RNA-Seq time-course analysis of neural precursor cell transcriptome in response to herpes simplex Virus-1 infection.

The neurogenic niches within the central nervous system serve as essential reservoirs for neural precursor cells (NPCs), playing a crucial role in neurogenesis. However, these NPCs are particularly vulnerable to infection by the herpes simplex virus 1 (HSV-1). In the present study, we investigated the changes in the transcriptome of NPCs in response to HSV-1 infection using bulk RNA-Seq, compared to those of uninfected samples, at different time points post infection and in the presence or absence of antivirals. The results showed that NPCs upon HSV-1 infection undergo a significant dysregulation of genes playing a crucial role in aspects of neurogenesis, including genes affecting NPC proliferation, migration, and differentiation. Our analysis revealed that the CREB signaling, which plays a crucial role in the regulation of neurogenesis and memory consolidation, was the most consistantly downregulated pathway, even in the presence of antivirals. Additionally, cholesterol biosynthesis was significantly downregulated in HSV-1-infected NPCs. The findings from this study, for the first time, offer insights into the intricate molecular mechanisms that underlie the neurogenesis impairment associated with HSV-1 infection.

Prevalence of Psychiatric Morbidity and Alcohol use Disorders Among Adolescent Indigenous Tribals from Three Indian States.

Background: Among the Indian adolescents, the prevalence of psychiatric morbidity and alcohol use disorders (AUD) are 7.3% and 1.3%. However, no separate data are available for indigenous tribal populations. This study estimated the prevalence of psychiatric morbidity and AUD and associated socio-demographic factors among adolescents in the tribal communities in three widely varying states in India. Methods: Using validated Indian versions of the MINI 6.0, MINI Kid 6.0, and ICD-10 criteria, we conducted a cross-sectional survey from January to May 2019 in three Indian sites: Valsad, Gujarat (western India); Nilgiris, Tamil Nadu (south India); and East Khasi Hills district of Meghalaya (north-east India) on 623 indigenous tribal adolescents. Results: Aggregate prevalence of any psychiatric morbidity was 15.9% (95% CI: 13.1-19.0) (males: 13.6%, 95% CI: 10.0-18.1; females: 17.9%, 95% CI: 13.9-22.6), with site-wise statistically significant differences: Gujarat: 23.8% (95% CI: 18.1-30.2), Meghalaya: 17.1% (95% CI: 12.4-22.7), Tamil Nadu: 6.2% (95% CI: 3.2-10.5). The prevalence of diagnostic groups was mood disorders 6.4% (n = 40), neurotic- and stress-related disorders 9.1% (n = 57), phobic anxiety disorder 6.3% (n = 39), AUD 2.7% (n = 17), behavioral and emotional disorders 2.7% (n = 17), and obsessive-compulsive disorder 2.2% (n = 14). These differed across the sites. Conclusion: The prevalence of psychiatric morbidity in adolescent tribals is approximately twice the national average. The most common psychiatric morbidities reported are mood (affective) disorders, neurotic- and stress-related disorders, phobic anxiety disorder, AUD, behavioral and emotional disorders, andobsessive-compulsive disorder.

Feasibility and acceptability of the Indian Autism Screening Questionnaire in clinical and community settings.

We developed and tested the Indian Autism Screening Questionnaire (IASQ), which was reported to be reliable and valid as compared to the Indian Scale for Assessment of Autism (ISAA) and the Childhood Autism Rating Scale -2 (CARS2). The present study describes the feasibility, acceptability, sociodemographic and developmental details of IASQ study participants in 5 settings- a psychiatry outpatients' clinic (n = 145), a specialised paediatric clinic (n = 24), a speciality disability centre (n = 174), a primary school (n = 41) and a government housing colony (n = 255). The IASQ could be easily administered and understood. Consistent with prior reports, the male-female ratio of participants with autism was 3.8:1. Developmental complications were reported more frequently in clinical settings, while delivery by Caesarean section was commoner among community-dwelling higher socioeconomic status mothers (53% of the officers' sample). Mothers of participants with autism more frequently reported Caesarean section birth for the proband (χ2 = 41.61, p < .0001) and prenatal and postnatal complications. Binary logistic regression confirmed that perinatal complications in the mother and father's (older) age at birth of the participant were associated with autism. The IASQ is a reliable, practical tool for screening for autism in clinical and non-clinical settings in India.

