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The c-Jun-NH2-terminal kinases (JNKs) regulate cell death, generally through the direct phosphorylation of both pro- and anti-apoptotic substrates. In this report, we demonstrate an alternate mechanism of JNK-mediated cell death involving the anti-apoptotic protein human apurinic/apyrimidinic endonuclease 1 (APE1). Treatment of cells with a variety of genotoxic stresses enhanced APE1-JNK (all isoforms of JNK1 or JNK2) interaction, specifically in cells undergoing apoptosis. Steady-state APE1 levels were decreased in these cells, in which APE1 is ubiquitinated and degraded in a JNK-dependent manner. Absence of JNKs reduced APE1 ubiquitination and increased its abundance. Mechanistically, the E3 ligase ITCH associates with both APE1 and JNK and is necessary for JNK-dependent APE1 ubiquitination and degradation. Structural models of the JNK-APE1 interaction support the observation of enhanced association of the complex in the presence of ubiquitin. The data together show a mechanism of JNK-mediated cell death by the degradation of APE1 through ITCH., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This paper proposes an unsupervised image-to-image (UI2I) translation model, called Perceptual Contrastive Generative Adversarial Network (PCGAN), which can mitigate the distortion problem to enhance performance of the traditional UI2I methods. The PCGAN is designed with a two-stage UI2I model. In the first stage of the PCGAN, it leverages a novel image warping to transform shapes of objects in input (source) images. In the second stage of the PCGAN, the residual prediction is devised in refinements of the outputs of the first stage of the PCGAN. To promote performance of the image warping, a loss function, called Perceptual Patch-Wise InfoNCE, is developed in the PCGAN to effectively memorize the visual correspondences between warped images and refined images. Experimental results on quantitative evaluation and visualization comparison for UI2I benchmarks show that the PCGAN is superior to other existing methods considered here., 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 © 2023 Elsevier Ltd. All rights reserved.)

Background: Acute blood pressure (BP) reduction is the first-line treatment for acute spontaneous intracerebral hemorrhage (ICH); however, recent research suggests that intensive BP reduction along with cerebral small vessel disease (cSVD) is a risk factor for remote DWI lesions (RDWILs). We aimed to delineate the interplay between cSVD and BP reduction therapy on the risk of RDWILs., Methods: We enrolled 303 patients who underwent brain magnetic resonance imaging within 7 days after acute spontaneous ICH. RDWILs were categorized as occurring in borderzone (BZ) or non-BZ areas. We examined the effect of cSVD, acute BP reduction, and their interaction on RDWILs., Results: RDWILs were observed in 34 (11%) patients (59.8 ± 10.3-years-old, 24% male). RDWILs were associated with a larger acute weighted average mean arterial pressure (MAP) reduction in the initial 24 h after ICH onset and a higher total cerebral microbleed (CMB) count. Intensive MAP changes (odds ratio (OR) per 10 mmHg 1.76, 95% confidence interval (CI) 1.03-3.20), total CMBs burden (OR per 10 CMBs 1.21, 95% CI 1.08-1.39), and presence of lobar CMBs (OR 7.33, 95% CI 1.59-55.6) were risk factors for RDWILs at BZ, but not at non-BZ. Furthermore, a significant interaction was observed between lobar CMBs and MAP reduction on increased risk of RDWILs at BZ ( p  = 0.030)., Conclusion: cSVD modulates the effect of acute BP reduction on the risk of RDWILs. Patients with extensive microangiopathy have a higher risk of developing cerebral ischemic changes in BZ during unstable hemodynamic status.

CRISPR-Cas9 genome editing has promising therapeutic potential for genetic diseases and cancers, but safety could be a concern. Here we use whole genomic analysis by 10x linked-read sequencing and optical genome mapping to interrogate the genome integrity after editing and in comparison to four parental cell lines. In addition to the previously reported large structural variants at on-target sites, we identify heretofore unexpected large chromosomal deletions (91.2 and 136 Kb) at atypical non-homologous off-target sites without sequence similarity to the sgRNA in two edited lines. The observed large structural variants induced by CRISPR-Cas9 editing in dividing cells may result in pathogenic consequences and thus limit the usefulness of the CRISPR-Cas9 editing system for disease modeling and gene therapy. In this work, our whole genomic analysis may provide a valuable strategy to ensure genome integrity after genomic editing to minimize the risk of unintended effects in research and clinical applications., (© 2023. Springer Nature Limited.)

The entire evolutionary trajectory of plants towards large and complex multi-cellular organisms has been accompanied by incessant interactions with omnipresent unicellular microbes. This led to the evolution of highly complex microbial communities, whose members display the entire spectrum of pathogenic to mutualistic behaviors. Plant roots are dynamic, fractally growing organs and even small Arabidopsis roots harbor millions of individual microbes of diverse taxa. It is evident that microbes at different positions on a root surface could experience fundamentally different environments, which, moreover, rapidly change over time. Differences in spatial scales between microbes and roots compares to humans and the cities they inhabit. Such considerations make it evident that mechanisms of root-microbe interactions can only be understood if analyzed at relevant spatial and temporal scales. This review attempts to provide an overview of the rapid recent progress that has been made in mapping and manipulating plant damage and immune responses at cellular resolution, as well as in visualizing bacterial communities and their transcriptional activities. We further discuss the impact that such approaches will have for a more predictive understanding of root-microbe interactions., Competing Interests: Declaration of competing interest The authors do not have any competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is the most common malignant neoplasm of the nasopharynx. Despite improvements in the clinical treatment strategies for NPC, NPC patients usually have poor survival rates because of late diagnosis, tumor metastasis, and recurrence. Therefore, the identification of potential diagnostic and prognostic markers for NPC is imperative. We investigated the differential expression of cell adhesion-related genes (gene ontology:0003779) and tumorigenesis-related genes (GSE12452) in patients with NPC. The correlations between synaptopodin-2 (SYNPO2) immune expression and clinicopathological features were analyzed using Pearson chi-square test. Multivariate analysis was performed using Cox proportional hazards model. SYNPO2 expression was significantly higher in NPC tumor tissues than in nontumor tissues. High SYNPO2 expression was significantly associated with the advanced disease stage (P = .006). Univariate analysis showed that high expression of SYNPO2 was associated with poor disease-specific survival, distal metastasis-free survival, and local recurrence-free survival in patients with NPC. Notably, our multivariate analysis demonstrated that high SYNPO2 expression was substantially correlated with inferior disease-specific survival (hazard ratio = 1.968, P = .012) and local recurrence-free survival (hazard ratio = 3.386, P = .001). Overall, our findings reveal that SYNPO2 may aid in the development of potential prognostic biomarkers for NPC patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Alkaline soils pose a conglomerate of constraints to plants, restricting the growth and fitness of non-adapted species in habitats with low active proton concentrations. To thrive under such conditions, plants have to compensate for a potential increase in cytosolic pH and restricted softening of the cell wall to invigorate cell elongation in a proton-depleted environment. To discern mechanisms that aid in the adaptation to external pH, we grew plants on media with pH values ranging from 5.5 to 8.5. Growth was severely restricted above pH 6.5 and associated with decreasing chlorophyll levels at alkaline pH. Bicarbonate treatment worsened plant performance, suggesting effects that differ from those exerted by pH as such. Transcriptional profiling of roots subjected to short-term transfer from optimal (pH 5.5) to alkaline (pH 7.5) media unveiled a large set of differentially expressed genes that were partially congruent with genes affected by low pH, bicarbonate, and nitrate, but showed only a very small overlap with genes responsive to the availability of iron. Further analysis of selected genes disclosed pronounced responsiveness of their expression over a wide range of external pH values. Alkalinity altered the expression of various proton/anion co-transporters, possibly to recalibrate cellular proton homeostasis. Co-expression analysis of pH-responsive genes identified a module of genes encoding proteins with putative functions in the regulation of root growth, which appears to be conserved in plants subjected to low pH or bicarbonate. Our analysis provides an inventory of pH-sensitive genes and allows comprehensive insights into processes that are orchestrated by external pH., 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 © 2023 Bailey, Hsieh, Tsai, Ravindran and Schmidt.)

Objective: Living liver donors need help to manage symptom distress and improve their quality of life. This study aims to test the effectiveness of a web-based symptom self-care instruction on symptom experience and health-related quality of life of living liver donors., Methods: This study was a randomized controlled trial. Participants were recruited from January 2019 to August 2020. Participants in the experimental group had access to a web-based symptom self-care instruction, which included text and video. The control group received routine care. The primary outcomes were symptom distress and quality of life., Results: A total of 90 living liver donors recruited in this study were assigned randomly to the web group (n = 46) and control group (n = 44). The symptom distress was significantly negatively correlated with quality of life at each data collection time. There was an interaction effect with the participants in the web group experiencing more symptom distress at three months after surgery than the control group (B = 3.616, 95% CI: 7.163-3.990, p = 0.046). There was no significant effect on the quality of life., Conclusion: Patients in the web-based self-care group had higher symptom distress than those in the control group three months after surgery, but there was no difference in quality of life. Future studies could add some interactive elements to the website and include a larger sample size., Registration: This study was registered at the Chinese Clinical Trial Registry (ChiCTR1900020518)., Competing Interests: 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., (© 2023 The Authors.)

