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Background: Gait function impairments are associated with the risk of various medical conditions in older adults. As gait function declines with advancing age, normative data are required for proper interpretation of gait function in older adults., Research Purpose: This study aimed to construct age-stratified normative data of non-dimensionally normalized temporal and spatial gait features in healthy older adults., Methods: We recruited 320 community-dwelling healthy adults aged 65 years or older from two prospective cohort studies. We stratified them into four age groups (65-69, 70-74, 75-79, and 80-84 years). Each age group comprised 40 men and 40 women. We obtained six gait features (cadence, step time, step time variability, step time asymmetry, gait speed, and step length) using a wearable inertia measurement unit attached on the skin overlying L3-L4 on the back. To mitigate the influence of body shape, we non-dimensionally normalized the gait features into unitless values using height and gravity., Result: The effect of age group was significant in all raw gait features (p < 0.001 for step time variability, speed and step length; p < 0.05 for cadence, step time and step time asymmetry), and that of sex was significant in the five raw gait features, except for step time asymmetry(p < 0.001 for cadence, step time, speed, and step length; p < 0.05 for step time asymmetry). When gait features were normalized, the effect of age group remained (p < 0.001 for all gait features), whereas that of sex disappeared (p > 0.05 for all gait features)., Significance: Our dimensionless normative data on gait features may be useful in comparative studies of gait function between sexes or ethnicities with different body shapes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: There are growing concerns about the impact of the COVID-19 pandemic on the mental health of older adults. We examined the effect of the pandemic on the risk of depression in older adults., Methods: We analyzed data from the prospective cohort study of Korean older adults, which has been followed every 2 years. Among the 2308 participants who completed both the third and the fourth follow-up assessments, 58.4% completed their fourth follow-up before the outbreak of COVID-19 and the rest completed it during the pandemic. We conducted face-to-face diagnostic interviews using Mini International Neuropsychiatric Interview and used Geriatric Depression Scale. We performed generalized estimating equations and logistic regression analyses., Results: The COVID-19 pandemic was associated with increased depressive symptoms in older adults [ b (standard error) = 0.42 (0.20), p = 0.040] and a doubling of the risk for incident depressive disorder even in euthymic older adults without a history of depression (odds ratio = 2.44, 95% confidence interval 1.18-5.02, p = 0.016). Less social activities, which was associated with the risk of depressive disorder before the pandemic, was not associated with the risk of depressive disorder during the pandemic. However, less family gatherings, which was not associated with the risk of depressive disorder before the pandemic, was associated with the doubled risk of depressive disorder during the pandemic., Conclusions: The COVID-19 pandemic significantly influences the risk of late-life depression in the community. Older adults with a lack of family gatherings may be particularly vulnerable.

Our previous studies have evaluated the bioactivities of a fucoidan isolated from Sargassum fusiforme (SF-F). To further investigate the health benefit of SF-F, in the present study, the protective effect of SF-F against ethanol (EtOH)-induced oxidative damage has been evaluated in in vitro and in vivo models. SF-F effectively improved the viability of EtOH-treated Chang liver cells by suppressing apoptosis. In addition, the in vivo test results indicate that SF-F significantly and dose-dependently increased the survival rate of zebrafish treated with EtOH. Further research results show that this action works through decreasing cell death via reduced lipid peroxidation by scavenging intracellular reactive oxygen species in EtOH-stimulated zebrafish. These results indicate that SF-F effectively protected Chang liver cells and zebrafish against EtOH-induced oxidative damage and suggest the potential of SF-F to be used as an ingredient in the functional food industry.

Although titanium (Ti) alloys have been widely employed as biomedical materials, they cannot achieve satisfactory osseointegration when implanted in the human body due to their biologically inert nature. Surface modification can enhance both their bioactivity and corrosion resistance. The present study employed a Ti-5Nb-5Mo alloy with a metastable α″ phase. This alloy may undergo phase changes after conventional high-temperature heat treatment, which can deteriorate its properties. This study heat-treated the anodized Ti-5Nb-5Mo alloy by using a low-temperature hydrothermal or vapor thermal method to analyze the effects of heat treatment on its apatite induction. The results revealed that the porous nanotube structure on the surface of the alloy was transformed into anatase nanoparticles after hydrothermal or vapor thermal treatment at 150 °C for 6 h. After immersion in simulated body fluid (SBF) for 7 days, the amount of apatite deposited on the surface of the vapor thermal-treated alloy exceeded that on the hydrothermal-treated alloy. Therefore, post-heat treatment of anodized Ti-5Nb-5Mo by using the vapor thermal method can enhance its apatite inductivity without altering its structure.

Background: Basic life support (BLS) education is essential for improving bystander cardiopulmonary resuscitation (CPR) rates, but the imparting of such education faces obstacles during the outbreak of emerging infectious diseases, such as COVID-19. When face-to-face teaching is limited, distance learning-blended learning (BL) or an online-only model-is encouraged. However, evidence regarding the effect of online-only CPR training is scarce, and comparative studies on classroom-based BL (CBL) are lacking. While other strategies have recommended self-directed learning and deliberate practice to enhance CPR education, no previous studies have incorporated all of these instructional methods into a BLS course., Objective: This study aimed to demonstrate a novel BLS training model-remote practice BL (RBL)-and compare its educational outcomes with those of the conventional CBL model., Methods: A static-group comparison study was conducted. It included RBL and CBL courses that shared the same paradigm, comprising online lectures, a deliberate practice session with Little Anne quality CPR (QCPR) manikin feedback, and a final assessment session. In the main intervention, the RBL group was required to perform distant self-directed deliberate practice and complete the final assessment via an online video conference. Manikin-rated CPR scores were measured as the primary outcome; the number of retakes of the final examination was the secondary outcome., Results: A total of 52 and 104 participants from the RBL and CBL groups, respectively, were eligible for data analysis. A comparison of the 2 groups revealed that there were more women in the RBL group than the CBL group (36/52, 69.2% vs 51/104, 49%, respectively; P=.02). After adjustment, there were no significant differences in scores for QCPR release (96.9 vs 96.4, respectively; P=.61), QCPR depth (99.2 vs 99.5, respectively; P=.27), or QCPR rate (94.9 vs 95.5, respectively; P=.83). The RBL group spent more days practicing before the final assessment (12.4 vs 8.9 days, respectively; P<.001) and also had a higher number of retakes (1.4 vs 1.1 times, respectively; P<.001)., Conclusions: We developed a remote practice BL-based method for online-only distant BLS CPR training. In terms of CPR performance, using remote self-directed deliberate practice was not inferior to the conventional classroom-based instructor-led method, although it tended to take more time to achieve the same effect., Trial Registration: Not applicable., (©Kah Meng Chong, Hsiang-Wen Yang, Hsien-Chin He, Wan-Ching Lien, Mei-Fen Yang, Chien-Yu Chi, Yen-Pin Chen, Chien-Hua Huang, Patrick Chow-In Ko. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 05.04.2023.)

