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Risk for schizophrenia peaks during early adulthood, a critical period for brain development. Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure. To address this question, we introduce a framework to estimate the effects of schizophrenia genetic variation on brain structure phenotypes across the life span. Five-hundred and six participants, including 30 schizophrenia probands, 200 of their relatives (aged 12-85 years) from 32 families with at least two first-degree schizophrenia relatives, and 276 unrelated controls, underwent MRI to assess regional cortical thickness (CT) and cortical surface area (CSA). Genetic variance decomposition analyses were conducted to distinguish among schizophrenia neurogenetic effects that are most salient before schizophrenia peak age-of-risk (i.e., early neurodevelopmental effects), after peak age-of-risk (late neurodevelopmental effects), and during the later plateau of age-of-risk (neurodegenerative effects). Genetic correlations between schizophrenia and cortical traits suggested early neurodevelopmental effects for frontal and insula CSA, late neurodevelopmental effects for overall CSA and frontal, parietal, and occipital CSA, and possible neurodegenerative effects for temporal CT and parietal CSA. Importantly, these developmental neurogenetic effects were specific to schizophrenia and not found with nonpsychotic depression. Our findings highlight the potentially dynamic nature of schizophrenia genetic effects across the lifespan and emphasize the utility of integrating neuroimaging methods with developmental behavior genetic approaches to elucidate the nature and timing of risk-conferring processes in psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The land application of biosolids can be subject to questions and concerns, suggesting a gap exists with public perception of biosolids. There is opposition amongst a segment of the population regarding the land application of biosolids in the Southern Interior of British Columbia in Canada. Kamloops and Merritt communities were assessed through a mailout survey to understand better public perceptions of biosolids risks and factors that influence attitudes towards biosolids management. Two thousand surveys were distributed proportionately between the communities. Response rates for Kamloops and Merritt were 22 and 24 percent, respectively. Kamloops and Merritt respondents generally identified differing risk perceptions around biosolids management. Kamloops respondents relative to Merritt were more accepting of the risks associated with biosolids. This acceptance is a likely result of Merritt residents' recent experience with application sites and proximity to biosolids projects, and the associated negative local media attention. Results from Kamloops highlighted that there is general support to find a productive use of biosolids. This research supports the notion that the 'beyond compliance' approach of conducting early engagement to obtain community support proactively may be valuable for any potentially controversial natural resource project, such as with biosolids land application projects.

Encephalitis, the most significant of the central nervous system (CNS) diseases caused by Herpes simplex virus 1 (HSV-1), may have long-term sequelae in survivors treated with acyclovir, the cause of which is unclear. HSV-1 exhibits a tropism toward neurogenic niches in CNS enriched with neural precursor cells (NPCs), which play a pivotal role in neurogenesis. NPCs are susceptible to HSV-1. There is a paucity of information regarding the influence of HSV-1 on neurogenesis in humans. We investigated HSV-1 infection of NPCs from two individuals. Our results show (i) HSV-1 impairs, to different extents, the proliferation, self-renewing, and, to an even greater extent, migration of NPCs from these two subjects; (ii) The protective effect of the gold-standard antiherpetic drug acyclovir (ACV) varies with viral dose and is incomplete. It is also subject to differences in terms of efficacy of the NPCs derived from these two individuals. These results suggest that the effects of HSV-1 may have on aspects of NPC neurogenesis may vary among individuals, even in the presence of acyclovir, and this may contribute to the heterogeneity of cognitive sequelae across encephalitis survivors. Further analysis of NPC cell lines from a larger number of individuals is warranted.

Objective:The aim of this study was to identify factors associated with acceptability and efficacy of yoga training (YT) for improving cognitive dysfunction in individuals with schizophrenia (SZ).Methods:We analysed data from two published clinical trials of YT for cognitive dysfunction among Indians with SZ: (1) a 21-day randomised controlled trial (RCT, N = 286), 3 and 6 months follow-up and (2) a 21-day open trial (n = 62). Multivariate analyses were conducted to examine the association of baseline characteristics (age, sex, socio-economic status, educational status, duration, and severity of illness) with improvement in cognition (i.e. attention and face memory) following YT. Factors associated with acceptability were identified by comparing baseline demographic variables between screened and enrolled participants as well as completers versus non-completers.Results:Enrolled participants were younger than screened persons who declined participation (t = 2.952, p = 0.003). No other characteristics were associated with study enrollment or completion. Regarding efficacy, schooling duration was nominally associated with greater and sustained cognitive improvement on a measure of facial memory. No other baseline characteristics were associated with efficacy of YT in the open trial, the RCT, or the combined samples (n = 148).Conclusions:YT is acceptable even among younger individuals with SZ. It also enhances specific cognitive functions, regardless of individual differences in selected psychosocial characteristics. Thus, yoga could be incorporated as adjunctive therapy for patients with SZ. Importantly, our results suggest cognitive dysfunction is remediable in persons with SZ across the age spectrum.

