Polygenic Scores Clarify the Relationship Between Mental Health and Gender Diversity.

Background: Gender-diverse individuals are at increased risk for mental health problems, but it is unclear whether this is due to shared environmental or genetic factors. Methods: In two SPARK samples, we tested for associations of 16 polygenic scores (PGSs) with quantitative measures of gender diversity and mental health. In study 1, 639 independent adults (59% autistic) reported their mental health with the Adult Self-Report and their gender diversity with the Gender Self-Report (GSR). The GSR has 2 dimensions: binary (degree of identification with the gender opposite that implied by sex designated at birth) and nonbinary (degree of identification with a gender that is neither male nor female). In study 2 (N = 5165), we used a categorical measure of gender identity. Results: In study 1, neuropsychiatric PGSs were positively associated with Adult Self-Report scores: externalizing was positively associated with the attention-deficit/hyperactivity disorder PGS (ß = 0.10 [0.03-0.17]), and internalizing was positively associated with the PGSs for depression (ß = 0.07 [0-0.14]) and neuroticism (ß = 0.10 [0.03-0.17]). Interestingly, GSR scores were not significantly associated with any neuropsychiatric PGS. However, GSR nonbinary was positively associated with the cognitive performance PGS (ß = 0.11 [0.05-0.18]), with the effect size comparable in magnitude to the associations of the neuropsychiatric PGSs with the Adult Self-Report. Additionally, GSR binary was positively associated with the nonheterosexual sexual behavior PGS (ß = 0.07 [0-0.14]). In study 2, the cognitive performance PGS effect replicated; transgender and nonbinary individuals had higher PGSs (t316 = 4.16). Conclusions: We showed that while gender diversity is phenotypically positively associated with mental health problems, the strongest PGS associations with gender diversity were with the cognitive performance PGS, not the neuropsychiatric PGSs.

This research explores the connection between gender diversity, mental health, and genetic factors. It reveals that gender-diverse individuals often experience more mental health issues. Interestingly, rather than finding evidence linking these mental health challenges to genetic risk factors, the study discovered a replicable positive correlation between gender diversity and genetic markers for higher cognitive performance. This suggests that gender-diverse individuals typically have more of these cognitive performance gene variants. Finally, the study presents some early evidence suggesting that interactions between the environment (e.g., stigma) and genetic risk explain some of the elevated risk to mental health in gender-diverse individuals.

Structure, Function, and Allosteric Regulation of the 20S Proteasome by the 11S/PA28 Family of Proteasome Activators.

The proteasome, a complex multi-catalytic protease machinery, orchestrates the protein degradation essential for maintaining cellular homeostasis, and its dysregulation also underlies many different types of diseases. Its function is regulated by many different mechanisms that encompass various factors such as proteasome activators (PAs), adaptor proteins, and post-translational modifications. This review highlights the unique characteristics of proteasomal regulation through the lens of a distinct family of regulators, the 11S, REGs, or PA26/PA28. This ATP-independent family, spanning from amoebas to mammals, exhibits a common architectural structure; yet, their cellular biology and criteria for protein degradation remain mostly elusive. We delve into their evolution and cellular biology, and contrast their structure and function comprehensively, emphasizing the unanswered questions regarding their regulatory mechanisms and broader roles in proteostasis. A deeper understanding of these processes will illuminate the roles of this regulatory family in biology and disease, thus contributing to the advancement of therapeutic strategies.

The Gender Self-Report: A multidimensional gender characterization tool for gender-diverse and cisgender youth and adults.

Gender identity is a core component of human experience, critical to account for in broad health, development, psychosocial research, and clinical practice. Yet, the psychometric characterization of gender has been impeded due to challenges in modeling the myriad gender self-descriptors, statistical power limitations related to multigroup analyses, and equity-related concerns regarding the accessibility of complex gender terminology. Therefore, this initiative employed an iterative multi-community-driven process to develop the Gender Self-Report (GSR), a multidimensional gender characterization tool, accessible to youth and adults, nonautistic and autistic people, and gender-diverse and cisgender individuals. In Study 1, the GSR was administered to 1,654 individuals, sampled through seven diversified recruitments to be representative across age (10-77 years), gender and sexuality diversity (∼33% each gender diverse, cisgender sexual minority, cisgender heterosexual), and autism status (> 33% autistic). A random half-split subsample was subjected to exploratory factor analytics, followed by confirmatory analytics in the full sample. Two stable factors emerged: Nonbinary Gender Diversity and Female-Male Continuum (FMC). FMC was transformed to Binary Gender Diversity based on designated sex at birth to reduce collinearity with designated sex at birth. Differential item functioning by age and autism status was employed to reduce item-response bias. Factors were internally reliable. Study 2 demonstrated the construct, convergent, and ecological validity of GSR factors. Of the 30 hypothesized validation comparisons, 26 were confirmed. The GSR provides a community-developed gender advocacy tool with 30 self-report items that avoid complex gender-related "insider" language and characterize diverse populations across continuous multidimensional binary and nonbinary gender traits. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The combination of autism and exceptional cognitive ability is associated with suicidal ideation.

