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Abstract Predicting the blood–brain barrier (BBB) permeability of small-molecule compounds using a novel artificial intelligence platform is necessary for drug discovery. Machine learning and a large language model on artificial intelligence (AI) tools improve the accuracy and shorten the time for new drug development. The primary goal of this research is to develop artificial intelligence (AI) computing models and novel deep learning architectures capable of predicting whether molecules can permeate the human blood–brain barrier (BBB). The in silico (computational) and in vitro (experimental) results were validated by the Natural Products Research Laboratories (NPRL) at China Medical University Hospital (CMUH). The transformer-based MegaMolBART was used as the simplified molecular input line entry system (SMILES) encoder with an XGBoost classifier as an in silico method to check if a molecule could cross through the BBB. We used Morgan or Circular fingerprints to apply the Morgan algorithm to a set of atomic invariants as a baseline encoder also with an XGBoost classifier to compare the results. BBB permeability was assessed in vitro using three-dimensional (3D) human BBB spheroids (human brain microvascular endothelial cells, brain vascular pericytes, and astrocytes). Using multiple BBB databases, the results of the final in silico transformer and XGBoost model achieved an area under the receiver operating characteristic curve of 0.88 on the held-out test dataset. Temozolomide (TMZ) and 21 randomly selected BBB permeable compounds (Pred scores = 1, indicating BBB-permeable) from the NPRL penetrated human BBB spheroid cells. No evidence suggests that ferulic acid or five BBB-impermeable compounds (Pred scores

It is well-established that disrupted autonomic nervous system (ANS) reactivity exacerbates risk for long-term maladjustment following childhood adversity (CA). However, few studies have integrated measures of both the sympathetic (SNS) and parasympathetic (PNS) branches of the ANS, resulting in a unidimensional understanding of ANS functioning as a mechanism of risk. Further, past work has primarily measured CA only at the aggregate level (e.g. “total CA”), necessitating further research to accurately characterize this risk pathway. The present study examines how CA, measured cumulatively and dimensionally (i.e. CA characterized by threat versus deprivation), moderates the association between the SNS and PNS at rest and in response to acute social and nonsocial stressors. Participants included 97 adolescents ages 10-15 (Mage = 12.22, SDage = 1.68) experiencing a range of CA and one accompanying caregiver. Participants completed questionnaires assessing prior CA exposure. SNS and PNS responses were then continuously measured during rest and two stress tasks. First, results indicate a blunting effect of cumulative CA and CA characterized by threat (e.g. physical abuse) on resting SNS activity. Second, in moderation analyses assessing ANS coordination, threat exposure emerged as a significant moderator of the association between SNS and PNS reactivity to social stress. Results suggest that CA characterized by threat may specifically impact physiologic regulation by disrupting the coordination of the two branches of the ANS. Disentangling the independent and concurrent engagement of biological stress response systems following CA remains an important target for research to identify the etiology of aberrant stress reactivity patterns.

The COVID-19 pandemic has brought unprecedented levels of stress to individuals in the U.S. and throughout the world. These high stress levels place individuals at risk for symptoms of anxiety, depression, and other psychiatric disorders. The current study applies a control-based model of coping to contribute to the development of evidence-based interventions to promote resilience. Data were collected online from April 22 through July 12, 2020. Data from two samples of U. S. community adults who completed an online battery of standardized questionnaires were combined (N = 709). More than a quarter reported moderate to severe levels of depression symptoms, and more than one-fifth reported moderate to severe levels of anxiety symptoms; symptom levels were higher among adults who reported more COVID-19-related stress. As hypothesized, multiple regression analyses indicated that greater use of primary and secondary control coping was associated with lower symptom levels, whereas greater use of disengagement coping was associated with higher symptom levels, above and beyond the association of stress with symptoms. Race and ethnicity emerged as important moderators of these associations, indicating that what constitutes adaptive coping varies according to characteristics of the individual. Implications for public health policy and clinical practice are discussed., Author(s): Mary Jo Coiro [sup.1] , Kelly H. Watson [sup.2] , Abby Ciriegio [sup.2] , Maile Jones [sup.2] , Amy R. Wolfson [sup.1] , Jennie Reisman [sup.2] , Bruce E. [...]

