Negative mood induction in children: An examination across mood, physiological, and cognitive variables.

Experimental mood induction procedures are commonly used in studies of children's emotions, although research on their effectiveness is lacking. Studies that support their effectiveness report sample-level changes in self-reported affect from pre- to post-induction, and a subset of children who do not self-report expected changes in affect (i.e., "nonresponders"). Given children's limited abilities to self-report their emotions, it is critical to know whether these paradigms also shift physiological and social-cognitive indices of emotion. We hypothesized increases in physiological reactivity and accuracy for discerning facial expressions of negative emotions from pre- to post-induction and smaller increases for nonresponders, Children (N = 80; 7- to 12-year-olds) completed a facial emotion recognition task and had an electrocardiogram recorded to index high-frequency heart rate variability (HF-HRV) before and after a mood induction procedure. The mood induction involved watching a 3-min sad film clip while attending to their feelings. In the sample overall, from pre- to post-mood induction, children self-reported significantly sadder affect, displayed significant increases in HF-HRV, and displayed significant increases in accuracy of recognizing facial emotion expressions congruent with the mood induced. One quarter (25%) of the sample did not self-report expected increases in sad affect. Contrary to expectations, responders and nonresponders did not differ in mood-induced changes in physiological reactivity or emotion recognition accuracy. These findings support that mood inductions are efficacious in shifting not only children's self-reported affect but also underlying physiological and social-cognitive processes. Furthermore, they are an effective methodology for research questions related to underlying processes even in self-reported nonresponders.

Neuronal correlates of intensification and acceptance of symptoms during exposure therapy in patients with obsessive-compulsive disorder.

Introduction: Cognitive behaviour therapy with exposure and response prevention is efficient in treating patients with obsessive-compulsive disorder (OCD). Nevertheless, it would be helpful for many patients to complement the therapeutic treatment with acceptance strategies to further increase the therapeutic benefit. The aim of the present study was to examine neurobiological responses to acceptance and intensification strategies during symptom provocation alongside the psychotherapeutic process. Method: A total of 23 patients diagnosed with OCD (subtype: washing/contamination fear) was instructed to utilise either an acceptance strategy (ACS) or an intensification strategy (INS) to cope with their emotional and cognitive reactions to personalised symptom-triggering and neutral pictures. Fourteen patients participated twice: at the beginning [T1] and at the end [T2] of an inpatient multimodal treatment including cognitive behaviour therapy with response prevention to assess functional variations. Results: For the contrast of T1 and T2, ACS showed increased brain activity in the left inferior frontal gyrus (IFG), left caudate body, and posterior cingulate gyrus (PCC). They also showed decreased activity in the left anterior insula. INS showed decreased activation in right lingual gyrus and right caudate body. At T2, ACS showed increased activation compared to INS in the left cerebrum: IFG, caudate nucleus, middle and superior temporal gyrus, and PCC/cuneus. For the comparison of T1 and T2, the ACS revealed increased brain activity in the left IFG, left caudate body, and right inferior parietal lobe. It showed decreased activity in the left anterior insula. The INS revealed decreased activity in right lingual gyrus and right caudate body.The psychometric questionnaires suggested that patients were able to reduce obsession, compulsion, and depression symptoms. Furthermore, patients rated the ACS as more useful for themselves compared with the INS. Conclusion: The increased left IFG activity using ACS (T1 vs. T2) could be interpreted as a better inhibitory top-down process, while the increased PCC response might be due to a better reappraisal strategy after therapy. ACS seems to mobilise neuronal activations under therapy, especially in the left hemisphere. Both strategies showed reductions in emotional networks as a neuronal correlate of therapy success. Overall, ACS may be more efficient than INS, as rated by the patients and as in accordance with neurobiological findings.

Active monitoring of long-eared owl (Asio otus) nestlings reveals widespread exposure to anticoagulant rodenticides across different agricultural landscapes.

