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BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) contribute to hepatocellular carcinoma (HCC) progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to pro-tumorigenic properties in the peritumoral area. APPROACH AND RESULTS: In single cell RNA-sequencing analysis of HCC patients, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area, and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DR‒ macrophages with CX3CR1 in the HCC adjacent region where α-SMA-expressing activated HSCs (aHSCs) showed co-localized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro co-culture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or co-culturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. CONCLUSION: We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.

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Purpose: We investigated potentially promising imaging findings and their combinations in the evaluation of cognitive decline. Materials and Methods: This retrospective study included 138 patients with subjective cognitive impairments, who underwent brain MRI. We classified the same group of patients into Alzheimer's disease (AD) and non-AD groups, based on the neuropsychiatric evaluation. We analyzed imaging findings, including white matter hyperintensity (WMH) and cerebral microbleeds (CMBs), using the Kruskal-Wallis test for group comparison, and receiver operating characteristic (ROC) curve analysis for assessing the diagnostic performance of imaging findings. Results: CMBs in the lobar or deep locations demonstrated higher prevalence in the patients with AD compared to those in the non-AD group. The presence of lobar CMBs combined with periventricular WMH (area under the ROC curve [AUC] = 0.702 [95% confidence interval: 0.599-0.806], p < 0.001) showed the highest performance in differentiation of AD from non-AD group. Conclusion: Combinations of imaging findings can serve as useful additive diagnostic tools in the assessment of cognitive decline.

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O-GlcNAcylation is a posttranslational modification where N-acetylglucosamine (O-GlcNAc) is attached and detached from a serine/threonine position by two enzymes: O-GlcNAc transferase and O-GlcNAcase. In addition to roles in diabetes and cancer, recent pharmacological and genetic studies have revealed that O-GlcNAcylation is involved in neuronal function, specifically synaptic transmission. Global alteration of the O-GlcNAc level does not affect basal synaptic transmission while the effect on synaptic plasticity is unclear. Although synaptic proteins that are O-GlcNAcylated are gradually being discovered, the mechanism of how O-GlcNAcylated synaptic protein modulate synaptic transmission has only been reported on CREB, synapsin, and GluA2 subunit of AMPAR. Future research enabling the manipulation of O-GlcNAcylation in individual synaptic proteins should reveal hidden aspects of O-GlcNAcylated synaptic proteins as modulators of synaptic transmission.

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AIM: To assess the acceptability and explore the utility of a novel digital platform designed as a student-facing well-being and mental health support. METHODS: An adapted version of i-spero® was piloted as a student-facing well-being support and as part of routine university-based mental health care. In both pathways, student participants completed baseline demographics and brief validated measures of well-being and mental health. Weekly measures of anxiety (GAD-7) and depression (PHQ-9) and a Week 8 Experience Survey were also scheduled. Integrated mixed methods analysis was used to assess acceptability and explore the utility of these platforms. RESULTS: Students in the well-being (n = 120) and care pathways (n = 121) were mostly female and between 19 and 22 years of age. Baseline screen positive rates for anxiety and depression were high in both the well-being (68%) and care pathways (80%). There was a substantial drop in adherence over Week 1 (50% well-being; 40% care) followed by minor attrition up to Week 8. Anxiety and depressive symptom levels improved from baseline in students who dropped out after Week 1 (p ≤ .06). The student experience was that i-spero® improved their emotional self-awareness, understanding of progress in care, and knowledge about when to seek help. Most students agreed (>75%) that i-spero® should form part of regular university student wellness support. CONCLUSIONS: Digital well-being and mental health support seems acceptable to university students; however, engagement and persistence are areas for further development. Such digital tools could make a positive contribution to an evidence-based stepped approach to student well-being and mental health support.