The highly conserved matrix protein 2 ectodomain (M2e) of influenza viruses presents a compelling vaccine antigen candidate for stemming the pandemic threat of the mutation-prone pathogen, yet the low immunogenicity of the diminutive M2e peptide renders vaccine development challenging. A highly potent M2e nanoshell vaccine that confers broad and durable influenza protectivity under a single vaccination is shown. Prepared via asymmetric ionic stabilization for nanoscopic curvature formation, polymeric nanoshells co-encapsulating high densities of M2e peptides and stimulator of interferon genes (STING) agonists are prepared. Robust and long-lasting protectivity against heterotypic influenza viruses is achieved with a single administration of the M2e nanoshells in mice. Mechanistically, molecular adjuvancy by the STING agonist and nanoshell-mediated prolongation of M2e antigen exposure in the lymph node follicles synergistically contribute to the heightened anti-M2e humoral responses. STING agonist-triggered T cell helper functions and extended residence of M2e peptides in the follicular dendritic cell network provide a favorable microenvironment that induces Th1-biased antibody production against the diminutive antigen. These findings highlight a versatile nanoparticulate design that leverages innate immune pathways for enhancing the immunogenicity of weak immunogens. The single-shot nanovaccine further provides a translationally viable platform for pandemic preparedness., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

This study aimed to assess the difference in the mesiodistal (MD) and buccolingual (BL) dimensions of primary first molars between Taiwanese boys and girls using a three-dimensional (3D) scanner (Microscribe G2 digitizer), record the coordinates in the 3D systems of Graph-R Project and reconstruct 3D images for subsequent analysis. We also determined whether the differences in these parameters between primary first molars and stainless steel crowns (SSC, 3M ESPE, No. 2-7) could be used as a reference for selecting a suitably-sized SSC and performing adjustments during restoration. The results indicated a statistically significant difference in the mesiodistal distance of lower primary first molar crowns between boys (7.75 ± 0.38 mm) and girls (7.41 ± 0.41 mm) ( p < 0.05) but no differences in the mesiodistal distance of upper primary first molars between the two sexes. The mean mesiodistal distances of the upper and lower primary first molars of boys were close to SSC size 4 and 3, respectively, while those of girls were close to size 3 in both arches. Overall, the buccolingual distance between the first maxillary and mandibular molars of Taiwanese children was greater than the buccolingual distance between the 3M ESPE SSC. Reducing the buccolingual length of the abutment teeth might quickly help achieve a better fit, reduce chair time, and minimize patient discomfort. In addition, trimming the mesial and distal metal margins of SSCs might help reduce microleakage from the crown margins and improve its retention and survival rate. In conclusion, the 3D scanning and analysis method used in this study can serve as a reference for fabricating SSC to achieve better crown adaptation and improve dental procedures., Competing Interests: The authors declare no conflict of interest., (©2023 The Author(s). Published by MRE Press.)

Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a clinical syndrome characterized by MRI findings of amyloid-related imaging abnormalities-edema (ARIA-E) suggestive of autoimmune and inflammatory reaction and hemorrhagic evidence of cerebral amyloid angiopathy. The longitudinal variation of amyloid PET and its imaging association with CAA-ri are undetermined. Moreover, tau PET in CAA-ri has been rarely investigated., Method: We retrospectively described two cases of CAA-ri. We provided the temporal change of amyloid and tau PET in the first case, and the cross-sectional finding of amyloid and tau PET in the second case. We also performed a literature review of the imaging features of amyloid PET in reported cases of CAA-ri., Results: In the first case, an 88-year-old male presented with progressive consciousness and gait disturbances over 2 months. MRI showed disseminated cortical superficial siderosis. Amyloid PET prior to and after the CAA-ri revealed focally decreased amyloid load in the region of ARIA-E. In the second case, a 72-year-old male was initially suspected to have central nervous system cryptococcosis but later diagnosed with CAA-ri because of the characteristic MRI features and good response to corticosteroid treatment; a subsequent amyloid scan revealed positive amyloid deposition of the brain. Neither case suggested an association between the region of ARIA-E and higher amyloid uptake on PET before or after onset of CAA-ri. Our literature review revealed variable findings related to amyloid burden in post-inflammatory regions in previously reported CAA-ri cases with available amyloid PET. Our case is the first report of longitudinal changes on amyloid PET and show focal decreases in amyloid load after the inflammatory process., Conclusion: This case series highlights the need to better explore the potential of longitudinal amyloid PET in the understanding of the mechanisms of CAA-ri., 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 © 2023 Yang, Chu, Tsai and Jeng.)

Breast cancer is a significant public health problem globally and prevention strategies have become of great interest as its incidence rises. Exploring the connection between dietary patterns and the reduction of breast cancer risk is considered a promising approach. High levels of fiber, phytochemicals, a good antioxidant profile, and a composition of advantageous fatty acids are characteristics of healthy dietary programs such as the Mediterranean diet. This review summarized and discussed the active compounds that are considered important in preventing breast cancer, including dietary components from recent related reports. These include polyunsaturated fatty acids, fiber, phytochemicals, and alcohol. Although the exact mechanism for preventing breast cancer using these dietary factors is not well understood, the combination of all the elements in a healthy diet plays a role in reducing breast cancer risk. Considering the elevated probability of breast cancer relapse and mortality, it is crucial to investigate the correlation between a nutritious dietary pattern and breast cancer, while identifying bioactive components that have the potential to mitigate the risk of breast cancer incidence.

Background: Cerebral venous outflow alterations contribute to central nervous system pathology in aging and neurodegenerative disorders and are potentially linked to underlying cerebral microangiopathy. We investigated whether cerebral venous reflux (CVR) is more closely associated with cerebral amyloid angiopathy (CAA) than hypertensive microangiopathy in intracerebral hemorrhage (ICH) survivors., Methods: This cross-sectional study included 122 patients of spontaneous ICH with magnetic resonance and positron emission tomography imaging studies (2014-2022) in Taiwan. The presence of CVR was defined as abnormal signal intensity in the dural venous sinus or internal jugular vein on magnetic resonance angiography. Cerebral amyloid load was measured using the Pittsburgh compound B standardized uptake value ratio. Clinical and imaging characteristics associated with CVR were evaluated in univariable and multivariable analyses. In the subset of patients with CAA, we applied univariable and multivariable linear regression analyses to evaluate the association between CVR and cerebral amyloid retention., Results: Compared with patients without CVR (n=84, 64.5±12.1 years), patients with CVR (n=38, 69.4±11.5 years) were significantly more likely to have CAA-ICH (53.7% versus 19.8%; P< 0.001) and had a higher cerebral amyloid load (standardized uptake value ratio [interquartile range], 1.28 [1.12-1.60] versus 1.06 [1.00-1.14]; P< 0.001). In a multivariable model, CVR was independently associated with CAA-ICH (odds ratio, 4.81 [95% CI, 1.74-13.27]; P =0.002) after adjustment for age, sex and conventional small vessel disease markers. In CAA-ICH, higher PiB retention was observed in patients with CVR than patients without CVR (standardized uptake value ratio [interquartile range], 1.34 [1.08-1.56] versus 1.09 [1.01-1.26]; P <0.001). In multivariable analysis after adjustment for potential confounders, the presence of CVR was independently associated with a higher amyloid load (standardized β=0.40; P =0.001)., Conclusions: In spontaneous ICH, CVR is associated with CAA and a higher amyloid burden. Our results suggest venous drainage dysfunction potentially plays a role in CAA and cerebral amyloid deposition.

Introduction: The worldwide coronavirus disease 2019 pandemic re-emphasises the importance of videoconferencing in supporting interactions between nursing home residents and their family and friends. However, there is a scarcity of comparative studies on how modalities of conferencing programs impact health outcomes. The purpose of this study was to compare laptop-based with smartphone-based videoconferencing programs on nursing home residents' perceptions of loneliness, depressive symptoms and social support., Methods: This retrospective secondary analysis used data from two previous studies on the effectiveness of videoconferencing programs (laptop-based and smartphone-based) to improve outcomes of loneliness, depressive symptoms and social support (type and source) among nursing home residents. Generalised estimating equations compared differences from baseline measures with measures at 1 and 3 months between the two groups with and without adjusting for the effects of confounding variables., Results: With the exception of age, there were no differences in demographics between participants in the laptop and smartphone groups. Neither changes from baseline in mean scores for loneliness nor depressive symptoms differed between groups. However, changes in mean scores from baseline between groups were significantly greater in the smartphone-based group compared with the laptop-based group for three types of social support: informational and appraisal at 1 and 3 months; and emotional at 3 months. Changes from baseline in mean scores for social support from friends (at 1 and 3 months) and other sources (at 3 months) were also significantly greater for the smartphone group compared with the laptop group., Discussion: The two modalities of videoconferencing did not differ in effects on depressive symptoms or loneliness. However, smartphones had a greater effect on the type and source of social support compared with laptops. Whether the small screen of a smartphone reduces users' anxiety and allows them to talk more on screen is worth studying.

