Fluctuations and individual differences in empathy interact with stress to predict mental health, parenting, and relationship outcomes.

Introduction: Empathy is a complex, multifaceted ability allowing for the most basic forms of social communication and plays a prominent role in multiple aspects of everyday lives. In this intensive longitudinal study, we assessed how empathy interacts with stress to predict central domains of psychosocial functioning: mental health, romantic relationships, and parenting. Methods: Fluctuations and individual differences in empathy were assessed across eight time points, where participants from the general population (N = 566) self-reported their empathy, stress, depressive symptoms, romantic satisfaction, and parental functioning. Results: Both trait and state aspects of empathy were associated with all psychosocial outcomes, with state empathy showing a stronger effect. Additionally, empathy components interacted with stress-emotional empathy better-predicted outcomes under high stress, while cognitive empathy under low stress. Discussion: Our findings advance the theoretical understanding of empathy, emphasizing the effects of state-dependent empathy fluctuations on our everyday mental and social lives.

Empathic disequilibrium as a new framework for understanding individual differences in psychopathology.

Introduction: Empathy is part of basic social cognition and is central to everyday interactions. Indeed, emotional and cognitive empathy deficits are related to various psychopathologies, yet the links reported have been inconsistent. Thus, the mechanism underlying these inconsistent links is poorly understood. At least a partial answer may lie in that the dependency between cognitive and emotional empathy has been overlooked. Here, we examined the (dis)equilibrium between emotional and cognitive empathy and how it relates to individual differences in clinical traits. We further examined a possible mediator of these links-emotional reactivity. Methods: Participants (N = 425) from the general population reported on their empathy, emotional reactivity, autistic traits, psychopathic tendencies, and symptoms of depression and anxiety. Results: Beyond empathy, both extremes of empathic disequilibrium were associated with various features of clinical conditions; Higher emotional relative to cognitive empathy was related to the social domain of autism and anxiety, while higher cognitive relative to emotional empathy was related to the non-social domain of autism, depression symptoms, and psychopathic tendencies. The associations with autistic traits, anxiety, and psychopathic tendencies were mediated by emotional reactivity. Discussion: Our findings suggest a new framework for understanding how individual variability in empathy is expressed in various psychopathologies.

Data-driven dissection of the fever effect in autism spectrum disorder.

Some individuals with autism spectrum disorder (ASD) demonstrate marked behavioral improvements during febrile episodes, in what is perhaps the only present-day means of modulating the core ASD phenotype. Understanding the nature of this so-called fever effect is therefore essential for leveraging this natural temporary relief of symptoms to a sustained efficacious intervention. Toward this goal, we used machine learning to analyze the rich clinical data of the Simons Simplex Collection, in which one out of every six children with ASD was reported to improve during febrile episodes, across multiple ASD domains. Reported behavioral improvements during febrile episodes were associated with maternal infection in pregnancy (OR = 1.7, 95% CI = [1.42, 2.03], P = 4.24 × 10-4 ) and gastrointestinal (GI) dysfunction (OR = 1.46, 95% CI = [1.15, 1.81], P = 1.94 × 10-3 ). Family members of children reported to improve when febrile have an increased prevalence of autoimmune disorders (OR = 1.43, 95% CI = [1.23, 1.67], P = 3.0 × 10-6 ), language disorders (OR = 1.63, 95% CI = [1.29, 2.04], P = 2.5 × 10-5 ), and neuropsychiatric disorders (OR = 1.59, 95% CI = [1.34, 1.89], P < 1 × 10-6 ). Since both GI abnormalities and maternal immune activation have been linked to ASD via proinflammatory cytokines, these results might suggest a possible involvement of immune dysregulation in the fever effect, consistent with findings in mouse models. This work advances our understanding of the fever-responsive ASD subtype and motivates the future studies to directly test the link between proinflammatory cytokines and behavioral modifications in individuals with ASD.

The IL-10 receptor inhibits cell extrinsic signals necessary for STAT1-dependent macrophage accumulation during colitis.

