Flavonoid gossypetin protects alveolar bone and limits inflammation in ligature-induced periodontitis in mice.

BACKGROUND: Bacterial-induced inflammation instigates the destruction of hard and soft tissues surrounding teeth in periodontitis. In severe cases, the increased number and activity of osteoclasts induces the resorption of alveolar bones, ultimately leading to tooth loss. Because of their diverse chemical structures and bioactivities, natural compounds are often suggested to treat a wide variety of diseases, including inflammatory disorders. METHODS: In the present study, we demonstrated an inhibitory effect of gossypetin, a hexahydroxy flavone, on osteoclast differentiation and bone resorption using in vitro culture of osteoclasts from mouse bone marrow macrophage (BMM) precursors and in vivo model of ligature-induced periodontitis in mice. RESULTS: Gossypetin significantly reduced the differentiation of osteoclasts from mouse BMM precursors in the presence of the receptor activator of nuclear factor κB ligand (RANKL). In vitro, gossypetin inhibited critical signaling events downstream of RANKL including the auto-amplification of nuclear factor of activated T-cells, cytoplasmic 1, Ca2+ oscillations, and the generation of reactive oxygen species. In a mouse ligature-induced periodontitis model, the administration of gossypetin significantly reduced osteoclastogenesis and alveolar bone resorption. Furthermore, gossypetin prevented the ligature-induced increase in macrophages and T cells and reduced the production of tumor necrosis factor-α and interleukin-6. CONCLUSION: Taken together, these results show anti-osteoclastogenic and anti-inflammatory effects of gossypetin, suggesting the potential use of this natural compound in periodontitis.

Endothelial and macrophage interactions in the angiogenic niche.

The interactions between vascular cells, especially endothelial cells, and macrophages play a pivotal role in maintaining the subtle balance of vascular biology, which is crucial for angiogenesis in both healthy and diseased states. These cells are central to ensuring a harmonious balance between tissue repair and preventing excessive angiogenic activity, which could lead to pathological conditions. Recent advances in sophisticated genetic engineering vivo models and novel sequencing approaches, such as single-cell RNA-sequencing, in immunobiology have significantly enhanced our understanding of the gene expression and behavior of macrophages. These insights offer new perspectives on the role macrophages play not only in development but also across various health conditions. In this review, we explore the complex interactions between multiple types of macrophages and endothelium, focusing on their impact on new blood vessel formation. By understanding these intricate interactions, we aim to provide insights into new methods for managing angiogenesis in various diseases, thereby offering hope for the development of novel therapeutic approaches.

Efficacy of Mobile App-Based Cognitive Behavioral Therapy for Insomnia: Multicenter, Single-Blind Randomized Clinical Trial.

BACKGROUND: Cognitive behavioral therapy for insomnia (CBTi) is the first-line therapy for chronic insomnia. Mobile app-based CBTi (MCBTi) can enhance the accessibility of CBTi treatment; however, few studies have evaluated the effectiveness of MCBTi using a multicenter, randomized controlled trial design. OBJECTIVE: We aimed to assess the efficacy of Somzz, an MCBTi that provides real-time and tailored feedback to users, through comparison with an active comparator app. METHODS: In our multicenter, single-blind randomized controlled trial study, participants were recruited from 3 university hospitals and randomized into a Somzz group and a sleep hygiene education (SHE) group at a 1:1 ratio. The intervention included 6 sessions for 6 weeks, with follow-up visits over a 4-month period. The Somzz group received audiovisual sleep education, guidance on relaxation therapy, and real-time feedback on sleep behavior. The primary outcome was the Insomnia Severity Index score, and secondary outcomes included sleep diary measures and mental health self-reports. We analyzed the outcomes based on the intention-to-treat principle. RESULTS: A total of 98 participants were randomized into the Somzz (n=49, 50%) and SHE (n=49, 50%) groups. Insomnia Severity Index scores for the Somzz group were significantly lower at the postintervention time point (9.0 vs 12.8; t95=3.85; F2,95=22.76; ηp2=0.13; P<.001) and at the 3-month follow-up visit (11.3 vs 14.7; t68=2.61; F2,68=5.85; ηp2=0.03; P=.01) compared to those of the SHE group. The Somzz group maintained their treatment effect at the postintervention time point and follow-ups, with a moderate to large effect size (Cohen d=-0.62 to -1.35; P<.01 in all cases). Furthermore, the Somzz group showed better sleep efficiency (t95=-3.32; F2,91=69.87; ηp2=0.41; P=.001), wake after sleep onset (t95=2.55; F2,91=51.81; ηp2=0.36; P=.01), satisfaction (t95=-2.05; F2,91=26.63; ηp2=0.20; P=.04) related to sleep, and mental health outcomes, including depression (t95=2.11; F2,94=29.64; ηp2=0.21; P=.04) and quality of life (t95=-3.13; F2,94=54.20; ηp2=0.33; P=.002), compared to the SHE group after the intervention. The attrition rate in the Somzz group was 12% (6/49). CONCLUSIONS: Somzz outperformed SHE in improving insomnia, mental health, and quality of life. The MCBTi can be a highly accessible, time-efficient, and effective treatment option for chronic insomnia, with high compliance. TRIAL REGISTRATION: Clinical Research Information Service (CRiS) KCT0007292; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=22214&search_page=L.

