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Abstract Clinical decision support systems (CDSSs) play a critical role in enhancing the efficiency of mental health care delivery and promoting patient engagement. Transdiagnostic approaches that utilize raw psychological and biological data enable personalized patient profiling and treatment. This study introduces a CDSS incorporating symptom profiling and drug recommendation for mental health care. Among the UK Biobank cohort, we analyzed 157,348 participants for symptom profiling and 14,358 participants with a drug prescription history for drug recommendation. Among the 1307 patients in the Samsung Medical Center cohort, 842 were eligible for analysis. Symptom profiling utilized demographic and questionnaire data, employing conventional clustering and community detection methods. Identified clusters were explored using diagnostic mapping, feature importance, and scoring. For drug recommendation, we employed cluster- and network-based approaches. The analysis identified nine clusters using k-means clustering and ten clusters with the Louvain method. Clusters were annotated for distinct features related to depression, anxiety, psychosis, drug addiction, and self-harm. For drug recommendation, drug prescription probabilities were retrieved for each cluster. A recommended list of drugs, including antidepressants, antipsychotics, mood stabilizers, and sedative–hypnotics, was provided to individual patients. This CDSS holds promise for efficient personalized mental health care and requires further validation and refinement with larger datasets, serving as a valuable tool for mental healthcare providers.

Background Suicide is a serious social problem among older adults. However, little is known about how multidimensional factors affect suicide of older adults. Aims We classify the multidimensional suicidal risk types of older adults based on their characteristics and identify differences in suicidal ideation. Method Data were obtained via a nationwide online survey targeting 612 older adults over the age of 55 years. A latent profile analysis identified three profiles, one of which represented the optimal situation for these adults. Results We identified three distinct multidimensional suicidal risk types in older adults: high-risk predicament (24.5%), moderate-risk predicament (57.7%) and abundant internal/external resources (17.8%). In particular, depression, a major risk factor for suicide, was found together with self-neglect in each group. Multiple regression analysis showed that older adults in the moderate-risk predicament and high-risk predicament groups were more likely to have suicidal ideation than those in the abundant internal/external resources group. Conclusions Our findings suggest that co-occurrence of depression and self-neglect represents a suicide risk pattern in high-risk older individuals. Therefore, local communities need to urgently screen and provide interventions for such older adults and strengthen their capacity for multidimensional aspects of life to prevent suicide in the long term.

Oncolytic viruses are of significant clinical interest due to their ability to directly infect and kill tumors and enhance the anti-tumor immune response. Previously, we developed KLS-3010, a novel oncolytic virus derived from the International Health Department-White (IHD-W) strain vaccinia virus, which has robust tumoricidal effects. In the present study, we generated a recombinant oncolytic virus, KLS-3020, by inserting three transgenes (hyaluronidase [PH-20], interleukin-12 [IL-12], and soluble programmed cell death 1 fused to the Fc domain [sPD1-Fc]) into KLS-3010 and investigated its anti-tumor efficacy and ability to induce anti-tumor immune responses in CT26.WT and B16F10 mouse tumor models. A single injection of KLS-3020 significantly decreased tumor growth. The roles of the transgenes were investigated using viruses expressing each single transgene alone and KLS-3020. PH-20 promoted virus spread and tumor immune cell infiltration, IL-12 activated and reprogrammed T cells to inflammatory phenotypes, and sPD1-Fc increased intra-tumoral populations of activated T cells. The tumor-specific systemic immune response and the abscopal tumor control elicited by KLS-3020 were demonstrated in the CT26.WT tumor model. The insertion of transgenes into KLS-3020 increased its anti-tumor efficacy, supporting further clinical investigation of KLS-3020 as a novel oncolytic immunotherapy.

Abstract Rumination is a cognitive style characterized by repetitive thoughts about one’s negative internal states and is a common symptom of depression. Previous studies have linked trait rumination to alterations in the default mode network, but predictive brain markers of rumination are lacking. Here, we adopt a predictive modeling approach to develop a neuroimaging marker of rumination based on the variance of dynamic resting-state functional connectivity and test it across 5 diverse subclinical and clinical samples (total n = 288). A whole-brain marker based on dynamic connectivity with the dorsomedial prefrontal cortex (dmPFC) emerges as generalizable across the subclinical datasets. A refined marker consisting of the most important features from a virtual lesion analysis further predicts depression scores of adults with major depressive disorder (n = 35). This study highlights the role of the dmPFC in trait rumination and provides a dynamic functional connectivity marker for rumination.