Background Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. Methods We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. Results Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. Conclusions We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.

Background Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. Results We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. Conclusions These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

An endogenous growth model with a simple climate system is used to examine the potential impacts of climate change on the capital-to-net income ratio and the net of depreciation share of income to capital, a measure of wealth concentration and income distribution between capital and labour respectively, over the next two centuries. If climate change only directly affects production, as usually assumed, the capital-to-net income ratio will increase as compared to what it would be in the absence of climate change. The capital-to-income ratio will increase even further if climate change affects labour productivity. In both cases, the increase in the ratio after 2100 is due to the stock of capital being depleted at a lower rate than net income is falling. However, the capital-to-net income ratio will be lower and eventually fall if damage from climate change increases the depreciation rate of capital; this decline is marginally reduced if climate change impacts both capital and labour productivity. In the case where climate change impacts the depreciation of capital, the ratio after 2100 is falling because the stock of capital is destroyed faster than net-income is falling. Furthermore, climate change reduces the net share of income accruing to capital in all scenarios with dramatic changes in the case of climate change affecting the depreciation of capital. Emissions abatement almost completely mitigates these impacts on the capital-to-net income ratio and the net share of income to capital.

Schizophrenia (SZ) is a common, potentially debilitating disorder. Over 70% of risk for SZ at the population level is attributable to genetic factors. Large-scale genome-wide association studies (GWAS) have revealed risk attributable to over 170 genomic loci, with varied effect sizes. Statistically, the most significant risk locus maps to the major histocompatibility complex (MHC) region on chromosome 6 (odds ratio ~1.28). One of the associated MHC loci involved the complement C4 gene. There is population-wide variation in C4 gene copy number, and SZ risk rises with the number of C4 genes that an individual’s genome encodes. C4 is a component of an immunologic defense mechanism that predates antibody-based adaptive immunity. In mammals, complement proteins also participate in neurodevelopment. Based on rodent model studies, it has been proposed that the C4-related risk for SZ could be explained by aberrant synaptic pruning—a developmental process also implicated in SZ risk. We review the synaptic pruning hypothesis and propose additional mechanisms to explain the C4-SZ link, including disruption in classical immunologic processes and changes in human endogenous retroviral sequences associated with C4. The evidence supporting these hypotheses is discussed, and empirical investigations are proposed.

Despite the potential economic efficiency and political economy benefits of revenue-neutrality, a deeper question remains about the feasibility of revenue-neutrality in practice. Revenue-neutrality is relatively simple to implement in an economic model, as counterfactuals are clearly defined. However, it is less clear in practice when a government actually implements a carbon tax what income tax or transfer levels would have been if the carbon tax had not been implemented. This paper aims to provide some perspective on this issue by presenting two examples of carbon taxes and revenue recycling implemented in Canada: the British Columbia revenue-neutral carbon tax (a carbon tax with offsetting tax cuts) and the Canadian federal government’s Fuel Charge and Climate Action incentive refundable tax credit (a carbon tax and dividend). Is revenue-neutrality possible in a practical sense with either of these types of policies, or is it at best a marketing gimmick to help sell carbon taxes to voters?

BackgroundTo test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438).MethodsWe examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections.ResultsSignificant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts.Conclusions:Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.

Schizophrenia has substantial variation in symptom severity, course of illness, and overall functioning. Earlier age of onset (AOO) is consistently associated with negative outcomes and yet the causes of this association are still unknown. We used a multiplex, extended pedigree design (total N = 771; 636 relatives from 43 multigenerational families with at least 2 relatives diagnosed with schizophrenia and 135 matched controls) to examine among the schizophrenia relatives (N = 103) the relationship between AOO and negative and positive symptom severity, cognition, and community functioning. Most importantly, we assessed whether there are shared genetic effects between AOO and negative symptoms, positive symptoms, cognition, and community functioning. As expected, earlier AOO was significantly correlated with increased severity of negative and positive symptoms and poorer cognition and community functioning among schizophrenia patients. Notably, the genetic correlation between AOO of schizophrenia and negative symptoms was significant (R(g) = −1.00, p = .007). Although the genetic correlations between AOO and positive symptoms, cognition, and community functioning were estimated at maximum and in the predicted direction, they were not statistically significant. AOO of schizophrenia itself was modestly heritable, although not significant and negative symptoms, positive symptoms, and cognition were all strongly and significantly heritable. In sum, we replicated prior findings indicating that earlier AOO is associated with increased symptom severity and extended the literature by detecting shared genetic effects between AOO and negative symptoms, suggestive of pleiotropy.

