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Purpose: The aim of this study was to evaluate treatment results in our hypopharyngeal cancer patients.Patients and Methods: A total of three hundred and ninety five hypopharyngeal cancer patients received radical treatment at our hospital; 96% were male. The majority were habitual smokers (88%), alcohol drinkers (73%) and/or betel quid chewers (51%). All patients received a CT scan or MRI for tumor staging before treatment. The stage distribution was stage I: 2 (0.5%); stage II: 22 (5.6%); stage III: 57 (14.4%) and stage IV: 314 (79.5%). Radical surgery was used first in 81 patients (20.5%), and the remaining patients (79.5%) received organ preservation-intended treatment (OPIT). In the OPIT group, 46 patients received radiotherapy alone, 156 patients received chemotherapy followed by radiotherapy (CT/RT) and 112 patients received concomitant chemo-radiotherapy (CCRT).Results: The five-year overall survival rates for stages I/II, III and IV were 49.5%, 47.4% and 18.6%, respectively. There was no significant difference in overall and disease-specific survival rates between patients who received radical surgery first and those who received OPIT. In the OPIT group, CCRT tended to preserve the larynx better (p = 0.088), with three-year larynx preservation rates of 44.8% for CCRT and 27.2% for CT/RT. Thirty-seven patients developed a second malignancy, with an annual incidence of 4.6%.Conclusions: There was no survival difference between OPIT and radical surgery in hypopharyngeal cancer patients at our hospital. CCRT may offer better laryngeal preservation than RT alone or CT/RT. However, prospective studies are still needed to confirm this finding. Additionally, second primary cancers are another important issue for hypopharyngeal cancer management. [ABSTRACT FROM AUTHOR]

Gross anatomy and neuroanatomy are fundamental subjects in medical education. However, learning different anatomical terms and understanding the complexity of the subjects are often challenging for medical students. At National Taiwan University, the 2020-2021 cohort adopted a face-to-face (F2F) learning strategy for gross anatomy and neuroanatomy lecture and laboratory courses until May 17, 2021. After the aforementioned date, the same cohort learned the rest of the gross anatomy and neuroanatomy courses via asynchronous online learning. This study aimed to evaluate the benefits of and students' preferences for F2F and asynchronous online learning strategies in learning gross anatomy and neuroanatomy. A survey with closed-ended and open-ended questions was used to quantitatively and qualitatively explore medical students' learning preferences for two teaching strategies in gross anatomy and neuroanatomy. The results identified different learning preferences among students in learning gross anatomy and neuroanatomy-satisfied with both learning strategies, satisfied with only F2F learning strategy, satisfied with only asynchronous online learning strategy, and satisfied with neither learning strategy. The survey results with closed-ended and open-ended questions showed that medical students preferred F2F learning for anatomical laboratory courses but favored asynchronous online learning for neuroanatomical laboratory courses. In addition, medical students considered peer discussion more critical in learning gross anatomy than neuroanatomy. These findings provide valuable information about medical students' preference for gross anatomy and neuroanatomy courses, which anatomy teachers can consider when planning to enhance their curriculum in the future., (© 2024 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Background: Having a sufficient number of gastroenterologists is important for protecting the digestive health of veterans. However, gastroenterology is among the most difficult medical specialties for recruitment at the US Department of Veterans Affairs (VA)., Methods: We surveyed VA gastroenterology section chiefs to learn about current barriers to recruitment and retention and to identify opportunities for improvement., Results: Of 131 VA gastroenterology section chiefs at VA medical centers who received the survey, 55 responded (42%). Thirty-six respondents (65%) reported current vacancies at their facilities (range, 1-4). Low salary and human resources challenges were the most frequently reported barriers to recruitment. Low salary and administrative burden, including lack of sufficient support staff, were the most frequently reported barriers to retention., Conclusions: While salary is the most frequently reported barrier to recruitment and retention, human resources challenges represent the second-most frequently reported barrier to recruitment. Administrative burden linked to suboptimal staffing support is the second most frequently reported barrier to retention. Efforts to raise salaries (higher than the current $400,000 ceiling), streamline human resources processes, and reduce administrative burden are needed to ensure a thriving VA gastroenterology workforce., Competing Interests: Author disclosures: Brian Hanson served as a consultant for Motus