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Background: Based on current research, it is known that the gastrointestinal tract microbiota and its genome play a crucial role in mental illnesses. Studies indicate a direct correlation between gastrointestinal tract microbiota and the onset of dementia, mediated by metabolic diseases and low-grade inflammation. The association between various gastrointestinal symptoms and neurodegenerative diseases has been recently discussed. However, there is a lack of research regarding the comparative effects of different surgical procedures on neurodegenerative diseases. Therefore, this study primarily focuses on comparing the association between various gastrointestinal surgeries and dementia, aiming to provide guidance for future clinical practice., Method: A nationwide study using the Taiwanese National Health Insurance Research Database included 26 059 patients diagnosed with dementia or Alzheimer's disease and 104 236 controls without diseases. Primary exposures were defined as alimentary surgeries, encompassing cholecystectomy, gastrectomy, bowel resection, and appendectomy. Conditional logistic regression was used to examine the odds ratio and 95% confidence interval for prior alimentary surgery between cases and controls., Results: The results showed that individuals with dementia had a higher rate of gastrectomy. Additionally, individuals with dementia seemed to exhibit a reduced rate of cholecystectomy and appendectomy. Regarding Alzheimer's disease, all four alimentary surgeries showed comparable trends to those observed with dementia. No significant interaction was observed between alimentary surgery and dementia among the four types of surgery evaluated., Conclusion: Our study demonstrates that gastrectomy is associated with an elevated risk of dementia. We aim to uncover more direct evidence in future experiments., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M pro ) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust M pro inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar M pro inhibitory potency (IC 50 = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC 50 = 0.078 µM, no cytotoxicity: CC 50 > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC 50 = 1.95 µM) and similar efficacy to ensitrelvir (EC 50 = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC 50 = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in M pro (EC 50 = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 M pro for clinical therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS -mutant metastatic colorectal cancer (mCRC)., Patients and Methods: This multicenter, open-label, single-arm study enrolled patients with KRAS -mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m 2 once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS -mutant CRC., Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis., Conclusion: Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS -mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).

