Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Hydro-bio-geo-socio-chemical interactions and the sustainability of residential landscapes.

Residential landscapes are essential to the sustainability of large areas of the United States. However, spatial and temporal variation across multiple domains complicates developing policies to balance these systems' environmental, economic, and equity dimensions. We conducted multidisciplinary studies in the Baltimore, MD, USA, metropolitan area to identify locations (hotspots) or times (hot moments) with a disproportionate influence on nitrogen export, a widespread environmental concern. Results showed high variation in the inherent vulnerability/sensitivity of individual parcels to cause environmental damage and in the knowledge and practices of individual managers. To the extent that hotspots are the result of management choices by homeowners, there are straightforward approaches to improve outcomes, e.g. fertilizer restrictions and incentives to reduce fertilizer use. If, however, hotspots arise from the configuration and inherent characteristics of parcels and neighborhoods, efforts to improve outcomes may involve more intensive and complex interventions, such as conversion to alternative ecosystem types.

Evidence of Antineutrinos from Distant Reactors Using Pure Water at SNO.

The SNO+ Collaboration reports the first evidence of reactor antineutrinos in a Cherenkov detector. The nearest nuclear reactors are located 240 km away in Ontario, Canada. This analysis uses events with energies lower than in any previous analysis with a large water Cherenkov detector. Two analytical methods are used to distinguish reactor antineutrinos from background events in 190 days of data and yield consistent evidence for antineutrinos with a combined significance of 3.5σ.

Current street tree communities reflect race-based housing policy and modern attempts to remedy environmental injustice.

Humans promote and inhibit other species on the urban landscape, shaping biodiversity patterns. Institutional racism may underlie the distribution of urban species by creating disproportionate resources in space and time. Here, we examine whether present-day street tree occupancy, diversity, and composition in Baltimore, MD, USA, neighborhoods reflect their 1937 classification into grades of loan risk-from most desirable (A = green) to least desirable (D = "redlined")-using racially discriminatory criteria. We find that neighborhoods that were redlined have consistently lower street tree α-diversity and are nine times less likely to have large (old) trees occupying a viable planting site. Simultaneously, redlined neighborhoods were locations of recent tree planting activities, with a high occupancy rate of small (young) trees. However, the community composition of these young trees exhibited lower species turnover and reordering across neighborhoods compared to those in higher grades, due to heavy reliance on a single tree species. Overall, while the negative effects of redlining remain detectable in present-day street tree communities, there are clear signs of recent investment. A strategy of planting diverse tree cohorts paired with investments in site rehabilitation and maintenance may be necessary if cities wish to overcome ecological feedbacks associated with legacies of environmental injustice.

Ten facts about land systems for sustainability.

Land use is central to addressing sustainability issues, including biodiversity conservation, climate change, food security, poverty alleviation, and sustainable energy. In this paper, we synthesize knowledge accumulated in land system science, the integrated study of terrestrial social-ecological systems, into 10 hard truths that have strong, general, empirical support. These facts help to explain the challenges of achieving sustainability in land use and thus also point toward solutions. The 10 facts are as follows: 1) Meanings and values of land are socially constructed and contested; 2) land systems exhibit complex behaviors with abrupt, hard-to-predict changes; 3) irreversible changes and path dependence are common features of land systems; 4) some land uses have a small footprint but very large impacts; 5) drivers and impacts of land-use change are globally interconnected and spill over to distant locations; 6) humanity lives on a used planet where all land provides benefits to societies; 7) land-use change usually entails trade-offs between different benefits-"win-wins" are thus rare; 8) land tenure and land-use claims are often unclear, overlapping, and contested; 9) the benefits and burdens from land are unequally distributed; and 10) land users have multiple, sometimes conflicting, ideas of what social and environmental justice entails. The facts have implications for governance, but do not provide fixed answers. Instead they constitute a set of core principles which can guide scientists, policy makers, and practitioners toward meeting sustainability challenges in land use.

Theoretical Perspectives of the Baltimore Ecosystem Study: Conceptual Evolution in a Social-Ecological Research Project.

The Earth's population will become more than 80% urban during this century. This threshold is often regarded as sufficient justification for pursuing urban ecology. However, pursuit has primarily focused on building empirical richness, and urban ecology theory is rarely discussed. The Baltimore Ecosystem Study (BES) has been grounded in theory since its inception and its two decades of data collection have stimulated progress toward comprehensive urban theory. Emerging urban ecology theory integrates biology, physical sciences, social sciences, and urban design, probes interdisciplinary frontiers while being founded on textbook disciplinary theories, and accommodates surprising empirical results. Theoretical growth in urban ecology has relied on refined frameworks, increased disciplinary scope, and longevity of interdisciplinary interactions. We describe the theories used by BES initially, and trace ongoing theoretical development that increasingly reflects the hybrid biological-physical-social nature of the Baltimore ecosystem. The specific mix of theories used in Baltimore likely will require modification when applied to other urban areas, but the developmental process, and the key results, will continue to benefit other urban social-ecological research projects.