Abstract Night shift work is associated with poor cardiometabolic outcomes, even post-retirement. However, the characteristics of cardiometabolic function in retired night shift workers (RNSW) compared to retired day workers (RDW) are not well-understood. Rigorous characterization of cardiometabolic dysfunction in RNSW and RDW will inform targeted risk stratification for RNSW. This observational study evaluated whether RNSW (n = 71) had poorer cardiometabolic function than RDW (n = 83). We conducted a multimodal assessment of cardiometabolic function including metabolic syndrome prevalence, brachial artery flow-mediated dilation, and carotid intima-media thickness. Main analyses tested overall group differences. Sex-stratified follow-up analyses tested group differences separately in men and women. RNSW had 2.6-times higher odds of metabolic syndrome prevalence than RDW in unadjusted analyses (95% CI [1.1,6.3]); this association was not significant when adjusting for age, race and education. RNSW and RDW (Mage = 68.4; 55% female) did not differ in percent flow-mediated dilation or carotid intima-media thickness. In sex-stratified analyses, women RNSW had 3.3-times higher odds of having high body mass index than women RDW (95% CI [1.2,10.4]). Men RNSW had 3.9-times higher odds of having high triglycerides than men RDW (95% CI [1.1,14.2]). No other group differences were observed. We found mixed evidence that night shift work exposure was associated with cardiometabolic dysfunction in retirement, possibly in a sex-specific manner.

This study examined within- and between-person associations between health-risk behaviors (smoking, drinking, insulin withholding) and type 1 diabetes (T1D) outcomes (adherence and HbA1c) during the high-risk transition from late adolescence to early emerging adulthood utilizing a 2-year longitudinal study. Beginning in the senior year of high school, participants (n = 197) with T1D completed measures of health-risk behaviors, adherence, and HbA1c annually at three time points. Health-risk behaviors were associated with poorer diabetes outcomes during the transition from late adolescence to early emerging adulthood. These results highlight the importance of monitoring health-risk behaviors regularly and intervening to reduce health-risk behaviors during this important developmental transition.

Measurement(s) Metabolomics Technology Type(s) high-performance liquid chromatography-electrospray ionisation tandem mass spectrometry Sample Characteristic - Organism Embryophyta

Summary The current exploratory pilot study examined whether social rhythm regularity, as measured by a social rhythm metric, was associated with: (1) the regularity of circadian rhythms and/or sleep regularity metrics; and (2) sleep quality, affective function and alcohol use. Late adolescents (18–22 years old) who drink alcohol (n = 36; 61.1% female, Mage = 21.26 years) completed a 14‐day ecological momentary assessment protocol, wore a wrist actigraph for 14 days, and completed two overnight visits (Thursday and Sunday) to assess dim light melatonin onset. Sleep regularity metrics included standard deviation, composite phase deviation, social jet lag and inter‐daily stability. We used dim light melatonin onset data to calculate the stability of the circadian phase (Sunday minus Thursday). Participants completed surveys and ecological momentary assessments that assessed global and daily sleep quality, affective function, and alcohol use. Correlational analysis and robust regression modelling were used. More regular social rhythms were associated with higher regularities of mid‐sleep timing based on standard deviations, but were not associated with other sleep regularity metrics or stability of the circadian phase. More regular social rhythms were associated with better sleep quality, but were not associated with affective function or alcohol use. Social rhythm regularity is a unique construct compared with existing sleep quality metrics. In contrast with the social zeitgeber hypothesis, social rhythm regularity was not associated with circadian rhythm regularity measured by dim light melatonin onset. However, social rhythm regularity may be an under‐recognized contributor to better sleep quality. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is an autoimmune disease mediated by NKG2D-expressing cytotoxic T lymphocytes destroying hair follicles in the skin. It is one of the most common autoimmune diseases, but there is no effective treatment modality approved by the FDA. Regulatory T cells (Tregs) are crucial for suppressing autoreactive T cells, and in the skin, they promote hair growth by inducing anagen. Based on this, we tested the therapeutic potential of expanded Tregs in AA using the C3H/HeJ mouse model. In mice with AA, NKG2D-expressing CD8 T cells widely infiltrate both haired and hairless skin areas, which have tissue-resident memory T-cell phenotypes. Tregs in the skin express CD25, CTLA-4, GATA-3, and Jagged1 and efficiently proliferate with IL-2 cytokine antibody complex. However, expanding Tregs in the skin did not induce anagen in normal mice, indicating that they are necessary but not sufficient for anagen induction. Also, they fail to suppress autoreactive CD8 T cells in the skin to reverse established AA in C3H/HeJ mice. These results suggest that Treg expansion alone is not sufficient for AA treatment, and combined immunotherapy is required.