The widespread use of anticoagulant rodenticides (ARs) poses a worldwide threat to farmland wildlife. These compounds accumulate in tissues of both target and non-target species, potentially endangering both direct consumers and their predators. However, investigations on ARs in blood of free-ranging predatory birds are rare. Here, the long-eared owl (Asio otus) has been used as a model predator to assess AR exposure in different agricultural landscapes from a Mediterranean semiarid region. A total of 69 owlets from 38 nests were blood-sampled over 2021 and 2022, aiming to detect AR residues and explore factors that determine their exposure, such as land uses. In addition, prothrombin time (PT) test was conducted to assess potential effects of AR contamination. Overall, nearly all the samples (98.6 %) tested positive for at least one compound and multiple ARs were found in most of the individuals (82.6 %). Among the ARs detected, flocoumafen was the most common compound (88.4 % of the samples). AR total concentration (ΣARs) in blood ranged from 0.06 to 34.18 ng mL-1, detecting the highest levels in the most intensively cultivated area. The analysis of owl pellets from 19 breeding territories showed relevant among-site differences in the contribution of rodents and birds into the diet of long-eared owls, supporting its high dietary plasticity and indicating AR presence at multiple trophic levels. Moreover, a positive and significant correlation was found between ΣARs and PT (Rho = 0.547, p < 0.001), which demonstrates the direct effect of ARs on free-living nestlings. Our results provide a preliminary overview of AR exposure in a little-studied owl species inhabiting agricultural and rural landscapes. Despite the low detected levels, these findings indicate widespread exposure -often to multiple compounds- from early life stages, which raises concern and draws attention to an ongoing and unresolved contamination issue.

Executive Function as a Predictor of Pain Perception in Healthy Young Adults.

OBJECTIVE: Pain's impact on executive function is understood and specific cognitive abilities may contribute to coping with pain, though past work is confounded by chronic pain populations. This study aims to understand how executive functioning may predict the experience of pain among healthy adults. It was hypothesized that poorer executive functioning would predict more intense pain perception. METHOD: A total of 172 young adults were recruited for participation. Three aspects of executive functioning (i.e., impulsivity, cognitive flexibility, working memory) were assessed before randomizing participants to varying types and levels of stimulated pain. RESULTS: Results supported the hypothesis that poorer performance on tasks of working memory predicts more intense pain perception. CONCLUSIONS: Findings are counter to past work that has found inhibition may be important for coping, and future research is needed to understand the impact of specific cognitive abilities as well as how this may differ for chronic pain.

Mild Cognitive Impairment Subtype Performance in Comparison to Healthy Older Controls on the NIH Toolbox and Cogstate.

BACKGROUND: Early detection is necessary for the treatment of dementia. Computerized testing has become more widely used in clinical trials; however, it is unclear how sensitive these measures are to early signs of neurodegeneration. We investigated the use of the NIH Toolbox-Cognition (NIHTB-CB) and Cogstate-Brief computerized neuropsychological batteries in the identification of mild cognitive impairment (MCI) versus healthy older adults [healthy control (HC)] and amnestic (aMCI) versus nonamnestic MCI (naMCI). Exploratory analyses include investigating potential racial differences. METHODS: Two hundred six older adults were diagnosed as aMCI (n = 58), naMCI (n = 15), or cognitively healthy (HC; n = 133). RESULTS: The NIH Toolbox-CB subtests of Flanker, Picture Sequence Memory, and Picture Vocabulary significantly differentiated MCI from HC. Further, subtests from both computerized batteries differentiated patients with aMCI from those with naMCI. Although the main effect of race differences was noted on tests and in diagnostic groups was significant, there were no significant race-by-test interactions. CONCLUSIONS: Computer-based subtests vary in their ability to help distinguish MCI subtypes, though these tests provide less expensive and easier-to-administer clinical screeners to help identify patients early who may qualify for more comprehensive evaluations. Further work is needed, however, to refine computerized tests to achieve better precision in distinguishing impairment subtypes.

Signatures of emotional face processing measured by event-related potentials in 7-month-old infants.