The reflex auriculo-cardiac (RAC), dynamic pulse reaction (Nogier reflex), or vascular autonomic signal was proposed by Nogier. It refers to the pulse changes that can occur in the radial artery immediately after auricular acupuncture is performed. RAC is helpful for the clinical practice of auricular acupuncture, but there is a lack of objective verification methods. Photoplethysmography (PPG) has been used to objectively calculate radial artery blood flow. This study used PPG via a smartphone to measure RAC induced by auricular acupuncture. Thirty subjects without major diseases were recruited to receive traditional needle and laser acupuncture. The Shen Men ear point and control points were stimulated for 20 s. PPG was continuously measured during the acupuncture. The PPG data were tested for differences with a paired t -test. The results showed that there were no statistical differences in the frequency and amplitude of PPG obtained before and after acupuncture, either with a traditional needle or laser acupuncture. However, interestingly, it was found that one patient with insomnia, one patient with viral respiratory symptoms, and two menstruating females exhibited changes in PPG within five seconds of needle placement. We hypothesized that RAC might be induced by auricular acupuncture and could be quantified by PPG, even among subjects suffering from mild diseases; however, auricular acupuncture might not induce a measurable RAC in totally healthy subjects.

Capacitive touch panels (CTPs) have the merits of being waterproof, antifouling, scratch resistant, and capable of rapid response, making them more popular in various touch electronic products. However, the CTP has a multilayer structure, and the background is a directional texture. The inspection work is more difficult when the defect area is small and occurs in the textured background. This study focused mainly on the automated defect inspection of CTPs with structural texture on the surface, using the spectral attributes of the discrete cosine transform (DCT) with the proposed three-way double-band Gaussian filtering (3W-DBGF) method. With consideration to the bandwidth and angle of the high-energy region combined with the characteristics of band filtering, threshold filtering, and Gaussian distribution filtering, the frequency values with higher energy are removed, and after reversal to the spatial space, the textured background can be weakened and the defects enhanced. Finally, we use simple statistics to set binarization threshold limits that can accurately separate defects from the background. The detection outcomes showed that the flaw detection rate of the DCT-based 3W-DBGF approach was 94.21%, the false-positive rate of the normal area was 1.97%, and the correct classification rate was 98.04%.

Aim: The aim of this study was to explore and examine the relationship between anxiety, acute pain intensity, and decision regret of living liver donors in the postoperative stage., Methods: This is a prospective correlational study. Data were collected consecutively for one year (from September 2017 to September 2018) at a medical center in northern Taiwan. Information about anxiety and acute pain intensity was collected preoperatively and on postoperative day (POD) 3 and POD 7. Satisfaction with pain management and decision regret was inquired about on POD 7., Results: Data of 57 consecutive living liver donors (56.1 % male, mean age 34.12 ± 9.92 years) were analyzed. Living liver donors experienced moderate anxiety and acute pain levels in the postoperative period. The mean score of decision regret was 12.63 (range 0-60), indicating a low level of regret. The acute pain intensity decreased significantly between POD 3 and POD 7 (p < .001); however, the anxiety level slightly increased (p = .031). Older and married living liver donors had higher anxiety levels. The satisfaction level of pain management was negatively correlated with the POD 7 acute pain intensity (r = -0.26, p = .049) and decision regret (r = -0.37, p = .005), but it was positively correlated with POD 7 anxiety (r = 0.38, p = .004)., Conclusions: The postoperative period was hard for living liver donors as they would experience moderate acute pain and anxiety. Although the decision regret was low, the satisfaction level of pain management would negatively affect it. Therefore, the effectiveness of pain management and anxiety management should be continually ensured in the postoperative period., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to investigate the relationship between depression in older nursing home residents and family caregivers' (FCGs) depressive status and reasons for involvement with residents., Design: This study employed a cross-sectional design., Setting: Eight nursing homes in northern Taiwan., Participants: A total of 139 older resident-FCG pairs were recruited., Measurements: Depression was measured with the Geriatric Depression Scale-Short Form for nursing home residents and the Center for Epidemiologic Studies Depression Scale-Short Form for family members. Depression and demographic data were collected with face-to-face interviews. The meaning ascribed to caregivers' nursing home visits was calibrated using the Family Meaning of Nursing-Home Visits scale. Multiple logistic regression was used to understand the factors related to residents' depressive symptoms., Results: Depressive symptoms were present in 58.3% of the nursing home residents ( n = 81). Depressive status of family members (Chi-square = 1.46, p = 0.23) or family's visiting frequency (Chi-square = 1.64, p = 0.44) did not differ between residents with or without depressive symptoms. Factors associated with an increased risk of residents having depressive symptoms were age, self-perceived health status, and having a caregiver motivated to visit to assuage their guilt., Conclusions: Visiting a family member to assuage their guilt was the only caregiver variable associated with depressive symptoms for nursing home residents. This finding suggests that developing interventions to improve personal relationships between nursing home residents and family members might facilitate the emotional support of caregivers and psychological support for older nursing home residents in Taiwan.

Low-dose computed tomography (LDCT) has emerged as a standard method for detecting early-stage lung cancer. However, the tedious computer tomography (CT) slide reading, patient-by-patient check, and lack of standard criteria to determine the vague but possible nodule leads to variable outcomes of CT slide interpretation. To determine the artificial intelligence (AI)-assisted CT examination, AI algorithm-assisted CT screening was embedded in the hospital picture archiving and communication system, and a 200 person-scaled clinical trial was conducted at two medical centers. With AI algorithm-assisted CT screening, the sensitivity of detecting nodules sized 4−5 mm, 6~10 mm, 11~20 mm, and >20 mm increased by 41%, 11.2%, 10.3%, and 18.7%, respectively. Remarkably, the overall sensitivity of detecting varied nodules increased by 20.7% from 67.7% to 88.4%. Furthermore, the sensitivity increased by 18.5% from 72.5% to 91% for detecting ground glass nodules (GGN), which is challenging for radiologists and physicians. The free-response operating characteristic (FROC) AI score was ≥0.4, and the AI algorithm standalone CT screening sensitivity reached >95% with an area under the localization receiver operating characteristic curve (LROC-AUC) of >0.88. Our study demonstrates that AI algorithm-embedded CT screening significantly ameliorates tedious LDCT practices for doctors.

The aims of the present study were to examine whether and how frailty impacts the outcomes of breast cancer. Data of women with breast cancer hospitalized during 2005 and 2018 were extracted from the US Nationwide Inpatient Sample (NIS) database. Frailty was identified using a novel algorithm, Hospital Frailty Risk Score (HFRS). Propensity-score (PS) matching was utilized to balance the baseline characteristics between frail and non-frail groups. In-hospital mortality, unfavorable discharge, prolonged length of stay (LOS), and total hospital cost were compared using univariate and multivariable logistic regression analyses. A total of 19,522 patients with metastatic (frailty n = 9,906; no frailty n = 9,716) and 135,200 with non-metastatic breast cancer (frailty n = 30,235; no frailty n = 104,965) were included. After adjustment, frailty was significantly and independently associated with higher risk for in-hospital mortality, unfavorable discharge, prolonged LOS, and greater hospital cost in both metastatic and non-metastatic diseases, in which the impacts of frailty was greater in women with non-metastatic disease. In stratified analysis, frailty had the greatest impact on in-hospital mortality among women had had non-metastatic disease and aged <50 years (aOR = 3.88; 95% CI: 1.95-7.73). In conclusion, frailty is associated with worse outcomes in women with breast cancer, and the effects are greater in non-metastatic disease and younger patients., Competing Interests: None., (AJCR Copyright © 2022.)