ACVR1/ALK2-p21 signaling axis modulates proliferation of the venous endothelium in the retinal vasculature.

The proliferation of the endothelium is a highly coordinated process to ensure the emergence, expansion, and homeostasis of the vasculature. While Bone Morphogenetic Protein (BMP) signaling fine-tunes the behaviors of endothelium in health and disease, how BMP signaling influences the proliferation of endothelium and therefore, modulates angiogenesis remains largely unknown. Here, we evaluated the role of Activin A Type I Receptor (ACVR1/ALK2), a key BMP receptor in the endothelium, in modulating the proliferation of endothelial cells. We show that ACVR1/ALK2 is a key modulator for the proliferation of endothelium in the retinal vessels. Loss of endothelial ALK2 leads to a significant reduction in endothelial proliferation and results in fewer branches/endothelial cells in the retinal vessels. Interestingly, venous endothelium appears to be more susceptible to ALK2 deletion. Mechanistically, ACVR1/ALK2 inhibits the expression of CDKN1A/p21, a critical negative regulator of cell cycle progression, in a SMAD1/5-dependent manner, thereby enabling the venous endothelium to undergo active proliferation by suppressing CDKN1A/p21. Taken together, our findings show that BMP signaling mediated by ACVR1/ALK2 provides a critical yet previously underappreciated input to modulate the proliferation of venous endothelium, thereby fine-tuning the context of angiogenesis in health and disease.

Childhood maltreatment and suicide attempts in major depression and bipolar disorders in South Korea: A prospective nationwide cohort study.

BACKGROUND: Childhood maltreatment (CM) is prevalent among patients with mood disorders and considered an important risk factor for suicide in the general population. Despite mood disorders being implicated in up to 60 % of completed suicides, the predictive role of CM on suicide attempt (SA) among early mood disorder patients remains poorly understood. METHODS: We enrolled 480 participants diagnosed with early-onset major depressive disorder (MDD), bipolar I disorder (BD I), and bipolar II disorder (BD II). Over an average of 60 weeks, participants underwent follow-up assessments at 12-week intervals. Using multivariate logistic regression, we examined the association between CM and SA history at baseline. Further, the Cox proportional hazard model assessed the predictive role of childhood maltreatment in SA during follow-up. RESULTS: At baseline, 38 % of the total participants reported SA history, with a follow-up prevalence of 10 %. Childhood maltreatment was significantly associated with past SAs and was a robust predictor of future SA, adjusting for relevant clinical risk factors. Emotional abuse and sexual abuse related to SA history, and physical abuse increased future SA risk. LIMITATIONS: Potential biases in reporting SA and childhood maltreatment, along with unexplored factors such as additional environmental and familial risks, may affect the study's findings. CONCLUSIONS: Childhood maltreatment emerged as a robust predictor of SA among early-onset mood disorder patients. Systematic evaluation of CM early in the clinical process may be crucial for effective risk management. Additionally, our findings highlight the importance of implementing proactive interventions for CM to prevent the onset of adverse psychological trajectories.