Recent advancements have elucidated the multifaceted roles of the Schlafen (SLFN) family, including SLFN5, SLFN11, SLFN12, SLFN13, and SLFN14, which are implicated in immunological responses. However, little is known about the roles of this gene family in relation to malignancy development. The current study aimed to explore the diagnostic and prognostic potential of Schlafen family genes in colorectal adenocarcinoma (COAD) through bioinformatics analysis. Leveraging advanced bioinformatics tools of bulk RNA-sequencing and single-cell sequencing, we conducted in-depth analyses of gene expressions, functional enrichment, and survival patterns of patients with colorectal cancer compared to normal tissue. Among Schlafen family genes, the transcription levels of SLFN5 in COAD tissues were significantly elevated and correlated with poor survival outcomes. Furthermore, SLFN5 regulated the immune response via Janus kinase (JAK)/signal transduction and activator of transcription (STAT)/interferon (IFN)-alpha/beta signaling. These chemokines in inflammation are associated with diabetes and metabolism, suggesting their involvement in altered cellular energetics for COAD progress. In addition, an immune cell deconvolution analysis indicated a correlation between SLFN5 expression and immune-related cell populations, such as regulatory T cells (Tregs). These findings highlighted the potential clinical significance of SLFN5 in COAD and provided insights into its involvement in the tumor microenvironment and immune regulation. Meanwhile, the drug discovery data of SFLN5 with potential targeted small molecules suggested its therapeutic potential for COAD. Collectively, the current research demonstrated that SFLN5 play crucial roles in tumor development and serve as a prospective biomarker for COAD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear. To address this, we established an in vitro model of mitochondrial complex I deficiency using induced pluripotent stem cell-derived RGCs (iPSC-RGCs) treated with a mitochondrial complex I inhibitor rotenone (Rot) to recapitulate LHON pathologies. The secretomes from Rot-treated iPSC-RGCs (Rot-iPSC-RGCs) were collected, and their treatment effect on human umbilical vein endothelial cells (HUVECs) was studied. Rot induced LHON-like characteristics in iPSC-RGCs, including decreased mitochondrial complex I activity and membrane potential, and increased mitochondrial reactive oxygen species (ROS) and apoptosis, leading to mitochondrial dysfunction. When HUVECs were exposed to conditioned media (CM) from Rot-iPSC-RGCs, the angiogenesis of HUVECs was suppressed compared to those treated with CM from control iPSC-RGCs (Ctrl-iPSC-RGCs). Angiogenesis-related proteins were altered in the secretomes from Rot-iPSC-RGC-derived CM, particularly angiopoietin, MMP-9, uPA, collagen XVIII, and VEGF were reduced. Notably, GeneMANIA analysis indicated that VEGFA emerged as the pivotal angiogenesis-related protein among the identified proteins secreted by health iPSC-RGCs but reduced in the secretomes from Rot-iPSC-RGCs. Quantitative real-time PCR and western blots confirmed the reduction of VEGFA at both transcription and translation levels, respectively. Our study reveals that Rot-iPSC-RGCs establish a microenvironment to diminish the angiogenic potential of vascular cells nearby, shedding light on the paracrine regulation of LHON-affected RGCs on retinal vasculature., 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 © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: This cross-sectional study aimed to characterize the differences of metabolic profiles and atherogenicity between various levels of fatigue severity in patients with major depressive disorder (MDD), and examine the extent to which metabolic abnormality correlates with fatigue severity., Methods: We recruited 119 patients with MDD and assessed fatigue severity using Krupp's Fatigue Severity Scale. Blood samples were collected to determine plasma levels of fasting glucose, high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol and low-density lipoprotein cholesterol. The atherogenic index of plasma (AIP) was calculated as log10 (triglycerides/HDL-C)., Results: MDD with severe fatigue were more likely to be younger (43.3 ± 10.3 years vs. 49.4 ± 8.5 years, p = 0.001), had a younger age of onset (34.7 ± 9.7 years vs. 40.7 ± 9.5 years, p = 0.001), demonstrated higher HAMD scores (18.0 ± 7.6 vs. 10.9 ± 7.5, p < 0.001), as well as lower HDL-C levels (48.5 ± 10.8 vs. 55.3 ± 13.9, p = 0.003), a greater prevalence of low HDL-C (43.9% vs. 22.6%, p = 0.015) and higher AIP levels (0.4 ± 0.3 vs. 0.3 ± 0.3, p = 0.046). Both a decreased plasma HDL-C level (OR = 0.95, 95% CI = 0.91-0.99, p = 0.009) and a diagnosis of low HDL-C (OR = 3.29, 95% CI = 1.27-8.57, p = 0.015) were significantly correlated with an increased risk of fatigue severity., Conclusion: HDL-C could potentially protect patients with MDD from severe fatigue and the associated risk of cardiovascular disease., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: This study intended to validate the competency-based approach through an entrustable professional activity in the nursing undergraduate education arena in Taiwan., Background: Entrustable professional activity is a recommended strategy to enhance nursing competencies and skills. It has been widely applied to nursing education in Western countries, especially graduate programs. However, its effects in eastern countries and undergraduate programs remain unclear., Design: A quasi-experimental comparison design was used., Method: The study is conducted at the Department of Nursing at a university in southern Taiwan. A total of 72 Two-Year Nursing Program students participated in the study. After implementing the designated entrustable professional activity in the Wound Care Nursing course, outcomes were measured using the Competency Inventory of Nursing Students, Learning Satisfaction and Objective Structured Clinical Examinations. These outcomes were then compared with post-test results at the end of the semester. About 90 % of students completed the study with the test group (n=31) receiving extra activity and the comparison group (n=34) receiving usual teaching. Data were analyzed through chi-square, paired t and Student's t-test., Results: The test group demonstrated significantly higher scores in perceived competency and clinical examinations than the comparison group. However, both groups experienced an increase in learning satisfaction without reaching a significant difference., Conclusion: Results of the study indicate that competency-based pedagogy, e.g., using entrustable professional activities, should be integrated into nursing curricula to meet the new American Association of Colleges of Nursing standards with compelling evidence., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC 50 ) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy., (© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Background: Clinical reasoning is an essential nursing competency that students must develop to provide safe patient care. Developing and utilizing unfolding case studies, which present constantly changing patient conditions to improve students' clinical reasoning and to foster communication and self-reflection, can help to achieve that imperative., Objectives: To develop an unfolding case study and to test its effectiveness in improving clinical reasoning, team collaboration, and self-directed learning., Design: A mixed methods design., Setting: One university in Southern Taiwan., Participants: Forty nursing students., Methods: An unfolding case study was developed based on the clinical reasoning model and unfolding cases model. The Nurses Clinical Reasoning Scale, Self-Directed Learning Instrument, and Questionnaire of Group Responsibility and Cooperation in Learning Teams were used. Forty nursing students completed questionnaires and nine of them participated in focus group discussions. Wilcoxon signed-rank, Spearman correlation, regression, and inductive content analysis were used to analyze data., Results: Students' abilities in clinical reasoning, self-directed learning, and team collaboration were statistically significantly improved after implementation of the unfolding case study. Emergent themes included "patient-centered communication," "group inspiration and learning," "thinking critically and reflecting on oneself," and "applying theoretical knowledge in care to meet patients' changing needs.", Conclusions: Unfolding case studies provide a safe environment in which nursing students may learn and apply knowledge to safe patient care., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms 1-5 . Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims and Objectives: To develop a Chinese version of a chronic wound health-related quality of life (QoL) instrument and to examine the psychometric properties of this instrument., Background: Existing QoL instruments are not tailored to the linguistic and cultural characteristics of Chinese-speaking patients; a version addressing this gap will increase clinical understanding of their healthcare experience and may help guide chronic wound care., Design: A methodological study., Methods: The method advanced by DeVellis (2017) was used to develop the instrument. An initial pool of 38 items was created. To optimize scale length and test reliability and validity, exploratory and confirmatory factor analyses were conducted. A total of 23 items formed the final pool. After two rounds of expert discussions, the average content validity index of the final 23 items was .89., Results: A total of 226 patients completed the instrument and were divided into two groups for further analysis. Exploratory factor analysis revealed that 15 items remained in four factors (social activity restrictions, physical and psychological disturbance, wound burden and daily life limitation), which accounted for 64.87% of the variance. Confirmatory factor analysis revealed an acceptable fit of the hypothesized factor structure and the convergent and discriminant validities were achieved. Cronbach's α coefficients for each factor were .807, .773, .799 and .713, respectively., Conclusion: The Chinese version of a chronic wound health-related QoL instrument consists of 15 items in four subscales and demonstrates good reliability and validity., Relevance to Clinical Practice: This instrument can be used intermittently or continuously to evaluate the treatment effect of chronic wounds by assessing health-related QoL. Scholars in Chinese-speaking regions may find this culturally compatible instrument useful when conducting studies related to chronic wounds., Patient or Public Contribution: Two hundred twenty-six participants provided their perspectives on health-related QoL., (© 2023 John Wiley & Sons Ltd.)

Background: Recent findings suggest a link between gout and the development of dementia. Early treatment with colchicine is recommended as a first-line therapy for gout flares. Animal studies demonstrate that colchicine could induce cognitive impairment. This cohort study aimed to investigate the association between colchicine use and the risk of developing dementia., Methods: In this nationwide cohort study, we performed comparative analysis on 6147 patients ≥40 years, with gout and colchicine new users against 6147 controls to assess subsequent dementia risk. The colchicine group and the control group (urate lowering therapy group) were matched on the bases of age, sex, index year, and comorbidities. All participants were followed for up to 14 years for a diagnosis of dementia considering medical records were retrospectively checked over this period. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Sensitivity analyses were performed to validate our findings., Results: The adjusted hazard ratio (aHR) of dementia for colchicine users was 1.45 (95% CI = 1.05, 1.99) relative to comparison group after adjusting for sex, age, and comorbidities. Sensitivity analysis aiming to minimize underdiagnosed occult dementia at the time of index year yielded consistent positive association. In higher accumulative dose colchicine group (cumulative defined daily dose [cDDD] >30), the aHR of dementia risk for colchicine users was 1.42 (95% CI = 1.03, 1.97) compared with nonusers. For those duration of colchicine use >30 days, the aHR was 1.53 (95% CI = 1.01-2.32) compared to the nonuser group., Conclusions: A significant risk of dementia was observed in this study in patients with gout using colchicine at higher cDDD and for a longer period. Further research is needed to elucidate the relationship between colchicine, gout, and dementia., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Porcine circovirus type 2 (PCV2) infection is ubiquitous around the world. Diagnosis of the porcine circovirus-associated disease requires clinic-pathological elements together with the quantification of viral loads. Furthermore, given pig farms in regions lacking access to sufficient laboratory equipment, developing diagnostic devices with high accuracy, accessibility, and affordability is a necessity., Objectives: This study aims to investigate two newly developed diagnostic tools that may satisfy these criteria., Methods: We collected 250 specimens, including 170 PCV2-positive and 80 PCV2-negative samples. The standard diagnosis and cycle threshold (Ct) values were determined by quantitative polymerase chain reaction (qPCR). Then, two point-of-care (POC) diagnostic platforms, convective polymerase chain reaction (cPCR, qualitative assay: positive or negative results are shown) and EZtargex (quantitative assay: Ct values are shown), were examined and analyzed., Results: The sensitivity and specificity of cPCR were 88.23% and 100%, respectively; the sensitivity and specificity of EZtargex were 87.65% and 100%, respectively. These assays also showed excellent concordance compared with the qPCR assay (κ = 0.828 for cPCR and κ = 0.820 for EZtargex). The statistical analysis showed a great diagnostic power of the EZtargex assay to discriminate between samples with different levels of positivity., Conclusions: The two point-of-care diagnostic platforms are accurate, rapid, convenient and require little training for PCV2 diagnosis. These POC platforms can discriminate viral loads to predict the clinical status of the animals. The current study provided evidence that these diagnostics were applicable with high sensitivity and specificity in the diagnosis of PCV2 infection in the field., Competing Interests: Schweitzer Biotech Company (SBC) Ltd. is the sponsor of the project. Hsieh WJ, Lin CC, and Ting JM. are employees of the SBC. However, the authors declare that the research was conducted with integrity, following all ethical guidelines. All other authors declare no competing interests., (© 2024 The Korean Society of Veterinary Science.)

