Structural neuroimaging correlates of social deficits are similar in autism spectrum disorder and attention-deficit/hyperactivity disorder: analysis from the POND Network

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal–parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to \u3c0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders

Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders

Oxytocin is a pituitary neuropeptide that affects social behaviour. Single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) have been shown to explain some variability in social abilities in control populations. Whether these variants similarly contribute to the severity of social deficits experienced by children with neurodevelopmental disorders is unclear. Social abilities were assessed in a group of children with autism spectrum disorder (ASD, n = 341) or attention deficit hyperactivity disorder (ADHD, n = 276) using two established social measures. Scores were compared by OXTR genotype (rs53576, rs237887, rs13316193, rs2254298). Unexpectedly, the two most frequently studied OXTR SNPs in the general population (rs53576 and rs2254298) were associated with an increased severity of social deficits in ASD (p \u3c 0.0001 and p = 0.0005), yet fewer social deficits in ADHD (p = 0.007 and p \u3c 0.0001). We conclude that these genetic modifier alleles are not inherently risk-conferring with respect to their impact on social abilities; molecular investigations are greatly needed

Neuropathic agents in the management of pruritus in burn injuries: a systematic review and meta-analysis

Objectives: Pruritus is a common and often distressing complication after a burn injury. The purpose of this review is to explore the efficacy of drugs classically used to treat neuropathic pain in the management of pruritus after burn injury. Methods: A systematic literature search of medical databases was conducted to find studies investigating drugs listed in the National Institute for Health and Care Excellence (NICE) guideline (CG173, “neuropathic pain in adults”) for the management of pruritus after burn injury in patients of any age. Controlled studies were stratified by the drug class studied and their risk of bias before conducting meta-analysis. A narrative review of case series or observational studies was presented. Severity of pruritus at any time point, with all quantitative and qualitative measures, was included. Results: Fifteen studies were included in the final analysis, 10 investigated the use of gabapentinoids, 4 studied doxepin, and 1 local anesthetic agents. Meta-analysis of three randomized controlled trials (RCTs) demonstrated that the use of gabapentinoids was associated with an improvement in mean VAS (Visual Analog Scale) 0–10 scores of 2.96 (95% confidence interval (95% CI) 1.20 to 4.73, p<0.001) when compared with placebo or antihistamine. A meta-analysis of four RCTs investigating topical doxepin showed an improvement in mean VAS scores of 1.82 (95% CI 0.55 to 3.09, p<0.001). However, when excluding two studies found to be at high risk of bias, no such improvement was found (−0.32, 95% CI −1.64 to –0.99, p=0.83). Conclusion: This study suggests that gabapentinoids are beneficial in the management of burn-related pruritus. There is a lack of evidence to suggest that doxepin is an effective treatment. Topical local anesthetic agents may be safe and beneficial, but studies are scarce

Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance

This white paper provides updated International Transporter Consortium (ITC) recommendations on transporters that are important in drug development following the 3rd ITC workshop. New additions include prospective evaluation of organic cation transporter 1 (OCT1) and retrospective evaluation of organic anion transporting polypeptide (OATP)2B1 because of their important roles in drug absorption, disposition, and effects. For the first time, the ITC underscores the importance of transporters involved in drug-induced vitamin deficiency (THTR2) and those involved in the disposition of biomarkers of organ function (OAT2 and bile acid transporters)

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder resulting from loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus, and infertility. Clinical features may be subtle and highly variable, making the diagnosis of PCD challenging. The diagnosis can be confirmed with ciliary ultrastructure analysis and/or molecular genetic testing of 32 PCD-associated genes. However, because of this genetic heterogeneity, comprehensive molecular genetic testing is not considered the standard of care, and the most efficient molecular approach has yet to be elucidated. Here, we propose a cost-effective and time-efficient molecular genetic algorithm to solve cases of PCD. We conducted targeted copy number variation (CNV) analysis and/or whole-exome sequencing on 20 families (22 patients) from a subset of 45 families (52 patients) with a clinical diagnosis of PCD who did not have a molecular genetic diagnosis after Sanger sequencing of 12 PCD-associated genes. This combined molecular genetic approach led to the identification of 4 of 20 (20%) families with clinically significant CNVs and 7 of 20 (35%) families with biallelic pathogenic mutations in recently identified PCD genes, resulting in an increased molecular genetic diagnostic rate of 55% (11/20). In patients with a clinical diagnosis of PCD, whole-exome sequencing followed by targeted CNV analysis results in an overall molecular genetic yield of 76% (34/45)

Defining extreme wildfire events: difficulties, challenges, and impacts

Every year worldwide some extraordinary wildfires occur, overwhelming suppressioncapabilities, causing substantial damages, and often resulting in fatalities. Given their increasingfrequency, there is a debate about how to address these wildfires with significant social impacts,but there is no agreement upon terminology to describe them. The concept of extreme wildfire event(EWE) has emerged to bring some coherence on this kind of events. It is increasingly used, often asa synonym of other terms related to wildfires of high intensity and size, but its definition remainselusive. The goal of this paper is to go beyond drawing on distinct disciplinary perspectives todevelop a holistic view of EWE as a social-ecological phenomenon. Based on literature review andusing a transdisciplinary approach, this paper proposes a definition of EWE as a process and anoutcome. Considering the lack of a consistent scale of gravity to leverage extreme wildfire eventssuch as in natural hazards (e.g., tornados, hurricanes and earthquakes) we present a proposal ofwildfire classification with seven categories based on measurable fire spread and behavior parametersand suppression difficulty. The categories 5 to 7 are labeled as EWE

Efficient production of foot-and-mouth disease virus empty capsids in insect cells following down regulation of 3C protease activity

Foot-and-mouth disease virus (FMDV) is a significant economically and distributed globally pathogen of Artiodactyla. Current vaccines are chemically inactivated whole virus particles that require large-scale virus growth in strict bio-containment with the associated risks of accidental release or incomplete inactivation. Non-infectious empty capsids are structural mimics of authentic particles with no associated risk and constitute an alternate vaccine candidate. Capsids self-assemble from the processed virus structural proteins, VP0, VP3 and VP1, which are released from the structural protein precursor P1-2A by the action of the virus-encoded 3C protease. To date recombinant empty capsid assembly has been limited by poor expression levels, restricting the development of empty capsids as a viable vaccine. Here expression of the FMDV structural protein precursor P1-2A in insect cells is shown to be efficient but linkage of the cognate 3C protease to the C-terminus reduces expression significantly. Inactivation of the 3C enzyme in a P1-2A-3C cassette allows expression and intermediate levels of 3C activity resulted in efficient processing of the P1-2A precursor into the structural proteins which assembled into empty capsids. Expression was independent of the insect host cell background and leads to capsids that are recognised as authentic by a range of anti-FMDV bovine sera suggesting their feasibility as an alternate vaccine