Autism with co-occurring exceptional cognitive ability is often accompanied by severe internalizing symptoms and feelings of inadequacy. Whether cognitive ability also translates into greater risk for suicidal ideation is unclear. To investigate this urgent question, we examined two samples of high-ability autistic individuals for factors that were predictive of suicidal ideation. In the first sample (N = 1,074 individuals seen at a clinic specializing in gifted/talented youth), we observed a striking excess of parent-reported suicidal ideation in autistic individuals with IQ ≥ 120 (Odds Ratio = 5.9, p=0.0007). In a separate sample of SPARK participants, we confirmed higher rates of suicidal thoughts compared to non-autistic children from the ABCD cohort (combined N = 16,049, Odds Ratio = 6.8, p<2.2e-16), and further that autistic children with suicidal thoughts had significantly higher cognitive ability (p<2.2e-16) than those without. Elevated polygenic scores (PGS) for cognitive performance were associated with increased suicidal thoughts (N = 1,983, Z=2.16,p=0.03), with PGS for educational attainment trending in the same direction (Z=1.4,p=0.17). Notably, similar results were found in parents of these autistic youth, where higher PGS for educational attainment was associated with increasing thoughts of suicide (N = 736, Z=2.28,p=0.02). Taken together, these results suggest that on a phenotypic and genetic level, increasing cognitive ability is an unexpected risk factor for suicidal ideation in individuals diagnosed with, or at risk for autism.

Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Clinical autism subscales have common genetic liabilities that are heritable, pleiotropic, and generalizable to the general population.

The complexity of autism's phenotypic spectra is well-known, yet most genetic research uses case-control status as the target trait. It is undetermined if autistic symptom domain severity underlying this heterogeneity is heritable and pleiotropic with other psychiatric and behavior traits in the same manner as autism case-control status. In N = 6064 autistic children in the SPARK cohort, we investigated the common genetic properties of twelve subscales from three clinical autism instruments measuring autistic traits: the Social Communication Questionnaire (SCQ), the Repetitive Behavior Scale-Revised (RBS-R), and the Developmental Coordination Disorder Questionnaire (DCDQ). Educational attainment polygenic scores (PGS) were significantly negatively correlated with eleven subscales, while ADHD and major depression PGS were positively correlated with ten and eight of the autism subscales, respectively. Loneliness and neuroticism PGS were also positively correlated with many subscales. Significant PGS by sex interactions were found-surprisingly, the autism case-control PGS was negatively correlated in females and had no strong correlation in males. SNP-heritability of the DCDQ subscales ranged from 0.04 to 0.08, RBS-R subscales ranged from 0.09 to 0.24, and SCQ subscales ranged from 0 to 0.12. GWAS in SPARK followed by estimation of polygenic scores (PGS) in the typically-developing ABCD cohort (N = 5285), revealed significant associations of RBS-R subscale PGS with autism-related behavioral traits, with several subscale PGS more strongly correlated than the autism case-control PGS. Overall, our analyses suggest that the clinical autism subscale traits show variability in SNP-heritability, PGS associations, and significant PGS by sex interactions, underscoring the heterogeneity in autistic traits at a genetic level. Furthermore, of the three instruments investigated, the RBS-R shows the greatest evidence of genetic signal in both (1) autistic samples (greater heritability) and (2) general population samples (strongest PGS associations).

Proteasome activator 28γ (PA28γ) allosterically activates trypsin-like proteolysis by binding to the α-ring of the 20S proteasome.