Previous studies have demonstrated that the size of the prey relative to the cuttlefish is important to the choice between tentacular strike and jump-on tactics. In the present study, we investigated the decision-making in the cuttlefish's tactical switch when preying on the same size prey. A servomotor system controlling the movement of a shrimp was used to elicit the cuttlefish's preying behavior. The success rate of prey capture and the kinematics of visual attack were examined systematically. The results showed that the jump-on behavior appeared mostly after a miss attack by previous tentacular strike on a moving shrimp. Compared with a visual attack with tentacles, the jump-on tactic has over a shorter attacking distance and wider attacking angles. Thus, these two different preying tactics have different operating ranges relative to the prey. More importantly, the cuttlefish can adjust their preying tactics adaptively depending on their prior preying experience., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Activated toll-like receptor (TLR) signaling has been well investigated in major depressive disorder (MDD). We previously reported that TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 play important roles in regulating the toll-like receptor 4 (TLR4) signaling pathway and may serve as novel targets in the pathogenesis of MDD. Recently, aberrant histone modification has been implicated in several psychiatric disorders, including schizophrenia and mood disorder; the most thoroughly studied modification is histone 3 lysine 4 tri-methylation (H3K4me3). In this work, we aimed to explore H3K4me3 differences in the promotors of genes encoding the abovementioned factors in patients with MDD, and whether they were altered after antidepressant treatment. A total of 30 MDD patients and 28 healthy controls were recruited. Peripheral blood mononuclear cells (PBMCs) were collected. The levels of H3K4me3 in the promoters of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 were measured through chromatin immunoprecipitation (ChIP) followed by DNA methylation assay. Analysis of covariance was used to evaluate between-group differences after adjusting for age, sex, BMI, and smoking. In comparison with healthy controls, patients with MDD showed significantly lower H3K4me3 levels in the promoters of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in PBMCs. These levels were not significantly altered after completion of a 4-week antidepressant treatment. To explore the association between depression severity and H3K4me3 levels, a multiple linear regression model was generated. The results revealed that levels of H3K4me3 in the TNIP2 promoters a negative correlation with the 17-item Hamilton Depression Rating Scale (HAND-17) score, whereas that of TLR4 had a positive correlation with this score. The present results suggest that decreased H3K4me3 levels in the promoters of the genes encoding TNFAIP3, TLR4, miR-146a, miR-155, and TNIP2 are involved in psychopathology of major depressive disorder., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Non-valvular atrial fibrillation (NVAF) is a common form of cardiac arrhythmia that affects 1-1.5% of adults and roughly 10% of elderly adults with dysphagia. Apixaban is an anticoagulant referred to as a factor Xa inhibitor, which has been shown to reduce the risk of stroke and systemic embolism in cases of NVAF. Our objective in the current study was to formulate an orally disintegrating film to facilitate the administration of apixaban to elderly patients who have difficulty swallowing. Researchers have used a wide variety of cellulose-based or non-cellulose-based polymers in a variety of combinations to achieve specific characteristics related to film formation, disintegration performance, drug content, in vitro drug release, and stability. One of the two formulations in this study was specify that bioequivalence criteria met with respect to Cmax of the reference drug (ELIQUIS®) in terms of pharmacokinetic profile. Further research will be required to assess the applicability of orodispersible films created using colloidal polymers of high and low molecular weights to other drugs with poor solubility in water., Competing Interests: Ta-Chien Lu and Catherine Lee filed patent application for the discovery of pharmaceutical composition and use of Apixaban film products for the treatment and prevention of thrombosis and related disorders on 03 June 2022 (20220387415 A1). The authors declare that they have no competing financial interests or personal relationships that may appear to influence the work reported in this paper., (© 2023 The Authors.)

Background: Case management can improve trauma patient outcomes from the acute to rehabilitation phases. However, a lack of evidence on the effects of case management in trauma patients makes it difficult to translate research findings into clinical practice., Objective: To examine the effects of case management on illness perception, coping strategies, and quality of life in trauma patients followed up to 9 months post-hospital discharge., Methods: A four-wave longitudinal experimental design was used. Patients with traumatic injury hospitalized at a regional hospital in southern Taiwan from 2019 to 2020 were randomly assigned to a case management (experimental) or a usual care (control) group. The intervention was implemented during hospitalization with a phone call follow-up about 2 weeks post-discharge. Illness perception, coping strategies, and health-related quality-of-life perceptions were measured at baseline, 3 months, 6 months, and 9 months after discharge. Generalized estimating equations were used for analysis., Results: Findings showed a significant difference in illness perception at 3 and 6 months and coping strategies used at 6 and 9 months after discharge between the two groups. No significant difference in the quality of life over time between the two groups was found., Conclusion: Although case management appears to help patients with traumatic injuries decrease illness perception and better cope with their injury, it did not significantly improve their quality of life 9 months after discharge. It is recommended that health care professionals develop long-term case management strategies for high-risk trauma patients., Competing Interests: The authors declared no conflicts of interest., (Copyright © 2023 Society of Trauma Nurses.)