The ability to distinguish facial emotions emerges in infancy. Although this ability has been shown to emerge between 5 and 7 months of age, the literature is less clear regarding the extent to which neural correlates of perception and attention play a role in processing of specific emotions. This study's main goal was to examine this question among infants. To this end, we presented angry, fearful, and happy faces to 7-month-old infants (N = 107, 51% female) while recording event-related brain potentials. The perceptual N290 component showed a heightened response for fearful and happy relative to angry faces. Attentional processing, indexed by the P400, showed some evidence of a heightened response for fearful relative to happy and angry faces. We did not observe robust differences by emotion in the negative central (Nc) component, although trends were consistent with previous work suggesting a heightened response to negatively valenced expressions. Results suggest that perceptual (N290) and attentional (P400) processing is sensitive to emotions in faces, but these processes do not provide evidence for a fear-specific bias across components.

Regulation of macrophage IFNγ-stimulated gene expression by the transcriptional coregulator CITED1.

Macrophages serve as a first line of defense against microbial pathogens. Exposure to interferon-γ (IFNγ) increases interferon-stimulated gene (ISG) expression in these cells, resulting in enhanced antimicrobial and proinflammatory activity. Although this response must be sufficiently vigorous to ensure the successful clearance of pathogens, it must also be carefully regulated to prevent tissue damage. This is controlled in part by CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), a transcriptional coregulator that limits ISG expression by inhibiting STAT1 and IRF1. Here, we show that the closely related Cited1 is an ISG, which is expressed in a STAT1-dependent manner, and that IFNγ stimulates the nuclear accumulation of CITED1 protein. In contrast to CITED2, ectopic CITED1 enhanced the expression of a subset of ISGs, including Ccl2, Ifit3b, Isg15 and Oas2. This effect was reversed in a Cited1-null cell line produced by CRISPR-based genomic editing. Collectively, these data show that CITED1 maintains proinflammatory gene expression during periods of prolonged IFNγ exposure and suggest that there is an antagonistic relationship between CITED proteins in the regulation of macrophage inflammatory function. This article has an associated First Person interview with the first author of the paper.

You feel me? A randomized trial of tDCS on pain empathy.

Pain empathy has a number of social benefits, but can be problematic in those who feel the pain of others too much. The current study examined the use of transcranial direct current stimulation (tDCS) as a modifier of pain empathy with the expectation that cathodal stimulation would decrease pain empathy. Anxiety and general empathy were controlled for, given past work demonstrating their impact on pain empathy. Participants were randomized to either active (cathodal; n = 55) or sham tDCS (n = 55) at 2 mA for 20 min while watching videos of painful events and completing a pain empathy simulation questionnaire. Bayesian linear regression analysis indicated no evidence that tDCS condition affected pain empathy. However, there was strong evidence in favor of a positive relationship between anxiety and pain empathy, and extreme evidence between general empathy and pain empathy. The current study examined a montage over the temporoparietal junction though future work should also investigate other areas related to pain empathy such as the anterior cingulate cortex. Results provide evidence of the need for stronger methodological considerations with regard to tDCS including larger sample sizes. Further, the connection between anxiety and pain empathy demonstrates the need for treatments to not only target classic anxiety symptoms, but other factors than may worsen daily functioning.

The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis.

While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbß3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.

Association of Weight at Different Ages and All-Cause Mortality Among Older Adults in the US.

Objective: Assess the association of BMI and BMI change with mortality. Methods: Using data from the Wisconsin Longitudinal Study (WLS) on participants born mainly in 1939 (n=4922), we investigated the associations between various measures of BMI across the life course (age 54 BMI; age 65 BMI; age 72 BMI; lifetime maximum BMI; BMI change between ages 54 and 65; BMI change between ages 65 and 72) and mortality. We also assessed whether these associations are mediated by late life health. Results: BMI at age 54 was more strongly associated with late life mortality than BMI at older ages. The association between BMI change and mortality varied based on the timing of weight change. Health at age 72, particularly self-rated health, diabetes, and physical functioning, mediated the observed associations. Conclusion: Knowing older people's weight at midlife and how their weight has changed may be more important in assessing late life mortality risk than their current weight.