Proteasome activator 28γ (PA28γ/REGγ) is a member of the 11S family of proteasomal regulators that is constitutively expressed in the nucleus and implicated in various diseases, including certain cancers and systemic lupus erythematosus. Despite years of investigation, how PA28γ functions to stimulate proteasomal protein degradation remains unclear. Alternative hypotheses have been proposed for the molecular mechanism of PA28γ, including the following: (1) substrate selection, (2) allosteric upregulation of the trypsin-like (T-L) site, (3) allosteric inhibition of the chymotrypsin-like (CT-L) and caspase-like (C-L) sites, (4) conversion of the CT-L or C-L sites to new T-L sites, and (5) gate opening alone or in combination with a previous hypothesis. Here, by mechanistically decoupling gating effects from active site effects, we unambiguously demonstrate that WT PA28γ allosterically activates the T-L site. We show PA28γ binding increases the Kcat/Km by 13-fold for T-L peptide substrates while having little-to-no effect on hydrolysis kinetics for CT-L or C-L substrates. Furthermore, mutagenesis and domain swaps of PA28γ reveal that it does not select for T-L peptide substrates through either the substrate entry pore or the distal intrinsically disordered region. We also show that a previously reported point mutation can functionally switch PA28γ from a T-L activating to a gate-opening activator in a mutually exclusive fashion. Finally, using cryogenic electron microscopy, we visualized the PA28γ-proteasome complex at 4.3 Šand confirmed its expected quaternary structure. The results of this study provide unambiguous evidence that PA28γ can function by binding the 20S proteasome to allosterically activate the T-L proteolytic site.

COVID-19 Life Events Spill-Over on Family Functioning and Adolescent Adjustment.

We examined US parent and youth perceptions of how life events, both positive and negative, associated with COVID-19 resulted in changes in family and youth functioning. Families (n = 105, 80% white, 48% male, and 87% mothers) completed surveys during the pandemic (May to July 2020) and 3 years prior (for youth ages M = 10.6, SD = 1.17 and M = 13.6, SD = 1.19). Declines in youth, though not parent, report of open family communication, parental support, and family satisfaction were found. Declines were associated with various domains of pandemic-related stress in parent report, though positive life events served as buffers. Pre-pandemic family functioning also predicted pandemic stress. Spillover effects in turn impacted youth functioning. The current findings shed light on how experiences of the pandemic are linked with family functioning and have implications for how to support families during this time.

Parents' responses to children's ingratitude are associated with children's gratitude and internalizing 3 years later.

The current study is the first to examine how parents respond to children's ingratitude and how such responses impact children's later gratitude and internalizing symptoms. We focused on parental responses in families with children aged 6-9 years when gratitude may be actively forming as part of socioemotional learning and other-oriented behavior. Parent-child dyads (n = 101; 52% female; 81% European American, 9% Asian/Asian American, 5% African American, 4% Latino) completed lab-based assessments at baseline and 3 years later. Results indicate that we can reliably assess and differentiate six parental responses to children's ingratitude (i.e., parental self-blame, distress, punishment, instruction, let-it-be, and give-in) using a novel scenario-based measure. Moreover, parents of older children reported more self-blame, distress, and let-it-be responses than those of younger children. More frequent distress and less frequent punishing and giving-in responses to ingratitude by parents predicted greater parent-reported child gratitude at follow-up whereas more frequent distress and less instruction and giving-in responses predicted greater child-reported gratitude at follow-up. Punishing responses also predicted greater later internalizing symptoms in children, whereas self-blame and distress responses predicted lower subsequent symptoms. Collectively, findings showed that parental responses to children's ingratitude predicted child gratitude and internalizing symptoms 3 years later, even after controlling for other factors comprising the parent ecology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Increased Fecal Bile Acid Excretion in a Significant Subset of Patients with Other Inflammatory Diarrheal Diseases.