Importance: Although couples may share many risk factors for depressive disorders in their lifetime, whether these factors mediate the shared risk of depressive disorders has rarely been investigated., Objectives: To identify the shared risk factors for depressive disorder in couples and investigate their mediating roles in the shared risk of depressive disorders among older adult couples., Design, Setting, and Participants: This nationwide, multicenter, community-based cohort study assessed 956 older adults from the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) and a cohort of their spouses (KLOSCAD-S) between January 1, 2019, to February 28, 2021., Exposures: Depressive disorders of the KLOSCAD participants., Main Outcomes and Measures: The mediating roles of shared factors in couples on the association between one spouse's depressive disorder and the other's risk of depressive disorders was examined using structural equation modeling., Results: A total of 956 KLOSCAD participants (385 women [40.3%] and 571 men [59.7%]; mean [SD] age, 75.1 [5.0] years) and their spouses (571 women [59.7%] and 385 men [40.3%]; mean [SD] age, 73.9 [6.1] years) were included. The depressive disorders of the KLOSCAD participants were associated with an almost 4-fold higher risk of depressive disorders in their spouses in the KLOSCAD-S cohort (odds ratio, 3.89; 95% CI, 2.06-7.19; P < .001). Social-emotional support mediated the association between depressive disorders in the KLOSCAD participants and their spouses' risk of depressive disorders by itself (β = 0.012; 95% CI, 0.001-0.024; P = .04; mediation proportion [MP] = 6.1%) and through chronic illness burden (β = 0.003; 95% CI, 0.000-0.006; P = .04; MP = 1.5%). Chronic medical illness burden (β = 0.025; 95% CI, 0.001-0.050; P = .04; MP = 12.6%) and presence of a cognitive disorder (β = 0.027; 95% CI, 0.003-0.051; P = .03; MP = 13.6%) mediated the association., Conclusions and Relevance: The risk factors shared by older adult couples may mediate approximately one-third of the spousal risk of depressive disorders. Identification of and intervention in the shared risk factors of depression among older adult couples may reduce the risk of depressive disorders in the spouses of older adults with depression.

Background/purpose: 5-Fluorouracil (5FU) is a commonly used anticancer drug. However, the severe oral mucositis induced by 5FU in about 60-70% of patients was a major cause of discontinuous therapy. Since oral dysbiosis induced by 5FU was well correlated with severity of oral mucositis and Porphyromonas gingivalis (P.g.) was a keystone pathogen of dysbiosis. Thus, in this study, we aimed to explore the novel regimens of 5FU combined with phytopolyphenols (curcumin, green tea polyphenols) as well as ZnSO 4 on antibacterial effects of cultured P.g. growth. In addition, similar regimens containing thioridazine (TRZ) were also tested for their antibacterial efficacy., Materials and Methods: The synergistic (Combination Index (CI) < 1) antiproliferation and anti-protease efficacies (IC50) of novel regimens on cultured P.g. were evaluated by OD600 and colorimetric method respectively., Results: The results obtained indicated that both novel regimens of 5FU and TRZ exhibited potent synergistic antibacterial effects against growth and protease of P.g., Conclusion: These novel regimens of 5-FU and TRZ were potent antibacterial agents which merit for further preclinical and clinical trials in management of oral mucositis, cancers and infectious diseases., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier.)

Background/purpose: Oral submucous fibrosis (OSF) is a premalignant disorder that is associated with betel nut chewing. The purpose of the study was to establish the role of histone deacetylase (HDAC) 8, one of histone deacetylases, in the regulation of fibrotic conditions to provide a therapeutic potential for OSF., Materials and Methods: First, we examined the expression of HDAC8 in fibrotic buccal mucosal fibroblasts (fBMFs) and OSF tissues. Markers of myofibroblasts and TGF-β signaling were conducted in fBMFs with HDAC8 knockdown were examined. Furthermore, epithelial-mesenchymal transition (EMT) markers, collagen gel contraction and migration ability were also examined in fBMFs transfected with sh-HDAC8. HDAC8 inhibitor was used to analyze the collagen gel contraction and wound healing ability in fBMFs., Results: We observed the mRNA expression of HDAC8 was significantly increased in fBMFs. Compared to normal tissues, the protein level of HDAC8 was upregulated in OSF. Next, mRNA and protein expression of HDAC8 was significantly decreased, accompanying downregulation of α-SMA and COL1A1 in fBMFs infected with sh-HDAC8. To determine the critical role of HDAC8 in OSF fibrogenesis, results revealed that TGF-β secretion and the expression of EMT transcription factor SNAIL and p-Smad were significantly decreased in HDAC8-knockdown fBMFs. We further demonstrated that collagen gel contraction and migration ability were significantly decreased in fBMFs transfected with sh-HDAC8. Last, results revealed that significantly reduced collagen gel contraction and wound healing ability in fBMFs with HDAC8 inhibitor treatment., Conclusion: We concluded that downregulation of HDAC8 alleviated the activities of myofibroblasts and TGF-β/Smad signaling pathway in OSF., Competing Interests: The authors have no conflicts of interest to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

The importance of early science, technology, engineering, and math (STEM) learning opportunities for all young children has become increasingly documented by research and recommended practices. In addition, high quality inclusive settings where all children can access and benefit from learning activities continues to demonstrate optimal outcomes for all children. This manuscript reports findings from a survey broadly disseminated related to early childhood practitioners' and directors' perceptions related to STEM and inclusion and explores what practices related to STEM and inclusion are currently being used by early childhood practitioners and directors. While the majority of respondents supported the importance of both STEM and inclusion, there were varied responses related to relevance for infants and toddlers and inconsistent reports of specific practices being used. The findings suggest the need to emphasize and provide professional development opportunities focused on STEM and inclusion for our early childhood workforce more explicitly. Additional implications for research and practice are discussed., Supplementary Information: The online version contains supplementary material available at 10.1007/s10643-023-01476-w., Competing Interests: Conflict of interestThe authors declare no conflicts of interest., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Cardiopulmonary resuscitation (CPR) education for the public may improve bystander intention to perform CPR on cardiac arrest patients. Studies have shown that different CPR education intervention methods can improve learning performance, with key indicators including attitude toward to CPR, intention to perform CPR, and degree of CPR knowledge and skills. The present study compared the traditional face-to-face method to hybrid and virtual reality (VR) methods to observe difference in learning performance and length of performance retention. This study adopted randomized controlled trial to compare CPR learning performance between traditional face-to-face, hybrid, and VR methods. Participants from each intervention group completed a pretest and 2 posttests. The measurement tools included an attitude and intention questionnaire, knowledge examination, and skill examination with a RESUSCI ANNE QCPR ® manikin. The performance among all participants in pretest showed no significant difference between the intervention groups, indicating no difference in their background attitude, knowledge, and skill level. Significant differences were observed in the average degree of intention to perform CPR between the hybrid and traditional groups in 1st and 2nd posttest. Compared to the pretest results, the posttests revealed significantly higher attitude toward CPR, intention to perform CPR, knowledge examination results, accuracy of overall chest compression, accuracy of CPR procedure, accuracy of AED usage, accuracy of chest compression rate, and accuracy of chest compression depth. The average time to reattending CPR learning and practice session was 11-12 weeks reported by participants. The hybrid and VR methods to CPR education resulted in the same level of improvement in learning performance as traditional face-to-face teaching. The suggested frequency for renewing CPR knowledge and skills is 12 weeks which may be considered in new strategies aimed at promoting CPR education and exposure to the public., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hypertension is the most common complication of chronic kidney disease (CKD) in children but is still poorly controlled. Nitric oxide (NO) deficiency plays a pivotal role in CKD and hypertension. NO is known to have health benefits, while NO typically has a short half-life and is not specifically targeted. In this study, we used a pediatric CKD model, which was induced in young rats by feeding them 0.25% adenine. We investigated two different NO donors, namely S-nitrosoglutathione (GSNO) and diethylenetriamine/NO adduct (DETA NONOate) via intraperitoneal injection at 10 mg/kg/day daily for 3 weeks. GSNO was delivered by Cu 2+ -doped zeolitic imidazolate framework (Cu/ZIF-8) nanoparticles to generate NO. As a result, we observed Cu/ZIF-8 nanoparticles were successfully loaded with GSNO and were able to release NO. Young rats fed with adenine displayed kidney dysfunction and hypertension at 9 weeks of age, which were prevented by GSNO-loaded nanoparticle or DETA NONOate treatment. GSNO-loaded nanoparticles reduced CKD-induced hypertension, which was related to an enhanced endogenous NO-generating system, reduced renal oxidative stress, and downregulated several components belonging to the classic renin-angiotensin (RAS) system. Our results cast new light on targeting NO delivery through the use of nanoparticles aiming to improve child-focused outcomes related to CKD worthy of clinical translation.

Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease of the nose and sinuses that affects more than 10% of the adult population worldwide. Currently, CRS is classified into endotypes according to the inflammatory response (Th1, Th2, and Th17) or the distribution of immune cells in the mucosa (eosinophilic and non-eosinophilic). CRS induces mucosal tissue remodeling. Extracellular matrix (ECM) accumulation, fibrin deposition, edema, immune cell infiltration, and angiogenesis are observed in the stromal region. Conversely, epithelial-to-mesenchymal transition (EMT), goblet cell hyperplasia, and increased epithelial permeability, hyperplasia, and metaplasia are found in the epithelium. Fibroblasts synthesize collagen and ECM, which create a structural skeleton of tissue and play an important role in the wound-healing process. This review discusses recent knowledge regarding the modulation of tissue remodeling by nasal fibroblasts in CRS.

Background: Glycolytic reprogramming is a key feature of chronic inflammatory disease. Extracellular matrix (ECM) produced by myofibroblasts plays an important role in tissue remodeling of nasal mucosa in chronic rhinosinusitis (CRS). This study aimed to determine whether glycolytic reprogramming contributes to myofibroblast differentiation and ECM production in nasal fibroblasts., Methods: Primary nasal fibroblasts were isolated from the nasal mucosa of patients with CRS. Glycolytic reprogramming was assessed by measuring the extracellular acidification and oxygen consumption rates in nasal fibroblast, with and without transforming growth factor beta 1 (TGF-β1) treatment. Expression of glycolytic enzymes and ECM components was measured by real-time polymerase chain reaction, western blotting, and immunocytochemical staining. Gene set enrichment analysis was performed using whole RNA-sequencing data of nasal mucosa of healthy donors and patients with CRS., Result: Glycolysis of nasal fibroblasts stimulated with TGF-B1 was upregulated along with glycolytic enzymes. Hypoxia-inducing factor (HIF)-1α was a high-level regulator of glycolysis, and increased HIF-1α expression promoted glycolysis of nasal fibroblasts, and inhibition of HIF-1α down-regulated myofibroblasts differentiation and ECM production., Conclusion: This study suggests that inhibition of the glycolytic enzyme and HIF-1α in nasal fibroblasts regulates myofibroblast differentiation and ECM generation associated with nasal mucosa remodeling., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte-neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-Cre ERT2 ; PKM2 f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.

Erwinia amylovora causes a devastating fire blight disease in apples and pears. One of the main virulence determinants in E. amylovora is the hypersensitive response (HR) and pathogenicity ( hrp )-type III secretion system (T3SS), which is activated by the RpoN-HrpL sigma factor cascade. However, the RpoN regulon in E. amylovora has not been investigated. In this study, we determined the RpoN regulon in E. amylovora by combining RNA-seq transcriptomic analysis with in silico binding site analysis. RNA-seq revealed that 262 genes, approximately 7.5% genes in the genome of E. amylovora , were differentially transcribed in the rpoN mutant as compared with the wild type. Specifically, genes associated with virulence, motility, nitrogen assimilation, the PspF system, stress response, and arginine biosynthesis are positively regulated by RpoN, whereas genes associated with biosynthesis of amino acids and sorbitol transport are negatively regulated by RpoN. In silico binding site analysis identified 46 potential target genes with a putative RpoN binding site, and the upstream sequences of six, three, and three genes also contain putative GlnG, PspF, and YfhA binding sites, respectively. Overall, RpoN directly regulates genes associated with virulence, nitrogen assimilation, the PspF system, motility and the YfhA/YfhK two-component regulatory system.

Objective: This study aimed to explore possible associations between molecular subtypes and site of distant metastasis in advanced breast cancer (ABC)., Methods: 3577 ABC patients were selected from 21 hospitals of seven geographic regions in China from 2012-2014. A questionnaire was designed to collect medical information regarding demographic characteristics, risk factors, molecular subtype, recurrence/metastasis information, and disease-free survival (DFS). The cancers were classified into Luminal A, Luminal B, HER2-enriched and Triple Negative subtypes. Chi-square test and multivariate Cox proportional hazard models were performed to explore the associations between molecular subtypes and distant metastasis sites., Results: A total of 2393 cases with molecular subtypes information were finally examined. Patients with Luminal A (51.1%) and Luminal B (44.7%) were most prone to bone metastasis, whereas liver metastasis was more frequently observed in HER2-enriched ABC patients (29.1%).The cumulative recurrence and metastasis rates of ABC patients at 36 months of DFS were the most significant within molecular types, of which Triple Negative was the highest (82.7%), while that of Luminal A was the lowest (58.4%). In the adjusted Cox regression analysis, Luminal B, HER2-enriched and Triple Negative subtypes increased the risk of visceral metastasis by 23%, 46% and 87% respectively. In addition, Triple Negative patients had a higher probability of brain metastasis (HR 3.07, 95% CI: 1.04-9.07)., Conclusion: Molecular subtypes can predict the preferential sites of distant metastasis, emphasizing that these associations were of great help in choices for surveillance, developing appropriate screening and cancer management strategies for follow-up and personalized therapy in ABC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer QZ declared a shared parent affiliation with the author TH to the handling editor at the time of review., (Copyright © 2023 Fan, Zhang, Yang, Yi, Ouyang, Yan, Wang, Hu, Jiang, Huang, Tong, Wang, Yin, Li, Yang, Yang, Teng, Sun, Cai, Li, Ouyang, He, Liu, Yang, Wang, Xu and Qiao.)

Biochar, as a soil amendment for synergizing the reduction of pollution and carbon emissions, shows great potential and future prospects in controlling antibiotic contamination. In order to research the effects of biochar on antibiotic behaviors in soil systematically, a Meta-analysis was conducted based on 20 studies published from 2011 to 2021. The results showed that the adsorption and degradation of antibiotics in the soil were significantly affected by the application rate and property of biochar. A 2% biochar application dose seemed to be the highest effect size (ES) of 0.19 on adsorption, while there was a significant effect (ES=0.23) on the degradation when the application rate was 5%. The specific surface area, polarity, stability, and aromaticity of biochar could increase the partition coefficient significantly, and the ES was 0.11, 0.13, 0.09, and 0.18, respectively, whereas the effects of antibiotic transport on the dose and property of biochar were insignificant. Biochar also indirectly controlled antibiotic behavior by altering the soil environment. However, the response of the coupling mechanism in antibiotic behaviors on biochar application into soil is still unclear. Moreover, the long-term and negative effects of biochar application in the field are still lacking basic data.

Introduction: Daytime napping is frequently seen in older adults. The longitudinal relationship between daytime napping and cognitive aging is unknown., Methods: Using data from 1401 participants of the Rush Memory and Aging Project, we examined the longitudinal change of daytime napping inferred objectively by actigraphy, and the association with incident Alzheimer's dementia during up to 14-year follow-up., Results: Older adults tended to nap longer and more frequently with aging, while the progression of Alzheimer's dementia accelerates this change by more than doubling the annual increases in nap duration/frequency. Longer and more frequent daytime naps were associated with higher risk of Alzheimer's dementia. Interestingly, more excessive (longer or more frequent) daytime napping was correlated with worse cognition a year later, and conversely, worse cognition was correlated with more excessive naps a year later., Discussion: Excessive daytime napping and Alzheimer's dementia may possess a bidirectional relationship or share common pathophysiological mechanisms., (© 2022 the Alzheimer's Association.)