Background: In endothelial cells, phospholipase C (PLC) β1-activated Ca 2+ is a crucial second messenger for the signaling pathways governing angiogenesis. PLCβ1 is inactivated by complexing with an intracellular protein called translin-associated factor X (TRAX). This study demonstrates specific interactions between Globo H ceramide (GHCer) and TRAX, which highlight a new angiogenic control through PLCβ1 activation., Methods: Globo-series glycosphingolipids (GSLs), including GHCer and stage-specific embryonic antigen-3 ceramide (SSEA3Cer), were analyzed using enzyme-linked immunosorbent assay (ELISA) and Biacore for their binding with TRAX. Angiogenic activities of GSLs in human umbilical vein endothelial cells (HUVECs) were evaluated. Molecular dynamics (MD) simulation was used to study conformations of GSLs and their molecular interactions with TRAX. Fluorescence resonance energy transfer (FRET) analysis of HUVECs by confocal microscopy was used to validate the release of PLCβ1 from TRAX. Furthermore, the in vivo angiogenic activity of extracellular vesicles (EVs) containing GHCer was confirmed using subcutaneous Matrigel plug assay in mice., Results: The results of ELISA and Biacore analysis showed a stable complex between recombinant TRAX and synthetic GHCer with KD of 40.9 nM. In contrast, SSEA3Cer lacking a fucose residue of GHCer at the terminal showed ~ 1000-fold decrease in the binding affinity. These results were consistent with their angiogenic activities in HUVECs. The MD simulation indicated that TRAX interacted with the glycan moiety of GHCer at amino acid Q223, Q219, L142, S141, and E216. At equilibrium the stable complex maintained 4.6 ± 1.3 H-bonds. TRAX containing double mutations with Q223A and Q219A lost its ability to interact with GHCer in both MD simulation and Biacore assays. Removal of the terminal fucose from GHCer to become SSEA3Cer resulted in decreased H-bonding to 1.2 ± 1.0 by the MD simulation. Such specific H-bonding was due to the conformational alteration in the whole glycan which was affected by the presence or absence of the fucose moiety. In addition, ELISA, Biacore, and in-cell FRET assays confirmed the competition between GHCer and PLCβ1 for binding to TRAX. Furthermore, the Matrigel plug assay showed robust vessel formation in the plug containing tumor-secreted EVs or synthetic GHCer, but not in the plug with SSEA3Cer. The FRET analysis also indicated the disruption of colocalization of TRAX and PLCβ1 in cells by GHCer derived from EVs., Conclusions: Overall, the fucose residue in GHCer dictated the glycan conformation for its complexing with TRAX to release TRAX-sequestered PLCβ1, leading to Ca 2+ mobilization in endothelial cells and enhancing angiogenesis in tumor microenvironments., (© 2022. The Author(s).)

Background: The accuracy of histopathology diagnosis largely depends on the pathologist's experience. It usually takes over 10 years to cultivate a senior pathologist, and small numbers of them lead to a high workload for those available. Meanwhile, inconsistent diagnostic results may arise among different pathologists, especially in complex cases, because diagnosis based on morphology is subjective. Computerized analysis based on deep learning has shown potential benefits as a diagnostic strategy., Methods: This research aims to automatically determine the location of gastric cancer (GC) in the images of GC slices through artificial intelligence. We use image data from a regional teaching hospital in Taiwan for training. We collect images of patients diagnosed with GC from January 1, 2019 to December 31, 2020. In this study, scanned images are used to dissect 13,600 images from 50 different patients with GC sections whose GC sections are stained with hematoxylin and eosin (H&E stained) through a whole slide scanner, the scanned images from 50 different GC slice patients are divided into 80% training combinations, 2200 images of 40 patients are trained. The remaining 20%, totaling 10 people, are validated from a test set of 550 images., Results: The validation results show that 91% of the correct rates are interpreted as GC images through deep learning. The sensitivity, specificity, PPV, and NPV were 84.9%, 94%, 87.7%, and 92.5%, respectively. After creating a 3D model through the grayscale value, the position of the GC is completely marked by the 3D model. The purpose of this research is to use artificial intelligence (AI) to determine the location of the GC in the image of GC slice., Conclusion: In patients undergoing pancreatectomy for pancreatic cancer, intraoperative infusion of lidocaine did not improve overall or disease-free survival. Reduced formation of circulating NETs was absent in pancreatic tumour tissue., Conclusion: For AI to assist pathologists in daily practice, to help a pathologist making a definite diagnosis is not the prime purpose at present time. The benefits could come from cancer screening and double-check quality control in a heavy workload which could distract the attention of pathologist during the time constraint examination process. We propose a two-steps method to identify cancerous areas in endoscopic gastric biopsy slices via deep learning. Then a 3D model is used to further mark all the positions of GC in the picture, and the model overcomes the problem that deep learning can't catch all GC., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022. Published by Elsevier B.V.)

Background: Trans-hepatic arterial chemoembolization (TACE) is a treatment option for liver cancer patients. It can prolong patients' survival but can also cause symptom distress. Symptom distress (SDs) can directly impact quality of life (QOL) and may indirectly influence QOL by lessening hope. In this study, we wanted to explore the mediating effect of hope on the relationship between SDs and QOL among patients with liver cancer receiving TACE., Methods: A cross-sectional study was conducted from December 20, 2017, to August 6, 2018, at a gastroenterology ward of a medical center. The participants were 92 liver cancer patients (69.6% male, mean age 67.8) who were admitted for TACE treatment. Information on SDs, hope, and QOL was collected by questionnaire on discharge day. Hayes' PROCESS model was used to test the mediating effect of hope on the relationship between SDs and QOL., Results: The mean score and standard deviation (SD) of SDs, hope, and QOL were 32.08 (SD = 6.22), 27.09 (SD = 3.51), and 55.16 (SD = 17.33), respectively. SDs negatively impacts quality of life. The total effect of SDs on QOL was - 1.41 (95% confidence interval [CI]: - 1.96, - 0.86). The indirect effect via the mediation of hope was - 0.95 (95% CI: - 1.7, - 0.45). Hope partially mediated the effect of SDs on QOL., Conclusion: SDs after TACE is vital; it directly reduces a patient's overall QOL and can indirectly hinder it by reducing the patient's hope. In addition to symptom management, interventions that help patients maintain their hope are key to improving QOL among patients receiving TACE., (© 2022. The Author(s).)

Competing Interests: There are no conflicts of interest.

For rectal cancer patients with stage T3-4 disease or positive lymph node, neoadjuvant concurrent chemoradiotherapy (CCRT) has become the standard treatment, but the clinical outcomes are still far from satisfactory. Accordingly, a more precise predictive tool such as genetic biomarkers is urgently required to optimize therapy decisions. Colorectal cancer (CRC) development has been considerably correlated with cellular metabolic process involving nucleotides, but the underlying molecular mechanisms remain unclear. In this study, we employed a transcriptome dataset comprising 46 rectal adenocarcinoma patients undergoing preoperative CCRT and focused on nucleobase-containing compound metabolic process (GO: 0055134) for data mining. We identified solute carrier family 28 member 2 (SLC28A2) as the most considerably upregulated gene among rectal cancer patients with CCRT resistance. Afterwards, there were a total of 172 rectal cancer tissue blocks procuring from our biobank, and the immunointensity of SLC28A2 was appraised utilizing immunohistochemical staining. Strong SLC28A2 immunointensity was significantly linked to female patients (p = 0.032), vascular invasion (p = 0.021), and post-CCRT tumor invasion and regional lymph node involvement (p < 0.001 and p = 0.005). Notably, patients with strong SLC28A2 immunointensity had no tumor downstaging (p < 0.001). Univariate analysis revealed that high SLC28A2 immunoexpression was considerably unfavorably linked to all three endpoints: local recurrence-free survival (LRFS), metastasis-free survival (MeFS), and disease-specific survival (DSS) (all p ≤ 0.0333). Moreover, both high SLC28A2 immunoexpression and low tumor regression grade were independently unfavorable prognostic factors for all three endpoints (all p ≤ 0.013) in the multivariate analysis. Utilizing function prediction analysis, SLC28A2 upregulation was more likely to be linked with stem cell homeostasis in rectal cancer. In brief, we demonstrated that high SLC28A2 immunoexpression is substantially linked to an advanced stage, poor response to CCRT, and worse patient survival. Consequently, SLC28A2 expression can be a valuable predictive and prognostic marker for rectal cancer patients and be an encouraging therapeutic target for those with CCRT resistance., Competing Interests: Conflict of interest 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 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Climate change causes devastating impacts with extreme weather conditions, such as flooding, polar ice caps melting, sea level rise, and droughts. Environmental conservation education is an important and ongoing project nowadays for all governments in the world. In this paper, a novel 3D virtual reality architecture in the metaverse (VRAM) is proposed to foster water resources education using modern information technology., Methods: A quasi-experimental study was performed to observe a comparison between learning involving VRAM and learning without VRAM. The 3D VRAM multimedia content comes from a picture book for learning environmental conservation concepts, based on the cognitive theory of multimedia learning to enhance human cognition. Learners wear VRAM helmets to run VRAM Android apps by entering the immersive environment for playing and/or interacting with 3D VRAM multimedia content in the metaverse. They shake their head to move the interaction sign to initiate interactive actions, such as replaying, going to consecutive video clips, displaying text annotations, and replying to questions when learning soil-and-water conservation course materials. Interactive portfolios of triggering actions are transferred to the cloud computing database immediately by the app., Results: Experimental results showed that participants who received instruction involving VRAM had significant improvement in their flow experience, learning motivation, learning interaction, self-efficacy, and presence in learning environmental conservation concepts., Conclusions: The novel VRAM is highly suitable for multimedia educational systems. Moreover, learners' interactive VRAM portfolios can be analyzed by big-data analytics to understand behaviors for using VRAM in the future to improve the quality of environmental conservation education.