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BACKGROUND: In our prior study, the authors determined that pulling on the superficial adipose layer is more effective in lifting the skin than pulling on the superficial musculoaponeurotic system (SMAS). Applying this concept of using the superficial adipose layer to transmit the lifting force to the skin, this study examined improvements in patients who underwent lateral midface lifting using our minimally invasive multilayer lifting technique and measured the duration of those improvements. METHODS: Along the hairline in front of the sideburns, a W-shaped zigzag incision of 3 to 8 mm in width and 3 to 4 cm in length was made. On the temporal scalp, 3 to 4 cm away from the first incision, a second incision was made more lateral/posterior to the first incision, and an elliptical excision of 3 to 5 mm in width and 3 to 4 cm in length was made. From the medial cut margin of the anterior first incision, the superficial temporal fascia/SMAS (the deep layer), and the superficial adipose layer (the superficial layer) were purchased with 3-0 polyester sutures, tunneled under the soft tissue, and fixed to the deep temporal fascia of the second posterior temporal incision. Prior to the excised temporal scalp closure, the dermis in the medial cut margin of the second incision was pulled to the rear as much as possible and fixed to the deep temporal fascia. RESULTS: The effects of surgery were monitored for 6 to 42 months after surgery. The nasolabial folds were improved. Skin elasticity also showed significant improvements, which lasted throughout the follow-up period (up to 42 mo). CONCLUSIONS: Unlike traditional wide dissection SMAS facelift, our method requires minimal incisions and does not require skin undermining. Therefore, the operating time is shorter, and postoperative swelling is minimized. In our technique, the superficial adipose layer, the superficial temporal fascia/SMAS, and the dermis were pulled individually to lift all layers of the lateral midface soft tissues. This results in a significant and long-lasting lateral midface rejuvenation.

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Oral lichen planus (OLP) is a chronic inflammatory disease that is characterized by the infiltration of T cells into the oral mucosa, causing the apoptosis of basal keratinocytes. OLP is a multifactorial disease of unknown etiology and is not solely caused by the malfunction of a single key gene but rather by various intracellular and extracellular factors. Non-coding RNAs play a critical role in immunological homeostasis and inflammatory response and are found in all cell types and bodily fluids, and their expression is closely regulated to preserve normal physiologies. The dysregulation of non-coding RNAs may be highly implicated in the onset and progression of diverse inflammatory disorders, including OLP. This narrative review summarizes the role of non-coding RNAs in molecular and cellular changes in the oral epithelium during OLP pathogenesis.

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Oral squamous cell carcinoma (OSCC) is a tumor with a poor prognosis and a high recurrence rate. Despite its high annual incidence worldwide, appropriate therapeutic strategies have not yet been developed. Consequently, the 5­year survival rate for OSCC is low when advanced stages or recurrence is diagnosed. Forkhead transcriptional factor O1 (FoxO1) is a key mediator for maintaining cellular homeostasis. FoxO1 can function as a tumor suppressor as well as an oncogene depending on the cancer type. Therefore, the precise molecular functions of FoxO1 need to be validated, considering intracellular factors and the extracellular environment. To the best of our knowledge, however, the roles of FoxO1 in OSCC have not yet been defined. The present study examined FoxO1 levels under pathological conditions (oral lichen planus and oral cancer) and selected an appropriate OSCC cell line (YD­9). Crispr/Cas9 was used to generate FoxO1­deficient YD­9 cells in which the protein levels of phospho ERK and phospho STAT3 were upregulated, promoting cancer proliferation and migration. In addition, FoxO1 reduction increased the levels of the cell proliferation markers phospho H3 (Ser10) and PCNA. FoxO1 loss significantly reduced cellular ROS levels and apoptosis in YD­9 cells. Collectively, the present study demonstrated that FoxO1 exerted an anti­tumor effect by suppressing proliferation and migration/invasion but promoting oxidative stress­linked cell death in YD­9 OSCC cells.