The locus coeruleus (LC) consists of noradrenergic (NA) neurons and plays an important role in controlling behaviours. Although much of the knowledge regarding LC functions comes from studying behavioural outcomes upon administration of muscarinic acetylcholine receptor (mAChR) agonists into the nucleus, the exact mechanisms remain unclear. Here, we report that the application of carbachol (CCh), an mAChR agonist, increased the spontaneous action potentials (sAPs) of both LC-NA neurons and local inhibitory interneurons (LC I-INs) in acute brain slices by activating M1/M3 mAChRs (m 1/3 AChRs). Optogenetic activation of LC I-INs evoked inhibitory postsynaptic currents (IPSCs) in LC-NA neurons that were mediated by γ-aminobutyric acid type A (GABA A ) and glycine receptors, and CCh application decreased the IPSC amplitude through a presynaptic mechanism by activating M4 mAChRs (m 4 AChRs). LC-NA neurons also exhibited spontaneous phasic-like activity (sPLA); CCh application increased the incidence of this activity. This effect of CCh application was not observed with blockade of GABA A and glycine receptors, suggesting that the sPLA enhancement occurred likely because of the decreased synaptic transmission of LC I-INs onto LC-NA neurons by the m 4 AChR activation and/or increased spiking rate of LC I-INs by the m 1/3 AChR activation, which could lead to fatigue of the synaptic transmission. In conclusion, we report that CCh application, while inhibiting their synaptic transmission, increases sAP rates of LC-NA neurons and LC I-INs. Collectively, these effects provide insight into the cellular mechanisms underlying the behaviour modulations following the administration of muscarinic receptor agonists into the LC reported by the previous studies., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Neuroinflammation plays a critical role in the neurological recovery of spinal cord injury (SCI). Adenosine can modulate neuroinflammation, whose uptake is mediated by nucleoside transporters. This study aimed to investigate the roles of equilibrative nucleoside transporter 1 (Ent1) in the inflammatory responses and functional recovery of SCI. Spinal cord contusion at the T10 dorsal portion was induced in mice to cause partial paralysis of the hindlimbs. Genetic deletion and pharmacological inhibition of Ent1 were used to evaluate the role of Ent1 in SCI. The outcomes were evaluated in terms of the Basso Mouse Scale (BMS), gait analysis, astrogliosis, microgliosis, and cytokine levels on day 14 post-injury. As a result, Ent1 deletion reduced neuroinflammation and improved the BMS score (4.88 ± 0.35 in Ent1 -/- vs. 3.78 ± 1.09 in Ent1 +/+ ) and stride length (3.74 ± 0.48 cm in Ent1 -/- vs. 2.82 ± 0.78 cm in Ent1 +/+ ) of mice with SCI. Along with the reduced lesion size, more preserved neurons were identified in the perilesional area of mice with Ent1 deletion (102 ± 23 in Ent1 -/- vs. 73 ± 10 in Ent1 +/+ ). The results of pharmacological inhibition were consistent with the findings of genetic deletion. Moreover, Ent1 inhibition decreased the protein level of complement 3 (an A1 marker), but increased the levels of S100 calcium-binding protein a10 (an A2 marker) and transforming growth factor-β, without changing the levels of inducible nitric oxide synthase (a M1 marker) and arginase 1 (a M2 marker) at the injured site. These findings indicate the important role of Ent1 in the pathogenesis and treatment of SCI., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Children with disabilities (CWD) tend to participate in fewer physical activities than typically developing children. During motor play, CWD often depend on teachers to provide direct instruction and frequent opportunities to practice motor skills, to interact with their peers, and learn new skills. To promote participation in physical activities for CWD, it is necessary to understand (a) teachers' perceptions about the importance of structured motor programs and (b) teachers' thoughts and concerns about implementing structured motor programs. The aim of this study was to understand teachers' perceptions about structured motor programs (e.g., obstacle course, bowling) and factors that may influence their motivation to implement them. Semi-structured interviews were conducted with 17 teachers who taught in inclusive preschools. Interview data were transcribed and analyzed to identify key themes. The results show that the majority of participants valued structured motor programs and were aware of the benefits of implementing such programs with preschoolers. Several teachers expressed concerns about meeting the expectations of a motor program and preschoolers' challenging behaviors during such programs. Implications for practice from this study include the need to (a) provide professional development to help teachers support preschoolers with disabilities in learning motor skills and understanding how to arrange and scaffold opportunities for children to participate in physical activities and gross motor play with their typically developing peers, and (b) create quality structured motor programs to ensure that all children have access to motor learning opportunities in inclusive preschool settings., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

The kilometer square array (KM2A) of the large high altitude air shower observatory (LHAASO) aims at surveying the northern γ-ray sky at energies above 10 TeV with unprecedented sensitivity. γ-ray observations have long been one of the most powerful tools for dark matter searches, as, e.g., high-energy γ rays could be produced by the decays of heavy dark matter particles. In this Letter, we present the first dark matter analysis with LHAASO-KM2A, using the first 340 days of data from 1/2-KM2A and 230 days of data from 3/4-KM2A. Several regions of interest are used to search for a signal and account for the residual cosmic-ray background after γ/hadron separation. We find no excess of dark matter signals, and thus place some of the strongest γ-ray constraints on the lifetime of heavy dark matter particles with mass between 10^{5} and 10^{9}  GeV. Our results with LHAASO are robust, and have important implications for dark matter interpretations of the diffuse astrophysical high-energy neutrino emission.

Heavy metal pollution in urban soils and dust is mostly caused by extensive anthropogenic activity during urbanization and industrialization. In this research study, the pollution characteristics, sources, ecological and human health risks of heavy metals in urban soil, and dust have been thoroughly evaluated. The research findings demonstrate that dust has a higher level of contamination than urban soil, such as Pb, Cu, and Zn metals are more contaminated in both urban soil and dust throughout the city, and Hg and As are also found in locations with a high concentration of heavy industrial companies. This implies that traffic emissions are still a significant source of metals in urban areas, though industrial companies also contribute. The health risk assessment model used to calculate human exposure revealed that the non-carcinogenic and carcinogenic risks of selected metals in soil and dust were generally in the low range, except for the carcinogenic risk from Cr in children. Statistical analysis revealed that Cr and Ni concentrations were mainly of natural origin, Cu and Zn have been sourced from traffic, whereas Pb, Hg, and As have been sourced from industrial activities. The overall recommendation is that the road traffic environment and municipal construction facilities need to be improved to ensure the sustainable development of the city's environment, while pollution from industrial waste is strongly controlled., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Traumatic brain injury (TBI) broadly degrades the normal function of the brain after a bump, blow, or jolt to the head. TBI leads to the aggravation of pre-existing brain dysfunction and promotes neurotoxic cascades that involve processes such as oxidative stress, loss of dendritic arborization, and zinc accumulation. Acid sphingomyelinase (ASMase) is an enzyme that hydrolyzes sphingomyelin to ceramide in cells. Under normal conditions, ceramide plays an important role in various physiological functions, such as differentiation and apoptosis. However, under pathological conditions, excessive ceramide production is toxic and activates the neuronal-death pathway. Therefore, we hypothesized that the inhibition of ASMase activity by imipramine would reduce ceramide formation and thus prevent TBI-induced neuronal death. To test our hypothesis, an ASMase inhibitor, imipramine (10 mg/kg, i.p.), was administrated to rats immediately after TBI. Based on the results of this study, we confirmed that imipramine significantly reduced ceramide formation, dendritic loss, oxidative stress, and neuronal death in the TBI-imipramine group compared with the TBI-vehicle group. Additionally, we validated that imipramine prevented TBI-induced cognitive dysfunction and the modified neurological severity score. Consequently, we suggest that ASMase inhibition may be a promising therapeutic strategy to reduce hippocampal neuronal death after TBI.