Acyclovir (ACV) is an effective antiviral agent for treating lytic Herpes Simplex virus, type 1 (HSV-1) infections, and it has dramatically reduced the mortality rate of herpes simplex encephalitis. However, HSV-1 resistance to ACV and its derivatives is being increasingly documented, particularly among immunocompromised individuals. The burgeoning drug resistance compels the search for a new generation of more efficacious anti-herpetic drugs. We have previously shown that trans-dihydrolycoricidine (R430), a lycorane-type alkaloid derivative, effectively inhibits HSV-1 infections in cultured cells. We now report that R430 also inhibits ACV-resistant HSV-1 strains, accompanied by global inhibition of viral gene transcription and enrichment of H3K27me3 methylation on viral gene promoters. Furthermore, we demonstrate that R430 prevents HSV-1 reactivation from latency in an ex vivo rodent model. Finally, among a panel of DNA viruses and RNA viruses, R430 inhibited Zika virus with high therapeutic index. Its therapeutic index is comparable to standard antiviral drugs, though it has greater toxicity in non-neuronal cells than in neuronal cells. Synthesis of additional derivatives could enable more efficacious antivirals and the identification of active pharmacophores.

Several studies have indicated infectious and immune-related abnormalities in schizophrenia (Scz), including elevated serum C-reactive protein (CRP) - a well-known proxy for infections/immune abnormalities. A portion of the genetic risk for Scz can be estimated using the polygenic risk score (PGRS). It is not known whether there is an interaction in the risks traceable to CRP and PGRS. Patients with Scz and individuals without psychosis were evaluated systematically using DSM IV criteria (N=794, N=446, respectively). To estimate risk for Scz attributable to CRP and PGRS, serum from these participants was assayed for CRP levels using enzyme linked immunosorbent assays. PGRS was estimated from common DNA polymorphisms associated with Scz from genome wide association studies. CRP level and PGRS were not significantly correlated. Using a generalized linear logistic model, case/control status was evaluated in relation to the following predictors: CRP, PGRS, and demographic variables. CRP and PGRS were individually associated with case status; CRP: odds ratio (OR) 1.27, 95% confidence intervals (95% CI) 1.12, 1.43; p = 0.0001; PGRS: OR 1.66, 95% CI 1.47, 1.89; p = 1.28 ×10-15. There were no significant interactions between PGRS and CRP for predicting Scz versus control status.

Background Studies from certain regions of the world indicate that consanguineous marriages are a risk factor for the development of schizophrenia in offspring. However the evidence is inconsistent partly due to methodological limitation of which hospital based recruitment contributing to significant bias. The studies from the Indian subcontinent, is scarce, where rates of consanguinity is high. Methods The schizophrenia patients living in a geographically defined rural south Indian community and randomly selected controls dwelling in the same community sharing sociocultural, economic and lifestyle factors were recruited. They were assessed for parental consanguinity using the clinical interviews as well as DNA-based estimates. The latter was conducted by calculating the coefficient of inbreeding ‘f’. A participant was considered to have consanguineous parentage if his/her parents shared a common ancestor no more remote than a great-great-grandparent, corresponding to DNA-based estimates of ‘f’ ≥ 0.0156. Results The rates of parental consanguinity assessed by clinical interview were comparable in both groups (Cases: 10.71 %, Controls: 7.25 %; χ2 = 0.493, p = 0.4825). However, DNA-based rates of parental consanguinity showed that ‘f’ was significantly higher among cases than controls (Mann-Whitney U = 11315.5; p = 0.022). Seventy-five cases (62.5 %) and 108 control participants (48.6 %) had ‘f’ ≥ 0.0156 (χ2 = 6.008; p = 0.014). The results were consistent across different quality control measures. Conclusion Schizophrenia is associated with higher parental consanguinity, suggesting a role for multiple recessive risk alleles in its etiology. Replication in future studies in diverse settings would add further strength to this.