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Sexually transmitted infections (STIs) have substantial morbidity and mortality worldwide, with over 1 million new infections occurring daily. Similarly, cardiovascular (CV) disease is the leading global cause of death and has tremendous impact on disability as well as quality of life. Several STIs have potential CV consequences and may precipitate reoccurrence of underlying CV comorbidity. Notably, untreated STIs and associated CV complications have an increased impact on marginalized individuals and those with limited access to health resources and care. Syphilis, human immunodeficiency virus, human papillomavirus, herpes simplex virus, hepatitis B, hepatitis C, cytomegalovirus, chlamydia, gonorrhea, and trichomoniasis have been identified as having CV implications. Yet, the data linking compromised CV health and STIs have not previously been summarized. The present review encapsulates the current knowledge surrounding the impacts of STIs on CV health as well as diagnostic and treatment strategies.

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Certain demographic groups are less likely to receive efficient Cardiopulmonary resuscitation (CPR), and poor representation of these groups in the manikins used for CPR simulation may play a role. The aim of the DIVERSE Study was to survey organizations that teach CPR to determine the demographic characteristics of the manikins they utilize for simulations. Institutions, businesses, and non-governmental organizations which provide CPR certification in North and Latin America were surveyed through a collaboration with the Emerging Leaders group of the Interamerican Society of Cardiology (SIAC). A total of 56 survey responses were received from North America (n = 18; 869 total manikins) and Latin America (n = 38; 1514 total manikins). Of the total manikins (n = 2383), 12% were non-white, 6% represented women, <1% represented a non-lean body habitus, and 1% represented pregnant individuals. Despite the importance of diverse manikin representation in simulation training, diverse representation is lacking in manikins used in North and Latin America.

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OBJECTIVE: To examine the impact of the COVID-19 pandemic on first year undergraduate student mental health. METHODS: As part of the Queen's University U-Flourish Student Well-Being and Academic Success study, three successive cohorts of students entering undergraduate studies in 2018 (pre-pandemic), 2019 (transitional), and 2020 (during pandemic) completed electronic surveys at entry and completion of first year. Validated self-report measures were used to assess mental health status including symptom levels of anxiety, depression, and insomnia, self-harm and frequency of substance use. Propensity matching and multivariable log-binomial regression were used in comparisons of mental health indicators across the cohorts. RESULTS: Clinically significant symptoms of depression, anxiety, insomnia, and self-harm were reported more frequently in the 2020-2021 cohort, coincident with remote learning and pandemic restrictions. In female students, screen positive rates for anxiety and depression, and suicidal ideation increased from about one-third to just under one-half in association with the pandemic (χ2, p < .01), while increases in mental health concerns were less pronounced among males. Among females, increases in clinically significant symptoms over first year appeared greatest during the pandemic year, while striking decreases in alcohol consumption in both females and males were reported in that same year. Studying under pandemic conditions had a negative impact on student well-being, social relationships and school connectedness, quality of learning experience, leisure activities, and optimism about future prospects. CONCLUSIONS: Mental health concerns including anxiety, depression and sleep problems increased in first year students during the pandemic, especially among females, while alcohol use declined. These findings highlight the negative mental health impact associated with studying under pandemic restrictions involving remote learning and social distancing.