Objective: To reduce the risk of locoregional recurrence, the addition of neoadjuvant concurrent chemoradiotherapy (CCRT) is recommended before surgical management for rectal cancer patients. However, despite identical tumor histology, individual patient response to neoadjuvant CCRT varies greatly. Accordingly, a comprehensive molecular characterization that is used to predict CCRT efficacy is instantly needed. Methods: Pearson's chi-squared test was utilized to correlate dehydrogenase/reductase 9 (DHRS9) expression with clinicopathological features. Survival curves were created applying the Kaplan-Meier method, and the log-rank test was conducted to compare prognostic utility between high and low DHRS9 expression groups. Multivariate Cox proportional hazards regression analysis was applied to identify independent prognostic biomarkers based on variables with prognostic utility at the univariate level. Results: Utilizing a public transcriptome dataset, we identified that the DHRS9 gene is the most considerably upregulated gene related to epithelial cell differentiation (GO: 0030855) among rectal cancer patients with CCRT resistance. Employing immunohistochemical staining, we also demonstrated that high DHRS9 immunoexpression is considerably associated with an aggressive clinical course and CCRT resistance in our rectal cancer cohort. Among all variables with prognostic utility at the univariate level, only high DHRS9 immunoexpression was independently unfavorably prognostic of all three endpoints (all p ≤ 0.048) in the multivariate analysis. In addition, applying bioinformatic analysis, we also linked DHRS9 with unrevealed functions, such as keratan sulfate and mucin synthesis which may be implicated in CCRT resistance. Conclusion: Altogether, DHRS9 expression may serve as a helpful predictive and prognostic biomarker and assist decision-making for rectal cancer patients who underwent neoadjuvant CCRT., 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 Chen, Hsu, Lee, Yang, Tian, Kuo, Li, Tsai, Wu, Yeh, Chou and Lai.)

Background and Purpose: Cerebral venous flow alterations potentially contribute to age-related white matter changes, but their role in small vessel disease has not been investigated., Methods: This study included 297 patients with hypertensive intracerebral hemorrhages (ICH) who underwent magnetic resonance imaging. Cerebral venous reflux (CVR) was defined as the presence of abnormal signal intensity in the dural venous sinuses or internal jugular vein on time-of-flight angiography. We investigated the association between CVR, dilated perivascular spaces (PVS), and recurrent stroke risk., Results: CVR was observed in 38 (12.8%) patients. Compared to patients without CVR those with CVR were more likely to have high grade (>20 in the number) dilated PVS in the basal ganglia (60.5% vs. 35.1%; adjusted odds ratio [aOR], 2.64; 95% confidence interval [CI], 1.25 to 5.60; P=0.011) and large PVS (>3 mm in diameter) (50.0% vs. 18.5%; aOR, 3.87; 95% CI, 1.85 to 8.09; P<0.001). During a median follow-up of 18 months, patients with CVR had a higher recurrent stroke rate (13.6%/year vs. 6.2%/year; aOR, 2.53; 95% CI, 1.09 to 5.84; P=0.03) than those without CVR., Conclusions: CVR may contribute to the formation of enlarged PVS and increase the risk of recurrent stroke in patients with hypertensive ICH.

PVC injection molding has constrained temperature and shear rate owing to its temperature sensitivity and high viscosity, as well as its low conductivity. Many challenges are associated with the PVC injection molding process used for producing PVC fittings with a multi-cavity mold. Once filling imbalance occurs, the gates and/or runner of the mold should be changed by machine tools, which is time- and cost-intensive. Using Moldex3D and the Taguchi method, this study reveals an approach to eliminate imbalanced filling of multi-cavity molds for PVC injection molding. The injection rate optimization of the filling stage is successfully verified to reduce the imbalance. Furthermore, the temperatures of the molded PVC fittings are only slightly increased by the change in injection rate. The temperatures of fittings in the filling and packing are lower than the degradation temperature of PVC. This approach may help technicians to obtain pilot-run samples for the optimization of molding parameters and ensure degradation-free PVC molding.

Background: Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the nasopharynx with high morbidity and mortality in Southeast Asia and south of China. Roundabout guidance receptor 1 (ROBO1) can regulate axonogenesis (axon-like protrusion), which may play an important role in migration. However, the roles of ROBO1 in NPC have not been clarified., Methods: A comparative analysis employing the NPC transcriptome (GSE12452) and the axonogenesis-related genes (GO: 0050772) was performed. In total, 124 tissue blocks from patients primarily diagnosed as NPC (1993-2002) were examined using immunohistochemical staining. The connections between clinicopathological variables and protein immunoexpression were analyzed by Pearson's chi-square test. The Kaplan-Meier method with a log-rank test was employed to plot survival curves. Multivariate analysis was performed using the Cox proportional hazards model to identify independent prognostic biomarker., Results: According to transcriptome analysis, we found that ROBO1 is significantly highly expressed in NPC tissues compared with normal tissues. The immunohistochemistry (IHC) staining showed that high expression of ROBO1 was significantly related to primary tumor (T1T2 and T3T4) ( P  = .024), nodal metastasis status (N0N1 and N2N3) ( P  = .030), stage (I-II and III-IV) ( P  = .019), and histological grade (keratinizing, non-keratinizing, and undifferentiated) ( P  = .065). Importantly, NPC patients with high ROBO1 expression had poorer disease-specific survival (DSS) ( P  = .0001), distal metastasis-free survival (DMeFS) ( P  < .0001), and local recurrence-free survival (LRFS) ( P  = .0001) compared with NPC patients with low ROBO1 expression through the uni-/multivariate and the Kaplan-Meier survival analyses., Conclusion: Our report indicates that ROBO1 might be a potential prognostic biomarker for NPC., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

The demand of bone grafting is increasing as the population ages worldwide. Although bone graft materials have been extensively developed over the decades, only a few injectable bone grafts are clinically available and none of them can be extruded from 18G needles. To overcome the existing treatment limitations, the aim of this study is to develop ideal injectable implants from biomaterials for minimally invasive surgery. An injectable composite bone graft containing calcium sulfate hemihydrate, tetracalcium phosphate, and anhydrous calcium hydrogen phosphate (CSH/CaP paste) was prepared with different CSH/CaP ratios and different concentrations of additives. The setting time, injectability, mechanical properties, and biocompatibility were evaluated. The developed injectable CSH/CaP paste (CSH/CaP 1:1 supplemented with 6% citric acid and 2% HPMC) presented good handling properties, great biocompatibility, and adequate mechanical strength. Furthermore, the paste was demonstrated to be extruded from a syringe equipped with 18G needles and exerted a great potential for minimally invasive surgery. The developed injectable implants with tissue repairing potentials will provide an ideal therapeutic strategy for minimally invasive surgery to apply in the treatment of maxillofacial defects, certain indications in the spine, inferior turbinate for empty nose syndrome (ENS), or reconstructive rhinoplasty.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with high morbidity and mortality worldwide. Although several mechanisms to account for deleterious immune effects were proposed, molecular description for the underlying alveolar structural alterations for COPD is lacking. Here, silencing of α1,6-fucosyltransferase (Fut8), the enzyme for core-fucosylation and highly expressed in lung stem cells, resulted in alveolar structural changes in lung organoids, recapitulating COPD. Site-specific mass spectrometry analysis demonstrated that the secreted protein acidic and rich in cysteine (SPARC), which binds collagen, contains a core-fucosylation site in its VCSNDN cf K glycopeptide. Biacore assay showed markedly reduced collagen binding of SPARC lacking core fucosylation. Molecular dynamics analysis revealed that core fucosylation of SPARC-induced dynamic conformational changes in its N-glycan, allowing terminal galactose and N-acetylglucosamine to interact with K150, P261 and H264 residues, thereby promoting collagen binding. Site-specific mutagenesis of these residues also resulted in low affinity for collagen binding. Moreover, loss of collagen and decline of core fucosylation were observed in COPD lung tissues. These findings provide a new mechanistic insight into the role of core fucosylation of SPARC in cell-matrix communication and contribution to the abnormal alveolar structures in COPD., (© 2022. The Author(s).)

Unlike that of glycol-modified Poly(ethylene terephthalate) (PETG), the crystallinity of PET can be post-adjusted to enhance the mechanical properties of 3D-printed parts such as food-contact tableware and bio-implants. The aforementioned PET material could be 3D printed to produce the desired parts for performance evaluation before mass production by injection molding. In this study, using differential scanning calorimetry (DSC), we examined the pellets, extruded filament, and printed specimen to identify variations in melting and crystalline temperatures, as well as crystallinity. It was also shown by Thermogravimetric Analyzer (TGA) that the addition of talcum powder increased the thermal stability of filament and resulted in an interaction between the fillers and polymer matrix. The crystallinities of the filament and printed specimen were then compared with the yield strengths and Young's moduli to confirm the effects of the decreased molecular weight of the extruded PET filament. The talcum powder effectively improved the viscosity of the PET melted during the extrusion process for the filament and then enhanced the crystallinity of the PET, thereby achieving a significantly higher Young's modulus. The printed PET specimen presented an excellent yield strength of 25 MPa and ductile properties with strain-at-break values of 30%, successfully indicating potential applications in food-contact tableware and bio-implants.