Background The prevalence of mental health disorders is increasing globally. Countries in South Asia, Southeast Asia and the Middle East regions carry high burdens of mental health need; however, there are relatively few mental health research publications from this region, suggesting inadequate research funds and a paucity of qualified research personnel. To increase and strengthen the pool of mental health researchers in India and Egypt, we conducted three psychiatric research programmes in these countries: the Training Program for Psychiatric Genetics in India (2002–2011), the Tri-National Training Program for Psychiatric Genetics (2009–2014) and the Cross-Fertilized Research Training for New Investigators in Egypt and India (2014–2019). A total of 66 trainees, including psychiatrists, psychiatric social workers, clinical psychologists and research psychologists, were supported in research development, which included didactic training, proposal development, hands-on research and manuscript preparation. Methods The aim of this study is to evaluate these three training programmes using the four-level Kirkpatrick Model of Training Evaluation that assesses reaction, learning, behaviour and outcomes. A descriptive analysis was used to explore the data collected throughout the duration of the three training programmes. Online surveys were crafted and sent to the mentors and trainees of the three programmes to supplement objective training data. Results In addition to positive changes in the areas of reaction, learning and behaviour, significant outcomes were demonstrated. As of the writing of this manuscript, the trainees published a total of 130 papers, 59 as first author. In addition, 26 trainees have co-authored papers with one or more trainees or mentors, which demonstrates successful research networking and collaboration. Conclusion Our findings suggest that our training approach is a successful model for building independent mental health researchers. This is a critical step in the development of effective mental health interventions in low- and middle-income countries.

IMPORTANCE: Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings. OBJECTIVE: To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. DESIGN, SETTING, AND PARTICIPANTS: This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing. MAIN OUTCOMES AND MEASURES: Associations of single-nucleotide polymorphisms and gene expression with schizophrenia. RESULTS: The study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10(−8)) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10(−4)). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10(−13)). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P = .004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development. CONCLUSIONS AND RELEVANCE: Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene’s role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment.

Background Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically. Methods Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ. Results There were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction. Conclusion Valproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection.

In this paper the simplest integrated assessment model is developed in order to illustrate to undergraduate students the economic issues associated with climate change. The growth model developed in this paper is an extension of the basic Solow model and includes a simple climate model. Even though the model is very simple it is very powerful in its predictions. Students use the model to explore various scenarios illustrating how economic activity today will inflict damages from higher temperatures on future generations. But students also observe that future generations will be richer than today’s generation due to productivity growth and population stabilization. Hence, the richer future generations will not be as rich as they would be without climate change. Since the cost of action is absorbed by the current generation and the benefits of action accrue to future generations students can conduct a cost-benefit analysis and explore the importance of the discount rate. The appendix provides step-by-step instructions for students to setup the model in MS Excel and to conduct simulations.

Background: Hepatitis C virus (HCV) infection is associated with cognitive dysfunction in clinic-based studies. The risk could be attributed to factors such as antiviral medications, substance abuse, or coincidental infection. Aim: The aim was to evaluate cognitive function in relation to HCV antibody titers in a community-based sample of asymptomatic individuals at low risk for substance abuse. Method: Adults were ascertained from a community in Mansoura, Egypt, where HCV is endemic (n = 258). Cognitive performance was evaluated using the Arabic version of the Penn Computerized Neurocognitive Battery. Substance abuse and psychopathology were also assessed. Antibodies to HCV and Toxoplasma gondii (TOX), a common protozoan that can affect cognition, were estimated using serological IgG assays. Results: The prevalence of HCV and TOX infection was 17.6% and 52.9%, respectively. HCV antibody titers were significantly associated with worse function in four cognitive tests for accuracy and three tests f...