Casos e óbitos por COVID-19 e tabagismo nas capitais e regiões brasileiras: estudo ecológico / COVID-19 cases and deaths and smoking in Brazilian capitals and regions: an ecological study / Casos y muertes por COVID-19 y tabaquismo en las capitales y regiones Brasileñas: estudio ecológico

Objetivo: Analisar a relação entre casos e óbitos por COVID-19 e o percentual de tabagistas nas capitais e regiões do Brasil. Métodos: Realizou-se estudo ecológico nas regiões brasileiras do número de casos e óbitos por COVID-19, de março a dezembro de 2020, e a prevalência de tabagismo em 2019, a partir dos bancos de dados do Painel Coronavírus da Secretaria de Vigilância em Saúde e do Sistema de Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico (VIGITEL ­ 2019). Com informações extraídas em janeiro de 2021, calcularam-se os coeficientes de incidência e mortalidade por COVID-19 por capital brasileira e região, bem como se utilizou a correlação de Pearson para verificar a relação entre as variáveis do estudo. Adotou-se nível de significância de 5%. Resultados: Análises bivariadas mostraram correlações positivas entre tabagistas do sexo feminino e coeficiente de incidência de COVID-19 nas capitais da região do Centro-Oeste (r=0,957; p=0,043), e entre fumantes do sexo masculino e coeficiente de mortalidade de COVID-19 nas capitais do Nordeste (r=0,706; p=0,034). Conclusão: O tabagismo teve impacto na incidência de casos e óbitos por COVID-19 em diversas capitais brasileiras, alertando que o fumo pode ser fator de predisposição e agravamento do estado clínico dos pacientes.

Objective: To analyze the relationship between COVID-19 cases and deaths and the percentage of smokers in the capitals and regions of Brazil. Methods: An ecological study was carried out in the Brazilian regions to assess the number of cases and deaths by COVID-19 from March to December 2020 and the prevalence of smoking in 2019 based on the Coronavirus Panel databases of the Health Surveillance Secretariat and the System for Surveillance of Risk and Protective Factors for Chronic Diseases by Telephone-based Survey (Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico - VIGITEL ­ 2019). With information extracted in January 2021, the COVID-19 incidence and mortality coefficients were calculated by Brazilian capital and region and Pearson's correlation was used to verify the relationship between the study variables. A significance level of 5% was adopted. Results: Bivariate analyses showed positive correlations between female smokers and COVID-19 incidence coefficient in capitals of the Midwest region (r=0.957; p=0.043), and between male smokers and COVID-19 mortality coefficient in the capitals of the Northeast (r=0.706; p=0.034). Conclusion: Smoking had an impact on the incidence of COVID-19 cases and deaths in several Brazilian capitals, which warns that smoking can be a predisposing factor and worsen the clinical status of patients.

Objetivo: Analizar la relación entre casos y muertes por COVID-19 y el porcentaje de tabaquistas en las capitales y regiones del Brasil. Métodos: Fue realizado estudio ecológico en las regiones brasileñas del número de casos y muertes por COVID-19, de marzo a diciembre de 2020, y la prevalencia de tabaquismo en 2019, a partir de bases de datos del Panel Coronavirus de la Secretaria de Vigilancia en Salud y del Sistema de Vigilancia de Factores de Riesgo y Protección para Enfermedades Crónicas por Encuesta Telefónica (VIGITEL ­ 2019). Con informaciones extraídas en enero de 2021, se calcularon los coeficientes de incidencia y mortandad por COVID-19 por capital brasileña y región, también se utilizó la correlación de Pearson para verificar la relación entre las variables del estudio. Fue adoptado nivel de significancia de 5%. Resultados: Los análisis bivariados mostraron correlaciones positivas entre tabaquistas del sexo femenino y coeficiente de incidencia de COVID-19 en las capitales de la región del Centro-Oeste (r=0,957; p=0,043), y entre fumadores del sexo masculino y coeficiente de mortandad de COVID-19 en las capitales del Nordeste (r=0,706; p=0,034). Conclusión: El tabaquismo tuvo impacto en la incidencia de casos y muertes por COVID-19 en diversas capitales brasileñas, advirtiendo que el humo puede ser factor de predisposición y agravamiento del estado clínico de los pacientes.

HD-tDCS as a neurorehabilitation technique for a case of post-anoxic leukoencephalopathy.