Reversible Solar Heating and Radiative Cooling Devices via Mechanically Guided Assembly of 3D Macro/Microstructures.

Solar heating and radiative cooling are promising solutions for decreasing global energy consumption because these strategies use the Sun (≈5800 K) as a heating source and outer space (≈3 K) as a cooling source. Although high-performance thermal management can be achieved using these eco-friendly methods, they are limited by daily temperature fluctuations and seasonal changes because of single-mode actuation. Herein, reversible solar heating and radiative cooling devices formed via the mechanically guided assembly of 3D architectures are demonstrated. The fabricated devices exhibit the following properties: i) The devices reversibly change between solar heating and radiative cooling under uniaxial strain, called dual-mode actuation. ii) The 3D platforms in the devices can use rigid/soft materials for functional layers owing to the optimized designs. iii) The devices can be used for dual-mode thermal management on a macro/microscale. The devices use black paint-coated polyimide (PI) films as solar absorbers with multilayered films comprising thin layers of polydimethylsiloxane/silver/PI, achieving heating and cooling temperatures of 59.5 and -11.9 °C, respectively. Moreover, mode changes according to the angle of the 3D structures are demonstrated and the heating/cooling performance with skin, glass, steel, aluminum, copper, and PI substrates is investigated.

Genetically Engineered CLDN18.2 CAR-T Cells Expressing Synthetic PD1/CD28 Fusion Receptors Produced Using a Lentiviral Vector.

This study aimed to develop synthetic Claudin18.2 (CLDN18.2) chimeric antigen receptor (CAR)-T (CAR-T) cells as a treatment for advanced gastric cancer using lentiviral vector genetic engineering technology that targets the CLDN18.2 antigen and simultaneously overcomes the immunosuppressive environment caused by programmed cell death protein 1 (PD-1). Synthetic CAR T cells are a promising approach in cancer immunotherapy but face many challenges in solid tumors. One of the major problems is immunosuppression caused by PD-1. CLDN18.2, a gastric-specific membrane protein, is considered a potential therapeutic target for gastric and other cancers. In our study, CLDN18.2 CAR was a second-generation CAR with inducible T-cell costimulatory (CD278), and CLDN18.2-PD1/CD28 CAR was a third-generation CAR, wherein the synthetic PD1/CD28 chimeric-switch receptor (CSR) was added to the second-generation CAR. In vitro, we detected the secretion levels of different cytokines and the killing ability of CAR-T cells. We found that the secretion of cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) secreted by three types of CAR-T cells was increased, and the killing ability against CLDN18.2-positive GC cells was enhanced. In vivo, we established a xenograft GC model and observed the antitumor effects and off-target toxicity of CAR-T cells. These results support that synthetic anti-CLDN18.2 CAR-T cells have antitumor effect and anti-CLDN18.2-PD1/CD28 CAR could provide a promising design strategy to improve the efficacy of CAR-T cells in advanced gastric cancer.

A water-soluble label for food products prevents packaging waste and counterfeiting.

Sustainability, humidity sensing and product origin are important features of food packaging. While waste generated from labelling and packaging causes environmental destruction, humidity can result in food spoilage during delivery and counterfeit-prone labelling undermines consumer trust. Here we introduce a food label based on a water-soluble nanocomposite ink with a high refractive index that addresses these issues. By patterning the nanocomposite ink using nanoimprint lithography, the resultant metasurface shows bright and vivid structural colours. This method makes it possible to quickly and inexpensively create patterns on large surfaces. A QR code is also developed that can provide up-to-date information on food products. Microprinting hidden in the QR code protects against counterfeiting, cannot be physically detached or replicated and may be used as a humidity indicator. Our proposed food label can reduce waste while ensuring customers receive accurate product information.

Causal dynamics of sleep, circadian rhythm, and mood symptoms in patients with major depression and bipolar disorder: insights from longitudinal wearable device data.