The purpose of this study was to investigate the concurrent and lagged effects of daily exercise on daily blood glucose level and affect among persons with type 1 diabetes (T1D). 199 persons with T1D (M.sub.age = 46.82) completed a 14-day diary in which they reported on their engagement in moderate to vigorous exercise for 30 min and positive and negative affect. Daily blood glucose (BG) was gathered through study-provided glucometers. Multilevel modeling examined the effects of daily variability in (within-person effects) and average levels of (between-person effects) daily exercise on BG and affect. On days when persons with T1D reported they exercised moderately to vigorously for 30 min, they had lower mean BG, higher risk for low BG, lower negative affect, and higher positive affect on the same day as well as lower mean BG on the following day. Engaging in daily exercise is important in managing daily blood glucose and affect among persons with T1D, but can be complicated by hypoglycemia., Author(s): Eunjin Lee Tracy [sup.1] , Cynthia A. Berg [sup.1] , Robert G. Kent de Grey [sup.1] , Nancy A. Allen [sup.2] , Michelle L. Litchman [sup.2] , Jonathan Butner [...]

Abstract Background MYCN amplification is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB. Here, the genomic characteristics of MYCN non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification. Methods Fifty-eight whole exome sequencing (WES) and forty-eight whole transcriptome sequencing (WTS) samples of MYCN non-amplified NB were analysed. Forty-one patients harboured WES and WTS pairs. Results In the MYCN non-amplified NB WES data, maximum recurrent mutations were found in MUC4 (26%), followed by RBMXL3 (19%), ALB (17%), and MUC16 and SEPD8 (14% each). Two gene fusions, CCDC32-CBX3 (10%) and SAMD5-SASH1 (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non-high-risk patients with ganglioneuroblastoma histology. Analysis of risk-group-specific biomarkers showed that several genes and gene sets were differentially expressed between the risk groups, and some immune-related pathways tended to be activated in the high-risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high-risk patients had significantly higher levels of TMB compared with the non-high-risk patients. Conclusions This study provides novel insights into the genomic background of MYCN non-amplified NB. Activation of immune-related pathways in the high-risk group and the results of TMB and mutational signature analyses collectively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB.

The domestic artificially sweetened beverage market has grown rapidly in recent years, and sodas have led this growth. This study investigated consumer food purchasing behavior of artificially sweetened sodas in terms of the food health stereotypes of “vice” and “virtue”; used to denote unhealthy and healthy food purchases, respectively. The study was conducted using consumer panel data collected by the Rural Development Administration from 2017 to 2020. Given the semi-continuous nature of artificially sweetened soda purchases, Cragg’s two-part model was used for the analysis. The probability of purchasing artificially sweetened sodas increased as expenditure on snacks (a vice food category) increased. However, of those panelists who purchased artificially sweetened sodas, expenditure on artificially sweetened sodas decreased with expenditure on snacks and increased with expenditure on fruits (a virtue food category). These results suggest that vicious-lifestyle consumers choose artificially sweetened sodas when they regulate eating habits, whereas virtuous-lifestyle consumers increase artificially sweetened soda expenditure for hedonic consumption to reduce guilt based on a sensible trade-off effect. [ABSTRACT FROM AUTHOR]