Post-anoxic leukoencephalopathy is a rare event that causes global demyelination secondary to anoxic injury. Given the nature and extent of the damage, cognitive and functional deficits are typically chronic even after standard therapies. Here, we describe a novel treatment approach that used high definition transcranial direct-current stimulation (HD-tDCS) with a 62-year-old male who was 5 years post-anoxic leukoencephalopathy secondary to an accidental drug overdose. HD-tDCS was administered over the left lateral prefrontal cortex across 29 daily sessions at 2 mA (20 min/session) in order to address dysexecutive behaviors. Results demonstrated improved delayed memory and trends for improved visuospatial and semantic fluency performance as well as improved insight and daily functioning, all of which returned to baseline by the end of a 10 week no-contact follow up period. Resting state fMRI connectivity results mirrored these changes by showing increased dorsal attention and cingulo-opercular but reduced ventral attention network connectivity after session 29, all of which returned to baseline at follow-up. These findings suggest HD-tDCS may benefit functioning even following serious and pervasive anoxic injury. Findings also suggest the need for continued HD-tDCS for maintenance purposes, though future work is needed to identify optimal dose-response information.

Prosocial Video Game Content, Empathy and Cognitive Ability in a Large Sample of Youth.

Whether playing video games with prosocial content has an influence on empathy among players remains contentious in the research literature. Some evidence suggests playing cooperatively with other gamers enhances empathy, but data have not conclusively linked prosocial content with empathy. Further, mechanisms of this potential relationship are unclear, and little work has been conducted on how cognitive skills, such as fluid reasoning, may mediate this relationship. The current study examines these relationships with a large sample of 3034 youth (27.2% female, Mage = 11.2; range 8-17 at time 1) in Singapore. Data were considered longitudinally across two years in three waves. Ultimately, no evidence emerged that prosocial content in video games had any impact on empathy related outcomes, nor was fluid reasoning a mediator variable for any relationship. However, variables such as social competence and depression and anxiety symptoms were highly related to empathy measures. This evidence adds to the growing debate in the field that video games may not dramatically alter, whether positively or negatively, the development of emotional and behavioral outcomes for youth.

Experiences of Discrimination and Depression Trajectories over Pregnancy.

INTRODUCTION: Research on risk factors for prenatal depression is critical to improve the understanding, prevention, and treatment of women's psychopathology. The current study examines the relation between experiences of racial discrimination and trajectories of depression symptoms over the course of pregnancy. METHOD: Participants completed standardized measures regarding symptoms of depression at four timepoints during pregnancy and reported on experiences of racial discrimination at one timepoint. Latent growth curve modeling was used to examine the relation between discrimination and initial levels (intercept) and trajectories (slope) of depression symptoms over pregnancy. RESULTS: Participants were 129 pregnant individuals recruited from obstetric clinics and oversampled for elevated depression symptoms. Thirty-six percent of the participants were living at or below 200% of the federal poverty line. Fifty-four percent of the sample identified as non-Latinx White, 26% as Latinx, and 13% as non-Latinx Black. An unconditional latent growth curve modeling revealed a negative quadratic trajectory of depression symptoms during pregnancy. When women's report of discrimination was added as a predictor of depression trajectories, discrimination predicted the initial value (intercept) of depression symptoms, but not change over the course of pregnancy (slope). Specifically, higher levels of experiences of discrimination were associated with higher levels of depression symptoms. When sociodemographic and contextual covariates were included in the model, a low family income-to-needs ratio was also related to higher levels of depression symptoms. CONCLUSIONS: These findings provide evidence that women's experiences of racial discrimination and family financial strain are risk factors for prenatal depression, with implications for screening, treatment, and policy.

COVID-19 Mortality At The Neighborhood Level: Racial And Ethnic Inequalities Deepened In Minnesota In 2020.