An open-label study of oral acetazolamide for the prevention of antipsychotic associated weight gain.

Background: Weight gain associated with atypical antipsychotic medications need to be well managed. We set out: 1. To test the effect of acetazolamide on weight gain associated with antipsychotics 2. To assess improvement in psychotic symptoms using the Brief Psychiatric Rating Scale score on patients receiving acetazolamide. Methods and Materials: This open-label study conducted after institutional ethical clearance from December 2018 to August 2020 included 34 drug-naive patients or patients on antipsychotic risperidone or olanzapine for less than one month. They were divided into two groups of 17 each as a case group (treatment as usual + acetazolamide) and a control group (treatment as usual) who were followed up for eight weeks. The patient's physical characteristics were recorded at baseline and during follow-ups. The Brief psychiatric rating scale (BPRS) and clinical global impression (CGI) scores were compared for the cases and controls. Results: The study showed non-significant reduction in the weight (-0.57 ± 1.06 kg), body mass index (BMI) (-0.23 ± 0.76 kg/m2) and abdominal circumference (-0.47 ± 1.37 cm) in the patients receiving oral acetazolamide at the end of two months as compared to controls where there was significant increase in the weight (+2.62 ± 1.09 kg), BMI (+1.03 ± 0.44 kg/m2) and abdominal circumference (+2.21 ± 1.33 cm, P = 0.001). Similarly, the BPRS and CGI scores were significantly reduced in both arms, with satisfaction rates better among the cases compared to controls. Conclusion: There was a non-significant reduction in the weight, body mass index, abdominal circumference, and brief psychiatric rating scale scores in patients treated with acetazolamide.Ethics committee protocol number: - 2018/244CTRI India registration number: CTRI/2019/05/018884.

A mentored hands-on training model for scaling up implementation and intervention research in India: "connecting the dots".

Despite the high burden of mental disorders in low- and middle-income countries (LMICs), less than 25% of those in need have access to appropriate services, in part due to a scarcity of locally relevant, evidence-based interventions and models of care. To address this gap, researchers from India and the United States and the Indian Council of Medical Research (ICMR) collaboratively developed a "Grantathon" model to provide mentored research training to 24 new principal investigators (PIs). This included a week-long didactic training, a customized web-based data entry/analysis system and a National Coordination Unit (NCU) to support PIs and track process objectives. Outcome objectives were assessed via scholarly output including publications, awards received and subsequent grants that were leveraged. Multiple mentorship strategies including collaborative problem-solving approaches were used to foster single-centre and multicentre research. Flexible, approachable and engaged support from mentors helped PIs overcome research barriers, and the NCU addressed local policy and day-to-day challenges through informal monthly review meetings. Bi-annual formal review presentations by all PIs continued through the COVID-19 pandemic, enabling interim results reporting and scientific review, also serving to reinforce accountability. To date, more than 33 publications, 47 scientific presentations, 12 awards, two measurement tools, five intervention manuals and eight research grants have been generated in an open-access environment. The Grantathon is a successful model for building research capacity and improving mental health research in India that could be adopted for use in other LMICs.

Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2.

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.

iPSC-Derived Neurons from Patients with POLG Mutations Exhibit Decreased Mitochondrial Content and Dendrite Simplification.