The contents and dynamics of spontaneous thought are important factors for personality traits and mental health. However, assessing spontaneous thoughts is challenging due to their unconstrained nature, and directing participants' attention to report their thoughts may fundamentally alter them. Here, we aimed to decode two key content dimensions of spontaneous thought-self-relevance and valence-directly from brain activity. To train functional MRI-based predictive models, we used individually generated personal stories as stimuli in a story-reading task to mimic narrative-like spontaneous thoughts (n = 49). We then tested these models on multiple test datasets (total n = 199). The default mode, ventral attention, and frontoparietal networks played key roles in the predictions, with the anterior insula and midcingulate cortex contributing to self-relevance prediction and the left temporoparietal junction and dorsomedial prefrontal cortex contributing to valence prediction. Overall, this study presents brain models of internal thoughts and emotions, highlighting the potential for the brain decoding of spontaneous thought. [ABSTRACT FROM AUTHOR]

As part of an ongoing natural product chemical research for the discovery of bioactive secondary metabolites with novel structures, wild fruiting bodies of Daedaleopsis confragosa were collected and subjected to chemical and biological analyses. We subjected the fractions derived from the methanol extract of the fruiting bodies of D. confragosa to bioactivity-guided fractionation because the methanol extract of D. confragosa showed antibacterial activity against Helicobacter pylori strain 51, according to our bioactivity screening. The n-hexane and dichloromethane fractions showed moderate to weak antibacterial activity against H. pylori strain 51, and the active fractions were analyzed for the isolation of antibacterial compounds. Liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis revealed that the n-hexane fraction contains several compounds which are absent in the other fractions, so the fraction was prioritized for further fractionation. Through chemical analysis of the active n-hexane and dichloromethane fractions, we isolated five ergosterol derivatives (1–5), and their chemical structures were determined to be demethylincisterol A3 (1), (20S,22E,24R)-ergosta-7,22-dien-3β,5α,6β-triol (2), (24S)-ergosta-7-ene-3β,5α,6β-triol (3), 5α,6α-epoxy-(22E,24R)-ergosta-7,22-dien-3β-ol (4), and 5α,6α-epoxy-(24R)-ergosta-7-en-3β-ol (5) by NMR spectroscopic analysis. This is the first report on the presence of ergosterol derivatives (1–5) in D. confragosa. Compound 1 showed the most potent anti-H. pylori activity with 33.9% inhibition, rendering it more potent than quercetin, a positive control. Compound 3 showed inhibitory activity comparable to that of quercetin. Distribution analysis of compound 1 revealed a wide presence of compound 1 in the kingdom Fungi. These findings indicate that demethylincisterol A3 (1) is a natural antibiotic that may be used in the development of novel antibiotics against H. pylori.

IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could block its interaction with IL-2Rα, which is mainly expressed on Tregs. This selectivity can enhance the anti-tumor effects of IL-2 by activating CD8 T and NK cells, while disfavoring Treg stimulation. Based on this, we newly developed a series of anti-human IL-2 (hIL-2) mAbs (TCB1-3) that selectively stimulate CD8 T and NK cells without overtly activating Tregs. Among them, the hIL-2/TCB2 complex (hIL-2/TCB2c) exerted the best efficacy by inducing a prodigious expansion of host memory phenotype (MP) CD8 T (60-fold) and NK cells (18-fold) with less efficient Treg proliferation (5-fold). As a result, there was an average eightfold increase in the ratio of MP CD8 to Tregs. Accordingly, hIL-2/TCB2c strongly inhibited the growth of B16F10, MC38, and CT26 tumors. More remarkably, hIL-2/TCB2c showed synergy with checkpoint inhibitors such as anti-CTLA-4 or PD1 antibodies, and resulted in almost complete regression of implanted tumors and resistance to secondary tumor challenge. For direct clinical use, we generated a humanized form of TCB2 that had equal immunostimulatory and anti-tumor efficacy as a murine one. Collectively, these results show that TCB2 can provide a potent immunotherapeutic modality either alone or together with checkpoint inhibitors in cancer patients.