BACKGROUND: Increased fecal bile acid excretion (IBAX) occurs in a third of patients with functional diarrhea. AIMS: To assess the prevalence of IBAX in benign inflammatory intestinal and colonic diseases presenting with chronic diarrhea. METHODS: All patients with known inflammatory diseases or resections who underwent 48 h fecal fat and BA testing for chronic diarrhea at a single center were included. Quiescent disease was based on clinical evaluation and serum, endoscopic and imaging studies. IBAX was defined by: > 2337 µmol total BA/48 h; or primary fecal BAs > 10%; or > 4% primary BA plus > 1000 µmol total BA /48 h. Demographics, fecal weight, fecal fat, stool frequency and consistency were collected. Nonparametric statistical analyses were used for group comparisons. RESULTS: Sixty patients had celiac disease (51 quiescent, 9 active), 66 microscopic colitis (MC: 34 collagenous, 32 lymphocytic), 18 ulcerative colitis (UC), and 47 Crohn's disease (CD). Overall, fecal fat, 48 h stool weight, frequency and consistency were not different among subgroups except for inflammatory bowel disease (IBD) based on disease location. Almost 50% patients with celiac disease and MC had IBAX, with a greater proportion with increased primary fecal BA. Among UC patients, rates of IBAX were higher with pancolonic disease. A high proportion of patients with ileal resection or CD affecting ileum or colon had IBAX. IBAX was present even with quiescent inflammation in UC or CD. CONCLUSIONS: A significant subset of patients with MC, quiescent celiac disease and IBD had increased fecal BA excretion, a potential additional therapeutic target for persistent diarrhea.

Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts.

BACKGROUND: Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. METHODS: Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. RESULTS: We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all [Formula: see text]), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text], respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ([Formula: see text], [Formula: see text]), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ([Formula: see text], [Formula: see text]). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ([Formula: see text], [Formula: see text], and [Formula: see text], [Formula: see text] for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: [Formula: see text]; testosterone: [Formula: see text] from 0.1%-ile to 99.9%-ile; SHBG: [Formula: see text] from 0.1%-ile to 99.9%-ile). LIMITATIONS: In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. CONCLUSIONS: These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.

Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort.

This study is the first genetically-informed investigation of avoidant/restrictive food intake disorder (ARFID), an eating disorder that profoundly impacts quality of life for those affected. ARFID is highly comorbid with autism, and we provide the first estimate of its prevalence in a large and phenotypically diverse autism cohort (a subsample of the SPARK study, N = 5,157 probands). This estimate, 21% (at a balanced accuracy 80%), is at the upper end of previous estimates from studies based on clinical samples, suggesting under-diagnosis and potentially lack of awareness among caretakers and clinicians. Although some studies suggest a decrease of disordered eating symptoms by age 6, our estimates indicate that up to 17% (at a balanced accuracy 87%) of parents of autistic children are also at heightened risk for ARFID, suggesting a lifelong risk for disordered eating. We were also able to provide the first estimates of narrow-sense heritability (h2) for ARFID risk, at 0.45. Genome-wide association revealed a single hit near ZSWIM6, a gene previously implicated in neurodevelopmental conditions. While, the current sample was not well-powered for GWAS, effect size and heritability estimates allowed us to project the sample sizes necessary to more robustly discover ARFID-linked loci via common variants. Further genetic analysis using polygenic risk scores (PRS) affirmed genetic links to autism as well as neuroticism and metabolic syndrome.

Coping and Mental Health in Early Adolescence during COVID-19.

The current longitudinal study examines changes in overall mental health symptomatology from before to after the COVID-19 outbreak in youth from the southeastern United States as well as the potential mitigating effects of self-efficacy, optimism, and coping. A sample of 105 parent-child dyads participated in the study (49% boys; 81% European American, 1% Alaska Native/American Indian, 9% Asian/Asian American; 4% Black/African American; 4% Latinx; and 4% other; 87% mothers; 25% high school graduate without college education; 30% degree from 4-year college; 45% graduate or professional school). Parents completed surveys when children were aged 6-9, 8-12, 9-13, and 12-16, with the last assessments occurring between May 13, 2020 and July 1, 2020 during the COVID-19 outbreak. Children also completed online surveys at ages 11-16 assessing self-efficacy, optimism, and coping. Multi-level modeling analyses showed a within-person increase in mental health symptoms from before to after the outbreak after controlling for changes associated with maturation. Symptom increases were mitigated in youth with greater self-efficacy and (to some extent) problem-focused engaged coping, and exacerbated in youth with greater emotion-focused engaged and disengaged coping. Implications of this work include the importance of reinforcing self-efficacy in youth during times of crisis, such as the pandemic, and the potential downsides of emotion-focused coping as an early response to the crisis for youth.