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

The construction of carbon-coated heterostructures of bimetallic sulfide is an effective technique to improve the electrochemical activity of anode materials in lithium-ion batteries. In this work, the carbon-coated heterostructured ZnS-FeS 2 is prepared by a two-step hydrothermal method. The crystallinity and nature of carbon-coating are confirmed by the investigation of XRD and Raman spectroscopy techniques. The nanoparticle morphology of ZnS and plate-like morphology of FeS 2 is established by TEM images. The chemical composition of heterostructure ZnS-FeS 2 @C is discovered by an XPS study. The CV results have disclosed the charge storage mechanism, which depends on the capacitive and diffusion process. The BET surface area (37.95 m 2 g -1 ) and lower R ct value (137 Ω) of ZnS-FeS 2 @C are beneficial to attain higher lithium-ion storage performance. It delivered a discharge capacity of 821 mAh g -1 in the 500th continuous cycle @ A g -1 , with a coulombic efficiency of around 100%, which is higher than the ZnS-FeS 2 heterostructure (512 mAh g -1 ). The proposed strategy can improve the electrochemical performance and stability of lithium-ion batteries, and can be helpful in finding highly effective anode materials for energy storage devices.

We have developed a novel molecular diagnostic platform (photothermal bead-based nucleic acid amplification test; pbbNAAT) that greatly improves the low sensitivity of direct loop-mediated isothermal amplification (LAMP) and allows for specific detection of LAMP amplicons in complex samples. The pbbNAAT integrates specific ligand-functionalized polypyrrole-coated iron oxide particles (PPy@IOs) capable of photothermal conversion and single-molecule magnetic capture of target analytes, the released nucleic acid, and LAMP-amplified products under external light energy control and magnetic manipulations. This allows for sample pretreatment, pbbLAMP amplification, and subsequent amplicon detection with bead-based ELISA in a one-stop microreactor without loss. In addition, photonic heating with PPy@IOs and external light control provide instant and uniform heating for thermolysis and pbbLAMP implementations. Moreover, it generates higher primer annealing stringency for LAMP primers in pbbLAMP; thus, it can detect pathogen-specific DNA accurately and promptly in pathogen-spiked complex materials. The sample pretreatment procedure of pbbNAAT can greatly reduce inhibitors originating from complex samples, which enables the maintenance of maximal enzyme activities for highly sensitive detection. More importantly, the pbbLAMP assay coupled with magnetic capture permits subsequent bead-based ELISA detection to determine true positive LAMP amplicons on PPy@IOs. The pbbNAAT platform has a high tolerance to inhibitors originating from complex samples, high analytical specificity, and limitation of detection (LoD) as low as 8 CFU/reaction to detect E. coli spiked in human whole blood, bovine milk, and can be completed in less than 1 h. Therefore, we believe that pbbNAAT can serve as a suitable direct LAMP platform for on-site POCTs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A large number of female goats are needed for the dairy goat industry; therefore, the development of a method to ensure the birth of more females than males in a single pregnancy will lead to economic benefits. Increasing the number of X-sperm would be an effective way to increase the proportion of female offspring. In this study, goat semen was incubated at pH 7.4 in alkaline diluent combined with resiquimod (R848) and the number of X-sperm was enriched by the swim-up method. The percentage of X-sperm was determined using the double TaqMan qPCR method. Sperm total motility, progressive motility, average path velocity, straight-line velocity, and curvilinear velocity were measured using a computer-aided sperm analysis system, and the functional parameters of the sperm plasma membrane, the acrosome, mitochondrial activity, ATP content, and reactive oxygen species levels were also measured. Lastly, the ratio of female embryos was determined by in vitro fertilization, and the number of female kids and the pregnancy rate of does was assessed by artificial insemination. The results showed that dilution of semen in an alkaline buffer containing R848 could enrich the number of X-sperm to 85.57% ± 3.27%. The progressive motility, average path velocity, straight-line velocity, curvilinear velocity, mitochondrial activity, and ATP level of the collected X-sperm-enriched semen were significantly reduced, but its total motility, plasma membrane, and acrosome were not affected. The in vitro fertilization experiments showed that the rate of female embryo production using X-sperm-rich seminal fluid could reach 83.25% (174/209), which was significantly higher than the proportion of female embryos in the control group, 47.71% ± 1.80% (104/218). As determined by artificial insemination, the number of female kids in the test group increased by 62.79% (243/387), which was significantly higher than that in the control group (47.65%, 193/405). There was no significant difference in pregnancy rate between the test group and the control group (71.71% vs. 78.48%). Therefore, this study demonstrated that use of a pH 7.4 diluent containing R848 is a simple and effective method of X-sperm enrichment for dairy goat production. Its application would allow does to produce more female offspring for herd expansion and milk production., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Kaposi sarcoma (KS) is a malignant vascular neoplasm caused by KS-associated herpesvirus (KSHV) infection. HIV plays a major role in KS pathogenesis. KS in HIV usually produces more malignant features than classic KS. Despite the close KS-HIV relationship, no study has reported the existence of HIV in KS tissue. We used ddPCR to detect HIV and KSHV in HIV+ KS samples and classic KS control. We verified KS cell types through immunohistochemistry and applied hypersensitive in situ hybridization (ISH) to detect HIV and KSHV in tumor cells. Furthermore, we co-stained samples with ISH and immunohistochemistry to identify HIV and KSHV in specific cell types. Regarding pathological stages, the KS were nodular (58.3%), plaque (33.3%), and patch (8.3%) tumors. Moreover, ddPCR revealed HIV in 58.3% of the KS samples. ISH revealed positive Pol/Gag mRNA signals in CD34 + tumor cells from HIV + patients (95.8%). HIV signals were absent in macrophages and other inflammatory cells. Most HIV + KS cells showed scattered reactive particles of HIV and KSHV. We demonstrated that HIV could infect CD34 + tumor cells and coexist with KSHV in KS, constituting a novel finding. We hypothesized that the direct KSHV-HIV interaction at the cellular level contributes to KS oncogenesis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The limited accessibility of medical specialists for Alzheimer's disease (AD) can make obtaining an accurate diagnosis in a timely manner challenging and may influence prognosis. We investigated whether VUNO Med-DeepBrain AD (DBAD) using a deep learning algorithm can be employed as a decision support service for the diagnosis of AD. This study included 98 elderly participants aged 60 years or older who visited the Seoul Asan Medical Center and the Korea Veterans Health Service. We administered a standard diagnostic assessment for diagnosing AD. DBAD and three panels of medical experts (ME) diagnosed participants with normal cognition (NC) or AD using T1-weighted magnetic resonance imaging. The accuracy (87.1% for DBAD and 84.3% for ME), sensitivity (93.3% for DBAD and 80.0% for ME), and specificity (85.5% for DBAD and 85.5% for ME) of both DBAD and ME for diagnosing AD were comparable; however, DBAD showed a higher trend in every analysis than ME diagnosis. DBAD may support the clinical decisions of physicians who are not specialized in AD; this may enhance the accessibility of AD diagnosis and treatment., (© 2022. The Author(s).)