Shift workers experience poor sleep and dysregulated cardiac autonomic function during sleep. However, it is unknown if this dysregulation persists into retirement, potentially accelerating the age‐associated risk for adverse cardiovascular outcomes. Using sleep deprivation as a physiological challenge to cardiovascular autonomic function, we compared heart rate (HR) and high‐frequency heart rate variability (HF‐HRV) during baseline and recovery sleep following sleep deprivation between retired night shift and day workers. Participants were retired night shift (N = 33) and day workers (N = 37) equated on age (mean [standard deviation] = 68.0 [5.6] years), sex (47% female), race/ethnicity (86% White), and body mass index. Participants completed a 60‐h lab protocol including one night of baseline polysomnography‐monitored sleep, followed by 36 h of sleep deprivation and one night of recovery sleep. Continuously recorded HR was used to calculate HF‐HRV. Linear mixed models compared HR and HF‐HRV during non‐rapid eye movement (NREM) and REM sleep between groups during baseline and recovery nights. Groups did not differ on HR or HF‐HRV during NREM or REM sleep (ps >.05) and did not show differential responses to sleep deprivation. In the full sample, HR increased and HF‐HRV decreased from baseline to recovery during NREM (ps <.05) and REM (ps <.01). Both groups exhibited cardiovascular autonomic changes during recovery sleep following 36 h of sleep deprivation. Sleep deprivation appears to induce cardiovascular autonomic changes that persist into recovery sleep in older adults, regardless of shift work history. This study aimed to determine whether night shift work exerts a long‐term effect on cardiovascular autonomic function. In older adults, regardless of shift work status, autonomic activity shifted during the first night of recovery sleep despite increased sleep depth. Therefore, the first night of recovery sleep may not be as restorative for cardiovascular autonomic function as initially believed. Instead, older adults may require additional nights of sleep to return to their baseline cardiac autonomic function. [ABSTRACT FROM AUTHOR]

High-throughput sequencing is used to identify somatic variants in cancer patients. Here, the authors perform panel-based profiling of 5095 clinical samples and demonstrate that many clinically-actionable variants have low variant allele fractions, requiring assays with high detection sensitivity.

Abstract Background Targeted deep sequencing is increasingly used to detect low-allelic fraction variants; it is therefore essential that errors that constitute baseline noise and impose a practical limit on detection are characterized. In the present study, we systematically evaluate the extent to which errors are incurred during specific steps of the capture-based targeted sequencing process. Results We removed most sequencing artifacts by filtering out low-quality bases and then analyze the remaining background noise. By recognizing that plasma DNA is naturally fragmented to be of a size comparable to that of mono-nucleosomal DNA, we were able to identify and characterize errors that are specifically associated with acoustic shearing. Two-thirds of C:G > A:T errors and one quarter of C:G > G:C errors were attributed to the oxidation of guanine during acoustic shearing, and this was further validated by comparative experiments conducted under different shearing conditions. The acoustic shearing step also causes A > G and A > T substitutions localized to the end bases of sheared DNA fragments, indicating a probable association of these errors with DNA breakage. Finally, the hybrid selection step contributes to one-third of the remaining C:G > A:T and one-fifth of the C > T errors. Conclusions The results of this study provide a comprehensive summary of various errors incurred during targeted deep sequencing, and their underlying causes. This information will be invaluable to drive technical improvements in this sequencing method, and may increase the future usage of targeted deep sequencing methods for low-allelic fraction variant detection.

Abstract Background Our previous study had identified the SNP (g.81966377T > C) and indel (g.81966364D > I) located in the promoter of APM1 to have a significant effect on marbling in Hanwoo. APM1 encodes an adipocytokine called adiponectin, which plays a significant role in lipogenesis. The aim of this study was to verify and validate the effect of the SNP and indel on marbling and other carcass traits in a large, representative, countrywide population of Hanwoo cattle. The carcass traits measured were marbling (MAR), backfat thickness (BFT), loin eye area (LEA), and carcass weight (CAW). Results Primers were designed to amplify 346 bp of the genomic segment that contained the targeted SNP (g.81966377) and the indel (g.81966364). After data curation, the genotypes of 8,378 individuals identified using direct sequencing analysis estimated frequencies for C (0.686) and T (0.314) respectively showing genotype frequencies for CC (0.470), CT (0.430) and TT (0.098). The genotypes were significantly associated with MAR, BFT and LEA. The indel had significant effect on marbling (P