Development and Validation of Early Warning Score Systems for COVID-19 Patients

COVID-19 is a major, urgent, and ongoing threat to global health. Globally more than 24 million have been infected and the disease has claimed more than a million lives as of October 2020. Predicting which patients will need respiratory support is important to guiding individual patient treatment and also to ensuring sufficient resources are available. We evaluated the ability of six common Early Warning Scores (EWS) to identify respiratory deterioration defined as the need for advanced respiratory support (high-flow nasal oxygen, continuous positive airways pressure, non-invasive ventilation, intubation) within a prediction window of 24 hours. We show these scores perform sub-optimally at this specific task. Therefore, we develop an alternative Early Warning Score based on a Gradient Boosting Trees (GBT) algorithm that is able to predict deterioration within the next 24 hours with high AUROC 94% and an accuracy, sensitivity and specificity of 70%, 96%, 70%, respectively. Our GBT model outperformed the best EWS (LDTEWS:NEWS), increasing the AUROC by 14%. Our GBT model makes the prediction based on the current and baseline measures of routinely available vital signs and blood tests.

Community attitudes on genetic research of gender identity, sexual orientation, and mental health.

Sex is an important factor in mental health, and a non-binary view of how variation in sex and gender influence mental health represents a new research frontier that may yield new insights. The recent acceleration of research into sexual orientation, gender identity, and mental health has generally been conducted without sufficient understanding of the opinions of sexual and gender minorities (SGM) toward this research. We surveyed 768 individuals, with an enrichment of LGBTQ+ stakeholders, for their opinions regarding genetic research of SGM and mental health. We found that the key predictors of attitudes toward genetic research specifically on SGM are 1) general attitudes toward genetic and mental health research 2) tolerance of SGM and associated behaviors and 3) age of the participant. Non-heterosexual stakeholder status was significantly associated with increased willingness to participate in genetic research if a biological basis for gender identity were discovered. We also found that heterosexual, cisgender participants with a low tolerance for SGM indicated their SGM views would be positively updated if science showed a biological basis for their behaviors and identities. These findings represent an important first step in understanding and engaging the LGBTQ+ stakeholder community in the context of genetic research.

Artificial intelligence driven assessment of routinely collected healthcare data is an effective screening test for COVID-19 in patients presenting to hospital

BackgroundRapid identification of COVID-19 is important for delivering care expediently and maintaining infection control. The early clinical course of SARS-CoV-2 infection can be difficult to distinguish from other undifferentiated medical presentations to hospital, however for operational reasons SARS-CoV-2 PCR testing can take up to 48 hours. Artificial Intelligence (AI) methods, trained using routinely collected clinical data, may allow front-door screening for COVID-19 within the first hour of presentation. MethodsDemographic, routine and prior clinical data were extracted for 170,510 sequential presentations to emergency and acute medical departments at a large UK teaching hospital group. We applied multivariate logistic regression, random forests and extreme gradient boosted trees to distinguish emergency department (ED) presentations and admissions due to COVID-19 from pre-pandemic controls. We performed stepwise addition of clinical feature sets and assessed performance using stratified 10-fold cross validation. Models were calibrated during training to achieve sensitivities of 70, 80 and 90% for identifying patients with COVID-19. To simulate real-world performance at different stages of an epidemic, we generated test sets with varying prevalences of COVID-19 and assessed predictive values. We prospectively validated our models for all patients presenting or admitted to our hospital group between 20th April and 6th May 2020, comparing model predictions to PCR test results. ResultsPresentation laboratory blood tests, point of care blood gas, and vital signs measurements for 115,394 emergency presentations and 72,310 admissions were analysed. Presentation laboratory tests and vital signs were most predictive of COVID-19 (maximum area under ROC curve [AUROC] 0.904 and 0.823, respectively). Sequential addition of informative variables improved model performance to AUROC 0.942. We developed two early-detection models to identify COVID-19, achieving sensitivities and specificities of 77.4% and 95.7% for our ED model amongst patients attending hospital, and 77.4% and 94.8% for our Admissions model amongst patients being admitted. Both models offer high negative predictive values (>99%) across a range of prevalences (<5%). In a two-week prospective validation period, our ED and Admissions models demonstrated 92.3% and 92.5% accuracy (AUROC 0.881 and 0.871 respectively) for all patients presenting or admitted to a large UK teaching hospital group. A sensitivity analysis to account for uncertainty in negative PCR results improves apparent accuracy (95.1% and 94.1%) and NPV (99.0% and 98.5%). Three laboratory blood markers, Eosinophils, Basophils, and C-Reactive Protein, alongside Calcium measured on blood-gas, and presentation Oxygen requirement were the most informative variables in our models. ConclusionArtificial intelligence techniques perform effectively as a screening test for COVID-19 in emergency departments and hospital admission units. Our models support rapid exclusion of the illness using routinely collected and readily available clinical measurements, guiding streaming of patients during the early phase of admission. BriefThe early clinical course of SARS-CoV-2 infection can be difficult to distinguish from other undifferentiated medical presentations to hospital, however viral specific real-time polymerase chain reaction (RT-PCR) testing has limited sensitivity and can take up to 48 hours for operational reasons. In this study, we develop two early-detection models to identify COVID-19 using routinely collected data typically available within one hour (laboratory tests, blood gas and vital signs) during 115,394 emergency presentations and 72,310 admissions to hospital. Our emergency department (ED) model achieved 77.4% sensitivity and 95.7% specificity (AUROC 0.939) for COVID-19 amongst all patients attending hospital, and Admissions model achieved 77.4% sensitivity and 94.8% specificity (AUROC 0.940) for the subset admitted to hospital. Both models achieve high negative predictive values (>99%) across a range of prevalences (<5%), facilitating rapid exclusion during triage to guide infection control. We prospectively validated our models across all patients presenting and admitted to a large UK teaching hospital group in a two-week test period, achieving 92.3% (n= 3,326, NPV: 97.6%, AUROC: 0.881) and 92.5% accuracy (n=1,715, NPV: 97.7%, AUROC: 0.871) in comparison to RT-PCR results. Sensitivity analyses to account for uncertainty in negative PCR results improves apparent accuracy (95.1% and 94.1%) and NPV (99.0% and 98.5%). Our artificial intelligence models perform effectively as a screening test for COVID-19 in emergency departments and hospital admission units, offering high impact in settings where rapid testing is unavailable.