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BACKGROUND: Mental health concerns are common among university students and maybe elevated among those with specific risk exposures. The study examined the association between childhood adversities and mental health outcomes among undergraduate university students and assessed whether psychosocial and behavioral factors mediate those associations. METHODS: The Queen's University Student Well-Being and Academic Success Survey identified two large cohorts of first-year undergraduate students entering university in Fall 2018 and 2019 (n = 5,943). At baseline, students reported sociodemographic information, family-related mental health history, childhood physical abuse, sexual abuse, peer bullying, and parental separation or divorce. Baseline and follow-up surveys in Spring 2019, Fall 2019, and Spring 2020 included validated measures of anxiety (7-item Generalized Anxiety Disorder) and depressive symptoms (9-item Patient Health Questionnaire ), non-suicidal self-harm, and suicidality, along with psychological processes and lifestyle variables. Repeated measures logistic regression using Generalized Estimating Equations was used to characterize the associations between childhood adversities and mental health outcomes and examine potential mediation. RESULTS: Adjusting for age, gender, ethnicity, familial mental illness, and parental education, any childhood abuse (odds ratio: 2.89; 95% confidence interval, 2.58 to 3.23) and parental separation or divorce (odds ratio: 1.29; 95% confidence interval, 1.12 to 1.50) were significantly associated with a composite indicator of mental health outcomes (either 9-item Patient Health Questionnaire score ≥10 or 7-item Generalized Anxiety Disorderscore ≥10 or suicidality or self-harm). The association with childhood abuse weakened when adjusted for perceived stress, self-esteem, and insomnia (odds ratio: 2.05; 95% confidence interval, 1.80 to 2.34), and that with parental divorce weakened when adjusted for self-esteem (odds ratio: 1.17; 95% confidence interval, 1.00 to 1.36). CONCLUSION: Childhood abuse and parental separation or divorce were associated with mental health concerns among university students. Childhood adversities may impact later mental health through an association with stress sensitivity, self-esteem, and sleep problems. The findings suggest that prevention and early intervention focusing on improving sleep, self-esteem, and coping with stress while considering the individual risk profile of help-seeking students may help support student mental health.

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Microglia are brain-resident macrophage-like cells that play critical roles in diverse pathophysiological conditions, including development, neurogenesis, tissue damage, and pathogenic infection. Identifying molecular switches that govern the fate and function of microglia would be valuable for maintaining brain homeostasis. Forkhead box protein O1 (FoxO1) is the first identified gene in the FoxO family and serves as a potent transcriptional regulator that participates in development, apoptosis, metabolism, and stress response. It has been recently reported that FoxO1 expression is downregulated in human microglia with age, but the role of FoxO1 has not been characterized so far. In the present study, we investigated the molecular function of FoxO1 in microglia by utilizing BV-2 cells. By generating FoxO1-deficient BV-2 microglia through Crispr/Cas9 system, we analyzed the influence of FoxO1 on redox status, metabolism, and polarization of microglia. Our data clearly showed that FoxO1 deficiency suppressed oxidative stress and cell death. In addition, FoxO1 level could modulate metabolic status and polarizing potential of BV-2 microglia. FoxO1 might be a critical element for the regulation of microglial cell physiology and the maintenance of the brain homeostasis.

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Background: Access to university mental health services is poorly characterized. Our objectives were to (1) assess patterns of access and (2) explore predictability of contact with student mental health services. Participants: Data derived from the U-Flourish study, which includes a survey of successive cohorts of incoming undergraduate students attending Queen's University, located in Ontario, Canada (Cohort 1: 2018, Cohort 2: 2019). Methods: Survey data sets were deterministically linked to administrative data provided by Student Wellness Services. Analyses included cross-tabulation, logistic and negative binomial regression. Predictive modeling used LASSO regression. Results: Baseline symptoms were robust determinants of access. For example, a PHQ-9 rating in the severe range (≥ 20) was associated with an OR of 9.71 (95% CI: 4.46-21.1). A predictive algorithm did not outperform cut point-based interpretation of PHQ-9 or GAD-7 ratings. Conclusions: Self-reported symptoms are consistently associated with service use, supporting the widespread use of symptom screens.