Green banana fruit with high resistant starch (RS) content has a potential to be a nutraceutical ingredient despite having an unpleasant astringency taste and is yet to be fully explored. In this study, the green banana after de-astringency treatment was employed for flour production, and the resulting flour was subjected to modification by the combined treatments of pullulanase debranching and annealing. The banana flour (BF) and the modified flour (MF) were compared with each other by evaluating their functional, thermal and structural properties. The BF showed a restricted-swelling pasting profile, behaving like a slightly chemically cross-linked starch; the MF exhibited less pronounced changes in pasting behavior with increased solubility and decreased swelling power and dispersed volume fraction at elevated temperatures. As compared with the BF, an enhanced thermal stability of the MF was observed, reflected in the endotherm shifting to higher temperatures with increased enthalpy. The BF displayed a C A -type polymorph, while the MF comprised a mixture of B- and V-type polymorphs with increased crystallinity. The MF showed an increased molecular order, reflected in an increase in short-range double helical order detected in the starch fingerprint regions of FT-IR spectra, and along with increased crystallinity, underlying its enhanced thermal stability. The modification treatment resulted in irregularly shaped flour particles with a more compact structure as revealed by morphological characters. The results of this study can provide useful information for the development of food products using the modified green banana flour with improved thermal stability and functional properties as a health-promoting ingredient., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: This paper explored the differences in perspectives on the core competencies of nurse preceptors among postgraduate-year nurses, clinical nursing preceptors and head nurses., Design: Cross-sectional design with nominal group technique (NGT)., Method: The sample consisted of 32 postgraduate-year nurses, 42 preceptors and 27 head nurses. Two rounds of NGT were used to collect the group opinions., Results: While the rank/level of importance varied, three groups all agreed that teaching traits, clinical nursing profession, communication and collaboration, teaching pedagogy, reaction of contingency and consultation of academic writing were important core competencies for nurse preceptors. The three groups disagreed on critical thinking and reflection, as well as lifelong learning. This study clarifies cognitive differences and expectations among three groups and can assist medical institutes in designing preceptor training courses., (© 2022 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

The complexity of lung adenocarcinoma (LUAD) including many interacting biological processes makes it difficult to find therapeutic biomarkers for treatment. Previous studies demonstrated that PSMG (proteasome assembly chaperone) family members regulate the degradation of abnormal proteins. However, transcript expressions of this gene family in LUAD still need to be more fully investigated. Therefore, we used a holistic bioinformatics approach to explore PSMG genes involved in LUAD patients by integrating several high-throughput databases and tools including The Cancer Genome Atlas (TCGA), and Kaplan-Meier plotter database. These data demonstrated that PSMG3 and PSMG4 were expressed at significantly higher levels in neoplastic cells than in normal lung tissues. Notably, increased expressions of these proteins were correlated with poor prognoses of lung cancer patients, which probably confirmed their fundamental roles in the staging of LUAD tumors. Meanwhile, it was also indicated that there were positive correlations between PSMG family genes and the immune response, metabolism of ubiquinone, cell cycle regulatory pathways, and heat shock protein 90 (HSP90)/phosphatidylinositol 3-kinase (PI3K)/Wnt signaling. Experimental data also confirmed that the knockdown of PSMG4 in LUAD cell lines decreased cell proliferation and influenced expressions of downstream molecules. Collectively, this study revealed that PSMG family members are novel prognostic biomarkers for LUAD progression, which also provide new therapeutic targets of LUAD patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER + ) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER + breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase ( GLUL ) might play essential roles in the recurrence of tamoxifen-resistant ER + patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates the tumor microenvironment for tamoxifen-resistant ER + breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL , which provide new targets for the treatment of tamoxifen-resistant breast cancer patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Advance directives (ADs) are used to respect the will of patients experiencing a terminal illness regarding preferred medical treatment and to protect their rights. However, the AD completion rate is low., Objective: The aim of this study was to explore the factors influencing patient intentions toward AD., Methods: The Theory of Planned Behavior was used as the framework for this study. This study used a cross-sectional design using a face-to-face interview with structured questionnaires. A total of 230 patients with cancer were recruited. Path analysis was used to examine the hypotheses., Results: Demographic variables were not correlated with patients' attitudes toward AD. Patients' knowledge of AD ( β = .68, t = 16.15, P < .00) and recognition of important others' attitudes toward AD ( β = .30, t = 10.74, P < .00) were predictors of patients' attitudes toward AD. Patients' attitudes toward AD ( β = .27, t = 3.74, P < .00) and behavior control over AD ( β = .09, t = 1.99, P < .04) predicted patients' intentions toward AD., Conclusion: Patients' knowledge of AD, the patients' important others' attitudes, and behavior control toward AD are predictively associated with the intention toward AD completion., Implications for Practice: Only when patients with cancer are provided an accessible approach for obtaining knowledge regarding AD and are given sufficient time and space can they and their significant others understand the meaning of AD and decide to complete one on their own terms., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Breast cancer is one of the leading deaths in all kinds of malignancies; therefore, it is important for early detection. At the primary tumor site, tumor cells could take on mesenchymal properties, termed the epithelial-to-mesenchymal transition (EMT). This process is partly regulated by members of the cadherin ( CDH ) family of genes, and it is an essential step in the formation of metastases. There has been a lot of study of the roles of some of the CDH family genes in cancer; however, a holistic approach examining the roles of distinct CDH family genes in the development of breast cancer remains largely unexplored. In the present study, we used a bioinformatics approach to examine expression profiles of CDH family genes using the Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), cBioPortal, MetaCore, and Tumor IMmune Estimation Resource (TIMER) platforms. We revealed that CDH1/2/4/11/12/13 messenger (m)RNA levels are overexpressed in breast cancer cells compared to normal cells and were correlated with poor prognoses in breast cancer patients' distant metastasis-free survival. An enrichment analysis showed that high expressions of CDH1/2/4/11/12/13 were significantly correlated with cell adhesion, the extracellular matrix remodeling process, the EMT, WNT/beta-catenin, and interleukin-mediated immune responses. Collectively, CDH1/2/4/11/12/13 are thought to be potential biomarkers for breast cancer progression and metastasis.

