Neurophysiological evidence of motor preparation in inner speech and the effect of content predictability.

Self-generated overt actions are preceded by a slow negativity as measured by electroencephalogram, which has been associated with motor preparation. Recent studies have shown that this neural activity is modulated by the predictability of action outcomes. It is unclear whether inner speech is also preceded by a motor-related negativity and influenced by the same factor. In three experiments, we compared the contingent negative variation elicited in a cue paradigm in an active vs. passive condition. In Experiment 1, participants produced an inner phoneme, at which an audible phoneme whose identity was unpredictable was concurrently presented. We found that while passive listening elicited a late contingent negative variation, inner speech production generated a more negative late contingent negative variation. In Experiment 2, the same pattern of results was found when participants were instead asked to overtly vocalize the phoneme. In Experiment 3, the identity of the audible phoneme was made predictable by establishing probabilistic expectations. We observed a smaller late contingent negative variation in the inner speech condition when the identity of the audible phoneme was predictable, but not in the passive condition. These findings suggest that inner speech is associated with motor preparatory activity that may also represent the predicted action-effects of covert actions.

Pubertal progression and its relationship to psychological and behavioral outcomes among adolescent boys.

Variations in pubertal timing and tempo have relevance to psychosocial development. Accounting for pubertal timing, tempo, and psychosocial development simultaneously in a model remains challenging. This study aimed to document the typology of pubertal development in a cohort of Taiwanese adolescent boys and then to examine how the associations between psychosocial variables across time vary by the patterns of pubertal development. A group of adolescent boys (n = 1,368) reported pubertal signs and psychosocial variables for 3 years since seventh grade. The growth mixture model revealed three major classes of pubertal transition: average pubertal growth, late-onset with rapid catch-up, and late-onset with slow catch-up. In a cross-lagged panel model, the multigroup analysis found the regression coefficients mostly invariant across all three classes, except those between deviant behavior and subsequent changes in depressive symptoms that were significantly positive only in the late-onset with slow catch-up group. Adolescent boys in this group were estimated to have the highest marginal level of depressive symptoms and deviant behavior in ninth grade among the three classes. Our study highlights the heterogeneity in boys' pubertal development and the role of the pubertal development pattern in their psychosocial development.

Moment-to-moment dynamics between auditory verbal hallucinations and negative affect and the role of beliefs about voices.

BACKGROUND: Negative affect (NA) has been suggested to be both an antecedent and a consequence of auditory verbal hallucinations (AVH). Furthermore, negative appraisals of voices have been theorized to contribute to the maintenance of AVH. Using the experience sampling method (ESM), this study examined the bi-directional relationship between NA and AVH, and the moderating effect of negative beliefs about voices. METHODS: Forty-seven patients diagnosed with schizophrenia spectrum disorders with frequent AVH completed a clinical interview, followed by ESM for 10 times a day over 6 days on an electronic device. Time-lagged analyses were conducted using multilevel regression modeling. Beliefs about voices were assessed at baseline. RESULTS: A total of 1654 data points were obtained. NA predicted an increase in AVH in the subsequent moment, and AVH predicted an increase in NA in the subsequent moment. Baseline beliefs about voices as malevolent and omnipotent significantly strengthened the association between NA and AVH within the same moment. In addition, the belief of omnipotence was associated with more hallucinatory experiences in the moment following NA. However, beliefs about voices were not associated directly with momentary levels of NA or AVH. CONCLUSIONS: Experiences of NA and AVH drove each other, forming a feedback loop that maintained the voices. The associations between NA and AVH, either within the same moment or across moments, were exacerbated by negative beliefs about voices. Our results suggest that affect-improving interventions may stop the feedback loop and reduce AVH frequency.

Moment-to-moment affective dynamics in schizophrenia and bipolar disorder.