Mutations in POLG, the gene encoding the catalytic subunit of DNA polymerase gamma, result in clinical syndromes characterized by mitochondrial DNA (mtDNA) depletion in affected tissues with variable organ involvement. The brain is one of the most affected organs, and symptoms include intractable seizures, developmental delay, dementia, and ataxia. Patient-derived induced pluripotent stem cells (iPSCs) provide opportunities to explore mechanisms in affected cell types and potential therapeutic strategies. Fibroblasts from two patients were reprogrammed to create new iPSC models of POLG-related mitochondrial diseases. Compared with iPSC-derived control neurons, mtDNA depletion was observed upon differentiation of the POLG-mutated lines to cortical neurons. POLG-mutated neurons exhibited neurite simplification with decreased mitochondrial content, abnormal mitochondrial structure and function, and increased cell death. Expression of the mitochondrial kinase PTEN-induced kinase 1 (PINK1) mRNA was decreased in patient neurons. Overexpression of PINK1 increased mitochondrial content and ATP:ADP ratios in neurites, decreasing cell death and rescuing neuritic complexity. These data indicate an intersection of polymerase gamma and PINK1 pathways that may offer a novel therapeutic option for patients affected by this spectrum of disorders.

Herpesvirus Infections in the Human Brain: A Neural Cell Model of the Complement System Derived from Induced Pluripotent Stem Cells.

BACKGROUND: Herpesviruses alter cognitive functions in humans following acute infections; progressive cognitive decline and dementia have also been suggested. It is important to understand the pathogenic mechanisms of such infections. The complement system - comprising functionally related proteins integral for systemic innate and adaptive immunity - is an important component of host responses. The complement system has specialized functions in the brain. Still, the dynamics of the brain complement system are still poorly understood. Many complement proteins have limited access to the brain from plasma, necessitating synthesis and specific regulation of expression in the brain; thus, complement protein synthesis, activation, regulation, and signaling should be investigated in human brain-relevant cellular models. Cells derived from human-induced pluripotent stem cells (hiPSCs) could enable tractable models. METHODS: Human-induced pluripotent stem cells were differentiated into neuronal (hi-N) and microglial (hi-M) cells that were cultured with primary culture human astrocyte-like cells (ha-D). Gene expression analyses and complement protein levels were analyzed in mono- and co-cultures. RESULTS: Transcript levels of complement proteins differ by cell type and co-culture conditions, with evidence for cellular crosstalk in co-cultures. Hi-N and hi-M cells have distinct patterns of expression of complement receptors, soluble factors, and regulatory proteins. hi-N cells produce complement factor 4 (C4) and factor B (FB), whereas hi-M cells produce complement factor 2 (C2) and complement factor 3 (C3). Thus, neither hi-N nor hi-M cells can form either of the C3-convertases - C4bC2a and C3bBb. However, when hi-N and hi-M cells are combined in co-cultures, both types of functional C3 convertase are produced, indicated by elevated levels of the cleaved C3 protein, C3a. CONCLUSIONS: hiPSC-derived co-culture models can be used to study viral infection in the brain, particularly complement receptor and function in relation to cellular "crosstalk." The models could be refined to further investigate pathogenic mechanisms.

The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids.

Intrauterine infections during pregnancy by herpes simplex virus (HSV) can cause significant neurodevelopmental deficits in the unborn/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.

Comparing the Indian Autism Screening Questionnaire (IASQ) and the Indian Scale for Assessment of Autism (ISAA) with the Childhood Autism Rating Scale-Second Edition (CARS2) in Indian settings.