Nociception is the neural process of encoding noxious stimuli and is typically accompanied by a reflex withdrawal response away from the potentially injurious stimulus. Studies on nociception in cephalopods have so far focused on octopus and squid, with no investigations to our knowledge on cuttlefish. Yet, these are an important species both in scientific and commercial use. Therefore, the present study demonstrated that a standard pain stimulus, acetic acid, induced grooming behaviour directed towards the injection site in cuttlefish and that the injection of lidocaine reduces grooming behaviours in acetic-acid-injected cuttlefish. Wound-directed behaviour demonstrates that the animal is aware of the damage; thus, when subjecting these animals to any painful treatments in the laboratory, researchers should consider alleviating pain by the administration of pain-relieving drugs.

Quantum two-level systems (TLSs) intrinsic to glasses induce decoherence in many modern quantum devices, such as superconducting qubits. Although the low-temperature physics of these TLSs is usually well-explained by a phenomenological standard tunneling model of independent TLSs, the nature of these TLSs, as well as their behavior out of equilibrium and at high energies above 1 K, remain inconclusive. Here we measure the non-equilibrium dielectric loss of TLSs in amorphous silicon using a superconducting resonator, where energies of TLSs are varied in time using a swept electric field. Our results show the existence of two distinct ensembles of TLSs, interacting weakly and strongly with phonons, where the latter also possesses anomalously large electric dipole moment. These results may shed new light on the low temperature characteristics of amorphous solids, and hold implications to experiments and applications in quantum devices using time-varying electric fields., (© 2022. The Author(s).)

Background: Infected deep sternal infection due to an associated infection of the prosthetic aortic graft is a devastating condition. Standard management requires the removal of the graft and substituting it with a new one. Often, removal of the prosthetic graft is close to impossible. Negative pressure wound therapy is currently the treatment of choice for patients with deep sternal infection. However, its use in deep sternal infection with exposed infected prosthetic aortic graft has not been well described., Methods: Eight patients were included in this study. All had type A aortic dissection of the ascending aorta and/or aortic arch., Results: There were 7 men and 1 woman. The median age was 53 years old (range 33-81 years old). The median number of days from the initial aortic operation to the diagnosis of infection was 20 days (range 14-52). The median length of stay in the intensive care unit was 17 days (range 6-338 days). The median time interval from the initial debridement to reconstruction was 20 days (range 6-43 days). The median number of times negative pressure wound therapy was changed was 4 (range 2-9). The most common flap used for reconstruction was the pectoralis major musculocutaneous flap in 7 patients, a free antero-lateral thigh flap in 1 patient, and pedicled omental flap in combination with pectoralis major musculocutaneous flap in 1 patient. One patient had persistent recurrent infection of the graft despite negative pressure wound therapy and flap reconstruction. The median length of follow-up was 38.5 months (range 4-120 months)., Conclusion: This small study suggests that negative pressure wound therapy could be used successfully for the management of deep sternal infection due to infected prosthetic aortic grafts. In most cases, it eliminated the need to replace the infected prosthetic aortic graft in high-risk patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Monkeypox virus (MPV) is a smallpox-like virus belonging to the genus Orthopoxvirus of the family Poxviridae. Unlike smallpox with no animal reservoir identified and patients suffering from milder symptoms with less mortality, several animals were confirmed to serve as natural hosts of MPV. The reemergence of a recently reported monkeypox epidemic outbreak in nonendemic countries has raised concerns about a global outburst. Since the underlying mechanism of animal-to-human transmission remains largely unknown, comprehensive analyses to discover principal differences in gene signatures during disease progression have become ever more critical. In this study, two MPV-infected in vitro models, including human immortal epithelial cancer (HeLa) cells and rhesus monkey ( Macaca mulatta ) kidney epithelial (MK2) cells, were chosen as the two subjects to identify alterations in gene expression profiles, together with co-regulated genes and pathways that are affected during monkeypox disease progression. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and MetaCore analyses, we discovered that elevated expression of genes associated with interleukins (ILs), G protein-coupled receptors (GPCRs), heat shock proteins (HSPs), Toll-like receptors (TLRs), and metabolic-related pathways play major roles in disease progression of both monkeypox-infected monkey MK2 and human HeLa cell lines. Interestingly, our analytical results also revealed that a cluster of differentiation 40 (CD40), plasmin, and histamine served as major regulators in the monkeypox-infected monkey MK2 cell line model, while interferons (IFNs), macrophages, and neutrophil-related signaling pathways dominated the monkeypox-infected human HeLa cell line model. Among immune pathways of interest, apart from traditional monkeypox-regulated signaling pathways such as nuclear factor- (NF- κ B), mitogen-activated protein kinases (MAPKs), and tumor necrosis factors (TNFs), we also identified highly significantly expressed genes in both monkey and human models that played pivotal roles during the progression of monkeypox infection, including CXCL1 , TNFAIP3 , BIRC3 , IL6 , CCL2 , ZC3H12A , IL11 , CSF2 , LIF , PTX3 , IER3 , EGR1 , ADORA2A , and DUOX1 , together with several epigenetic regulators, such as histone cluster family gene members, HIST1H3D , HIST1H2BJ , etc. These findings might contribute to specific underlying mechanisms related to the pathophysiology and provide suggestions regarding modes of transmission, post-infectious sequelae, and vaccine development for monkeypox in the future., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Do Thi Minh Xuan et al.)

Internationally, the impact of venous leg ulcers (VLUs) on the quality of life is well recognised; however, in Taiwan, the focus is only on chronic wound management. This cross-sectional correlational study conducted at the cardiovascular and plastic surgery clinics of a regional teaching hospital between August 2019 and June 2020 investigates venous clinical severity, pain, fatigue, depression, sleep quality, quality of life, and related factors among 167 patients with VLUs. The potential predictors of the quality of life in terms of activities were venous clinical severity (P < 0.001), pain (P = 0.004), and fatigue (P < 0.001) after adjusting for covariates. The potential predictors of the quality of life in terms of the psychological domain were marital status (single/divorced) (P = 0.016), marital status (widowed) (P = 0.027), venous clinical severity (P < 0.001), pain (P = 0.001), and fatigue (P = 0.002). The potential predictors of the quality of life with regard to symptoms were venous clinical severity (P < 0.001), pain (P < 0.001), fatigue (P = 0.001), and depression (P = 0.038). These potential predictors can serve as the basis of interventions for patients with VLUs, such as those related to nutrition or training in wound dressing., (© 2021 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

The competency-based approach has been advocated in medical education in recent years to strengthen the professional competencies and skills of medical professionals entering their residency. Entrustable professional activity (EPA), which consists of clinical tasks, core competencies, and milestones, is a recommended competency-based training program focused on the learning process of trainees. EPA emphasizes that trainers evaluate their trainees' learning repeatedly and provide feedback so that these trainees have an opportunity to correct their behaviors. However, EPAs have not yet been widely implemented in school-based nursing education. The purpose of this essay was to introduce the concept, connotations, development stage, and application of EPAs. The dilemmas and recommendations of EPA development in Taiwan are also presented.