Herein, this work aims to fabricate well-ordered nanonetwork epoxy resin modified with poly(butyl acrylate)- b -poly(methyl methacrylate) (PBA- b -PMMA) block copolymer (BCP) for enhanced energy dissipation using a self-assembled diblock copolymer of polystyrene- b -poly(dimethylsiloxane) (PS- b -PDMS) with gyroid and diamond structures as templates. A systematic study of mechanical properties using nanoindentation of epoxy resin with gyroid- and diamond-structures after modification revealed significant enhancement in energy dissipation, with the values of 0.36 ± 0.02 nJ (gyroid) and 0.43 ± 0.03 nJ (diamond), respectively, when compared to intrinsic epoxy resin (approximately 0.02 ± 0.002 nJ) with brittle characteristics. This enhanced property is attributed to the synergic effect of the deliberate structure with well-ordered nanonetwork texture and the toughening of BCP-based modifiers at the molecular level. In addition to the deliberate structural effect from the nanonetwork texture, the BCP modifier composed of epoxy-philic hard segment and epoxy-phobic soft segment led to dispersed soft-segment domains in the nanonetwork-structured epoxy matrix with superior interfacial strength for the enhancement of applied energy dissipation.

Background: Hip fractures are one of the most serious injuries affecting older adults. Evidence-based knowledge regarding the functional status of older persons after hip fracture can provide information critical for developing effective continuous-care and rehabilitation programs., Purpose: This study was developed to examine the post-hospital-discharge outcome measures and predictors of functional status in older adults in Indonesia after hip fracture surgery., Methods: The functional status of 109 patients discharged from an orthopedic hospital in Indonesia after hip fracture surgery was evaluated in this prospective cohort study. Functional status was evaluated using measures of physical and independent activities of daily living (PADL and IADL, respectively) at 1, 3, and 6 months postdischarge. Predictors of changes in functional status, including age, length of hospital stay, comorbidity, prefracture walking ability, type of surgery, status of depression and nutrition, type of insurance, and residential status (urban vs. rural), were also examined. Data were analyzed using generalized estimating equations., Results: Significant improvements in PADL were found at 3 and 6 months, and significant improvements in IADL were found at 6 months. Predictors of poor outcomes found in this study included age, a dependent prefracture walking ability, depression, and having public health insurance., Conclusions/implications for Practice: The findings of this study support the effectiveness of using presurgery assessments to identify individuals at a higher postdischarge risk of having poor PADL and IADL outcomes. Home nursing or subacute rehabilitation is recommended to improve and maintain functional status in older persons after hip fracture surgery. In addition, interventions and rehabilitation should take into consideration different recovery periods for PADL and IADL after hospital discharge after hip fracture surgery., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Many challenges are associated with the injection molding process for forming a rib-structured pallet (1100 mm × 1100 mm × 140 mm, length × width × height) because greater flowing resistance through the rib channels within the pallet can induce insufficient filling. Essentially, multi-gate filling involves a sequential valve gate system, which helps to spread the filling front with fewer weld lines. Based on the presetting of the sequential scheme of the valve gates, actual measurements of pallet flatness using the ATOS scan system were compared to numerical warpage measurements of a pallet derived by Moldex3D 2020. In this study, we propose a sequential scheme by actuating the valve gates to open once the flow front spreads towards them; then, actual warpage measurements of a pallet are compared with numerical measurements. The results show that the warpage of the top surface of the pallet is 5.144 mm in actual measurements and 5.729 mm in simulation. The results all indicated small warpage with respect to the pallet size. The simulation and actual measurements of flatness are in excellent agreement; the difference in top flatness between the simulated and actual pallet is 0.59 mm, while the bottom flatness difference is 0.035 mm. By adjusting the cooling water temperature, increasing the mold temperature, and decreasing the material temperature, overall flatness and warpage displacement can be reduced.

Developing battery-supercapacitor hybrid devices (BSHs) is viewed as an efficient route to shorten the gap between supercapacitors and batteries. In this study, a composite hydrogel consisting of perylene tetracarboxylic diimide (PTCDI) and reduced graphene oxide (rGO) is tested as the anode for BSHs in the electrolyte of ammonium acetate (NH 4 Ac) with a record concentration of 32 molality (m). This water-in-salt electrolyte exhibits a wide electrochemical stability window of 2.13 V and high conductivity of 23.3 mS cm -1 even at -12 °C. Molecular dynamics calculations and spectroscopic measurements reveal that a favorable water-acetate interaction occurs in a high concentration NH 4 Ac electrolyte. On the other hand, the study of electrode kinetics in 32 m NH 4 Ac demonstrates a high capacitive contribution to charge storage in PTCDI-rGO although an electrode redox reaction involves reversible enolization of carbonyl groups in PTCDI. This result suggests fast NH 4 + -ion intercalation kinetics in charge-discharge processes. Furthermore, the electrode performance is improved by optimizing the loading amount of rGO in composites. The best-performing composite electrode delivers the maximum capacity of 165 mAh g -1 at 0.5 A g -1 and sustains a great capacity retention of 66% at 8 A g -1 . Finally, an all-organic BSH device is tested in a broad temperature window from -20 to 50 °C and is well operated at 1.9 V regardless of operating temperatures. Due to the synergetic effect of splendid electrolyte properties and high anode capacities, BSH devices possess the maximum energy density of 12.9 Wh kg -1 at the power density of 827 W kg -1 and retain 74 % of the initial capacity after 3000 cycles at 1 A g -1 . Our study paves a novel route towards designing inexpensive and environmentally friendly BSH devices with high performances., 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 © 2021 Elsevier Inc. All rights reserved.)

Many challenges are associated with the injection compression molding process for producing a half-pallet (1320 mm × 1110 mm × 75 mm, length × width × height), which is butt-welded to another one for enhancing its strength. This pooled high-density polyethylene (HDPE) pallet is able to endure the impacts of a heavy load and a low ambient temperature. Reducing the warpage of a half-pallet is, therefore, essential for reducing the residual internal stress within the welded portions. An advanced Moldex3D package helps to detail the temperature distribution and warpage of a half-pallet. The pre-setting molding parameters from a mass-production factory produce half-pallets with worse flatness. In this investigation on using appropriate cooling water temperatures within the core and cavity plates of the mold, the numerical results show that the warpage of the top surface of the half-pallet was 11.549 mm, low warpage with respect to this large-scale pallet. Furthermore, the compression speed of 50-60 mm/s may have produced a low flatness of the half-pallet in this study.

Background: Urothelial carcinoma (UC) patients often bear clinical and genetic heterogeneity, which may differ in management and prognosis. Especially, patients with advanced/metastatic UC generally have a poor prognosis and survive for only few months. The Wnt/β-catenin signaling is found to be highly activated in several cancers, including UC. However, accumulated evidence has shown discordance between the Wnt/β-catenin signaling and UC carcinogenesis. Accordingly, we aim to get a better understanding of the molecular characterization of UC, focusing on the Wnt signaling, which may add value to guiding management more precisely., Patients and Methods: Clinical data and pathological features were retrospectively surveyed. The correlations of secreted Frizzled-related protein 2 (SFRP2) immunoexpression with clinicopathological features were analyzed by Pearson's chi-square test. The Kaplan-Meier method with a log-rank test was employed to plot survival curves. All significant features from the univariate analysis were incorporated into the Cox regression model for multivariate analysis., Results: Following data mining on a transcriptome dataset (GSE31684), we identified that 8 transcripts in relation to the Wnt signaling pathway (GO: 0016055) were significantly upregulated in advanced/metastatic bladder tumors. Among these transcripts, the SFRP2 level showed the most significant upregulation. Additionally, as SFRP2 is a putative Wnt inhibitor and may be expressed by stroma, we were interested in examining the immunoexpression and clinical relevance of stromal and tumoral SFRP2 in our urothelial carcinoma cohorts containing 295 urinary bladder UC (UBUC) and 340 upper urinary tract UC (UTUC) patients. We observed that high SFRP2 expression in stroma but not in tumors is significantly linked to aggressive UC features, including high tumor stage and histological grade, positive nodal metastasis, the presence of vascular and perineural invasion, and high mitotic activity in UBUC and UTUC. Moreover, high stromal SFRP2 expression significantly and independently predicted worse clinical outcomes in UBUC and UTUC. Utilizing bioinformatic analysis, we further noticed that stromal SFRP2 may link epithelial-mesenchymal transition (EMT) to UC progression., Conclusion: Collectively, these results imply that stromal SFRP2 may exert oncogenic function beyond its Wnt antagonistic ability, and stromal SFRP2 expression can provide prognostic and therapeutic implications for UC patients., Competing Interests: Author C-CC is employed by Genetics Generation Advancement Corp. The remaining 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 Lai, Chiu, Kuo, Tsai, Wu, Tseng, Liu, Hsing, Huang and Li.)