BACKGROUND: Sleep and circadian rhythm disruptions are common in patients with mood disorders. The intricate relationship between these disruptions and mood has been investigated, but their causal dynamics remain unknown. METHODS: We analysed data from 139 patients (76 female, mean age = 23.5 ± 3.64 years) with mood disorders who participated in a prospective observational study in South Korea. The patients wore wearable devices to monitor sleep and engaged in smartphone-delivered ecological momentary assessment of mood symptoms. Using a mathematical model, we estimated their daily circadian phase based on sleep data. Subsequently, we obtained daily time series for sleep/circadian phase estimates and mood symptoms spanning >40,000 days. We analysed the causal relationship between the time series using transfer entropy, a non-linear causal inference method. FINDINGS: The transfer entropy analysis suggested causality from circadian phase disturbance to mood symptoms in both patients with MDD (n = 45) and BD type I (n = 35), as 66.7% and 85.7% of the patients with a large dataset (>600 days) showed causality, but not in patients with BD type II (n = 59). Surprisingly, no causal relationship was suggested between sleep phase disturbances and mood symptoms. INTERPRETATION: Our findings suggest that in patients with mood disorders, circadian phase disturbances directly precede mood symptoms. This underscores the potential of targeting circadian rhythms in digital medicine, such as sleep or light exposure interventions, to restore circadian phase and thereby manage mood disorders effectively. FUNDING: Institute for Basic Science, the Human Frontiers Science Program Organization, the National Research Foundation of Korea, and the Ministry of Health & Welfare of South Korea.

Identifying predictive factors for mood recurrence in early-onset major mood disorders: A 4-year, multicenter, prospective cohort study.

We investigate the predictive factors of the mood recurrence in patients with early-onset major mood disorders from a prospective observational cohort study from July 2015 to December 2019. A total of 495 patients were classified into three groups according to recurrence during the cohort observation period: recurrence group with (hypo)manic or mixed features (MMR), recurrence group with only depressive features (ODR), and no recurrence group (NR). As a result, the baseline diagnosis of bipolar disorder type 1 (BDI) and bipolar disorder type 2 (BDII), along with a familial history of BD, are strong predictors of the MMR. The discrepancies in wake-up times between weekdays and weekends, along with disrupted circadian rhythms, are identified as a notable predictor of ODR. Our findings confirm that we need to be aware of different predictors for each form of mood recurrences in patients with early-onset mood disorders. In clinical practice, we expect that information obtained from the initial assessment of patients with mood disorders, such as mood disorder type, family history of BD, regularity of wake-up time, and disruption of circadian rhythms, can help predict the risk of recurrence for each patient, allowing for early detection and timely intervention.

Multi-domain automated patterning of DNA-functionalized hydrogels.

DNA-functionalized hydrogels are capable of sensing oligonucleotides, proteins, and small molecules, and specific DNA sequences sensed in the hydrogels' environment can induce changes in these hydrogels' shape and fluorescence. Fabricating DNA-functionalized hydrogel architectures with multiple domains could make it possible to sense multiple molecules and undergo more complicated macroscopic changes, such as changing fluorescence or changing the shapes of regions of the hydrogel architecture. However, automatically fabricating multi-domain DNA-functionalized hydrogel architectures, capable of enabling the construction of hydrogel architectures with tens to hundreds of different domains, presents a significant challenge. We describe a platform for fabricating multi-domain DNA-functionalized hydrogels automatically at the micron scale, where reaction and diffusion processes can be coupled to program material behavior. Using this platform, the hydrogels' material properties, such as shape and fluorescence, can be programmed, and the fabricated hydrogels can sense their environment. DNA-functionalized hydrogel architectures with domain sizes as small as 10 microns and with up to 4 different types of domains can be automatically fabricated using ink volumes as low as 50 µL. We also demonstrate that hydrogels fabricated using this platform exhibit responses similar to those of DNA-functionalized hydrogels fabricated using other methods by demonstrating that DNA sequences can hybridize within them and that they can undergo DNA sequence-induced shape change.