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications., Purpose: In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells., Methods: The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively., Results: In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC 50 values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G 0 /G 1 phase and followed by the cells undergoing apoptosis., Conclusion: O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The propagation of the hepatitis C virus (HCV) is regulated in part by the phosphorylation of its nonstructural protein NS5A that undergoes sequential phosphorylation on several highly conserved serine residues and switches from a hypo- to a hyperphosphorylated state. Previous studies have shown that NS5A sequential phosphorylation requires NS3 encoded on the same NS3-NS4A-NS4B-NS5A polyprotein. Subtle mutations in NS3 without affecting its protease activity could affect NS5A phosphorylation. Given the ATPase domain in the NS3 COOH terminus, we tested whether NS3 participates in NS5A phosphorylation similarly to the nucleoside diphosphate kinase-like activity of the rotavirus NSP2 nucleoside triphosphatase (NTPase). Mutations in the NS3 ATP-binding motifs blunted NS5A hyperphosphorylation and phosphorylation at serines 225, 232, and 235, whereas a mutation in the RNA-binding domain did not. The phosphorylation events were not rescued with wild-type NS3 provided in trans . When provided with an NS3 ATPase-compatible ATP analog, N 6 -benzyl-ATP-γ-S, thiophosphorylated NS5A was detected in the cells expressing the wild-type NS3-NS5B polyprotein. The thiophosphorylation level was lower in the cells expressing NS3-NS5B with a mutation in the NS3 ATP-binding domain. In vitro assays with a synthetic peptide and purified wild-type NS3 followed by dot blotting and mass spectrometry found weak NS5A phosphorylation at serines 222 and 225 that was sensitive to an inhibitor of casein kinase Iα but not helicase. When casein kinase Iα was included in the assay, much stronger phosphorylation was observed at serines 225, 232, and 235. We concluded that NS5A sequential phosphorylation requires the ATP-binding domain of the NS3 helicase and that casein kinase Iα is a potent NS5A kinase. IMPORTANCE For more than 20 years, NS3 was known to participate in NS5A sequential phosphorylation. In the present study, we show for the first time that the ATP-binding domain of NS3 is involved in NS5A phosphorylation. In vitro assays showed that casein kinase Iα is a very potent kinase responsible for NS5A phosphorylation at serines 225, 232, and 235. Our data suggest that ATP binding by NS3 probably results in conformational changes that recruit casein kinase Iα to phosphorylate NS5A, initially at S225 and subsequently at S232 and S235. Our discovery reveals intricate requirements of the structural integrity of NS3 for NS5A hyperphosphorylation and HCV replication.

Patient participation in healthcare activities is key to producing successful patient-centered care. However, little is known about both nurses' and patients' perspectives regarding patient participation in East Asia. This paper compared and contrasted perspectives of patient participation in healthcare activities between nurses and patients, using a qualitative study with a purposive sample of 39 nurses and 15 patients. A semi-structured interview was applied to focus groups for nurses, and to face-to-face interviews for patients. Content analysis was utilized to analyze the data, and common themes and subthemes were identified showing three similarities (authoritative culture, participation behaviors, and obstacles to participation), and two differences (sources of acquiring patient-related health information, and responsible party). Nurses and patients did not entirely view participation in healthcare activities congruently. Relevant clinical practices are also suggested, including respecting patients' autonomy, nurses' using layman's language for explanations, patients' understanding the meaning behind their participation behaviors, recognizing obstacles faced in enhancing patient participation with adjusted nursing workload, actively providing needed health information, and leading patients to realize that they will be responsible for their health behaviors after discharge., (© 2021 John Wiley & Sons Australia, Ltd.)

Despite numerous studies demonstrating the cognitive ability of cephalopods, there is currently no study showing an emotion-like behavior in this group of animals. To examine whether cuttlefish have different internal states, we developed a behavioral paradigm to assess if prior surprised events are able to alter the choice made by cuttlefish. By presenting unexpected food rewards to cuttlefish before the test, we investigated whether the reaction time of choosing between two shrimps, an intuitive response toward the prey without previous learning, at three different levels of discriminative tests (easy, difficult, and ambiguous), are different compared to the one without an unexpected reward. This behavioral paradigm serves to demonstrate whether cuttlefish are aware of ambiguous situations, and their choice outcome and reaction time are dependent of their internal states. The results show that the response latency was significantly shortened in the difficult and ambiguous tests when choosing from two shrimps that are either moderately different in size or similar sizes, respectively, when cuttlefish have received unexpected rewards before the test. These results were compared with tests during which the cuttlefish did not receive any reward in advance. Furthermore, this shortening of latency did not result in a difference in choice outcome during the difficult and ambiguous tests. Interestingly, even when cuttlefish have obtained the expected food rewards or simply made tentacular strike without prey capture each time before test, these prior experiences were sufficient to shorten the response latency in the difficult and ambiguous tests. However, different from the result of unexpected rewards, food consumption alone or prey capture failure did affect the choice outcome during the simple and difficult tests. Taken together, our findings suggest that pre-test treatments of unexpected and expected rewards or simply unsuccessful visual attack seem to induce cuttlefish to adopt different foraging behaviors. This context dependent decision making suggests that cuttlefish's foraging strategies are influenced by the previously surprised event and their internal states. It also shows a speed-accuracy tradeoff in difficult and ambiguous situations when foraging for prey. This observation may lead to a future investigation of the presence of emotional state in cephalopods., (© 2022. The Author(s).)