The environmental Kuznets curve hypothesis suggests that at high income levels, economic growth is accompanied by decreasing concentrations of air pollutants. We examine the relationship between four common air pollutants and income across Canadian provinces and metropolitan areas. Our study improves upon past studies of the relationship in Canada in two ways. First, our use of panel methods and pollution concentration data from individual monitoring stations allows for a much larger sample size than previous Canadian studies. Furthermore, our econometric modeling approach separates and identifies the relative magnitudes of the scale, composition, and technique effects. Our results are as expected for annual average concentrations of sulfur dioxide, nitrogen dioxide, and carbon monoxide: a positive effect of increases in the scale of the economy was completely offset by improvements in technology and changes in the composition of output. Similar results are found for ground-level ozone when choosing the measure used to assess the Canada-Wide Standard; however, the results when using annual average concentrations of ozone are much different. We attribute this difference to the focus of government policy to reduce short-term, rather than long-term, exposure to ozone. Resume Selon l'hypothese de la courbe environnementale de Kuznets, lorsque les niveaux de revenu sont eleves, la croissance economique s'accompagne d'une diminution des concentrations de polluants atmospheriques. Dans la presente etude, nous analysons le lien entre quatre polluants atmospheriques courants et le revenu, dans differentes provinces et regions metropolitaines canadiennes. Notre etude bonifie les etudes anterieures sur l'existence de ce lien au Canada, et ce, pour deux raisons. Premierement, le fait d'utiliser des methodes de panel et des donnees sur les concentrations de polluants provenant des stations de surveillance permet des echantillons de taille plus importante que ceux des etudes canadiennes anterieures. Deuxiemement, notre modele econometrique distingue l'effet d'echelle, l'effet de composition et l'effet technique et en determine l'ampleur relative. Les resultats de notre etude sont fondes sur des concentrations moyennes annuelles de dioxyde de soufre, de dioxyde d'azote et de monoxyde de carbone : l'un des effets positifs decoulant de la croissance economique a ete entierement contrebalance par des ameliorations technologiques et des changements dans la composition de la production. Des resultats similaires ont ete obtenus dans le cas de l'ozone tropospherique lors du choix de la methode visant a evaluer les standards pancanadiens (SP); toutefois, les resultats obtenus a partir des concentrations moyennes annuelles d'ozone different considerablement. Nous attribuons cet ecart a la politique gouvernementale axee sur la reduction a court terme, plutot qu'a long terme, de l'exposition a l'ozone.

Background A variety of neurological disorders including neurodegenerative diseases and infection by neurotropic viruses can cause structural and functional changes in the central nervous system (CNS), resulting in long-term neurological sequelae. An improved understanding of the pathogenesis of these disorders is important for developing efficacious interventions. Human induced pluripotent stem cells (hiPSCs) offer an extraordinary window for modeling pathogen-CNS interactions, and other cellular interactions, in three-dimensional (3D) neuronal cultures that can recapitulate several aspects of in vivo brain tissue. Methods Herein, we describe a prototype of scaffold-free hiPSC-based adherent 3D (A-3D) human neuronal cultures in 96-well plates. To test their suitability for drug screening, A-3D neuronal cultures were infected with herpes simplex virus type 1 (HSV-1) with or without acyclovir. Results The half maximal inhibitory concentration (IC50) of acyclovir was 3.14 μM and 3.12 μM determined using flow cytometry and the CX7 High Content Screening platform, respectively. Conclusions Our A-3D neuronal cultures provide an unprecedented opportunity for high-content drug screening programs to treat human CNS infections. Electronic supplementary material The online version of this article (10.1186/s13287-018-0881-6) contains supplementary material, which is available to authorized users.

This article uses a representative agent model and Canadian data to calculate the optimal gasoline taxes for Ontario and the Greater Toronto-Hamilton Area (GTHA) in a second-best setting with pre-existing distortionary income taxes. The results suggest a second-best optimal gasoline tax of 40.57 cents per litre in 2006 Canadian dollars for the GTHA that is much higher than the current tax rate of 24.7 cents per litre, and also higher than recently proposed increases. The resulting value is insensitive to whether the additional revenue is used to reduce taxes on income or to incrementally fund increased public transit infrastructure (the Big Move plan). However, in the absence of a regional tax, the second-best optimal gasoline tax for Ontario as a whole of 28.51 cents per litre in 2006 Canadian dollars is slightly higher than the current tax rate and in line with proposed increases.

With the globalization of biomedical research and the advent of "precision medicine," there is increased need for translation of neuropsychological tests, such as computerized batteries that can be incorporated in large-scale genomic studies. Estimates of translational validity are obtained by administering the test in the original and the translated versions to bilingual individuals. We investigated the translation of a neuropsychological battery from English to Arabic and how practice effects influence translational validity estimates.The Penn computerized neurocognitive battery (Penn CNB) includes tests that were validated with functional neuroimaging and provides measures of accuracy and speed of performance in several cognitive domains. To develop an Arabic version of the CNB, the English version was translated into Arabic, then back translated and revised. The Arabic and the original English versions were administered in a randomized crossover design to bilingual participants (N = 22).Performance varied by cognitive domain, but generally improved at the second session regardless of the language of the initial test. When performance on the English and Arabic version was compared, significant positive correlations were detected for accuracy in 8/13 cognitive domains and for speed in 4/13 domains (r = .02 to .97). When the practice estimates using linear models were incorporated, the translational validity estimates improved substantially (accuracy, r = .50-.96, speed, r = .63-.92, all correlations, p = .05 or better).While crossover designs control for order effects on average performance, practice effects, regardless of language, still need to be removed to obtain estimates of translational validity. When practice effect is controlled for, the Arabic and English versions of the Penn-CNB are well correlated, and the Arabic version is suitable for use in research.