Abstract There is an increasing interest in developing artificial intelligence (AI) systems to process and interpret electronic health records (EHRs). Natural language processing (NLP) powered by pretrained language models is the key technology for medical AI systems utilizing clinical narratives. However, there are few clinical language models, the largest of which trained in the clinical domain is comparatively small at 110 million parameters (compared with billions of parameters in the general domain). It is not clear how large clinical language models with billions of parameters can help medical AI systems utilize unstructured EHRs. In this study, we develop from scratch a large clinical language model—GatorTron—using >90 billion words of text (including >82 billion words of de-identified clinical text) and systematically evaluate it on five clinical NLP tasks including clinical concept extraction, medical relation extraction, semantic textual similarity, natural language inference (NLI), and medical question answering (MQA). We examine how (1) scaling up the number of parameters and (2) scaling up the size of the training data could benefit these NLP tasks. GatorTron models scale up the clinical language model from 110 million to 8.9 billion parameters and improve five clinical NLP tasks (e.g., 9.6% and 9.5% improvement in accuracy for NLI and MQA), which can be applied to medical AI systems to improve healthcare delivery. The GatorTron models are publicly available at: https://catalog.ngc.nvidia.com/orgs/nvidia/teams/clara/models/gatortron_og .

Regulatory efforts are hypothesized to affect associations between emotions and physiology (i.e., concordance) to facilitate adaptive functioning. Assessing the role of coping on physiological–emotional concordance during ecologically relevant scenarios can elucidate whether concordance can serve as a biomarker of risk or resilience. The present study assessed self‐reported coping as a moderator of minute‐to‐minute associations between autonomic nervous system activity and emotions (i.e., physiological–emotional concordance) in caregivers (N = 97) and adolescents (N = 97; ages 10–15) during a dyadic conflict task. Models included physiological variables (sympathetic, skin conductance level [SCL]; and parasympathetic, respiratory sinus arrhythmia [RSA]) and their interaction (SCL × RSA) as predictors of emotions, with coping variables as moderators. Caregivers' use of primary control coping (e.g., problem solving and emotional expression) and secondary control coping (e.g., cognitive reappraisal and acceptance) use in response to family stress predicted more positive emotional experiences during the laboratory conflict task. Adolescents' use of secondary control coping moderated the SCL–emotion association, such that increases in momentary SCL were associated with more positive emotion ratings for youth reporting higher secondary control coping. For youth who report more adaptive trait‐level coping skills, momentary changes in SCL may reflect active engagement and attentiveness to facilitate more positive emotional experiences. Findings advance our understanding of the interrelationships between physiological responses and psychological experiences during relevant, interactive scenarios. Autonomic responses are differentially related to affective states depending on the coping strategies that adolescents employ, suggesting that concordance may be associated with intervention targets (i.e., coping skills). Regulatory efforts are hypothesized to affect physiological–emotional associations to facilitate adaptive functioning. Results suggest that autonomic responses differentially relate to emotions based on coping. For adolescents utilizing more secondary control coping skills, momentary skin conductance level changes may reflect active engagement and attentiveness to facilitate more positive emotional experiences. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) presents patients and individuals at risk for HD with significant levels of stress. However, relatively little research has examined how individuals cope with stress related to the disease or the association of specific coping strategies with psychological symptoms. Objective: This study examined the ways in which HD patients and at-risk individuals cope with HD-related stress using a control-based model of coping and the association of coping strategies with symptoms of depression and anxiety. Methods: HD patients (n = 49) and at-risk individuals (n = 76) completed the Responses to Stress Questionnaire – Huntington's Disease Version to assess coping strategies in response to HD-related stress, as well as standardized measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Results: Patients and at-risk individuals reported using comparable levels of primary control coping, secondary control coping, and disengagement coping strategies. In linear regression analyses, only secondary control coping was significantly associated with lower depression (β= –0.62, p < 0.001) and anxiety (β= –0.59, p < 0.001) symptoms in patients and at-risk individuals (β= –0.55, p < 0.001 and β= –0.50, p < 0.001, respectively). Conclusions: Secondary control coping may be beneficial for both HD patients and at-risk individuals. Future research using the control-based model of coping in longitudinal studies with the HD population is needed, and future interventions could test the effects of cognitive reframing and acceptance as coping strategies for families affected by HD. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a neurodegenerative disease that presents families with significant numbers of stressful events. However, relatively little empirical research has characterized the stressors encountered by members of HD-affected families and their correlations with psychological symptoms. Objective: This study examined frequencies of specific stressors in HD patients and at-risk individuals and the correlates of these stressors with demographics, disease characteristics, and symptoms of depression and anxiety. Methods: HD patients (n = 57) and at-risk individuals (n = 81) completed the Responses to Stress Questionnaire –Huntington's Disease Version to assess HD-related stressors. Participants completed measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Results: Patients endorsed a mean number of 5.05 stressors (SD = 2.74) out of the 10-item list. Demographics were not related to total stressors, but disease characteristics were significantly related to specific stressors. At-risk individuals endorsed a mean number of 3.20 stressors (SD = 2.65) out of the 11-item list. Age and sex were significantly related to specific stressors. Total number of stressors was significantly related to depression (β=0.67, p < 0.001) and anxiety symptoms (β=0.58, p < 0.001) in patients and at-risk individuals (β=0.35, p = 0.003 and β=0.32, p = 0.006, respectively). Conclusions: hese findings emphasize the significant burden of stress experienced by HD patients and at-risk individuals. We highlight a need for more specific stress-based measures and psychosocial support interventions for HD-affected families. [ABSTRACT FROM AUTHOR]