Iron (Fe) is an indispensable micronutrient for plant growth and development. Since both deficiency, as well as a surplus of Fe, can be detrimental to plant health, plants need to constantly tune uptake rates to maintain an optimum level of Fe. Quantification of Fe serves as an important parameter for analyzing the fitness of plants from different accessions, or mutants and transgenic lines with altered expression of specific genes. To quantify metals in plant samples, methods based on inductively coupled plasma-optical emission spectrometry (ICP-OES) or inductively coupled plasma-mass spectrometry (ICP-MS) have been widely employed. Although these methods are highly accurate, these methodologies rely on sophisticated equipment which is not always available. Moreover, ICP-OES and ICP-MS allow for surveying several metals in the same sample, which may not be necessary if only the Fe status is to be determined. Here, we outline a simple and cost-efficient protocol to quantify Fe concentrations in roots and shoots of Arabidopsis seedlings, by using a spectroscopy-based assay to quantify Fe 2+ -BPDS 3 complexes against a set of standards. This protocol provides a fast and reproducible method to determine Fe levels in plant samples with high precision and low costs, which does not depend on expensive equipment and expertise to operate such equipment., Competing Interests: Competing interestsThe authors declare no conflict of interest., (Copyright © 2022 The Authors; exclusive licensee Bio-protocol LLC.)

Objectives: Radiological diagnosis of subtypes of cerebral small vessel diseases remains challenging. This study aimed to explore the spatial distribution of cerebral microbleeds (CMBs) in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) in contrast to cerebral amyloid angiopathy (CAA) in the lobar regions., Methods: Thirty-two patients with CADASIL and 33 patients with probable CAA were prospectively and consecutively included. On 3-Tesla susceptibility-weighted magnetic resonance images, CMBs were analyzed for incidence and volume within atlas-based regions of interest, followed by voxel-wise analysis using risk mapping. The distribution of CMBs was correlated with the status of hypertension. Correlation and group differences with a p-value less than 0.05 were considered to be significant., Results: As compared with the CAA group, the CADASIL group presents a larger CMB volume in hippocampus/amygdala and white matter (nonparametric analysis of covariance, p = 0.014 and 0.037, respectively), a smaller CMB volume in parietal lobe (p = 0.038), and a higher incidence in hippocampus/amygdala, white matter, and insula (logistic regression, p = 0.019, 0.024, and 0.30, respectively). As part of the exclusion criteria of probable CAA, thalamus, basal ganglia, and pons exhibit greater CMB volume/incidence in the CADASIL group. In CADASIL patients, hot spots of CMBs are identified in the putamen and posteromedial thalamus; hypertension is associated with larger CMB volumes in insula, basal ganglia, and pons., Conclusions: The spatial distribution of CMBs is differentiable between CADASIL and CAA in lobar regions. In CADASIL patients, hypertension has a region-dependent mediating effect on the CMB volume., Key Points: • The topological distribution of lobar CMBs is differentiable between CADASIL and CAA. • In CADASIL patients, hypertension mediates CMB volume and the mediation is region dependent. • CMB risk mapping allows for voxel-wise exploration of CMB distribution and reveals hot spots in the putamen and posteromedial thalamus in CADASIL., (© 2021. The Author(s).)

Background: Promotion of hematoma resolution in a timely manner reduces intracerebral hemorrhage (ICH) brain injury induced by toxic blood components and subsequent neuroinflammation. The meningeal lymphatic system is responsible for clearance of macromolecules and pathogenic substances from the central nervous system; however, its role in intraparenchymal hematoma clearance and ICH outcomes is unknown. In the present study, we aimed to understand the contribution of the meningeal lymphatic system to ICH pathologies and to test whether pharmacological enhancement of meningeal lymphatic function promotes hematoma resolution and brain recovery after ICH., Methods: Immunofluorescence of whole-mount meninges was used to measure complexity and coverage level of meningeal lymphatic vasculature following ICH induction. Fluorescent microbeads and PKH-26-labeled erythrocytes were used to evaluate drainage function of the meningeal lymphatic system. Visudyne treatment, deep cervical lymph node ligation, and VEGF (vascular endothelial growth factor)-C injection were performed to manipulate meningeal lymphatic function. Neurobehavioral performance and hematoma volume were assayed by the cylinder test and histological measurements. Iron deposition, residual erythrocytes, neuronal loss, and astrogliosis were assessed by immunohistochemistry and antibody-based fluorescence staining., Results: Meningeal lymphangiogenesis and enhanced lymphatic drainage occurred during the late phase of ICH. Ablation and blockage of meningeal lymphatic vessels impeded hematoma clearance, whereas pharmacological enhancement of their function reduced hematoma volume, improved behavioral performance, and reduced brain residual erythrocytes, iron deposition, neuronal loss, and astroglial activation., Conclusions: Early enhancement of meningeal lymphatic function is beneficial for ICH recovery. Targeting the meningeal lymphatic system is therefore a potential therapeutic approach for treating ICH.

Background: Type 2 diabetes mellitus (T2DM) is caused by a combination of environmental, genetic, and epigenetic factors including, fasting blood glucose (FBG), genetic variant rs841853, and cg19693031 methylation. We evaluated the interaction between rs841853 and cg19693031 on the FBG levels of non-diabetic Taiwanese adults., Methods: We used Taiwan Biobank (TWB) data collected between 2008 and 2016. The TWB data source contains information on basic demographics, personal lifestyles, medical history, methylation, and genotype. The study participants included 1300 people with DNA methylation data. The association of cg19693031 methylation (stratified into quartiles) with rs841853 and FBG was determined using multiple linear regression analysis. The beta-coefficients (β) and p-values were estimated., Results: The mean ± standard deviation (SD) of FBG in rs841853-CC individuals (92.07 ± 7.78) did not differ significantly from that in the CA + AA individuals (91.62 ± 7.14). However, the cg19693031 methylation levels were significantly different in the two groups (0.7716 ± 0.05 in CC individuals and 0.7631 ± 0.05 in CA + AA individuals (p = 0.002). The cg19693031 methylation levels according to quartiles were β < 0.738592 (< Q1), 0.738592 ≤ 0.769992 (Q1-Q2), 0.769992 ≤ 0.800918 (Q2-Q3), and β ≥ 0.800918 (≥ Q3). FBG increased with decreasing cg19693031 methylation levels in a dose-response manner (p trend  = 0.005). The β-coefficient was - 0.0236 (p = 0.965) for Q2-Q3, 1.0317 (p = 0.058) for Q1-Q2, and 1.3336 (p = 0.019 for < Q1 compared to the reference quartile (≥ Q3). The genetic variant rs841853 was not significantly associated with FBG. However, its interaction with cg19693031 methylation was significant (p-value = 0.036). Based on stratification by rs841853 genotypes, only the CC group retained the inverse and dose-response association between FBG and cg19693031 methylation. The β (p-value) was 0.8082 (0.255) for Q2-Q3, 1.6930 (0.022) for Q1-Q2, and 2.2190 (0.004) for < Q1 compared to the reference quartile (≥ Q3). The p trend was 0.002., Conclusion: Summarily, methylation at cg19693031 was inversely associated with fasting blood glucose in a dose-dependent manner. The inverse association was more prominent in rs841853-CC individuals, suggesting that rs841853 could modulate the association between cg19693031 methylation and FBG. Our results suggest that genetic variants may be involved in epigenetic mechanisms associated with FBG, a hallmark of diabetes. Therefore, integrating genetic and epigenetic data may provide more insight into the early-onset of diabetes., (© 2022. The Author(s).)