Objective: To design and verify a CMOS 256-pixel photovoltaic-powered subretinal prosthetic chip with key advances over the state-of-the-art. The three key advances are: 1) automatic adaptation to changing background illuminance levels; 2) increase of injection charges with reduced crosstalk leakage charges, enhanced charge balance, and low process variations; 3) stable stimulation voltage to keep the safety of water window., Methods: The novel auto-adaptive pixel circuit is designed to realize the Michealis - Menten equation (MME) so that the automatic adaptation to changing background illuminance can be achieved. Both improved biphasic constant current stimulator (CCS) via bi-directional shared electrodes (BDSEs) with optimized stimulation pattern and improved constant current generator/ring oscillator are designed to achieve the above second advance on injection charges. The closed-loop charge pump is designed to achieve the third advance., Results: The measured dynamic range of image illuminance is increased to 54.7 dB. The maximum stimulation charge is 8.89nC. The measured stimulation current mismatch is 1.7% and the measured residual charge is 0.150 nC. The measured variations of stimulation frequencies are from 26 Hz to 29.7 Hz. The results of ex vivo tests have shown that the proposed subretinal chip can evoke spiking responses of RGCs. The function of adaptation process to background illuminance has also been verified., Conclusion and Significance: Through both electrical measurement and ex vivo tests, the functions of designed subretinal chip have been validated successfully. It is shown that the proposed subretinal chip is a promising solution for subretinal prostheses.

To compare overall number of downstream tests and total costs between negative exercise stress echocardiograms (ESE) or cardiac computed tomography angiography scans (CCTA) in symptomatic Tricare beneficiaries suspected of having coronary artery disease (CAD). This is a retrospective cohort study examining 651 propensity-matched patients who underwent ESE or CCTA with normal results between 2008 and 2014 at the United States' largest Department of Defense hospital. The total number of additional downstream tests over the next five years was determined. The total costs associated with each arm, inclusive of the initial test and all subsequent tests, were calculated using the 2018 Medicare Physician Fee Schedule. 18.5 percent of patients with a normal ESE result underwent some additional form of cardiac testing over the five years after initial testing compared to 12.8 percent of patients with a normal CCTA. The absolute difference in total number of downstream tests between both study groups was 5.7 percent (p = 0.03). When factoring the costs of the initial test as well as the downstream tests, the ESE group was associated with overall lower costs compared to the CCTA group, 351 United States Dollars (USD) versus 496 USD (p < 0.0001). This study demonstrates that, when compared to CCTA, ESE is associated with a higher total number of downstream tests, but overall lower total costs when chosen as initial testing strategy for suspected CAD., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

The complexity of breast cancer includes many interacting biological processes that make it difficult to find appropriate therapeutic treatments. Therefore, identifying potential diagnostic and prognostic biomarkers is urgently needed. Previous studies demonstrated that 26S proteasome delta subunit, non-ATPase (PSMD) family members significantly contribute to the degradation of damaged, misfolded, abnormal, and foreign proteins. However, transcriptional expressions of PSMD family genes in breast cancer still remain largely unexplored. Consequently, we used a holistic bioinformatics approach to explore PSMD genes involved in breast cancer patients by integrating several high-throughput databases, including The Cancer Genome Atlas (TCGA), cBioPortal, Oncomine, and Kaplan-Meier plotter. These data demonstrated that PSMD1, PSMD2, PSMD3, PSMD7, PSMD10, PSMD12, and PSMD14 were expressed at significantly higher levels in breast cancer tissue compared to normal tissues. Notably, the increased expressions of PSMD family genes were correlated with poor prognoses of breast cancer patients, which suggests their roles in tumorigenesis. Meanwhile, network and pathway analyses also indicated that PSMD family genes were positively correlated with ubiquinone metabolism, immune system, and cell-cycle regulatory pathways. Collectively, this study revealed that PSMD family members are potential prognostic biomarkers for breast cancer progression and possible promising clinical therapeutic targets.

The complexity of breast cancer includes many interacting biological processes, and proteasome alpha (PSMA) subunits are reported to be involved in many cancerous diseases, although the transcriptomic expression of this gene family in breast cancer still needs to be more thoroughly investigated. Consequently, we used a holistic bioinformatics approach to study the PSMA genes involved in breast cancer by integrating several well-established high-throughput databases and tools, such as cBioPortal, Oncomine, and the Kaplan-Meier plotter. Additionally, correlations of breast cancer patient survival and PSMA messenger RNA expressions were also studied. The results demonstrated that breast cancer tissues had higher expression levels of PSMA genes compared to normal breast tissues. Furthermore, PSMA2 , PSMA3 , PSMA4 , PSMA6 , and PSMA7 showed high expression levels, which were correlated with poor survival of breast cancer patients. In contrast, PSMA5 and PSMA8 had high expression levels, which were associated with good prognoses. We also found that PSMA family genes were positively correlated with the cell cycle, ubiquinone metabolism, oxidative stress, and immune response signaling, including antigen presentation by major histocompatibility class, interferon-gamma, and the cluster of differentiation signaling. Collectively, these findings suggest that PSMA genes have the potential to serve as novel biomarkers and therapeutic targets for breast cancer. Nevertheless, the bioinformatic results from the present study would be strengthened with experimental validation in the future by prospective studies on the underlying biological mechanisms of PSMA genes and breast cancer.

To evaluate the potential benefit of HyperArc (HA) fractionated stereotactic radiotherapy (FSRT) for the benign brain lesion. Sixteen patients with a single deep-seated, centrally located benign brain lesion treated by CyberKnife (CK, G4 cone-based model) were enrolled. Treatment plans for HA with two different optimization algorithms (SRS NTO and ALDO) and coplanar RapidArc (RA) were generated for each patient to meet the corresponding treatment plan criteria. These four FSRT treatment plans were divided into two groups-the homogeneous delivery group (HA-SRS NTO and coplanar RA) and the inhomogeneous delivery group (HA-ALDO and cone-based CK)-to compare for dosimetric outcomes. For homogeneous delivery, the brain V5, V12, and V24 and the mean brainstem dose were significantly lower with the HA-SRS NTO plans than with the coplanar RA plans. The conformity index, high and intermediate dose spillage, and gradient radius were significantly better with the HA-SRS NTO plans than with the coplanar RA plans. For inhomogeneous delivery, the HA-ALDO exhibited superior PTV coverage levels to the cone-based CK plans. Almost all the doses delivered to organs at risk and dose distribution metrics were significantly better with the HA-ALDO plans than with the cone-based CK plans. Good dosimetric distribution makes HA an attractive FSRT technique for the treatment of benign brain lesions., (© 2021. The Author(s).)