To develop Arabic versions of English language questionnaires to estimate morningness/eveningness and sleep variables.We translated the Composite scale of morningness (CSM) and the sleep timing questionnaire (STQ) [with added siesta questions] into Arabic; the Arabic versions were then back translated. The revised Arabic and the original English versions were next administered to bi-lingual Egyptians using a crossover design (n=25). The Arabic versions of both scales were subsequently administered to an independent Egyptian sample (n=79) and the siesta variables examined in relation to the CSM.Satisfactory correlations were present between the English and Arabic versions for total CSM scores (Spearman's ρ=0.90, p0.001). All but one of the STQ variables were significantly correlated (Spearman's ρ=0.45-0.88, p≤0.05). In the Arabic version, the frequency of siesta naps per week was significantly correlated with the total CSM score, with evening types taking more naps (Spearman's ρ=-0.23, p≤0.05).Arabic versions of the STQ and CSM have been developed in Egypt, and are freely available. They can be used for behavioral research related to sleep and circadian function and can be adapted for use in other Arab speaking populations.

This paper uses a partial equilibrium trade model to evaluate British Columbia's (BC) log export restrictions. The results of a recently published paper on the topic rely on two key assumptions. They assumed BC has a ban on log exports and that any incremental BC log exports will not affect the world price for logs. This note uses the same data, but a more nuanced model, to show that from BC's perspective unlimited log exports is not necessarily preferred to a policy allowing limited log exports.

Background There is a critical gap between needs and available resources for mental health treatment across the world, particularly in low- and middle-income countries (LMICs). In countries committed to increasing resources to address these needs it is important to conduct research, not only to assess the depth of mental health needs and the current provision of public and private mental health services, but also to examine implementation methods and evaluate mental health approaches to determine which methods are most effective in local contexts. However, research resources in many LMICs are inadequate, largely because conventional research training is time-consuming and expensive. Adapting a hackathon model may be a feasible method of increasing capacity for mental health services research in resource-poor countries. Methods To explore the feasibility of this approach, we developed a ‘grantathon’, i.e. a research training workshop, to build capacity among new investigators on implementation research of Indian government-funded mental health programmes, which was based on a need expressed by government agencies. The workshop was conducted in Delhi, India, and brought together junior faculty members working in mental health services settings throughout the country, experienced international behavioural health researchers and representatives of the Indian Council for Medical Research (ICMR), the prime Indian medical research funding agency. Pre- and post-assessments were used to capture changes in participants’ perceived abilities to develop proposals, design research studies, evaluate outcomes and develop collaborations with ICMR and other researchers. Process measures were used to track the number of single-or multi-site proposals that were generated and funded. Results Participants (n = 24) generated 12 single- or multi-site research grant applications that will be funded by ICMR. Conclusion The grantathon model described herein can be modified to build mental health services research capacity in other contexts. Given that this workshop not only was conceptualised and delivered but also returned results in less than 1 year, this model has the potential to quickly build research capacity and ultimately reduce the mental health treatment gap in resource-limited settings.

Background Herpes simplex virus, type 1 (HSV-1) infects over 3.4 billion people, world-wide. Though it can cause encephalitis, in the vast majority it is asymptomatic, with lifelong latent infection in neurons. HSV-1 infected individuals have greater cognitive dysfunction than uninfected individuals, particularly persons with schizophrenia – even without encephalitis. We investigated whether HSV-1 related cognitive dysfunction is progressive or remediable. Methods In a prospective naturalistic follow up sample (PNFU), temporal changes in cognitive functions were analyzed in relation to baseline HSV-1 infection in persons with/without schizophrenia (N = 226). Independently, in a randomized controlled trial (RCT), HSV-1 infected, clinically stabilized SZ outpatients received Valacyclovir (VAL, an HSV-1 specific antiviral, 1.5 G twice daily for 16 weeks) or placebo (PLA) added to standard antipsychotic treatment, using a stratified randomization design, following placebo run-in (N = 67). In both samples, HSV-1 infection (seropositivity) was estimated using serum IgG antibodies. Clinical evaluations were blinded to HSV-1 or treatment status. Standardized Z scores for accuracy on eight cognitive domains were analyzed for temporal trajectories using generalized linear models (PNFU) and VAL/PLA differences compared with intent to treat analyses (RCT). Results PNFU : At baseline, HSV-1 infected participants had significantly lower accuracy scores for Emotion Identification and Discrimination (EMOD), Spatial memory and Spatial ability, regardless of SZ diagnosis (p = 0.025, 0.029, 0.046, respectively). They also had significantly steeper temporal worsening for EMOD (p = 0.03). RCT : EMOD improved in VAL-treated patients (p = 0.048, Cohen's d = 0.43). Conclusions A proportion of age related decline in EMOD is attributable to HSV-1 infection.

