Abstract Background There is mixed evidence for an association between autism spectrum disorder (ASD) and emotion recognition deficits. We sought to assess the bidirectionality of this association using phenotypic and genetic data in a large community sample. Methods Analyses were conducted in three stages. First, we examined the bidirectional association between autistic traits at age 8 years and emotion recognition task (ERT) responses at age 24 years (Study 1; N=3,562); and between Diagnostic Analysis of Non-Verbal Accuracy (DANVA) emotion recognition responses at age 8 years and autistic traits at age 10 years (Study 2; N=9,071). Next, we used genetic analyses (Study 3) to examine the association between polygenic risk scores for ASD and these phenotypes. The genetic correlation between ASD and ERT responses at age 24 was also estimated. Analyses were conducted in the Avon Longitudinal Study of Parents and Children. Results Autistic traits at age 8 years were negatively associated with later total correct responses on ERT in Study 1 (b=- 0.18; 95% CI: −0.27 to −0.09). We also found evidence of an association in Study 2 ( b =-0.04; 95% CI: −0.05 to −0.03). We found the opposite association i.e., positive, between the ASD polygenic risk score and ERT ( b =0.40; 95% CI: 0.10 to 0.70); however, this association varied across different p-value thresholds so should be interpreted with caution. We did not find evidence of a genetic correlation between ASD and ERT. Conclusion We found an observational association between poorer emotion recognition and increased autistic traits. Our genetic analyses revealed an association between ASD polygenic risk and the ERT outcome, which may suggest a shared genetic aetiology between these or a potential causal pathway. Our results may inform interventions targeting emotion recognition.
CASE DESCRIPTION 5 cats (9 eyes) were evaluated for surgical correction of bilateral eyelid agenesis. CLINICAL FINDINGS All eyes lacked > 25% of the temporal upper eyelid, and all cats had clinical signs attributable to chronic ocular exposure. Abnormalities were limited to the ocular surface in the 4 female cats, whereas the sole male cat had additional abnormalities consistent with anterior segment dysgenesis. TREATMENT AND OUTCOME A modified Roberts-Bistner procedure involving 2-octyl cyanoacrylate (2OCA) was performed on 9 eyes; 1 eye was enucleated. Surgical wounds in the initial 3 eyes were closed with 2OCA plus sutures, and flaps were lined with conjunctiva. The technique was optimized for remaining eyes by use of a single suture for flap apposition, no conjunctival lining of flaps, and 2OCA alone for wound closure. Median duration of surgery was 35 minutes/eye for the initial 3 eyes versus 16 minutes/eye for the subsequent 6 eyes treated with the optimized procedure. After surgery, all cats had complete palpebral reflexes and resolution of clinical signs of ocular irritation. Minor complications in the early postoperative period included eyelid swelling (n = 9), poor cosmesis (7), and persistent epiphora (3). By the second recheck examination, swelling had resolved and cosmesis was considered excellent. Two eyes with epiphora had been treated with the initial modified procedure and required cryoepilation for resolution of epiphora. CLINICAL RELEVANCE The modified Roberts-Bistner procedure for eyelid agenesis involving 2OCA for wound closure provided functional, cosmetic eyelids that improved comfort and provided protection of the ocular surface in affected cats.
Abstract Background DNA methylation is associated with body mass index (BMI), but it is not clear if methylation scores are biomarkers for extant BMI or predictive of future BMI. Here, we explore the causal nature and predictive utility of DNA methylation measured in peripheral blood with BMI and cardiometabolic traits. Methods Analyses were conducted across the life course using the ARIES cohort of mothers ( n = 792) and children ( n = 906), for whom DNA methylation and genetic profiles and BMI at multiple time points (3 in children at birth, in childhood and in adolescence; 2 in mothers during pregnancy and in middle age) were available. Genetic and DNA methylation scores for BMI were derived using published associations between BMI and DNA methylation and genotype. Causal relationships between methylation and BMI were assessed using Mendelian randomisation and cross-lagged models. Results The DNA methylation scores in adult women explained 10% of extant BMI variance. However, less extant variance was explained by scores generated in the same women during pregnancy (2% BMI variance) and in older children (15–17 years; 3% BMI variance). Similarly, little extant variance was explained in younger children (at birth and at 7 years; 1% and 2%, respectively). These associations remained following adjustment for smoking exposure and education levels. The DNA methylation score was found to be a poor predictor of future BMI using linear and cross-lagged models, suggesting that DNA methylation variation does not cause later variation in BMI. However, there was some evidence to suggest that BMI is predictive of later DNA methylation. Mendelian randomisation analyses also support this direction of effect, although evidence is weak. Finally, we find that DNA methylation scores for BMI are associated with extant cardiometabolic traits independently of BMI and genetic score. Conclusion The age-specific nature of DNA methylation associations with BMI, lack of causal relationship and limited predictive ability of future BMI indicate that DNA methylation is likely influenced by BMI and might more accurately be considered a biomarker of BMI and related outcomes rather than a predictor. Future epigenome-wide association studies may benefit from further examining associations between early DNA methylation and later health outcomes.