Effects of a Rice-Farming Simulation Video Game on Nature Relatedness, Nutritional Status, and Psychological State in Urban-Dwelling Adults During the COVID-19 Pandemic: Randomized Waitlist Controlled Trial.

BACKGROUND: During the COVID-19 pandemic, urban inhabitants faced significant challenges in maintaining connections with nature, adhering to nutritional guidelines, and managing mental well-being. OBJECTIVE: Recognizing the urgent need for innovative approaches, this study was designed to explore the potential benefits of a specific digital intervention, the rice-farming simulation game Sakuna: Of Rice and Ruin, for nature relatedness, nutritional behaviors, and psychological well-being. METHODS: A total of 66 adults without any prior major psychiatric disorders residing in an urban area were recruited for the study. They were randomly assigned to 2 groups through block randomization: the immediate intervention group (IIG; 34/66, 52%) and the waitlist group (32/66, 48%). Participants in the IIG were instructed to play the game for at least 4 days per week for 3 weeks, with each session lasting from 30 minutes to 3 hours. Assessments were performed at baseline, week 1, and week 3. The Nature Relatedness Scale (NR) and Nutrition Quotient Scale were used to evaluate nature relatedness and nutritional state, respectively. Furthermore, psychological state was assessed using the World Health Organization Quality of Life-Brief Version (WHOQOL-BREF), Brief Fear of Negative Evaluation Scale, Social Avoidance and Distress Scale, Toronto Alexithymia Scale, State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression Scale Revised, and Korean Resilience Quotient. RESULTS: This study's results revealed significant time interactions between the IIG and waitlist group for both the total NR score (P=.001) and the score of the self subdomain of NR (P<.001), indicating an impact of the game on nature relatedness. No group×time interactions were found for the total Nutrition Quotient Scale and subdomain scores, although both groups showed increases from baseline. For psychological state, a significant group×time interaction was observed in the total WHOQOL-BREF score (P=.049), suggesting an impact of the game on quality of life. The psychological (P=.01), social (P=.003), and environmental (P=.04) subdomains of the WHOQOL-BREF showed only a significant time effect. Other psychological scales did not display any significant changes (all P>.05). CONCLUSIONS: Our findings suggest that the rice-farming game intervention might have positive effects on nature relatedness, nature-friendly dietary behaviors, quality of life, anxiety, depression, interpersonal relationships, and resilience among urban adults during the COVID-19 pandemic. The impact of pronature games in confined urban environments provides valuable evidence of how digital technologies can be used to enhance urban residents' affinity for nature and psychological well-being. This understanding can be extended in the future to other digital platforms, such as metaverses. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0007657; http://tinyurl.com/yck7zxp7.

Differential effect of cancer-associated fibroblast-derived extracellular vesicles on cisplatin resistance in oral squamous cell carcinoma via miR-876-3p.

Rationale: Platinum-based chemotherapy is commonly used for treating solid tumors, but drug resistance often limits its effectiveness. Cancer-associated fibroblast (CAF)-derived extracellular vesicle (EV), which carry various miRNAs, have been implicated in chemotherapy resistance. However, the molecular mechanism through which CAFs modulate cisplatin resistance in oral squamous cell carcinoma (OSCC) is not well understood. We employed two distinct primary CAF types with differential impacts on cancer progression: CAF-P, representing a more aggressive cancer-promoting category, and CAF-D, characterized by properties that moderately delay cancer progression. Consequently, we sought to investigate whether the two CAF types differentially affect cisplatin sensitivity and the underlying molecular mechanism. Methods: The secretion profile was examined by utilizing an antibody microarray with conditioned medium obtained from the co-culture of OSCC cells and two types of primary CAFs. The effect of CAF-dependent factors on cisplatin resistance was investigated by utilizing conditioned media (CM) and extracellular vesicle (EVs) derived from CAFs. The impacts of candidate genes were confirmed using gain- and loss-of-function analyses in spheroids and organoids, and a mouse xenograft. Lastly, we compared the expression pattern of the candidate genes in tissues from OSCC patients exhibiting different responses to cisplatin. Results: When OSCC cells were cultured with conditioned media (CM) from the two different CAF groups, cisplatin resistance increased only under CAF-P CM. OSCC cells specifically expressed insulin-like growth factor binding protein 3 (IGFBP3) after co-culture with CAF-D. Meanwhile, IGFBP3-knockdown OSCC cells acquired cisplatin resistance in CAF-D CM. IGFBP3 expression was promoted by GATA-binding protein 1 (GATA1), a transcription factor targeted by miR-876-3p, which was enriched only in CAF-P-derived EV. Treatment with CAF-P EV carrying miR-876-3p antagomir decreased cisplatin resistance compared to control miRNA-carrying CAF-P EV. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, there was a positive correlation between IGFBP3 and GATA1 expression and cisplatin sensitivity in OSCC tissues from patients. Conclusion: These results provide insights for overcoming cisplatin resistance, especially concerning EVs within the tumor microenvironment. Furthermore, it is anticipated that the expression levels of GATA1 and miR-876-3p, along with IGFBP3, could aid in the prediction of cisplatin resistance.