Brugada electrocardiogram (ECG) pattern describes a characteristic right bundle branch block (RBBB) appearance with persistent ST-segment elevation in precordial leads V1 to V3, often associated with Brugada syndrome, a genetic sodium channelopathy, in the absence of ischemic or structural heart disease. Known triggers such as fever, electrolyte abnormalities, medications, or recreational drugs may elicit such an ECG pattern without a clear clinical significance yet creating a dilemma for clinicians providing care in the urgent setting. We present a case of reversible Brugada electrocardiogram pattern (BEP) after recreational use of delta-8-tetrahydrocannabinol (THC) and explore the need for further research on the safety of such an over-the-counter supplement., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Jo et al.)

Aim: The aim of this study was to explore core competencies of nurse preceptors based on the perspectives of postgraduate-year nurses, nurse preceptors and head nurses., Background: Perspectives of core competencies of nurse preceptors are varied among postgraduate-year nurses, nurse preceptors and head nurses, which makes it difficult to establish preceptor training programs and develop evaluation instruments., Design: A nominal group technique study., Methods: A nominal group technique procedure was applied to small-group and large-group discussion. The participants were recruited from the inpatient units at five nonprofit hospitals, each having over 1000 patient beds, in Taiwan. A total of 101 participants were involved in this study: 32 postgraduate-year nurses, 42 nurse preceptors and 27 head nurses, who were respectively sorted into five, six and four small groups with six to eight members in each group. After applying nominal group technique procedure, the core competencies were scored and ranked. Based on the final scores and ranking, the core competencies that the participants felt to be most important for nurse preceptors were identified. The expert panel then integrated these core competencies and derived a consensus., Results: Seven core competencies of nurse preceptors were derived, in order of declining importance: teaching traits, clinical nursing profession, communication and collaboration, teaching pedagogy, reaction of contingency, critical thinking and reflection and consultation on academic writing. All participants perceived that teaching traits (198 points) and clinical nursing profession (161 points) were the most important. Consultation of academic writing is unique, which may be due to the clinical ladder system still being implemented in Taiwan., Conclusions: The nominal group technique is an efficient and proper method to conduct a consensus for specific issues or values among individuals and groups. The results of this study can facilitate the development of evaluation indicators or instruments as well as provide a direction of continuing education program for preceptor training., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Pathogenic coronaviruses include Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2. These viruses have induced outbreaks worldwide, and there are currently no effective medications against them. Therefore, there is an urgent need to develop potential drugs against coronaviruses., Methods: High-throughput technology is widely used to explore differences in messenger (m)RNA and micro (mi)RNA expression profiles, especially to investigate protein-protein interactions and search for new therapeutic compounds. We integrated miRNA and mRNA expression profiles in MERS-CoV-infected cells and compared them to mock-infected controls from public databases., Results: Through the bioinformatics analysis, there were 251 upregulated genes and eight highly differentiated miRNAs that overlapped in the two datasets. External validation verified that these genes had high expression in MERS-CoV-infected cells, including RC3H1, NF-κB, CD69, TNFAIP3, LEAP-2, DUSP10, CREB5, CXCL2, etc. We revealed that immune, olfactory or sensory system-related, and signal-transduction networks were discovered from upregulated mRNAs in MERS-CoV-infected cells. In total, 115 genes were predicted to be related to miRNAs, with the intersection of upregulated mRNAs and miRNA-targeting prediction genes such as TCF4, NR3C1, and POU2F2. Through the Connectivity Map (CMap) platform, we suggested potential compounds to use against MERS-CoV infection, including diethylcarbamazine, harpagoside, bumetanide, enalapril, and valproic acid., Conclusions: The present study illustrates the crucial roles of miRNA-mRNA interacting networks in MERS-CoV-infected cells. The genes we identified are potential targets for treating MERS-CoV infection; however, these could possibly be extended to other coronavirus infections., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Background: Research has shown that nursing interventions are able to affect short-term outcomes in patients with injury. However, evidence based on a comprehensive nurse-led intervention may be beneficial for trauma care., Purpose: This study was designed to assess the effect of a nursing intervention on the illness perceptions and quality of life of patients with injury., Methods: A two-group experimental design and a follow-up period of 12 months were used. Ninety-four patients were randomly assigned to either the experimental group or the control group. A nurse-led cognitive behavioral therapy intervention was used to improve outcomes., Results: The illness perception variables of "personal control" and "treatment control" were found to be significantly improved in the experimental group at 3 months after discharge, whereas "emotional perception" was significantly improved at 6 months after discharge. The intervention was also shown to improve "social quality of life" at 6 and 12 months after injury., Conclusions: This study adds new knowledge related to nursing interventions for patients with injury in terms of the intervention achieving longer-term effects than the interventions examined in previous studies. The results highlight the importance of providing interprofessional collaborative care. However, the intervention protocol should be tested further in future studies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc.)

The purpose of this study was to evaluate the feasibility and efficacy of HyperArc (HA) for recurrent nasopharyngeal cancer (NPC) by comparing it with the CyberKnife system (CK). Fifteen patients with recurrent nasopharyngeal cancer who were treated using the noncoplanar cone-based robotic CK system were enrolled. CK was delivered with a median dose of 37.5 Gy in 5 fractions. The delivered CK treatment plans were the sources for the corresponding homogeneous HA (HA-H) and inhomogeneous HA (HA-IH) plans. The HA-H plans were generated to meet the corresponding treatment plan criteria for the CK plans. The HA-IH plans were designed to emulate the corresponding inhomogeneous CK isodose distributions. These three SBRT treatment plans were compared with target coverage, sparing of organs at risk (OARs), and dose distribution metrics. The HA-H and HA-IH plans consistently exhibited CTV and PTV coverage levels similar or better to those of the CK plans but significantly reduced the dose to OARs. Using the HA techniques (both HA-H and HA-IH plans), the mean maximal doses to the spinal cord, brainstem, optic nerves, and optic chiasm were reduced by approximately 60%, compared to the CK plans. The high dose spillage, conformity, and homogeneity indices of the HA-H plans were significantly better than those of the CK plans. The HA-IH plans showed faster dose falloff and similar conformity of the HA-H plans and dose heterogeneity of the CK plans. Here we demonstrated the HA treatment plan system for recurrent NPC is feasible, either homogeneous or inhomogeneous delivery. Excellent sparing of OARs and dosimetric distribution and very efficient delivery make HA an attractive SBRT technique for recurrent NPC treatment., (Copyright © 2020 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)