Background The way in which socioeconomic status (SES) moderates the etiology of reading attainment has been explored many times, with past work often finding that genetic influences are suppressed under conditions of socioeconomic deprivation and more fully realized under conditions of socioeconomic advantage: a gene–SES interaction. Additionally, past work has pointed toward the presence of gene–location interactions, with the relative influence of genes and environment varying across geographic regions of the same country/state. Method This study investigates the extent to which SES and geographical location interact to moderate the genetic and environmental components of reading attainment. Utilizing data from 2,135 twin pairs in Florida (mean age 13.82 years, range 10.71–17.77), the study operationalized reading attainment as reading comprehension scores from a statewide test and SES as household income. We applied a spatial twin analysis procedure to investigate how twin genetic and environmental estimates vary by geographic location. We then expanded this analysis to explore how the moderating role of SES on said genetic and environmental influences also varied by geographic location. Results A gene–SES interaction was found, with heritability of reading being suppressed in lower‐ (23%) versus higher‐SES homes (78%). The magnitude of the moderating parameters were not consistent by location, however, and ranged from −0.10 to 0.10 for the moderating effect on genetic influences, and from −0.30 to 0.05 for the moderating effect on environmental influences. For smaller areas and those with less socioeconomic variability, the magnitude of the genetic moderating parameter was high, giving rise to more fully realized genetic influences on reading there. Conclusions SES significantly influences reading variability. However, a child's home location matters in both the overall etiology and how strongly SES moderates said etiologies. These results point toward the presence of multiple significant environmental factors that simultaneously, and inseparably, influence the underlying etiology of reading attainment.
Background: Sleep abnormalities are common in schizophrenia, often appearing before psychosis onset; however, the mechanisms behind this are uncertain. We investigated whether genetic risk for schizophrenia is associated with sleep phenotypes.Methods: We used data from 6,058 children and 2,302 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC). We examined associations between a polygenic risk score for schizophrenia and sleep duration in both children and mothers, and nightmares in children, along with genetic covariances between these traits.Results: Polygenic risk for schizophrenia was associated with increased risk of nightmares (OR=1.07, 95% CI: 1.01, 1.14, p=0.02) in children, and also with less sleep (β=-44.52, 95% CI: −88.98, −0.07; p=0.05). We observed a similar relationship with sleep duration in mothers, although evidence was much weaker (p=0.38). Finally, we found evidence of genetic covariance between schizophrenia risk and reduced sleep duration in children and mothers, and between schizophrenia risk and nightmares in children.Conclusions: These molecular genetic results support recent findings from twin analysis that show genetic overlap between sleep disturbances and psychotic-like experiences. They also show, to our knowledge for the first time, a genetic correlation between schizophrenia liability and risk of nightmares in childhood.
Systemic Sclerosis(SSc) is a rare autoimmune disease with fibrosis, changes in the skin, vasculature, joints and internal organs. Diffuse disease involves lung, heart and kidney and 10-year mortality is >35%.[1] Raynaud's attacks occur in ~95% of SSc patients. Severe Raynaud's (RP) affects patients' health status more than depression, obesity, and heart disease.[2] No treatment for Raynaud's is approved, but calcium channel blockers (CCBs) are first-line treatment. Cilnidipine, a 4th generation CCB approved for hypertension in Asia, has been shown to be safer than other CCBs in treating hypertension, and has beneficial effects on the kidney and heart. Cilnidipine is more selective for N-type Ca channels, and improves analgesia, sympathetic, autonomic and endothelial function.[3] Cilnidipine might be repurposed for SSc-RP patients.
Objectives
We studied safety and preliminary efficacy of cilnidipine use in SSc-RP, dose response and co-administration of a low dose PDE-V inhibitor. Results are compared to a 2017 meta-analysis of CCB use in SSc-RP.
Methods
RECONNOITER-1 is a two-part, planned 76 patient trial. In Part 1, we evaluated safety, dose, efficacy and co-administration of tadalafil. Dose groups were cilnidipine 10mg and 20mg, alone and with tadalafil 5mg, tadalafil alone and placebo. The 1° endpoint was reduction in weekly frequency of RP. 2° endpoints included Raynaud's Condition Score (RCS), pain, severity, duration, and a validated PRO (SHAQ). The DSMB reviewed data on the first 27 patients in 8/2022.