Residential household yard care practices along urban-exurban gradients in six climatically-diverse U.S. metropolitan areas.

Residential land is expanding in the United States, and lawn now covers more area than the country's leading irrigated crop by area. Given that lawns are widespread across diverse climatic regions and there is rising concern about the environmental impacts associated with their management, there is a clear need to understand the geographic variation, drivers, and outcomes of common yard care practices. We hypothesized that 1) income, age, and the number of neighbors known by name will be positively associated with the odds of having irrigated, fertilized, or applied pesticides in the last year, 2) irrigation, fertilization, and pesticide application will vary quadratically with population density, with the highest odds in suburban areas, and 3) the odds of irrigating will vary by climate, but fertilization and pesticide application will not. We used multi-level models to systematically address nested spatial scales within and across six U.S. metropolitan areas-Boston, Baltimore, Miami, Minneapolis-St. Paul, Phoenix, and Los Angeles. We found significant variation in yard care practices at the household (the relationship with income was positive), urban-exurban gradient (the relationship with population density was an inverted U), and regional scales (city-to-city variation). A multi-level modeling framework was useful for discerning these scale-dependent outcomes because this approach controls for autocorrelation at multiple spatial scales. Our findings may guide policies or programs seeking to mitigate the potentially deleterious outcomes associated with water use and chemical application, by identifying the subpopulations most likely to irrigate, fertilize, and/or apply pesticides.

Gamma Ray Glow Observations at 20-km Altitude.

In the spring of 2017 an ER-2 aircraft campaign was undertaken over continental United States to observe energetic radiation from thunderstorms and lightning. The payload consisted of a suite of instruments designed to detect optical signals, electric fields, and gamma rays from lightning. Starting from Georgia, USA, 16 flights were performed, for a total of about 70 flight hours at a cruise altitude of 20 km. Of these, 45 flight hours were over thunderstorm regions. An analysis of two gamma ray glow events that were observed over Colorado at 21:47 UT on 8 May 2017 is presented. We explore the charge structure of the cloud system, as well as possible mechanisms that can produce the gamma ray glows. The thundercloud system we passed during the gamma ray glow observation had strong convection in the core of the cloud system. Electric field measurements combined with radar and radio measurements suggest an inverted charge structure, with an upper negative charge layer and a lower positive charge layer. Based on modeling results, we were not able to unambiguously determine the production mechanism. Possible mechanisms are either an enhancement of cosmic background locally (above or below 20 km) by an electric field below the local threshold or an enhancement of the cosmic background inside the cloud but then with normal polarity and an electric field well above the Relativistic Runaway Electron Avalanche threshold.

Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls.

BACKGROUND: Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders. METHODS: We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia. RESULTS: Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50. CONCLUSIONS: Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.

ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties.

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.

The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders.

The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

A Multisample Analysis of Psychometric Properties for the Malaysian Adapted Sport Anxiety Scale-2 Among Youth Athletes.

This study examined psychometric properties of a Malaysian-language Sport Anxiety Scale-2 (SAS-2) in three separate studies. Study 1 examined the criterion validity and internal consistency of SAS-2 among 119 developmental hockey players. Measures of trait anxiety and mood states along with digit vigilance, choice reaction time, and depth perception tests were administered. Regression analysis revealed that somatic anxiety and concentration disruption were significantly associated with sustained attention. Worry was significantly associated with depth perception but not sustained attention. Pearson correlation coefficients also revealed significant relationships between SAS-2 subscales and negative mood state dimensions. Study 2 examined the convergent and discriminant validity of SAS-2 by correlating it with state anxiety measured by the CSAI-2R. Significant positive relationships were obtained between SAS-2 subscales and somatic and cognitive state anxiety. Conversely, state self-confidence was negatively related to SAS-2 subscales. In addition, significant differences were observed between men and women in somatic anxiety. Study 3 examined the factorial validity of the Malaysian SAS-2 using confirmatory factor analysis in a sample of 539 young athletes. Confirmatory factor analysis results provided strong support for the SAS-2 factor structure. Path loadings exceeding 0.5 indicated convergent validity among the subscales, and low to moderate subscale intercorrelations provided evidence of discriminant validity. Overall, the results supported the criterion and construct validity of this Malaysian-language SAS-2 instrument.

COMT Val158Met and MTHFR C677T moderate risk of schizophrenia in response to childhood adversity.