The loss of IL-10R function leads to severe early onset colitis and, in murine models, is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed, STAT1-/- mice exhibit defects in colonic macrophage accumulation after Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNγR, an inducer of STAT1 activation. Radiation chimeras demonstrated that reduced accumulation of STAT1-deficient macrophages was based on a cell-intrinsic defect. Unexpectedly, mixed radiation chimeras generated with both wild-type and IL-10R-deficient bone marrow indicated that rather than directly interfering with STAT1 function, IL-10R inhibits the generation of cell extrinsic signals that promote the accumulation of immature macrophages. These results define the essential mechanisms controlling the inflammatory macrophage accumulation in inflammatory bowel diseases.

Web and social media searches highlight menstrual irregularities as a global concern in COVID-19 vaccinations.

Delineation of public concerns that prevent vaccine compliance is a major step in generating assurances and enhancing the success of COVID-19 prevention programs. We therefore sought to identify public concerns associated with COVID-19 vaccines, as reflected by web and social media searches, with a focus on menstrual irregularities. We used trajectory analyses of web and social media search data in combination with global COVID-19 data to reveal time-dependent correlations between vaccination rates and the relative volume of vaccine and period related searches. A surge of period and vaccine related Google searches followed the introduction of Covid vaccines around the world, and the commencement of vaccination programs in English speaking countries and across the United States. The relative volume of searches such as "Covid vaccine menstrual irregularities", "Covid vaccine menstrual period", "Pfizer vaccine menstruation", and "Moderna vaccine menstruation" was each significantly correlated with vaccination rates (Spearman r = 0.42-0.88, P = 4.33 × 10-34-1.55 × 10-5), and significantly different before and after the introduction of Covid vaccines (Mann-Whitney P = 2.00 × 10-21-7.10 × 10-20). TikTok users were more engaged in period problems in 2021 than ever before. International, national, and state-level correlations between COVID-19 vaccinations and online activity demonstrate a global major concern of vaccine-related menstrual irregularities. Whether it is a potential side effect or an unfounded worry, monitoring of web and social media activity could reveal the public perception of COVID-19 prevention efforts, which could then be directly addressed and translated into insightful public health strategies.

Reexamining empathy in autism: Empathic disequilibrium as a novel predictor of autism diagnosis and autistic traits.

A large body of research showed that autistic people have intact emotional (affective) empathy alongside reduced cognitive empathy. However, there are mixed findings and these call for a more subtle understanding of empathy in autism. Empathic disequilibrium refers to the imbalance between emotional and cognitive empathy and is associated with a higher number of autistic traits in the typical population. Here we examined whether empathic disequilibrium predicts both the number of autistic traits and autism diagnosis. In a large sample of autistic (N = 1905) and typical individuals (N = 3009), we examined empathic disequilibrium and empathy as predictors of autistic traits and autism diagnosis, using a polynomial regression with response surface analysis. Empathy and autistic traits were measured using validated self-report questionnaires. Both empathic disequilibrium and empathy predicted linearly and non-linearly autism diagnosis and autistic traits. Specifically, a tendency towards higher emotional than cognitive empathy (empathic disequilibrium towards emotional empathy) predicted both autism diagnosis and the social domain of autistic traits, while higher cognitive than emotional empathy was associated with the non-social domain of autism. Empathic disequilibrium was also more prominent in autistic females. This study provides evidence that beyond empathy as was measured thus far, empathic disequilibrium offers a novel analytical approach for examining the role of empathy. Empathic disequilibrium allows for a more nuanced understanding of the links between empathy and autism. LAY SUMMARY: Many autistic individuals report feelings of excessive empathy, yet their experience is not reflected by most of the current literature, typically suggesting that autism is characterized by intact emotional and reduced cognitive empathy. To fill this gap, we looked at both ends of the imbalance between these components, termed empathic disequilibrium. We show that, like empathy, empathic disequilibrium is related to autism diagnosis and traits, and thus may provide a more nuanced understanding of empathy and its link with autism.

Clinical Phenotypes and Outcomes in Monogenic Versus Non-monogenic Very Early Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Over 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES]. METHODS: Patients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. RESULTS: This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. CONCLUSIONS: Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.

Human mitochondrial RNA modifications associate with tissue-specific changes in gene expression, and are affected by sunlight and UV exposure.