Background: Antimicrobial resistance is a public health problem that threatens the efficacy of antibiotics. Incorrect knowledge of antibiotics may lead to their inappropriate use, hinder their effectiveness, and cause antibiotic resistance. Population-based educational campaigns have been found to have either mixed or no effect on improving knowledge and appropriate antibiotic practices, suggesting the need for more targeted approaches in tailoring education for specific subpopulations. Women are the primary caregivers of their families and are more willing to contact healthcare providers. They had greater knowledge of antibiotics and better adherence to the completion of the antibiotic regimen. Therefore, they are suitable for prioritization in a campaign program. Objective: This study examined the knowledge and practices of female visitors to health centers in Malang, Indonesia with respect to antibiotic use. Methods: This cross-sectional study was conducted in Malang, Indonesia, in July and August 2018. Data were collected from 677 women. Multivariate logistic regression was performed to identify the potential factors associated with antibiotic knowledge, self-medication, and completion of antibiotic regimens. Results: Overall, 82.7% of respondents were aware that antibiotics are used against bacteria, while 38.4% reported self-medication with antibiotics and 51.7% reported completing antibiotic regimens. Women with higher education, previous antibiotic use experience, and very easy accessibility to primary doctors were more likely to have high antibiotic knowledge than those with primary education, no antibiotic use in the previous year, and easy/other level of accessibility to primary doctors. Subjects residing in urban areas and with less accessibility to primary doctors were more likely to self-medicate with antibiotics. Additionally, the completion of antibiotic regimens was positively associated with access to a primary care doctor and high antibiotic knowledge. Conclusion: IF Policymakers tend to reduce inappropriate antibiotic use among women. Priority advocates are recommended for urban residents who have experiences of antibiotic use in the previous year. It is therefore important to increase their awareness, particularly regarding diseases against which antibiotics are effective, and activities such as unnecessary use of antibiotics in healthy animals, which may affect their overall effectiveness among humans. More communication channels should be included in the overall scheme to improve the public awareness and accessibility of health professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yunita, Yang, Chen, Kao, Lu, Wen, To and Huang.)

External signaling controls cell-cycle entry until cells irreversibly commit to the cell cycle to ensure faithful DNA replication. This process is tightly regulated by cyclin-dependent kinases (CDKs) and the retinoblastoma protein (Rb). Here, using live-cell sensors for CDK4/6 and CDK2 activities, we propose that CDK4/6 initiates Rb inactivation and CDK2 activation, which coordinates the timing of cell-cycle commitment and sequential G1/S transition. Our data show that CDK4/6 activation induces Rb inactivation and thereby E2F activation, driving a gradual increase in CDK2 activity. We found that rapid CDK4/6 inhibition can reverse cell-cycle entry until CDK2 activity reaches to high levels. This suggests that high CDK2 activity is required to initiate CDK2-Rb positive feedback and CDK4/6-indpendent cell-cycle progression. Since CDK2 activation also facilitates initiation of DNA replication, the timing of CDK2-Rb positive feedback is coupled with the G1/S transition. Our experiments, which acutely increased CDK2 activity by cyclin E1 overexpression, indicate that cells commit to the cell cycle before triggering DNA replication. Together, our data suggest that CDK4/6 inactivates Rb to begin E2F and CDK2 activation, and high CDK2 activity is necessary and sufficient to generate a bistable switch for Rb phosphorylation before DNA replication. These findings highlight how cells initiate the cell cycle and subsequently commit to the cell cycle before the G1/S transition., (© 2022. The Author(s).)

Background/purpose: Porphyromonas gingivalis (P.g.) played a keystone pathogen not only in initiation and progression of periodontitis but also as a risk factor involved in systemic diseases (Alzheimer's disease, cancers, diabetes, osteoporosis etc.). Developments of effective and safe drugs to inhibit P.g. growth are urgent. In this study, we aimed at approaching novel regimens so called (PTM) by combination of repurposing drugs including phytopolyphenols (P) (curcumin, tea polyphenols), targeting drugs (T) such as cisplatin or memantine and metal ions(M) (ZnSO 4 )., Materials and Methods: The synergistic (combination Index (CI) < 1) antiproliferation and anti-protease efficacies (IC50) of novel regimens on cultured P.g. were evaluated by OD600 and colorimetric method respectively., Results: The results obtained revealed that these novel regimens (PTM) synergistically (combination index, CI < 1) exerted not only antiproliferative but also anti-gingipain protease effects of P.g. The concentrations for 50% inhibition (IC50) of novel regimens on P.g. growth and gingipains were greatly decreased as compared with those of cisplatin and memantine alone., Conclusion: Since these novel regimens exerted potent anti-bacterial effects on both planktonic and biofilm P.g., it is encouraged for further preclinical and clinical trials., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Personalized medicine is a new medical concept to achieve patient-centered care. In dentistry, it is recognized for the customization of operative strategies and managements for oral diseases. Access cavity preparation in endodontic treatment is an irreversible procedure. Endodontic training will be more realistic by the implementation of clinical relevant 3D virtual reality technology. In this article, the authors first presented a personized case from a real patient to provide assess cavity preparation in haptic virtual reality dental simulator Simodont® (Nissin Dental Products Inc., Nieuw-Vennep, Netherlands). The practical framework to generate STL from cone beam computed tomography was demonstrated. A case of virtual tooth #26 access cavity preparation in Simodont® was established for trainee unlimited practices before performing the clinical procedure on a real patient. Taken together, access cavity preparation in a virtual environment using a 3D personized tooth may minimize procedural errors and facilitate clinical treatment outcome., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

There are no studies on the optimal intrusion force in orthodontic patients with the existing root resorption (RR). The study aimed to analyze the optimal intrusion force for central incisors with existing horizontal root resorption using the finite element method (FEM). We calculated the optimal intrusion force using the finite element method and curve fitting. We found that with the increase of the maxillary central incisor's root horizontal resorption length, the optimal intrusion force interval's median gradually increases. If the resorption length is more significant than 1/2 of the root length, it is not recommended to use intrusion force theoretically.

Aims: Low caspofungin exposure is frequently encountered in patients with invasive candidiasis caused by Candida albicans. This study aimed to investigate the effects of caspofungin on C. albicans at sub-inhibitory concentrations., Methods and Results: First, a comparative transcriptomics analysis was performed on C. albicans receiving caspofungin at sub-minimum inhibitory concentrations (sub-MICs). The results showed that caspofungin significantly changed the mRNA expression profile in DAY185, with DE-mRNAs enriched in the functions of cell wall biosynthesis, metabolism, etc. Subsequently, cellular fitness, cell aggregation, energy metabolism activity and the proportion of persister cells of C. albicans were quantitatively and/or qualitatively assessed after sub-MIC caspofungin exposure. No significant changes in cell fitness and aggregation formation were observed during treatment of C. albicans with sub-MIC caspofungin. In C. albicans aggregation treated with sub-MIC caspofungin, we observed a decrease in respiratory metabolism and an increase in persister cells; this effect was more pronounced in als1ΔΔ than in DAY185., Conclusions: Pre-exposure to sub-MIC caspofungin suppresses C. albicans respiratory metabolism and promotes persister cell development., Significance and Impact of the Study: Caspofungin should be used with caution in patients with C. albicans infections, as anti-infection therapy may fail due to persister cells., (© 2022 Society for Applied Microbiology.)

Atrial fibrillation (AF) is largely underdiagnosed. Previous studies using deep neural networks with large datasets have shown that screening AF with a 12-lead electrocardiogram (ECG) during sinus rhythm (SR) is possible. However, the poor availability of these trained models and the small size of the retrievable datasets limit its reproducibility. This study proposes an approach to generate explainable features for detecting AF during SR with limited data. We collected 94,224 12-lead ECGs from 64,196 patients from Taipei Medical University Hospital. We selected ECGs during SR from 213 patients before AF diagnosis and randomly selected 247 age-matched participants without AF records as the controls. We developed a signal-processing technique, MA-UPEMD, to isolate P waves, and quantified the spatial and temporal features using principal component analysis and inter-lead relationships. By combining these features, the machine learning models yielded AUC of 0.64. We showed that, even with this limited dataset, the P wave, representing atrial electrical activity, is depicted by our proposed approach. The extracted features performed better than the bandpass filter-extracted P waves and deep neural network model. We provided a physiologically explainable and reproducible approach for classifying patients with AF during SR.