OBJECTIVE: Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. METHODS: We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs). RESULTS: Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. CONCLUSION: MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia.

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder.

Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder.

Regular Exercise to Prevent the Recurrence of Gestational Diabetes Mellitus: A Randomized Controlled Trial.

OBJECTIVE: To investigate the effect of a supervised home-based exercise program on the recurrence and severity of gestational diabetes mellitus (GDM) together with other aspects of maternal health and obstetric and neonatal outcomes. METHODS: This randomized controlled trial allocated women with a history of GDM to an exercise intervention (14-week supervised home-based stationary cycling program) or to a control group (standard care) at 13±1 weeks of gestation. The primary outcome was a diagnosis of GDM. Secondary outcomes included maternal fitness, psychological well-being, and obstetric and neonatal outcomes. A sample size of 180 (90 in each group) was required to attain 80% power to detect a 40% reduction in the incidence of GDM. RESULTS: Between June 2011 and July 2014, 205 women provided written consent and completed baseline assessments. Of these, 33 (16%) were subsequently excluded as a result of an elevated baseline oral glucose tolerance test (OGTT), leaving 172 randomized to exercise (n=85) or control (n=87). Three women miscarried before the assessment of outcome measures (control=2; exercise=1). All remaining women completed the postintervention OGTT. The recurrence rate of GDM was similar between groups (control 40% [n=34]; exercise 40.5% [n=34]; P=.95) and the severity of GDM at diagnosis was unaffected by the exercise program with similar glucose and insulin responses to the OGTT (glucose 2 hours post-OGTT 7.7±1.5 compared with 7.6±1.6 mmol/L; P>.05). Maternal fitness was improved by the exercise program (P<.01) and psychological distress was reduced (P=.02). There were no differences in obstetric and neonatal outcomes between groups (P>.05). CONCLUSION: Supervised home-based exercise started at 14 weeks of gestation did not prevent the recurrence of GDM; however, it was associated with important benefits for maternal fitness and psychological well-being. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01283854.

CACNA1C hypermethylation is associated with bipolar disorder.

The CACNA1C gene, encoding a subunit of the L-type voltage-gated calcium channel is one of the best-supported susceptibility genes for bipolar disorder (BD). Genome-wide association studies have identified a cluster of non-coding single-nucleotide polymorphisms (SNPs) in intron 3 to be highly associated with BD and schizophrenia. The mechanism by which these SNPs confer risk of BD appears to be through an altered regulation of CACNA1C expression. The role of CACNA1C DNA methylation in BD has not yet been addressed. The aim of this study was to investigate if CACNA1C DNA methylation is altered in BD. First, the methylation status of five CpG islands (CGIs) across CACNA1C in blood from BD subjects (n=40) and healthy controls (n=38) was determined. Four islands were almost completely methylated or completely unmethylated, while one island (CGI 3) in intron 3 displayed intermediate methylation levels. In the main analysis, the methylation status of CGI 3 was analyzed in a larger sample of BD subjects (n=582) and control individuals (n=319). Out of six CpG sites that were investigated, five sites showed significant hypermethylation in cases (lowest P=1.16 × 10(-7) for CpG35). Nearby SNPs were found to influence the methylation level, and we identified rs2238056 in intron 3 as the strongest methylation quantitative trait locus (P=2.6 × 10(-7)) for CpG35. In addition, we found an increased methylation in females, and no difference between bipolar I and II. In conclusion, we find that CACNA1C methylation is associated with BD and suggest that the regulatory effect of the non-coding risk variants involves a shift in DNA methylation.

Toward an Understanding of Citywide Urban Environmental Governance: An Examination of Stewardship Networks in Baltimore and Seattle.

Efforts to create more sustainable cities are evident in the proliferation of sustainability policies in cities worldwide. It has become widely proposed that the success of these urban sustainability initiatives will require city agencies to partner with, and even cede authority to, organizations from other sectors and levels of government. Yet the resulting collaborative networks are often poorly understood, and the study of large whole networks has been a challenge for researchers. We believe that a better understanding of citywide environmental governance networks can inform evaluations of their effectiveness, thus contributing to improved environmental management. Through two citywide surveys in Baltimore and Seattle, we collected data on the attributes of environmental stewardship organizations and their network relationships. We applied missing data treatment approaches and conducted social network and comparative analyses to examine (a) the organizational composition of the network, and (b) how information and knowledge are shared throughout the network. Findings revealed similarities in the number of actors and their distribution across sectors, but considerable variation in the types and locations of environmental stewardship activities, and in the number and distribution of network ties in the networks of each city. We discuss the results and potential implications of network research for urban sustainability governance.