A variable number tandem repeat polymorphism (VNTR) in the period 3 (PER3) gene has been associated with heritable sleep and circadian variables, including self-rated chronotypes, polysomnographic (PSG) variables, insomnia and circadian sleep-wake disorders. This report describes novel molecular and clinical analyses of PER3 VNTR polymorphisms to better define their functional consequences. As the PER3 VNTR is located in the exonic (protein coding) region of PER3, we initially investigated whether both alleles (variants) are transcribed into messenger RNA in human fibroblasts. The VNTR showed bi-allelic gene expression. We next investigated genetic associations in relation to clinical variables in 274 older adult Caucasian individuals. Independent variables included genotypes for the PER3 VNTR as well as a representative set of single nucleotide polymorphisms (SNPs) that tag common variants at the PER3 locus (linkage disequilibrium (LD) between genetic variants < 0.5). In order to comprehensively evaluate variables analyzed individually in prior analyses, dependent measures included PSG total sleep time and sleep latency, self-rated chronotype, estimated with the Composite Scale (CS), and lifestyle regularity, estimated using the social rhythm metric (SRM). Initially, genetic polymorphisms were individually analyzed in relation to each outcome variable using analysis of variance (ANOVA). Nominally significant associations were further tested using regression analyses that incorporated individual ANOVA-associated DNA variants as potential predictors and each of the selected sleep/circadian variables as outcomes. The covariates included age, gender, body mass index and an index of medical co-morbidity. Significant genetic associations with the VNTR were not detected with the sleep or circadian variables. Nominally significant associations were detected between SNP rs1012477 and CS scores (p = 0.003) and between rs10462021 and SRM (p = 0.047); rs11579477 and average delta power (p = 0.043) (analyses uncorrected for multiple comparisons). In conclusion, alleles of the VNTR are expressed at the transcript level and may have a functional effect in cells expressing the PER3 gene. PER3 polymorphisms had a modest impact on selected sleep/circadian variables in our sample, suggesting that PER3 is associated with sleep and circadian function beyond VNTR polymorphisms. Further replicate analyses in larger, independent samples are recommended.

Twitter is useful for academic economists to follow current research and public policy and to engage with their colleagues, students, and the general public. It is also a great place to gather information relevant to undergraduate economics courses. A course specific twitter hashtag embedded in a Learning Management System (LMS) is an easy way to share this supplemental information with students. This article contains a detailed, step-by-step guide to embedding a twitter feed within a LMS. Examples of how twitter can be used to share information to students in a Principles of Macroeconomics course are provided. Student survey results indicate that although most students did not access the shared information on a weekly basis, most thought that the twitter feed helped connect the course material to real-world and stimulated their interest in macroeconomics. Students who accessed the shared information at least monthly felt more strongly (than students who never or rarely accessed the information) that the twitter feed helped connect the course material to real-world examples, was worthwhile, and stimulated their interest in macroeconomics.

Persistent infection with Herpes Simplex viruses (HSV) and other brain infections is consistently associated with cognitive impairment. These infections can also affect sleep. Thus, sleep abnormalities could explain the cognitive dysfunction. We investigated the association between sleep variables and persistent HSV-1, HSV-2, cytomegalovirus (CMV) and Toxoplasma gondii (Tox) infections. Sleep data were collected from older adults with or without insomnia (N = 311, total); a subset completed polysomnographic and actigraphy studies (N = 145). No significant associations were found between the infections and insomnia or the remaining sleep variables following corrections for multiple comparisons. Sleep dysfunction is unlikely to explain the infection-related cognitive dysfunction.