Results
The ITT population was 27 patients, the mITT 24. Results are reported for the mITT population. Cilnidipine-only treated patients(n=7) had a reduction in weekly attacks of 42.2% versus 18.9% in placebo(n=4) Dose response was seen in weekly attack frequency and severity. Response was greater in the higher cilnidipine dose group on attack duration and RCS. Tadalafil increased treatment effect with 10 mg but not with 20 mg. Cilnidipine at either dose was well tolerated and only Grade 1 mild AEs were reported with cilnidipine (17.6%), with no treatment discontinuations due to AEs. The DSMB halted Part 1 early based on meeting study goals.
Conclusion
In this preliminary study, cilnidipine was well-tolerated and efficacy trends were seen. A published metanalysis of CCB use for RP finds AE's >46% and treatment discontinuation in >30% of patients.[4] Cilnidipine appears superior in safety to commonly used CCBs (P= 0.0247). Our results replicate the improved safety in hypertension treatment. PRO results (SHAQ) also favor the 20 mg dose of cilinidipine over placebo with significance over placebo, depsite the small numbers (p=0.0115). Increased N-type channel blockade may increase safety and efficacy with the drug. Part 2 will compare Cilnidipine 20mg daily to placebo in a crossover trial in 38 patients.
Andrew Sternlicht Shareholder of: I own shares of Aisa Pharma, Inc., the company that supported this study. I am not paid by Aisa Pharma. I did discover and develop the use of the drug discussed in this abstract., Michael Shanahan Grant/research support from: This research was supported by a grant from Aisa Pharma., Erin Morton: None declared, Elizabeth Briggs: None declared, Ivana Hunt: None declared, Zoey Reed: None declared, Amanda Weragoda: None declared, Lashika Weerakoon: None declared, Meredith Todd Consultant of: Aisa Pharma Australia, Pty Ltd, Employee of: Aisa Pharma Australia, Pty Ltd.
Loneliness and social isolation are important public health concerns due to their associations with a range of health outcomes. However, it is difficult to ascertain whether loneliness and social isolation cause those outcomes or whether the observed associations are biased by confounding and reverse causation. In this study we used a triangulation approach combining observational analysis, sibling control design, and Mendelian Randomisation (a genetically informed causal inference approach), to draw robust conclusions about these relationships. Using a combination of publicly available genome-wide association study (N= 17,526 to 2,083,151) and UK Biobank data (N= 8,075 to 414,432), we examined relationships between loneliness and social isolation and outcomes related to physical health, mental health and wellbeing and general health (reflecting both physical and mental health e.g., multimorbidity). Our results provide evidence for causal effects of loneliness and social isolation on poorer mental health and wellbeing and of loneliness on poorer general health. Evidence was generally stronger for loneliness compared to social isolation. We do not find evidence of effects on specific physical health outcomes; however, we cannot definitively rule out causal relationships. Interventions targeting loneliness and social isolation may be effective strategies for improving general health, mental health and wellbeing outcomes.
The genetic and environmental aetiology of autistic and Attention Deficit Hyperactivity Disorder (ADHD) traits is known to vary spatially, but does this translate into variation in the association of specific common genetic variants?
Abstract Background and Aims Initial use of drugs such as tobacco and alcohol may lead to subsequent more problematic drug use – the ‘gateway’ hypothesis. However, observed associations may be due to a shared underlying risk factor, such as trait impulsivity. We used bidirectional Mendelian Randomisation (MR) to test the gateway hypothesis. Design Our main method was inverse-variance weighted (IVW) MR, with other methods included as sensitivity analyses (where consistent results across methods would raise confidence in our primary results). MR is a genetic instrumental variable approach used to support stronger causal inference in observational studies. Setting European ancestry individuals. Participants Genome-wide association summary data for smoking initiation, alcoholic drinks per week, cannabis use and dependence, cocaine and opioid dependence (N=1,749 to 1,232,091). Measurements Genetic variants for exposure. Findings We found evidence of causal effects from smoking initiation to increased drinks per week (IVW: β=0.06; 95% CI=0.03 to 0.09; p=9.44×10 −06 ), cannabis use (IVW: OR=1.34; 95% CI=1.24 to 1.44; p=1.95×10 −14 ), and cannabis dependence (IVW: OR=1.68; 95% CI=1.12 to 2.51; p=0.01). We also found evidence of an effect of cannabis use on increased likelihood of smoking initiation (IVW: OR=1.39; 95% CI=1.08 to 1.80; p=0.01). We did not find evidence of an effect of drinks per week on other substance use outcomes, except weak evidence of an effect on cannabis use. We found weak evidence of an effect of opioid dependence on increased drinks per week (IVW: β=0.002; 95% CI=0.0005 to 0.003; p=8.61×10 −03 ). Conclusions Smoking initiation may lead to increased alcohol consumption, cannabis use and dependence. Cannabis use may also lead to smoking initiation, and opioid dependence to alcohol consumption. However, given tobacco and alcohol use typically begin before other drug use, these results may reflect a shared risk factor, or a bidirectional effect for cannabis use. Further research should explore potentially shared risk factors.
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