Smart building block with colored radiative cooling devices and quantum dot light emitting diodes.

In this study, we design a smart building block with quantum-dot light-emitting diode (QLED) and colored radiative cooling devices. A smart light-emitting building block is fabricated using a bottom-inverted QLED that emits green light, an insulating layer, and a top radiative cooling structure that emits mid-infrared light. The heat generated during QLED operation is measured and analyzed to investigate the correlation between heat and QLED degradation. The top cooling part is designed to have no impact on the QLED's performance and utilizes Ag-polydimethylsiloxane as a visible-light reflector and mid-infrared absorber/emitter. For the colored cooling part, white radiative cooling paint is used instead of Ag-polydimethylsiloxane to improve cooling performance, and red and yellow paints are employed to realize vivid red and yellow colors, respectively. We demonstrate a smart imitation house system with a smart light-emitting building block as the roof and analyze the cooling of the heat generated during QLED operation. A maximum cooling effect of up to 9.6 °C is observed compared to the imitation house system without the smart light-emitting building block, effectively dissipating heat generated during QLED operation. The smart light-emitting building block presented in this study opens new avenues in the fields of lighting and cooling systems.

Vivid Colored Cooling Structure Managing Full Solar Spectrum via Near-Infrared Reflection and Photoluminescence.

Colored radiative cooling (CRC) offers an attractive alternative for surface and space cooling, while preserving the aesthetics of an object. However, there has been no study on the CRC using phosphors in regard to vivid coloration, sophisticated performance investigation, retention of properties, functionality, and structural flexibility all at once. Thus, to manage the entire solar spectrum, a colored cooling structure comprising a near-infrared (NIR)-reflective bottom layer and a top colored layer with a phosphor-embedded polymer matrix is proposed. The structure is paintable, vividly colored, hydrophobic, and ultraviolet (UV) and water resistant. In the daytime outdoor measurement, the structure with red, orange, and yellow colors exhibited lower temperature than a control group using commercial white paint by 4.7 °C, 7.2 °C, and 7.4 °C, respectively. After precise theoretical and experimental time-tracing temperature validation, the CRC performance enhancement from NIR reflection and photoluminescence effects was thoroughly analyzed, and a temperature reduction of up to 16.1 °C was achieved for the orange-colored structure. Furthermore, experiments of hydrophobicity infusion and exposure to UV and deionized water verified the durability of the colored cooling structure. In addition, flexible-film-type colored cooling structures were demonstrated using different bottom reflective layers, such as a silver thin film and porous aluminum oxide particle-embedded poly(vinylidene fluoride-co-hexafluoropropylene), suggesting the potential applicability of these colored cooling structures for vivid-colored, functional, and durable CRC.

Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion.

Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-α, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis.

Ensemble Approach to Combining Episode Prediction Models Using Sequential Circadian Rhythm Sensor Data from Mental Health Patients.