Substantial racial and ethnic disparities in COVID-19 mortality have been observed at the state and national levels. However, less is known about how race and ethnicity and neighborhood-level disadvantage may intersect to contribute to both COVID-19 mortality and excess mortality during the pandemic. To assess this potential interaction of race and ethnicity with neighborhood disadvantage, we link death certificate data from Minnesota from the period 2017-20 to the Area Deprivation Index to examine hyperlocal disparities in mortality. Black, Indigenous, and people of color (BIPOC) standardized COVID-19 mortality was 459 deaths per 100,000 population in the most disadvantaged neighborhoods compared with 126 per 100,000 in the most advantaged. Total mortality increased in 2020 by 14 percent for non-Hispanic White people and 41 percent for BIPOC. Statistical decompositions show that most of this growth in racial and ethnic disparity is associated with mortality gaps between White people and communities of color within the same levels of area disadvantage, rather than with the fact that White people live in more advantaged areas. Policy interventions to reduce COVID-19 mortality must consider neighborhood context.

Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.

Importance: Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants. Objective: To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing. Design, Setting, and Participants: This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form. Main Outcomes and Measures: Number of pathogenic or likely pathogenic (P/LP) variants identified. Results: This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen. Conclusions and Relevance: Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.

Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation.

The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs. Among all individuals tested, 5.4% had a splicing VUS. If RNA analysis were to contribute supporting evidence to variant interpretation, we estimated that splicing VUSs would be reclassified in 1.7% of individuals in our cohort. This would result in a clinically significant result (i.e., P/LP) in 0.1% of individuals overall because most reclassifications would change VUSs to likely benign. In ClinVar, splicing VUSs were 4.8% of reported variants and could benefit from RNA analysis. In the Genome Aggregation Database (gnomAD), splicing variants comprised 9.4% of variants in protein-coding genes; most were rare, precluding unambiguous classification as benign. Splicing variants were depleted in genes associated with dominant inheritance and haploinsufficiency, although some genes had rare variants at essential splice sites or had common splicing variants that were most likely compatible with normal gene function. Overall, we describe the contribution of splicing variants to hereditary disease, the potential utility of RNA analysis for reclassifying splicing VUSs, and how natural variation may confound clinical interpretation of splicing variants.

Exposure to prenatal maternal distress and infant white matter neurodevelopment.

The prenatal period represents a critical time for brain growth and development. These rapid neurological advances render the fetus susceptible to various influences with life-long implications for mental health. Maternal distress signals are a dominant early life influence, contributing to birth outcomes and risk for offspring psychopathology. This prospective longitudinal study evaluated the association between prenatal maternal distress and infant white matter microstructure. Participants included a racially and socioeconomically diverse sample of 85 mother-infant dyads. Prenatal distress was assessed at 17 and 29 weeks' gestational age (GA). Infant structural data were collected via diffusion tensor imaging at 42-45 weeks' postconceptional age. Findings demonstrated that higher prenatal maternal distress at 29 weeks' GA was associated with increased fractional anisotropy (b = .283, t(64) = 2.319, p = .024) and with increased axial diffusivity (b = .254, t(64) = 2.067, p = .043) within the right anterior cingulate white matter tract. No other significant associations were found with prenatal distress exposure and tract fractional anisotropy or axial diffusivity at 29 weeks' GA, nor earlier in gestation.

College Selectivity and Later-Life Memory Function: Evidence From the Wisconsin Longitudinal Study.

Research has shown a consistent association between college completion and laterlife cognition. We extend this work by examining whether college selectivity-the achievement level required to gain admission to a college-is associated with memory functioning more than 50 years later. We analyze data from 10,317 participants in the 1957-2011 Wisconsin Longitudinal Study to examine the relationship between college selectivity and later-life memory. Models control for childhood, midlife socioeconomic status, and later-life health and adjust for selection bias. Selective college attendance was associated with small benefits in memory at age of 72 even after accounting for socioeconomic status in both childhood and midlife and later-life health. The results of this study suggest that college selectivity may be an important component of the education-cognitive functioning relationship that has modest implications for intracohort differences in later-life cognition.

Tranexamic acid and traumatic brain injuries.

The CRASH-3 trial examined the use of tranexamic acid (TXA) in patients with intracranial bleeding secondary to traumatic brain injury. The trial demonstrated that TXA, an antifibrinolytic medication, reduces mortality in patients with mild to moderate head injuries. However, because of the trial's multiple limitations, TXA cannot yet be called the gold standard.