Background: Heart rate complexity, derived from nonlinear heart rate variability (HRV), has been shown to help predict the outcomes of various diseases. Changes in heart rate complexity before and after paroxysmal atrial fibrillation (PAF) events are unclear., Objectives: To evaluate changes in heart rate complexity through nonlinear HRV before and after PAF events., Methods: We enrolled 65 patients (72 ± 12.34 years old, 31 females) with 99 PAF events who received 24-hour Holter recording, and analyzed nonlinear HRV variables including Poincaré plot analysis, sample entropy (SampEn), and multiscale entropy (MSE). HRV analyses were applied to a 20-minute window before the onset and after the termination of PAF events. HRV parameters were evaluated and compared based on eight different 5-minute time segments, as we divided each 20-minute window into four segments of 5 minutes each., Results: SampEn and MSE 1~5 significantly decreased before the onset of PAF events, whereas SampEn, MSE 1~5 and MSE 6~20 significantly increased after the termination of PAF events. SD1 and SD2, which are nonlinear HRV parameters calculated via Poincaré plot analysis, did not significantly change before the PAF events, however they both decreased significantly after termination., Conclusions: Heart rate complexity significantly decreased before the initiation and increased after the termination of PAF events, which indicates the crucial role of nonlinear heart rate dynamics in the initiation and termination of PAF.

The polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) rs9679162 and mRNA expression were associated with treatment outcome in various cancers. However, the relation of GALNT14 and head and neck cancer were nuclear. A total of 199 patients with head and neck squamous cell carcinoma (HNSCC) were collected in this study, including oral SCC (OSCC), oropharyngeal SCC (OPSCC), laryngeal SCC (LSCC), and others. The DNA and RNA of cancer tissues were extracted using the TRI Reagent method. The rs9679162 was analyzed using polymerase chain reaction (PCR) and sequencing methods in 199 DNA specimens, and the mRNA expression was analyzed using quantitative reverse transcription PCR (RT-qPCR) methods in 68 paired RNA specimens of non-cancerous matched tissues (NCMT) and tumor tissues. The results showed that the genotype of TT, TG, and GG appeared at 30%, 44%, and 26%, respectively. Non-TT genotype or G alleotype were associated with alcohol, betel nut, and cigarette using among patients with OSCC, and it also affected the treatment and survival of patients with OSCC and LSCC. High GALNT14 mRNA expression levels increased lymphatic metastasis of patients with HNSCC, and treatment and survival in patients with OPSCC. Overall, the GALNT14 -rs9679162 genotype and mRNA expression level can be used as indicators of HNSCC treatment prognosis.

Background: Head and neck squamous cell carcinomas (HNSCCs) are derived from the mucosal linings of the upper aerodigestive tract, salivary glands, thyroid, oropharynx, larynx, and hypopharynx. The present study aimed to identify the novel genes and pathways underlying HNSCC. Despite the advances in HNSCC research, diagnosis, and treatment, its incidence continues to rise, and the mortality of advanced HNSCC is expected to increase by 50%. Therefore, there is an urgent need for effective biomarkers to predict HNSCC patients' prognosis and provide guidance to the personalized treatment. Methods: Both HNSCC clinical and gene expression data were abstracted from The Cancer Genome Atlas (TCGA) database. Intersecting analysis was adopted between the gene expression matrix of HNSCC patients from TCGA database to extract TME-related genes. Differential gene expression analysis between HNSCC tissue samples and normal tissue samples was performed by R software. Then, HNSCC patients were categorized into clusters 1 and 2 via NMF. Next, TME-related prognosis genes ( p < 0.05) were analyzed by univariate Cox regression analysis, LASSO Cox regression analysis, and multivariate Cox regression analysis. Finally, nine genes were selected to construct a prognostic risk model and a prognostic gene signature. We also established a nomogram using relevant clinical parameters and a risk score. The Kaplan-Meier curve, survival analysis, time-dependent receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and the concordance index (C-index) were carried out to assess the accuracy of the prognostic risk model and nomogram. Potential molecular mechanisms were revealed by gene set enrichment analysis (GSEA). Additionally, gene correlation analysis and immune cell correlation analysis were conducted for further enriching our results. Results: A novel HNSCC prognostic model was established based on the nine genes (GTSE1, LRRN4CL, CRYAB, SHOX2, ASNS, KRT23, ANGPT2, HOXA9, and CARD11). The value of area under the ROC curves (AUCs) (0.769, 0.841, and 0.816) in TCGA whole set showed that the model effectively predicted the 1-, 3-, and 5-year overall survival (OS). Results of the Cox regression assessment confirmed the nine-gene signature as a reliable independent prognostic factor in HNSCC patients. The prognostic nomogram developed using multivariate Cox regression analysis showed a superior C-index over other clinical signatures. Also, the calibration curve had a high level of concordance between estimated OS and the observed OS. This showed that its clinical net can precisely estimate the one-, three-, and five-year OS in HNSCC patients. The gene set enrichment analysis (GSEA) to some extent revealed the immune- and tumor-linked cascades. Conclusion: In conclusion, the TME-related nine-gene signature and nomogram can effectively improve the estimation of prognosis in patients with HNSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Zhou, Yang and Wang.)

Background: Several studies have indicated possible associations between age and the prognosis of breast cancer (BC), but limited data are available from hospital-based multicenter studies in China. This study aimed to explore the associations between age at initial diagnosis of BC and the risk of recurrence or metastasis among Chinese women with newly diagnosed advanced breast cancer (ABC) and provide treatment decision support for BC patients of different ages to medical workers., Methods: The medical records of patients newly diagnosed with ABC were obtained from 21 hospitals in seven geographic regions in China from 2012 to 2014. Patients' general information, clinicopathological features at first diagnosis, treatment information, and prognosis were retrospectively collected based on the self-designed case report form (CRF). Cox proportional hazards regression models were used to determine hazard ratios (HR) and 95% confidence intervals (CI) for the associations between age groups and the risk of recurrence and metastasis., Results: A total of 1,852 cases were included in the final analysis. Age at initial diagnosis was shown to be significantly related to hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtypes, and the number of lymph node metastasis (all P<0.05). Patients aged <35 years were more likely to have bone metastasis (45.6%). Patients aged ≥65 years had a lower percentage of receiving surgery (87.1%), adjuvant chemotherapy (61.3%), adjuvant radiotherapy (35.5%), and adjuvant endocrine therapy (30.6%) than the other groups (all P<0.05). Compared with patients aged <35 years, the risk of recurrence or metastasis in those aged 55-64 years was significantly higher (HR age 55-64 =1.24, 95% CI: 1.04-1.47), and the risk of bone metastasis and lung metastasis in those aged 35-44 years was lower (HR bone metastasis =0.74, 95% CI: 0.59-0.93; HR lung metastasis =0.70, 95% CI: 0.53-0.93). After adjusting for stage, grade, and molecular subtype, surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant radiotherapy, adjuvant endocrine therapy, and family history of BC, patients aged 35-44 years still had a significantly reduced risk of bone metastasis and lung metastasis by 31% and 52%, respectively (HR bone metastasis =0.69, 95% CI: 0.48-0.98; HR lung metastasis =0.48, 95% CI: 0.31-0.74)., Conclusions: Age at initial diagnosis is related to the clinicopathological characteristics and treatment pattern. Although the risk of site-specific metastasis varies by age, age is not an independent factor influencing the risk of total recurrence and metastasis. In accordance with current clinical practice guidelines for BC, however, precise treatment shall be chosen personally for patients whose ages at initial diagnosis are different., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-302/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Importance: The association between social support and dementia risk has been debated. Most previous prospective studies have not differentiated the subtypes of social support., Objective: To examine whether the association between social support and risk of dementia differs by subtype of social support and by sex., Design, Setting, and Participants: This nationwide prospective cohort study included randomly sampled South Korean adults 60 years or older. The study was launched November 1, 2010, with follow-up every 2 years until November 30, 2020. The 5852 participants who completed the assessment for social support and were not diagnosed as having dementia, severe psychiatric disorders including major depressive disorder, or major neurological disorders at the baseline assessment were included in the analysis., Exposures: Geriatric psychiatrists administered the structured diagnostic interviews and physical examinations to every participant based on the Korean version of the Consortium to Establish a Registry for Alzheimer Disease (CERAD-K) Assessment Packet Clinical Assessment Battery., Main Outcomes and Measures: Baseline levels of emotional and tangible support using the Medical Outcomes Survey Social Support Survey., Results: Among the 5852 participants (mean [SD] age, 69.8 [6.6] years; 3315 women [56.6%]; mean [SD] follow-up duration, 5.9 [2.4] years), 237 (4.0%) had incident all-cause dementia and 160 (2.7%) had incident Alzheimer disease (AD) subtype of dementia. Compared with women who reported having emotional support, those with low emotional support had almost a 2-fold higher incidence of all-cause dementia (18.4 [95% CI, 13.6-23.2] vs 10.7 [95% CI, 9.0-12.5] per 1000 person-years) and AD (14.4 [95% CI, 10.2-18.6] vs 7.8 [95% CI, 6.3-9.3] per 1000 person-years). Adjusted Cox proportional hazard analysis revealed that low emotional support was associated with increased risk of all-cause dementia (hazard ratio, 1.61 [95% CI, 1.10-2.36]; P = .02) and AD (hazard ratio, 1.66 [95% CI, 1.07-2.57]; P = .02) only in women. Low tangible support was not associated with a risk of all-cause dementia or AD regardless of sex., Conclusions and Relevance: The findings of this cohort study suggest that older women with low emotional support constitute a population at risk for dementia. The level of emotional support should be included in risk assessments of dementia.