RNA-DNA differences (RDD) have previously been identified in the human mitochondrial RNA (mt-RNA) transcripts, yet their functional impact is poorly understood. By analyzing 4928 RNA-seq samples from 23 body sites, we found that mtDNA gene expression negatively correlated with the levels of both m1A 947 16 S rRNA modification (mtDNA position 2617) and the m1A 1812 ND5 mRNA modification (mtDNA position 13,710) in 15 and 14 body sites, respectively. Such correlation was not evident in all tested brain tissues, thus suggesting a tissue-specific impact of these modifications on mtDNA gene expression. To assess the response of the tested modifications to environmental cues, we analyzed pairs of skin samples that were either exposed to the sun or not. We found that the correlations of mtDNA gene expression with both mt-RNA modifications were compromised upon sun exposure. As a first step to explore the underlying mechanism, we analyzed RNA-seq data from keratinocytes that were exposed to increasing doses of UV irradiation. Similar to sun exposure, we found a significant decrease in mtDNA gene expression upon increase in UV dosage. In contrast, there was a significant increase in the m1A 947 16 S rRNA modification levels upon elevation in UV dose. Finally, we identified candidate modulators of such responses. Taken together, our results indicate that mt-RNA modifications functionally correlate with mtDNA gene expression, and responds to environmental cues, hence supporting their physiological importance.

Multimodal bioinformatic analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles.

BACKGROUND: Loss of tectonin ß-propeller repeat-containing 2 (TECPR2) function has been implicated in an array of neurodegenerative disorders, yet its physiological function remains largely unknown. Understanding TECPR2 function is essential for developing much needed precision therapeutics for TECPR2-related diseases. METHODS: We leveraged considerable amounts of functional data to obtain a comprehensive perspective of the role of TECPR2 in health and disease. We integrated expression patterns, population variation, phylogenetic profiling, protein-protein interactions and regulatory network data for a minimally biased multimodal functional analysis. Genes and proteins linked to TECPR2 via multiple lines of evidence were subject to functional enrichment analyses to identify molecular mechanisms involving TECPR2. RESULTS: TECPR2 was found to be part of a tight neurodevelopmental gene expression programme that includes KIF1A, ATXN1, TOM1L2 and FA2H, all implicated in neurological diseases. Functional enrichment analyses of TECPR2-related genes converged on a role in late autophagy and ribosomal processes. Large-scale population variation data demonstrated that this role is non-redundant. CONCLUSIONS: TECPR2 might serve as an indicator for the energy balance between protein synthesis and autophagy, and a marker for diseases associated with their imbalance, such as Alzheimer's disease and Huntington's disease. Specifically, we speculate that TECPR2 plays an important role as a proteostasis regulator during synaptogenesis, highlighting its importance in developing neurons. By advancing our understanding of TECPR2 function, this work provides an essential stepping stone towards the development of precision diagnostics and targeted treatment options for TECPR2-related disorders.

The Effect of Antibiotic Treatment of Early Childhood Shigellosis on Long-Term Prevalence of Attention Deficit/Hyperactivity Disorder.

It has recently been shown that children with early shigellosis are at increased risk of attention deficit/hyperactivity disorder (ADHD). This study aimed to evaluate the association between antibiotic treatment of shigellosis with long-term ADHD rates. A retrospective cohort study was conducted that included all the Leumit Health Services (LHS) enrollees aged 5-18 years between 2000-2018 with a documented Shigella-positive gastroenteritis before the age of 3 years. Of the 5176 children who were positive for Shigella gastroenteritis before the age of 3 years, 972 (18.8%) were treated with antibiotics early (<5 days), 250 (4.8%) were treated late (≥5 days), and 3954 children (76.4%) were not prescribed antibiotics. Late antibiotic treatment was associated with significantly increased rates of ADHD (adjusted OR = 1.61; 95% CI, 1.1-2.3). Early treatment with antibiotics was not associated with increased ADHD rates (adjusted OR = 1.02; 95% CI, 0.8-1.3). In conclusion, late antibiotic treatment of early childhood shigellosis was associated with increased rates of ADHD.