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Indium gallium nitride (InGaN)-based micro-LEDs (µLEDs) are suitable for meeting ever-increasing demands for high-performance displays owing to their high efficiency, brightness and stability1-5. However, µLEDs have a large problem in that the external quantum efficiency (EQE) decreases with the size reduction6-9. Here we demonstrate a blue InGaN/GaN multiple quantum well (MQW) nanorod-LED (nLED) with high EQE. To overcome the size-dependent EQE reduction problem8,9, we studied the interaction between the GaN surface and the sidewall passivation layer through various analyses. Minimizing the point defects created during the passivation process is crucial to manufacturing high-performance nLEDs. Notably, the sol-gel method is advantageous for the passivation because SiO2 nanoparticles are adsorbed on the GaN surface, thereby minimizing its atomic interactions. The fabricated nLEDs showed an EQE of 20.2 ± 0.6%, the highest EQE value ever reported for the LED in the nanoscale. This work opens the way for manufacturing self-emissive nLED displays that can become an enabling technology for next-generation displays.

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Electrogustometry (EGM) is one of the most useful diagnostic tools widely used to evaluate the taste function by measuring the perception threshold to electrogustatory stimuli on the tongue. However, the effects of oral environments on electrogustometric threshold (EGMT) remain to be established despite its simple applicability. Thus, this study aims to determine the effect of mucosal dryness on EGMT in 68 healthy subjects. The experiment was conducted in two different conditions. First, the baseline EGMT was measured when the dryness of the tongue surface was normal. Second, the EGMT was remeasured after the tongue was intentionally desiccated. The current study showed that the mean of the EGMT was significantly increased when the tongue was desiccated, possibly indicating the reduced sensitivity to electrogustatory stimuli. Such an alteration may be related to the disturbed EGM electrical circuit through the dried mucosa with enhanced impedance. Thus, these findings suggested that mucosal dryness should be considered for better evaluation of gustatory function using EGM.

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BACKGROUND: Perfectionism, low self-esteem and external locus of control are psychological constructs linked to insomnia, anxiety and depression. Examining how these constructs impact mental health and serve as risk factors for the development of clinically significant symptoms may help direct psychological support resources and preventative measures for university students. AIMS: To longitudinally examine associations between the aforementioned psychological constructs and symptoms of insomnia, anxiety and depression in a large representative sample of first-year university students. METHOD: Electronic surveys including validated measures of the predictors and outcomes were emailed to all first-year undergraduate students at entry to a major Canadian university, and followed up on at conclusion of the academic year. RESULTS: Compared with healthy sleepers, students screening positive for insomnia had lower self-esteem, higher self-evaluative perfectionism and increased external locus of control (all P < 0.001). Self-evaluative perfectionism (standardised ß = 0.13, P < 0.01), self-esteem (ß = -0.30, P < 0.001) and external locus of control (ß = 0.07, P = 0.02) measured at entry were significantly associated with insomnia symptoms at follow-up. Insomnia symptoms at entry were strong predictors of symptoms of depression (ß = 0.15, P < 0.001) and anxiety (ß = 0.16, P < 0.001) at follow-up, even after controlling for baseline symptoms of those disorders. CONCLUSIONS: Perfectionism, low self-esteem and external locus of control may predispose the development of insomnia symptoms in university students. In turn, insomnia symptoms appear to be robust predictors for depressive and anxiety symptoms. Sleep may be an important prevention target in university students.

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OBJECTIVES: To explore the impact of the COVID-19 pandemic on the experiences and mental health of university students. DESIGN: A cross-sectional study consisting of an electronic survey about students' experiences and concerns during the pandemic and the associated impact. In addition to the quantitative analysis, free-text responses were extracted and analysed using a framework technique. SETTING: Queen's University in Canada and the University of Oxford in the UK. PARTICIPANTS: Undergraduate students at Queen's University and first-year undergraduate students at the University of Oxford were invited to complete the COVID-19 supplement survey. This study included data from 3013 Queen's students as the primary focus and 339 Oxford students as a secondary comparison. RESULTS: Females at Queen's reported greater adherence to government recommendations to prevent the spread of COVID-19 (91.3% vs 86.7%, χ2 p<0.01) and were more likely to self-isolate (63.9% vs 57.0%, χ2 p<0.01) than males. A similar trend was seen among Oxford students. Students' concerns were wide ranging including those related to their learning experience, finances and future academic and career prospects. 78.9% of Queen's students and 50.4% of first-year Oxford students reported worries about the long-term impact on their academic and job prospects. A sizeable proportion of students also reported that the pandemic negatively impacted their plans to continue at university (29.4% of Queen's, 14.2% of Oxford) and disrupted activities important to their mental well-being. Key themes identified in the qualitative component included the negative impacts of social isolation, challenging academic changes and disruption to support services and means of coping. CONCLUSIONS: Overall, findings underscore the importance of addressing areas of student concern and the aspects of student life negatively impacted by the pandemic in order to maintain student well-being and support a successful university experience.