The Indian Autism Screening Questionnaire (IASQ), derived from the Indian Scale for Assessment of Autism ISAA (the mandated tool for autism in India), is an autism screening instrument for use in the general population by minimally trained workers. While ISAA has 40 items with four anchor points, the IASQ is a 10-item questionnaire with yes/no answers. It was initially validated using the ISAA. During its development the ISAA was itself compared to the Childhood Autism Rating Scale version 1 (ISAA Manual). In the present study, we evaluated both the ISAA and the IASQ in relation to the Childhood Autism Rating Scale version 2 (CARS-2). METHODS: Participants were recruited from three settings: a referral clinic for neurodevelopmental conditions run by the Department of Paediatrics of a tertiary care teaching hospital (NDC OPD), the outpatient department of an institute for disability and rehabilitation (NIEPID), and from the community (CGOC). Persons between ages 3-18 were recruited following consent or assent (parent and child/adolescent). The IASQ was administered by a minimally trained administrator. It was followed by ISAA and the CARS-2 (in alternating order, by different evaluators blind to each other) (CARS2 SV (Standard Version) and CARS2 HF (High Functioning) as applicable). Sensitivity, specificity and area under the Receiver Operator Characteristics (ROC) curve were calculated for IASQ and CARS2, as well as for ISAA and CARS2. Concordance between CARS2 and ISAA was calculated using kappa coefficient. RESULTS: A total of 285 participants (NIEPD n = 124; NDC OPD, n = 4; CGOC n = 157) (a total of 70 with autism and 215 controls) participated. IASQ and CARS2 were administered on 285 participants, while IASQ and ISAA were administered on 264 participants. When IASQ was compared to CARS2, sensitivity was 97%, specificity 81%, PPV 63%, NPV 99% at cut off 1 while these values were 97%, 92%, 79% and 99% respectively at cut off 2. There was high concordance between CARS2 and ISAA (Kappa 0.907, p<0.0001). CONCLUSIONS: IASQ has satisfactory sensitivity, specificity and concordance when compared with CARS2; it can be used for screening children with autism in community. The ISAA also showed a high concordance with CARS2, as it had with the older version of CARS.

Age-dependent patterns of schizophrenia genetic risk affect cognition.

Cognition shares substantial genetic overlap with schizophrenia, yet it remains unclear whether such genetic effects become significant during developmental periods of elevated risk for schizophrenia, such as the peak age of onset. We introduce an investigative framework integrating epidemiological, developmental, and genetic approaches to determine whether genetic effects shared between schizophrenia and cognition are significant across periods of differing risk for schizophrenia onset, and whether these effects are shared with depression. 771 European-American participants, including 636 (ages 15-84 years) from families with at least two first-degree relatives with schizophrenia and 135 unrelated controls, were divided into three age-risk groups based on ages relative to epidemiological age of onset patterns for schizophrenia: Pre-Peak (before peak age-of-onset: 15 to 22 years), Post-Peak (after peak age-of-onset: 23-42 years), and Plateau (during plateau of age-of-onset: over 42 years). For general cognition and 11 specific cognitive traits, we estimated genetic correlations with schizophrenia and with depression within each age-risk group. Genetic effects shared between deficits in general cognition and schizophrenia were nonsignificant before peak age of onset, yet were high and significant after peak age of onset and during the plateau of onset. These age-dependent genetic effects were largely consistent across specific cognitive traits and not transdiagnostically shared with depression. Schizophrenia genetic effects appear to influence cognitive traits in an age-dependent manner, supporting late developmental and perhaps neurodegenerative models that hypothesize increased expression of schizophrenia risk genes during and after the peak age of risk. Our findings underscore the utility of cognitive traits for tracking schizophrenia genetic effects across the lifespan.

Exploring static and dynamic relationships between burden of disease and research funding in the United States.