BACKGROUND: Affective disturbances in schizophrenia and bipolar disorder may represent a transdiagnostic etiological process as well as a target of intervention. Hypotheses on similarities and differences in various parameters of affective dynamics (intensity, successive/acute changes, variability, and reactivity to stress) between the two disorders were tested. METHODS: Experience sampling method was used to assess dynamics of positive and negative affect, 10 times a day over 6 consecutive days. Patients with schizophrenia (n = 46) and patients with bipolar disorder (n = 46) were compared against age-matched healthy controls (n = 46). RESULTS: Compared to controls, the schizophrenia group had significantly more intense momentary negative affect, a lower likelihood of acute changes in positive affect, and reduced within-person variability of positive affect. The bipolar disorder group was not significantly different from either the schizophrenia group or the healthy control group on any affect indexes. Within the schizophrenia group, level of depression was associated with weaker reactivity to stress for negative affect. Within the bipolar disorder group, level of depression was associated with lower positive affect. CONCLUSIONS: Patients with schizophrenia endured a more stable and negative affective state than healthy individuals, and were less likely to be uplifted in response to happenings in daily life. There is little evidence that these affective constructs characterize the psychopathology of bipolar disorder; such investigation may have been limited by the heterogeneity within group. Our findings supported the clinical importance of assessing multiple facets of affective dynamics beyond the mean levels of intensity.

Reference compounds for characterizing cellular injury in high-content cellular morphology assays.

Robust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. Here we generate cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A diversity of compounds that cause cellular damage produces bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.

An approach for collaborative development of a federated biomedical knowledge graph-based question-answering system: Question-of-the-Month challenges.

Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph-based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly "Question-of-the-Month (QotM) Challenge" series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.

Longitudinal bifactor modeling of anxiety, depression and schizotypy - The role of rumination as a shared mechanism.

A bifactor model with a general (p) factor reflecting shared variance and specific factors reflecting additional variance in individual symptoms has been introduced to explain common co-occurrence among anxiety, depression and schizotypy. However, longitudinal evidence is lacking and the validity of bifactor modeling is debatable. The current study aimed to examine the presence of the p factor together with specific factors in accounting for relationships between anxiety, depression and schizotypy both cross-sectionally and longitudinally, and to investigate the relationship between these factors and rumination. A validated sample of university students were surveyed on levels of anxiety, depression, schizotypy and rumination at baseline (N = 2291), one year (N = 1833) and two years (N = 1656). Models were estimated using exploratory structural equation modeling (ESEM) and compared at each time point. Longitudinal invariance of the best-fitting model was examined and all potential within- and between-factor stability pathways were tested in an SEM framework. A bifactor model with a p factor and four specific factors (representing residual information of composite anxiety and depression, cognitive-perceptual, interpersonal and disorganized schizotypy respectively) consistently outperformed a correlated-factors model. The bifactor structure appeared longitudinally stable. Within-factor stabilities were moderate, and between-factor pathways reflected a few significant interactions, mostly involving the p factor. Rumination was independently associated with p and four specific factors at each time point. Therefore, there is a p factor accounting for concurrent and sequential co-occurrence of anxiety, depression and schizotypy. Rumination explained partly the p and specific factors. Transdiagnostic interventions should target rumination.

A randomised controlled trial of metacognitive training for psychosis, depression, and belief flexibility.

BACKGROUND: Metacognitive training (MCT) has been shown to be effective in reducing psychotic symptoms, including delusions. However, less is known on whether MCT, or its specific modules, are effective in ameliorating reasoning biases e.g. belief flexibility. As inflexibility in appraisal has been associated with psychosis and major depressive disorder (MDD), this study examined the efficacy of a 4-session MCT on delusions, depression, and belief flexibility, in two clinical groups (Psychosis and Depression). METHODS: This study adopted a single-blind randomised controlled design, with patients with schizophrenia spectrum disorders (and delusions) and patients with MDD being randomised, respectively, into the MCT condition or a treatment-as-usual (TAU) condition. The MCT intervention consisted of specific modules targeting belief flexibility. Participants were assessed before and after treatment, and at 1- and 6-month follow-ups. RESULTS: Among the 113 participants, 27 patients with psychosis and 29 patients with MDD attended MCT. There were significant improvements in psychotic symptoms, especially delusions, for the Psychosis group, and in depressive symptoms for the MDD group. Symptom improvements following MCT were of large effect sizes, were significantly greater than TAU, and persisted at 6-month. Belief flexibility also improved in both groups, although changes were smaller in size and were not significantly greater than TAU. LIMITATIONS: An active control condition was not included. CONCLUSIONS: This study demonstrated large and stable symptom reductions in delusions and depression, and smaller (yet stable) improvement in belief flexibility across groups, following a 4-session MCT, carrying implications for transdiagnostic process-based interventions and their mechanisms of change.