Managing mood disorders poses challenges in counseling and drug treatment, owing to limitations. Counseling is the most effective during hospital visits, and the side effects of drugs can be burdensome. Patient empowerment is crucial for understanding and managing these triggers. The daily monitoring of mental health and the utilization of episode prediction tools can enable self-management and provide doctors with insights into worsening lifestyle patterns. In this study, we test and validate whether the prediction of future depressive episodes in individuals with depression can be achieved by using lifelog sequence data collected from digital device sensors. Diverse models such as random forest, hidden Markov model, and recurrent neural network were used to analyze the time-series data and make predictions about the occurrence of depressive episodes in the near future. The models were then combined into a hybrid model. The prediction accuracy of the hybrid model was 0.78; especially in the prediction of rare episode events, the F1-score performance was approximately 1.88 times higher than that of the dummy model. We explored factors such as data sequence size, train-to-test data ratio, and class-labeling time slots that can affect the model performance to determine the combinations of parameters that optimize the model performance. Our findings are especially valuable because they are experimental results derived from large-scale participant data analyzed over a long period of time.

Potential effectiveness of digital therapeutics specialized in executive functions as adjunctive treatment for clinical symptoms of attention-deficit/hyperactivity disorder: a feasibility study.

Introduction: The role of digital therapeutics (DTx) in the effective management of attention deficit/hyperactivity disorder (ADHD) is beginning to gain clinical attention. Therefore, it is essential to verify their potential efficacy. Method: We aimed to investigate the improvement in the clinical symptoms of ADHD by using DTx AimDT01 (NUROW) (AIMMED Co., Ltd., Seoul, Korea) specialized in executive functions. NUROW, which consists of Go/No-go Task- and N-Back/Updating-based training modules and a personalized adaptive algorithm system that adjusts the difficulty level according to the user's performance, was implemented on 30 Korean children with ADHD aged 6 to 12 years. The children were instructed to use the DTx for 15 min daily for 4 weeks. The Comprehensive attention test (CAT) and Childhood Behavior Checklist (CBCL) were used to assess the children at baseline and endpoint. In contrast, the ADHD-Rating Scale (ARS) and PsyToolkit were used weekly and followed up at 1 month, for any sustained effect. Repeated measures ANOVA was used to identify differences between the participants during visits, while t-tests and Wilcoxon signed-rank tests were used to identify changes before and after the DTx. Results: We included 27 participants with ADHD in this analysis. The ARS inattention (F = 4.080, p = 0.010), hyperactivity (F = 5.998. p < 0.001), and sum (F = 5.902, p < 0.001) significantly improved. After applying NUROW, internalized (t = -3.557, p = 0.001, 95% CI = -3.682--0.985), other (Z = -3.434, p = 0.001, effect size = -0.661), and sum scores (t = -3.081, p = 0.005, 95% CI = -10.126--2.022) were significantly changed in the CBCL. The overall effect was confirmed in the ARS sustained effect analysis even after 1 month of discontinuing the DTx intervention. Discussion: According to caregivers, the findings indicate that DTx holds potential effect as an adjunctive treatment in children with ADHD, especially in subjective clinical symptoms. Future studies will require detailed development and application targeting specific clinical domains using DTx with sufficient sample sizes.Clinical trial registration: KCT0007579.

Association between Plasma Metabolic Profiles of the Antidepressant Escitalopram and Clinical Response in Subjects with Depression.

Liquid chromatography/electrospray ionization-mass spectrometry revealed plasma metabolic profiles for the antidepressant drug escitalopram (ECTP) and associated clinical responses in subjects with major depressive disorder (MDD). Metabolic profiles contribute to variations in responses to drug treatment of depression. To assess clinical responses and treatment outcomes, we quantified the levels of metabolites, including those of the parent drug, in plasma samples collected at different time points (days 0, 7, 14, and 42) during treatment of seven patients with MDD. Results showed that mean plasma levels of key metabolites and ECTP at day 7 were significantly associated with the clinical response at 42 days after treatment. Statistical analyses, including principal component analysis, of key metabolites and ECTP samples at different time points clearly distinguished the clinical responders from non-responder subjects. Although further validation with a larger cohort is necessary, our results indicate that early improvement and plasma levels of key metabolites and ECTP are predictive of therapeutic treatment outcomes and thus can be used to guide the use of ECTP.