BACKGROUND: The relationship between burden of disease and research funding has been examined cross-sectionally, but temporal patterns have not been investigated. It is logical to assume that temporal improvements in disability-adjusted life-years (DALYs) reflect benefits from research funding; such assumptions are tempered by an unknown lag time for emergence of benefits from research. METHODS: We studied National Institutes of Health (NIH) research fund allocations and United States DALY estimates for overlapping disease categories (matched disease categories, MDC, N = 38). Using a general linear model, we separately analysed DALYs for MDCs in 2017 in relation to NIH research allocations in 2017 and 2007. We also examined how changes in DALYs were related to cumulative NIH research funding (2006-2017). After regressing DALY change on summed funding, we obtained model residuals as estimates of the discrepancy for each MDC between observed and expected change in burden, given funding. RESULTS: In 2017, there was a positive association between NIH research fund allocations and DALYs for the same year (F1,36 = 16.087, p = 0.0002921; slope = 0.35020; model R2 = 0.3088), suggesting proportionate allocation. There was a positive association between 2017 DALYs and 2007 NIH research allocation, implying a beneficial impact of research (F1,36 = 15.754, p = 0.0003; slope = 0.8845; model R2 = 0.3044). In contrast, there was a nonsignificant association between summed NIH funding and percent change in DALYs over 2006-2017 (F1,36 = 0.199; p = 0.65; beta coefficient = -1.144). When MDCs were ordered based on residuals, HIV/AIDS ranked first. Mental, neurologic or substance abuse (MNS) disorders comprised most residuals in the lower half. CONCLUSIONS: NIH fund allocation is proportional to DALYs for MDCs. Temporal changes in DALYs vary by MDCs, but they are not significantly related to cumulative research outlays. Further analysis of temporal changes in DALYs could help to inform research outlays for MDCs and to study the impact of research.

Age-dependent effects of schizophrenia genetic risk on cortical thickness and cortical surface area: Evaluating evidence for neurodevelopmental and neurodegenerative models of schizophrenia.

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).

Feasibility, acceptability and evaluation of meditation to augment yoga practice among persons diagnosed with schizophrenia.

OBJECTIVE: To design a meditation protocol and test its feasibility, acceptability and efficacy in conjunction with yoga training (YT) for persons with schizophrenia (SZ). METHODS: The meditation protocol consisted of Anapana (observing normal respiration) and Yoga Nidra (supine, restful awareness). In a single-blind randomised controlled trial, medicated and clinically stable outpatients diagnosed with SZ were randomised to receive treatment as usual (TAU), TAU augmented with YT or TAU augmented with meditation and yoga training (MYT) for 3 weeks (N = 145). Acceptability, clinical, social and cognitive functions were assessed after 3-week and 3-month post-randomisation using within-group and between-group analyses with repeated measures multivariate tests. RESULTS: No group-wise differences in compliance, study discontinuation, major/serious side effects or adverse events were noted. For six assessed clinical variables, the direction of changes were in the desired direction and the effect sizes were greater in the MYT group compared with the TAU group at both time points. Changes in social function variables were greater at 3 months than at 3 weeks. Nominally significant improvement in individual cognitive domains were noted in all groups at both time points. All effect sizes were in the small to medium range. CONCLUSION: MYT is feasible and acceptable and shows modest benefits for persons with SZ. MYT can also improve quality of life and clinical symptoms. Larger studies of longer duration are warranted.

Variations in Aspects of Neural Precursor Cell Neurogenesis in a Human Model of HSV-1 Infection.

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.

Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth.