Objective: Limited research has characterized cancer‐related stress (CRS) among families of childhood cancer survivors. We examined the prevalence of CRS among survivors and caregivers, as well as its association with health risk perceptions (i.e., prognosis, risk for diminished quality of life) and views of survivor quality of life (QoL). Methods: At five years post‐diagnosis or relapse, survivors (n = 100; Mage = 15.84 years; 89% White), mothers (n = 127), and fathers (n = 59) reported their CRS. Perceived prognosis and risk for diminished QoL were rated on a 0%–100% visual analogue scale, while the PedsQL assessed QoL. Results: CRS was low (M = 1.6–1.8, scale: 1–4); mothers reported greater stress than survivors, p = 0.038, d = 0.25. There was an indirect effect of survivors' perceived prognosis on their QoL through CRS, CI = 0.04 to 0.25, R2 = 0.32. Among mothers, there was an indirect effect of perceived prognosis/risk for diminished QoL on their reports of survivor QoL through CRS, CI = 0.03 to 0.23 and −0.15 to −0.03, R2 = 0.28 and 0.32, respectively. There were no indirect effects among fathers. Conclusions: CRS may be an important, modifiable factor that could improve survivors' QoL. Research is needed to examine how CRS changes over time to assess the utility of interventions among female survivors, mothers, and those with lower prognosis estimates. [ABSTRACT FROM AUTHOR]

Objectives: We identified types of interventions used by bereaved family members and examined associations with demographic and medical factors. Furthermore, we examined associations between distress and intervention use among bereaved families. Methods: Bereaved families (n = 85) were recruited from three children's hospitals 3–12 months after their child died of cancer. One eligible sibling (ages 8–17) per family was randomly selected for participation. During home visits 1-year post-death, parents reported on their own and the sibling's intervention use, helpfulness, and dose (self-help books, support groups, therapy, medication), and distress, defined as internalizing, externalizing, and total problems (Adult Self Report, Child Behavior Checklist). Results: Fifty percent of mothers used medications (n = 43); utilization was low among fathers (17%, n = 9) and siblings (5%, n = 4). Individuals with more total problems were more likely to use medications (mothers: rpb = 0.27; p = 0.02; fathers: rpb = 0.32; p = 0.02; siblings: rpb = 0.26; p = 0.02). Mothers and siblings with more total problems used more services (r = 0.24; p = 0.03 and r = 0.29; p = 0.01, respectively). Among mothers, the overall regression was significant, R 2 = 0.11, F (2, 80) = 4.954, p = 0.01; the deceased child's age at death was significantly associated with total services used (b = 0.052, p = 0.022). Among fathers, the overall regression was significant, R 2 = 0.216, F (3, 49) = 4.492, p = 0.007; race and years of education were significantly associated with total services used (b = 0.750, p = 0.030 and b = 0.154, p = 0.010). Among siblings, the overall regression was significant R 2 = 0.088, F (2, 80) = 3.867, p = 0.025; greater total problems were significantly associated with total services used (b = 0.012, p = 0.007). Significance of results: Although few background factors were related to intervention use, bereaved mothers and siblings may seek services if they have more distress. Healthcare providers should be aware of the types of services that are most often utilized and helpful to bereaved families to connect them with appropriate resources. Future research should investigate other predictors of intervention use and outcomes after the death of a child. [ABSTRACT FROM AUTHOR]