Objective: The effects of mood disorders on mortality may be mediated by their effects on the risk of dementia, and interventions to reduce the occurrence of dementia may reduce their overall mortality. This study aimed to investigate the direct effects of depressive and bipolar disorders on the 6-year risk of mortality and also their indirect effects on mortality due to their effect on the risk of dementia., Methods: A total of 5101 Koreans were selected from a community-based prospective cohort study, and 6-year risks of mortality and dementia in participants with depressive and bipolar disorders were estimated by Cox proportional hazard analysis. The direct and indirect effects of depressive and bipolar disorders on the risk of mortality were estimated using structural equation modeling., Results: The depressive and bipolar disorder groups showed 51% and 85% higher 6-year mortality, and 82% and 127% higher risk of dementia, respectively, compared to euthymic controls. The effects of depressive and bipolar disorders on mortality were mainly mediated by their effects on the risk of dementia in a structural equation model. The direct effects of each mood disorder on mortality were not significant., Conclusion: Both depressive and bipolar disorders increased the risks of mortality and dementia, and the effects of mood disorders on mortality were mainly mediated through dementia. As dementia occurs later in life than mood disorders, measures to prevent it may effectively reduce mortality in individuals with a history of mood disorders, as well as being more feasible than attempting to control other causes of death.

Chronic kidney disease (CKD) is the most neglected chronic disease affecting over 750 million persons in the world. Currently, many patients with cancers or other chronic diseases (i.e., CKD) struggle to receive clinical treatment or examination due to hospitals cancelling or delaying in the COVID-19 pandemic, which may increase the risk of death. Cystatin C (Cys C) has been proposed as a potential glomerular filtration rate (GFR) marker for the early detection of acute kidney injury and CKD. However, most traditional methods for Cys C detection are immunoassays using serum as a sample and are tedious to perform and economically burdensome. To diagnose the disease in the early stage and carry out daily management during the current pandemic, we developed an integration of hydrogel microneedle patch (HMNP) and lateral flow cassette (LFC) to rapidly detect Cys C in skin interstitial fluid (ISF) in 25 min for blood-free CKD management anytime and anywhere by the naked eye that can reduce the impact of an individual's quality of life and life expectancy. Conceivably, this strategy presents a wide scope in the application of numerous other diseases if corresponding analytes are available in skin ISF., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Clinical dentistry is a complex activity which the procedure of most dental treatment are almost irreversible changes. Patient safety is a major challenge in clinical dental care. This is the reason why simulation-based learning and training is emphasized in dental education. In this article, the authors presented the clinical relevant haptic simulation learning and training in tooth preparation. The practical framework to set up the simulation environment from real patients in haptic 3D virtual reality dental training simulator Simodont® (Nissin Dental Products Inc., Nieuw-Vennep, Netherlands). Then, the trainee can repeatedly practice in Simodont® before performing the clinical procedure on real patient. Taken together, the implementation of this model in dental education may not only enhance trainees' self-confidence and performance, but also facilitate patient safety during clinical dental care., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Competing Interests: The authors have no conflicts of interest relevant to this article.

Seizure is a common neurological presentation in patients visiting the emergency department (ED) that requires time for evaluation and observation. Timely decision and disposition standards for seizure patients need to be established to prevent overcrowding in the ED and achieve patients' safety. Here, we conducted a retrospective cohort study to predict early seizure recurrence in the ED (ES-RED). We randomly assigned 688 patients to the derivation and validation cohorts (2:1 ratio). Prediction equations extracted routine clinical and laboratory information from EDs using logistic regression (Model 1) and machine learning (Model 2) methods. The prediction equations showed good predictive performance, the area under the receiver operating characteristics curve showing 0.808 in Model 1 [95% confidential interval (CI): 0.761-0.853] and 0.805 in Model 2 [95% CI: 0.747-0.857] in the derivation cohort. In the external validation, the models showed strong prediction performance of 0.739 [95% CI: 0.640-0.824] in Model 1 and 0.738 [95% CI: 0.645-0.819] in Model 2. Intriguingly, the lowest quartile group showed no ES-RED after 6 h. The ES-RED calculator, our proposed prediction equation, would provide strong evidence for safe and appropriate disposition of adult resolved seizure patients from EDs, reducing overcrowding and delays and improving patient safety.

Recent studies have revealed the significant role of the competing endogenous RNA (ceRNA) network in human diseases. However, systematic analysis of the ceRNA mechanism in chronic rhinosinusitis with nasal polyps (CRSwNP) is limited. In this study, we constructed a competitive endogenous RNA (ceRNA) network and identified a potential regulatory axis in CRSwNP based on bioinformatics analysis and experimental verification. We obtained lncRNA, miRNA, and mRNA expression profiles from the Gene Expression Omnibus. After analysis of CRSwNP patients and the control groups, we identified 565 DE-lncRNAs, 23 DE-miRNAs, and 1799 DE-mRNAs by the DESeq2 R package or limma R package. Enrichment analysis of 1799 DE-mRNAs showed that CRSwNP was associated with inflammation and immunity. Moreover, we identified 21 lncRNAs, 8 miRNAs and 8 mRNAs to construct the lncRNA-miRNA-mRNA ceRNA network. A potential MIAT/miR-125a/IRF4 axis was determined according to the degree and positive correlation between a lncRNA and its competitive endogenous mRNAs. The GSEA results suggested that IRF4 may be involved in immune cell infiltration. The validation of another dataset confirmed that MIAT and IRF4 were differentially expressed between the CRSwNP and control groups. The area under the ROC curve (AUC) of MIAT and IRF4 was 0.944. The CIBERSORT analysis revealed that eosinophils and M2 macrophages may be involved in the CRSwNP process. MIAT was correlated with dendritic cells and M2 macrophages, and IRF4 was correlated with dendritic cells. Finally, to validate the key genes, we performed in-silico validation using another dataset and experimental validation using immunohistochemistry, immunofluorescence, and Western blot. In summary, the constructed novel MIAT/miR-125a/IRF4 axis may play a critical role in the development and progression of CRSwNP. We believe that the ceRNA network and immune cell infiltration could offer further insight into novel molecular therapeutic targets for CRSwNP., (© 2022. The Author(s).)