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Snakebite envenomation is a neglected tropical disease which can result in morbidity and mortality. Cardiac implications are poorly understood due to the low frequency of cardiotoxicity combined with a lack of robust information, as snakebites commonly occur in remote and rural areas. This review aims to assess cardiovascular implications of snakebite envenoming and proposes an algorithm for screening of cardiovascular manifestations. A systematic review was performed and 29 articles relating to cardiovascular involvement in snakebite envenomation were selected. Cardiovascular involvement seems to be rare and includes a wide spectrum of outcomes, such as myocardial infarction, ventricular dysfunction, hypotension, cardiac arrest, and myocarditis. In a significant proportion of the cases analyzed (24.39%), the cardiovascular manifestations had major consequences (cardiac arrest, myocardial infarction, malignant ventricular arrhythmias, or death). Clinical monitoring, physical examination, and early electrocardiogram should be considered as key measures to detect cardiovascular involvement in patients with evidence of systemic illness.

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BACKGROUND: Glioblastoma (GBM) is the most aggressive tumor residing within the central nervous system, with extremely poor prognosis. Although the cytotoxic effects of ginsenoside F2 (GF2) on GBM were previously suggested, the precise anti-GBM mechanism of GF2 remains unclear. The aim of this study was to explore the anti-cancer molecular mechanism of GF2 toward human GBM. METHODS: GF2-driven cellular toxicity was confirmed in two different GBM cells, U373 and Hs683. To test mitochondrial impairment driven by GF2, we examined the mitochondrial membrane potential, OCR, and ATP production. An intracellular redox imbalance was identified by measuring the relative ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), glutaredoxin (GLRX) mRNA expression, intracellular NAD+ level, and AMPK phosphorylation status. RESULTS: GF2 increased the percentage of cleaved caspase 3-positive cells and γH2AX signal intensities, confirming that GF2 shows the cytotoxicity against GBM. GO enrichment analysis suggested that the mitochondrial function could be negatively influenced by GF2. GF2 reduced the mitochondrial membrane potential, basal mitochondrial respiratory rate, and ATP production capacity. Our results showed that GF2 downregulated the relative GSH/GSSG, intracellular NAD+ level, and GLRX expression, suggesting that GF2 may alter the intracellular redox balance that led to mitochondrial impairment. CONCLUSION: GF2 reduces mitochondrial membrane potential, inhibits cellular oxygen consumption, activates AMPK signaling, and induces cell death. Our study examined the potential vulnerability of mitochondrial activity in GBM, and this may hold therapeutic promise.

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Aging is characterized by a progressive decline or loss of physiological functions, leading to increased susceptibility to disease or death. Several aging hallmarks, including genomic instability, cellular senescence, and mitochondrial dysfunction, have been suggested, which often lead to the numerous aging disorders. The periodontium, a complex structure surrounding and supporting the teeth, is composed of the gingiva, periodontal ligament, cementum, and alveolar bone. Supportive and protective roles of the periodontium are very critical to sustain life, but the periodontium undergoes morphological and physiological changes with age. In this review, we summarize the current knowledge of molecular and cellular physiological changes in the periodontium, by focusing on soft tissues including gingiva and periodontal ligament.