women who have been followed since 1995, invited all of its participants to provide a DNA sample for future research, only 51 % of those participants agreed to do so. Responders were significantly older and more health conscious than non-responders. The Black Women's Health Study is a unique resource, but this low level of response and its resulting self-selection bias are now the norm in contemporary epidemiologic, and especially cohort, studies. Epidemiology desperately needs new approaches that work better and cost less. The literature on predictors of response focuses too narrowly on participant characteristics and does not identify any clear steps studies can take to increase participation. To improve research quality, cost-efficiency, and long-term sustainability of studies, epidemiology can and should approach, analyze, and leverage response-rate data more creatively and extensively than most studies have done to date.

Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m(2)/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m(2)/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.

Case. A 55-year-old male with a chronic isolated grade 3 PCL injury who demonstrates a positive quadriceps active test without activating his quadriceps musculature. Conclusion. Gravity and hamstring contraction posteriorly translate the tibia into a subluxed position. Subsequent gastrocnemius contraction with the knee flexed causes an anterior tibial translation by virtue of the mass enlargement of the gastrocnemius muscular bulk, the string of a bow effect, and the anterior origin of the gastrocnemius in relation to the posterior border of the subluxed tibia aided by the normal posterior tibial slope.

Background Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

OBJECTIVE: To explore the relations between trauma exposure and anxiety and depression among college students, and to determine whether trait mindfulness may moderate these relations. PARTICIPANTS: Self-report survey data from 2,336 college sophomores was drawn from a larger university-wide study (“Spit for Science”). METHODS: We constructed multiple linear regression models using past-year trauma exposure, trait mindfulness, and their multiplicative interaction to predict current anxiety and depressive symptom severity, while controlling for covariates. RESULTS: Mindfulness was associated with lower levels of depression and anxiety symptom severity. Trauma was a significant predictor of anxiety, but not depression, and high levels of mindfulness attenuated the association between trauma exposure and higher anxiety symptom severity. CONCLUSIONS: These results have implications for the treatment and prevention of anxiety among trauma-exposed college students and provides a basis for further research into the mechanisms through which mindfulness may facilitate positive mental health.

Genome-wide association studies have identified hundreds of genetic associations for complex psychiatric disorders and cognitive traits. However, interpretation of most of these findings is complicated by the presence of many significant and highly correlated genetic variants located in non-coding regions. Here, we address this issue by creating a high-resolution map of the three-dimensional (3D) genome organization by applying Hi-C to adult and fetal brain cortex with concomitant RNA-seq, open chromatin (ATAC-seq), and ChIP-seq data (H3K27ac, H3K4me3, and CTCF). Extensive analyses established the quality, information content, and salience of these new Hi-C data. We used these data to connect 938 significant genetic loci for schizophrenia, intelligence, ADHD, alcohol dependence, Alzheimer's disease, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depression, and educational attainment to 8,595 genes (with 42.1% of these genes implicated more than once). We show that assigning genes to traits based on proximity provides a limited view of the complexity of GWAS findings and that gene set analyses based on functional genomic data provide an expanded view of the biological processes involved in the etiology of schizophrenia and other complex brain traits.

BackgroundIdentifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology. College-age individuals are under-represented in genomic analyses thus far, and the majority of work has focused on the clinical disorder or cognitive abilities rather than normal-range behavioral outcomes.MethodsThis study examined a sample of emerging adults 18–22 years of age (N = 5947) to construct an atlas of polygenic risk for 33 traits predicting relevant phenotypic outcomes. Twenty-eight hypotheses were tested based on the previous literature on samples of European ancestry, and the availability of rich assessment data allowed for polygenic predictions across 55 psychological and medical phenotypes.ResultsPolygenic risk for schizophrenia (SZ) in emerging adults predicted anxiety, depression, nicotine use, trauma, and family history of psychological disorders. Polygenic risk for neuroticism predicted anxiety, depression, phobia, panic, neuroticism, and was correlated with polygenic risk for cardiovascular disease.ConclusionsThese results demonstrate the extensive impact of genetic risk for SZ, neuroticism, and major depression on a range of health outcomes in early adulthood. Minimal cross-ancestry replication of these phenomic patterns of polygenic influence underscores the need for more genome-wide association studies of non-European populations.

Maraviroc is a C‐C chemokine receptor type‐5 antagonist approved for the treatment of HIV‐1. Previous studies show that cytochrome P450 3A5 (CYP3A5) plays a role in maraviroc metabolism. CYP3A5 is subject to a genetic polymorphism. The presence of 2 functional alleles (CYP3A5*1/*1) confers the extensive metabolism phenotype, which is rare in whites but common in blacks. The effect of CYP3A5 genotype on maraviroc and/or metabolite pharmacokinetics was evaluated in 2 clinical studies: a post hoc analysis from a phase 2b/3 study ({"type":"clinical-trial","attrs":{"text":"NCT00098293","term_id":"NCT00098293"}}NCT00098293) conducted in 494 HIV‐1–infected subjects (study 1) in which the impact on maraviroc efficacy in 303 subjects was also assessed, and a study conducted in 47 healthy volunteers (study 2). In study 2 ({"type":"clinical-trial","attrs":{"text":"NCT02625207","term_id":"NCT02625207"}}NCT02625207), extensive metabolizers had 26% to 37% lower mean area under the concentration‐time curve compared with poor metabolizers (no CYP3A5*1 alleles). This effect diminished to 17% in the presence of potent CYP3A inhibition. The effect of CYP3A5 genotype was greatest in the formation of the metabolite (1S,2S)‐2‐hydroxymaraviroc. In study 1, the CYP3A5*1/*1 genotype unexpectedly had higher maraviroc area under the curve predictions (20%) compared with those with no CYP3A5*1 alleles. The reason for this disparity remains unclear. The proportions of subjects with viral loads