Background: The purpose of this preliminary study was to explore whether a smart clothes-assisted home-nursing care program could benefit family caregivers and their care recipients., Methods: Family caregivers in charge of a care recipient's living situation participated in this convergent parallel, mixed methods study. We recruited older persons with dementia (n = 7) and those discharged following hip-fracture surgery (n = 6) from neurological clinics and surgical wards of a medical center, respectively, along with their family caregivers: three spouses, eight sons, one daughter, and one daughter-in-law. Care recipients were asked to wear a smart vest at least 4 days/week for 6 months, which contained a coin-size monitor hidden in an inner pocket. Sensors installed in bedrooms and living areas received signals from the smart clothing, which were transmitted to a mobile phone app of homecare nurses, who provided caregivers with transmitted information regarding activities, emergency situations and suggestions for caregiving activities. Outcomes included changes from baseline in caregivers' preparedness and depressive symptoms collected at 1- and 3-months, which were analyzed with Friedman's non-parametric test of repeated measures with post-hoc analysis. Transcripts of face-to-face semi-structured interview data about caregivers' experiences were analyzed to identify descriptive, interpretative, and pattern codes., Results: Preparedness did not change from baseline at either 1- or 3-months for family caregivers of persons with dementia. However, depressive symptoms decreased significantly at 1-month and 3-months compared with baseline, but not between 1-months and 3-months. Analysis of the interview data revealed the smart clothes program increased family caregivers' knowledge of the care recipient's situation and condition, informed healthcare providers of the care recipient's physical health and cognitive status, helped homecare nurses provide timely interventions, balanced the care recipient's exercise and safety, motivated recipients to exercise, helped family caregivers balance work and caregiving, and provided guidance for caregiving activities., Conclusions: Experiences with the smart clothes-assisted home-nursing care program directly benefited family caregivers, which provided indirect benefits to the care recipients due to the timely interventions and caregiving guidance from homecare nurses. These benefits suggest a smart-clothes-assisted program might be beneficial for all family caregivers., (© 2022. The Author(s).)

The investigation of plastic pallet molding, assisted by a sequential valve gate system, has not yet been performed due to the limitations of the pallet scale. Furthermore, at present, the application of recycled plastics by chemical industries has become extremely popular around the world. This study aimed to determine pallet flatness experimentally and numerically using recycled polypropylene with a large-scale pallet. Short-shot testing on injection molding was performed to obtain short-shot samples for confirmation of the flow front during simulated filling. The real injected pallet profile, which was measured by an ATOS, was compared after confirmation to the numerical profile of the pallet. The pallet's flatness was accurately compared to the real experimental and numerical results. By adjusting the temperature of the cooling channel within the cavity plate to 55 °C, the flatness of the pallet achieved by the newly proposed sequential valve gate-opening scheme was about 7 mm, which meets the height directional warpage standard determined by the pre-set sequential scheme. The numerical flatness is in line with existing flatness values for pallets. Furthermore, the proposed cooling temperature gives the highest yield in terms of pallet molding from the perspective of the stakeholders.

Background: The unusual high dialysis prevalence and upper urinary tract urothelial carcinoma (UTUC) incidence in Taiwan may attribute to aristolochic acid (AA), which is nephrotoxic and carcinogenic, exposure. AA can cause a unique mutagenic pattern showing A:T to T:A transversions (mutational Signature 22) analyzed by whole exome sequencing (WES). However, a fast and cost-effective tool is still lacking for clinical practice. To address this issue, we developed an efficient and quantitative platform for the quantitation of AA and tried to link AA detection with clinical outcomes and decipher the genomic landscape of UTUC in Taiwan., Patients and Methods: We recruited 61 patients with de novo onset of UTUC after kidney transplantation who underwent radical nephroureterectomy. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform was developed for the quantitation of AA. Pearson's chi-square test, Kaplan-Meier method, and Cox proportional hazard model were utilized to assess the correlations among AA detection, clinicopathological characteristics, and clinical outcomes. Seven tumors and seven paired normal tissues were sequenced using WES (approximately 800x sequencing depth) and analyzed by bioinformatic tool., Results: We found that high level of 7-(deoxyadenosin-N 6 -yl)aristolactam I (dA-AL-I) detected in paired normal tissues was significantly correlated with fast UTUC initiation times after renal transplantation ( p = 0.035) and with no use of sirolimus ( p = 0.046). Using WES analysis, we further observed that all tumor samples were featured by Signature 22 mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-associated gene mutations, p53 mutations, no fibroblast growth factor receptor 3 ( FGFR3 ) mutation, and high tumor mutation burden (TMB). Especially, mammalian target of rapamycin (mTOR) activation predominated in dA-AL-I-detected samples compared with those without dA-AL-I detection and might be associated with UTUC initiation through cell proliferation and suppression of UTUC progression via autophagy inhibition., Conclusion: Accordingly, dA-AL-I detection can provide more direct evidence to AA exposure and serve as a more specific predictive and prognostic biomarker for patients with de novo onset of UTUC after kidney transplantation., 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 Lai, Wu, Kong, Tsai, Chen, Cheng, Luo and Li.)

Introduction: Nasopharyngeal carcinoma (NPC) is the most common malignant tumor in southern China and Southeast Asia. Although substantial research on NPC has been conducted, the resulting improvement in clinical outcomes remains very disappointing. NPC treatment typically involves radiation therapy and chemotherapy, but the high incidence of metastasis and recurrence in NPC patients result in poor survival. Therefore, identifying potential biomarkers and discovering therapeutic targets are necessary to design tailored treatments based on the genetic profiles of NPC patients. Methods: Correlations of protein immunostaining with clinicopathological features were analyzed by Pearson's χ 2 test. The Kaplan-Meier method with a log-rank test was used to generate survival curves. Multivariate analysis was performed using the Cox proportional hazards model. Results: In this study, we comparatively analyzed cytoskeletal organization and biogenesis (GO:0007010) and tumorigenesis in the NPC transcriptome (GSE12452) and found that formin-like 2 ( FMNL2 ) expression was significantly upregulated in NPC tumor tissues. Moreover, high FMNL2 expression was significantly correlated with primary tumor stage ( p = 0.001), lymph node status ( p = 0.004), cancer stage ( p = 0.006), and histological grade ( p = 0.040). More importantly, high FMNL2 expression was significantly correlated with poor survival in NPC patients according to univariate analysis and multivariate analysis. Conclusion: This study reveals that FMNL2 may be an important potential biomarker for evaluating the prognosis of NPC patients., (© 2022 S. Karger AG, Basel.)

Background: Family caregivers play an important role for patients admitted to the intensive care unit (ICU), and delirium is a common clinical syndrome. Little is known about the experiences of family caregivers when a relative is a patient with delirium, especially for caregivers in Asian cultures., Aims and Objective: To understand the experience of family caregivers with a family member as a patient with delirium in the ICU in Taiwan., Design: A descriptive qualitative study with in-depth face-to-face semi-structured interviews., Methods: Interviews were conducted with 20 family caregivers of 20 patients with delirium in the ICU of a hospital in northern Taiwan., Results: The core theme describing the phenomenon of family caregivers of a patient with delirium was "Sailing in a sea of perplexity," which described family caregivers' uncertainty of navigating the ICU and providing support for a relative. Three subthemes described the core theme: (a) perplexity of the ICU environment, (b) perplexity of making decisions, and (c) perplexity of Chinese cultural constraints., Conclusion: "Sailing in a sea of perplexity" underscores how uncertainty among family caregivers of patients with delirium in ICUs can lead to feelings of fear and anxiety. Therefore, nursing professionals should not only focus on patient care but also be sensitive to caregivers' feelings of uncertainty and their cultural beliefs., Relevance to Clinical Practice: Unfamiliarity and lack of knowledge about intensive care and patient treatments were a source of family caregivers' perplexity. To reduce uncertainty, we recommend increased communication between staff and caregivers. Hospitals can also provide information on their websites, including treatment of delirium and visitation hours. Information access could be enhanced by developing a smartphone app linked to a QR code that families can scan to obtain information, which would be useful during restricted visitation., (© 2021 British Association of Critical Care Nurses.)

Cerebral small vessel disease is one of the most common causes of cognitive decline and stroke. While several lines of evidence have established a relationship between inflammation and cerebrovascular pathology, the mechanistic link has not yet been elucidated. Recent studies suggest activation of immune mediators, including the soluble form of triggering receptor expressed on myeloid cells 2 (TREM2), may be critical regulators. In this study, we compared the plasma levels of soluble TREM2 and its correlations with neuroimaging markers and cerebral amyloid load in 10 patients with Alzheimer's disease and 66 survivors of spontaneous intracerebral haemorrhage with cerebral amyloid angiopathy or hypertensive small vessel disease, two of the most common types of sporadic small vessel disease. We performed brain MRI and 11C-Pittsburgh compound B PET for all participants to evaluate radiological small vessel disease markers and cerebral amyloid burden, and 18F-T807 PET in a subgroup of patients to evaluate cortical tau pathology. Plasma soluble TREM2 levels were comparable between patients with Alzheimer's disease and small vessel disease (P = 0.690). In patients with small vessel disease, plasma soluble TREM2 was significantly associated with white matter hyperintensity volume (P < 0.001), but not with cerebral amyloid load. Among patients with Alzheimer's disease and cerebral amyloid angiopathy, plasma soluble TREM2 was independently associated with a tau-positive scan (P = 0.001) and white matter hyperintensity volume (P = 0.013), but not amyloid load (P = 0.221). Our results indicate plasma soluble TREM2 is associated with white matter hyperintensity independent of amyloid and tau pathology. These findings highlight the potential utility of plasma soluble TREM2 as a strong predictive marker for small vessel disease-related white matter injury and hold clinical implications for targeting the innate immune response when treating this disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: The authors declare no conflict of interest.