Herpes Simplex virus, type 1 (HSV-1) causes cold sores, keratitis and rarely, fatal encephalitis. The infection is life long, with sensory ganglia serving as reservoirs of latent infection. Recently, exposure to HSV-1 has also been repeatedly associated with reduced cognitive function among healthy individuals without prior encephalitis. Though HSV-1 does not elevate risk for schizophrenia (SZ) per se, exposure is likewise associated with impaired cognitive functions among SZ patients. The range of cognitive changes observed in HSV-1 exposed persons has not been investigated systematically, nor is it known whether interaction between HSV-1 exposure and SZ related factors contributes to the impairment among SZ patients. Persons with or without schizophrenia/schizophreniform disorder (N = 298 total, DSM IV criteria) were assessed for HSV-1 exposure using serum HSV-1 antibody titers. The Penn Computerized Neurocognitive battery was used to assess eight cognitive domains with respect to accuracy and speed. There were no significant case-control differences in HSV-1 exposure. The SZ/schizophreniform disorder cases were significantly impaired in all cognitive domains compared with the controls. HSV-1 exposure was also associated with reduced cognitive function in the entire sample, but the magnitude of the effects and their patterns differed from the SZ related changes. Further, statistically significant interactions between HSV-1 exposure and SZ case status were not detected. HSV-1 exposure does not elevate risk for SZ, but it is associated with reduced function in specific cognitive domains regardless of SZ diagnostic status. An ‘epidiagnostic’ model for the association is proposed to explain the results.

This paper applies principal component analysis to investigate the linkages, or dominant co-fluctuation patterns, of per capita carbon dioxide emissions across countries for the time period 1950–2000. Energy resource world markets are investigated as an offsetting mechanism possibly coordinating emission fluctuations between countries. The results of the analysis provide evidence that world energy resource markets are acting as a coordinating mechanism for emission fluctuations in most cases. The results also suggest that until recently the dominant emission co-fluctuation pattern for developed countries differs from the dominant emission co-fluctuation pattern for developing countries. The common fluctuation pattern found in the 1984–2000 time period suggests that an offsetting mechanism does exist and will help contain global per capita emissions into the future. The strong degree that emissions are linked between countries and energy markets acting as an offsetting mechanism suggests that to be successful a global agreement to address climate change must require emission reductions by all major emitters, not just the developed countries.

Objectives Disruption of circadian function has been observed in several human disorders, including bipolar disorder (BD). Research into these disorders can be facilitated by human cellular models that evaluate external factors (zeitgebers) that impact circadian pacemaker activity. Incorporating a firefly luciferase reporter system into human fibroblasts provides a facile, bioluminescent readout that estimates circadian phase, while leaving the cells intact. We evaluated whether this system can be adapted to clinical BD research and whether it can incorporate zeitgeber challenge paradigms. Methods Fibroblasts from patients with bipolar I disorder (BD-I) (n = 13) and controls (n = 12) were infected ex vivo with a lentiviral reporter incorporating the promoter sequences for Bmal1, a circadian gene to drive expression of the firefly luciferase gene. Following synchronization, the bioluminescence was used to estimate period length. Phase response curves (PRCs) were also generated following forskolin challenge and the phase response patterns were characterized. Results Period length and PRCs could be estimated reliably from the constructs. There were no significant case-control differences in period length, with a nonsignificant trend for differences in PRCs following the phase-setting experiments. Conclusions An ex vivo cellular fibroblast-based model can be used to investigate circadian function in BD-I. It can be generated from specific individuals and this could usefully complement ongoing circadian clinical research.

The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n = 182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

Patients with schizophrenia and their relatives have reduced prevalence of rheumatoid arthritis. Schizophrenia and rheumatoid arthritis genome-wide association studies also indicate negative genetic correlations, suggesting that there may be shared pathogenesis at the DNA level or downstream. A portion of the inverse prevalence could be attributed to pleiotropy, i.e., variants of a single nucleotide polymorphism that could confer differential risk for these disorders. To study the basis for such an interrelationship, we initially compared lists of single nucleotide polymorphisms with significant genetic associations (p, Schizophrenia and rheumatoid arthritis: Exploring the link Researchers in the USA identify variations in eight genes that potentially confer differential risk for schizophrenia and rheumatoid arthritis. Previous studies have shown that patients with schizophrenia (and their relatives) have a reduced risk of developing rheumatoid arthritis and vice versa. Vishwajit Nimgaonkar, Madhavi Ganapathiraju and colleagues at the University of Pittsburgh compared single nucleotide variations in the genetic code that are significantly associated with these diseases. They found that the inverse risk between these disorders could be due to differences harbored in eight genes. Computational analyses of the protein interactomes of genes associated exclusively with rheumatoid arthritis and those with schizophrenia revealed common interacting partners that are known to be involved in immune and inflammatory responses, and shared disease pathways. Additional investigation of these proteins could shed further light on shared disease mechanisms.