Gratitude Conversations: An Experimental Trial of an Online Parenting Tool.

Gratitude is associated with a host of positive outcomes; yet, little is understood about the ways in which parents may foster gratitude in their children. The current study allows for the examination of one possible mechanism, namely parent-child conversations, that may be used to encourage gratitude in children. Using a rigorous experimental design, we tested whether an online program that was designed to enrich parents' skills in having conversations about gratitude with their children was effective in changing parents' socialization behaviors and children's gratitude. Results demonstrated that parents can successfully utilize an online program to enhance their gratitude-related communication. This training permeates other aspects of how parents socialize gratitude in children and positively impacts children's gratitude moments. Implications for program development and understanding the role of parents in the development of children's gratitude are discussed.

A comparative analysis of genetic hearing loss phenotypes in European/American and Japanese populations.

We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (KCNQ4, TECTA, WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in KCNQ4; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for TECTA and WFS1. Identifying the drivers of ethnic differences will refine our understanding of phenotype-genotype relationships and the biology of hearing and deafness.

Factors Influencing Presence or Absence of Laterality During Pharyngeal Bolus Clearance.

PURPOSE: The aim of this study was to identify factors influencing pharyngeal laterality of bolus clearance through the pharyngoesophageal segment. METHOD: Two swallowing trials (5-ml nectar-thickened liquid and 5-ml pudding) administered in the anteroposterior viewing plane during videofluoroscopy were extracted from a normative database of 195 healthy adult participants. Each swallow was determined as either having no laterality, right dominance/right side only, or left dominance/left side only. Descriptive measures were performed on all data variables. Chi-square tests were performed to determine the relationship between laterality and several factors, including age category, sex, race, and swallow task. RESULTS: The majority of swallows demonstrated no laterality. No significant associations were observed between laterality and the following factors: age category, race, or swallow task. Significant differences in laterality were observed between males and females, with females more likely to demonstrate no laterality. CONCLUSIONS: Majority of swallows in the current healthy sample demonstrated no laterality preference. If present, males were more likely to demonstrate laterality compared to females. Laterality observed during videofluoroscopy does not imply impairment if there are no other factors present influencing bolus flow into the esophagus (e.g., mass). Study findings further define typical swallowing behaviors, allowing clinicians to better delineate normal variations from true impairment. Further research should include a larger sample of individuals aged 80 years and older, as well as additional swallowing tasks, to further investigate patient- and bolus-related factors on laterality.