The SARS (Severe Acute Respiratory Syndrome) pandemic in Hong Kong: effects on the subjective wellbeing of elderly and younger people.

OBJECTIVES: This study examined the impact of the Severe Acute Respiratory Syndrome (SARS) outbreak in Hong Kong in 2003, on the subjective wellbeing (SWB) of elderly people and a younger comparative sample. The Personal Wellbeing Index (PWI), a contemporary instrument employed to measure SWB, was also examined for its psychometric performance to substantiate its use. METHOD: A total of 302 older adults (age 65 + years) and 158 younger adults (age 35-46 years) were recruited from different districts. Data were collected by individual face-to-face interviews. RESULT: While elderly people living in severely infected districts showed significantly lower levels of SWB, these levels and those of the younger sample were found to remain within the normative range. A major mitigating factor was an increased sense of community-connectedness. Other characteristics linked to low wellbeing levels included chronic illness, female gender, low education and unemployment. The living districts, characterized by varying extents of infection, had stronger associations with SWB than participants' age. The PWI demonstrated good psychometric performance and also more robustness with elderly people, including its sensitivity to the sense of population threat. CONCLUSION: Psychological resilience was identified among both the elderly and younger age-groups in Hong Kong during the SARS pandemic. The PWI is verified as a suitable instrument for SWB measurements.

Transitions of Developmental Trajectories of Depressive Symptoms Between Junior and Senior High School Among Youths in Taiwan: Linkages to Symptoms in Young Adulthood.

We investigated the heterogeneous developmental trajectories of depressive symptoms in junior and senior high school, the transitions to different trajectories after entering senior high school, and the linkages to the development of depressive symptoms in early adulthood among Taiwanese adolescents. An eight-wave longitudinal data set was analyzed, including 2687 Taiwanese adolescents (51.2% boys, M age = 14.3 at first wave). Using a manual three-step latent transition growth mixture model, we found that a three-class solution fit the data for both junior high school (termed high-improving, cumulative, and JS-low-stable) and senior high school period (termed heightening, moderate-stable, and HS-low-stable). The depressive symptoms of most individuals maintained at a low level (i.e., low-stable) from adolescence to early adulthood; however, nearly a quarter of the adolescents reported depressive symptoms that were moderately or highly severe in senior high school and beyond. More than 30% of the participants experienced transitioning into a different developmental trajectory between junior and senior high school. When perceiving a higher level of paternal behavioral control, adolescents categorized in the high-improving class in junior high school would have a higher chance to transition to the moderate-stable class than to HS-low-stable class in senior high school. Adolescent boys and girls did not differ in the probability of transitioning between trajectories across junior and senior high school. However, a clear and consistent pattern of symptoms between late adolescence and early adulthood was not observed. These results help elucidate the heterogeneity and fluidity associated with the development of depressive symptoms between early adolescence and early adulthood in light of school transition among youths in Taiwan.

Association of parental warmth and harsh discipline with developmental trajectories of depressive symptoms among adolescents in Chinese society.

This article examines the relationship between parenting styles and the development of depressive symptoms among adolescents. We analyzed a nationally representative longitudinal data set of adolescents aged 12 to 14 in Taiwan. Results from growth mixture modeling revealed a nonlinear increase in the intensity of depressive symptoms between early and middle adolescence. More pronounced depressive symptoms in earlier years were also shown to be associated with more rapid development of similar symptoms later in adolescence. Perceived parenting styles, as manifest in parental warmth and harsh discipline, were categorized into 4 latent heterogeneous classes: attentive, reserved, austere, and conflicting. Adolescents living under austere parenting tend to report the most pronounced depressive symptoms from early to middle adolescence; however, the development of symptoms in this group was the slowest. We also discuss the role of harsh parenting in Chinese culture, as it pertains to the roles traditionally assumed by the father and mother.