Importance: Establishing genetic contributions to the transmission of bipolar disorder (BD) from parents to offspring may inform the risk of developing this disorder and further serve to validate BD in youth. Objective: To evaluate the specific association of BD polygenic risk scores (PRSs) on the familial transmission and validity of pediatric BD. Design, Setting, and Participants: This community-based case-control longitudinal study (Pittsburgh Biological Offspring Study) included parents with BD I/II and their offspring and parents without BD (healthy or non-BD psychopathology) and their offspring. Participants were recruited between March 2001 and May 2007, and analysis took place from December 2020 to September 2021. Exposures: PRSs for BD, major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder. Main Outcomes and Measures: Participants were prospectively evaluated using standardized interviews blind to parental diagnosis. DNA was extracted from saliva and genotyped. PRSs were constructed based on independent large-scale genome-wide association studies. Results: A total of 156 parents with BD I/II and 180 parents without BD (mean [SD] age, 39.6 [7.9] years; 241 female [72%]) as well as 251 offspring of parents with BD and 158 offspring of parents without BD (mean [SD] age, 10.4 [4.7] years; 213 female [52%]) of European ancestry were analyzed. Participants were assessed a mean of 6.7 times during a mean (SD) of 13 (3.4) years of follow-up (84% retention). More offspring of parents with BD developed BD (58 [23.1%] vs 8 [5.1%]; P < .001) and depression (126 [50.2%] vs 52 [32.9%]; P < .001) compared with offspring of parents without BD. BD PRS was higher in both parents and offspring with BD than parents and offspring without BD (parents: odds ratio, 1.50; 95% CI, 1.19-1.89; P < .001; explained 4.8% of the phenotypic variance vs offspring: hazard ratio, 1.34; 95% CI, 1.03-1.7; P = .02; explained 5.0% of the phenotypic variance). BD PRS did not differ across BD subtypes. In a model combining parental and offspring BD PRS, the parental BD PRS association with offspring BD was fully mediated by offspring BD PRS (hazard ratio, 1.40; 95% CI, 1.05-1.86; P = .02). Parental BD had a stronger direct association than parental or offspring BD PRS with offspring BD risk (hazard ratio, 5.21; 95% CI, 1.86-14.62; P = .002), explaining 30% of the variance. Parental and offspring BD PRS explained 6% of the BD onset variance beyond parental diagnosis. There were no significant between-group differences in PRSs for major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder in parents or offspring and they were not significantly associated with BD onset. Conclusions and Relevance: The findings of this study add to the extant clinical validation of BD in youth. Parental BD and offspring BD PRS independently associated with the risk of BD in offspring. Although this is promising, the association of BD PRS was relatively small and cannot be used alone to determine BD risk until further developments occur.

Parental consanguinity among patients with schizophrenia in a rural community of South India: A clinical and genetic investigation.

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.

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs.

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.

Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees.

BACKGROUND: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. METHODS: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. RESULTS: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. CONCLUSIONS: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery.

Psychometric properties of a screening tool for autism in the community-The Indian Autism Screening Questionnaire (IASQ).

INTRODUCTION: Currently available screening questionnaires for Autism spectrum disorders were tested in developed countries, but many require additional training and many are unsuitable for older individuals, thus reducing their utility in lower/ middle- income countries. We aimed to derive a simplified questionnaire that could be used to screen persons in India. METHODS: We have previously validated Indian Scale for Assessment of Autism (ISAA), that is now mandated for disability assessment by the Government of India. This detailed tool requires intensive training and it is time consuming. It was used to derive a new screening questionnaire: 1) items most frequently scored as positive by participants with autism in original ISAA validation study were modified for binary scoring following expert review. 2) In a new sample, clinically diagnosed individuals with/without autism were administered the screening tool and ISAA following written informed consent. Its psychometric properties were determined. RESULTS: A 10-item scale named Indian Autism Screening Questionnaire (IASQ) was prepared in Hindi and English. Thereafter 145 parents/caregivers of participants (autism, n = 90, other psychiatric disorders, n = 55) (ages 3-18), were administered IASQ and ISAA (parents/caregivers plus observation) by separate interviewers, blind to each other and to diagnosis. At a cutoff of 1, sensitivity was 99%, specificity 62%, Positive Predictive Value 81%, and Negative Predictive Value 95%. Test-retest reliability was r = 0.767 (CI = 0.62-0.86) and interrater reliability- Krippendorff"s-alpha was 0.872. The area under Receiver Operating Characteristic Curve (ROC) was 95%. There was a significant difference on IASQ-scores between participants with and without a clinical diagnosis of Autism (t = 14.57, p<0.0001). DISCUSSION: The IASQ is a simple, easy to use screening tool with satisfactory reliability and validity, that can be administered to caregivers in 15 minutes and provides information about DSM 5 criteria for autism. It may be applicable outside India, following additional adaptation, for community-based studies.