Prospective enterprise-level molecular genotyping of a cohort of cancer patients.

Ongoing cancer genome characterization studies continue to elucidate the spectrum of genomic abnormalities that drive many cancers, and in the clinical arena assessment of the driver genetic alterations in patients is playing an increasingly important diagnostic and/or prognostic role for many cancer types. However, the landscape of genomic abnormalities is still unknown for less common cancers, and the influence of specific genotypes on clinical behavior is often still unclear. To address some of these deficiencies, we developed Profile, a prospective cohort study to obtain genomic information on all patients at a large tertiary care medical center for cancer-related care. We enrolled patients with any cancer diagnosis, and, for each patient (unselected for cancer site or type) we applied mass spectrometric genotyping (OncoMap) of 471 common recurrent mutations in 41 cancer-related genes. We report the results of the first 5000 patients, of which 26% exhibited potentially actionable somatic mutations. These observations indicate the utility of genotyping in advancing the field of precision oncology.

Determining the site of origin of mucinous adenocarcinoma: an immunohistochemical study of 175 cases.

Mucinous adenocarcinomas (MAs) of various origins may have a similar histologic appearance and frequently metastasize to distant sites, which often causes diagnostic problems in surgical pathology practice. The immunohistochemical profiles of MAs of various origins have not been well studied. We investigated the expression of 10 immunohistochemical markers (CK7, CK20, CDX-2, ß-catenin, MUC-1, MUC-2, MUC-6, ER, WT-1, and PAX-8) in 175 cases of MA, including 69 cases from the lower gastrointestinal (GI) tract, 41 from the upper GI tract, 27 from gynecologic organs, 4 from the urinary bladder, 18 from the breast, and 16 from the lung. We found that lower GI MAs (colon, rectum, and anus) frequently expressed CDX-2 (42 of 42, 100%; 33 of 42 with homogenous positivity, 79%), MUC-2 (42 of 42; 100%), CK20 (41 of 42; 98%), and ß-catenin (nuclear) (27 of 42; 64%) and rarely expressed MUC-6 (2 of 42; 5%) and CK7 (8 of 42; 19%). Most of the CK7-positive cases were from the rectum and anus (7 of 8; 88%). The expression of these markers in appendiceal MAs was similar to that of low GI tract MAs, except for a lower percentage of homogenous CDX-2 (3 of 27; 11%) and nuclear ß-catenin (3 of 27; 11%) expression. Unlike their lower GI tract counterparts, the upper GI tract MAs (ampulla, pancreas/biliary tree, and stomach/esophagus) frequently expressed CK7 (38 of 41; 93%) and MUC-6 (31 of 41; 76%) and were rarely homogenously positive for CDX-2 (4 of 41; 10%) and nuclear positive for ß-catenin (8 of 41; 19%). Breast MAs were frequently positive for CK7 (18 of 18; 100%), MUC-1 (18 of 18; 100%), MUC-2 (18 of 18; 100%), ER (16 of 18; 89%), MUC-6 (9 of 18; 50%), and WT-1 (9 of 18; 50%). Lung MAs were frequently positive for CK7 (16 of 16; 100%) and MUC-1 (15 of 16; 94%). Gynecologic MAs were positive for CK7 (25 of 27; 93%) and PAX-8 (13 of 27; 48%). We conclude that homogenous CDX-2 and nuclear ß-catenin expressions are commonly seen in lower GI tract MAs. In contrast, appendiceal MAs are usually heterogenously positive for CDX-2 and show cytoplasmic positivity for ß-catenin. Unlike lower GI tract MAs, upper GI tract MAs are frequently positive for CK7 and MUC-6. As is the case in appendiceal MAs, the upper GI tract MAs may also be heterogenously positive for CDX-2. Breast MAs are positive for ER and WT-1, whereas gynecologic MAs are positive for PAX-8 and negative for WT-1.