GI. The other authors have no conflicts to disclose., (Copyright © 2024 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Introduction: Little has been reported about the clinical relevance and trajectories of symptoms in end-stage liver disease (ESLD). The purpose of this prospective study was to identify trajectories of change in symptom burden over the course of 12 months in adults with ESLD., Methods: Patients were recruited from hepatology clinics at 2 healthcare systems. Validated measures were used to assess physical and psychological symptoms. Latent growth mixture modeling and survival and growth modeling were used to analyze the survey data., Results: Data were available for 192 patients (mean age 56.5 ± 11.1 years, 64.1% male, mean Model for ESLD (MELD) 3.0 19.2 ± 5.1, ethyl alcohol as primary etiology 33.9%, ascites 88.5%, encephalopathy 70.8%); there were 38 deaths and 39 liver transplantations over 12 months. Two symptom trajectories were identified: 62 patients (32.3%) had high and unmitigated symptoms, and 130 (67.7%) had lower and improving symptoms. Patients with high and unmitigated symptoms had twice the hazard of all-cause mortality (subhazard ratio 2.53, 95% confidence interval: 1.32-4.83) and had worse physical ( P < 0.001) and mental quality of life ( P = 0.012) compared with patients with lower and improving symptoms. Symptom trajectories were not associated with MELD 3.0 scores ( P = 0.395). Female sex, social support, and level of religiosity were significant predictors of symptom trajectories ( P < 0.05 for all)., Discussion: There seems to be 2 distinct phenotypes of symptom experience in patients with ESLD that is independent of disease severity and associated with sex, social support, religiosity, and mortality. Identifying patients with high symptom burden can help optimize their care., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Chronic liver disease is a significant global neglected public health problem. End-stage liver disease is associated with substantial symptom complexity, disability, and care needs that require assistance from informal family care partners. Research on these care partners' caregiver burden or strain, symptoms, and quality of life is sparse and has not focused on these variables as co-occurring or in the context of the quality of the relationship care partners have with the patients., Objectives: The purpose of this study was to provide a collective presentation of patterns and determinants of well-being as measured by caregiver strain, depression, sleep, and quality of life in a cohort of informal family care partners for adult outpatients with end-stage liver disease., Methods: Care partners (aged >18 years) were recruited from two liver clinics within two tertiary healthcare systems and invited to complete a cross-sectional survey. They completed the Multidimensional Caregiver Strain Index, Patient Health Questionnaire, Pittsburgh Sleep Quality Index, Short Form Health Survey, and Mutuality Scale. Descriptive statistics and latent class mixture modeling were used to analyze these data., Results: The sample was predominantly female and White. The well-being of care partners was diminished. Three distinct classes of well-being were identified: mildly diminished (53.2%), moderately diminished (39.0%), and severely diminished (7.8%). Those at a greater risk of worse well-being were younger and spouses and had poorer relationship quality with the patients., Discussion: To improve the well-being of care partners in moderately and severely diminished classes, assessing and addressing caregiver strain and co-occurring symptoms is essential. Addressing the strain and symptoms has the potential to maintain or optimize care partners' ability to provide care to patients. Future researchers should include longitudinal and dyadic studies to examine how patients' disease progression and symptoms may affect family care partners' well-being and vice versa., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

It can be difficult for some students to learn three-dimensional anatomical structure concepts. While virtual reality (VR) systems have been reported as helpful for learning, there has been scarce research on either VR teaching strategies or the influence of visually induced motion sickness (VIMS) in the context of large anatomy classes (i.e., over 100 students). The study thus aimed to (1) establish a VR anatomy instruction video for a large class; (2) determine how many students experience VIMS when watching a VR anatomy instruction video; (3) evaluate the influence of VIMS on VR anatomy video-based learning; and (4) examine whether a small screen size alleviates VIMS. Laboratory course students viewing a VR anatomy instruction video about the vascular system were invited to participate in the questionnaire survey. Anatomy faculty and staff participated in an experimental trial to determine whether small screen size could alleviate VIMS. The Likert scale survey revealed that students reported the VR strategy as advantageous and appropriate for large classes, but that it cannot replace practical dissection. Of the total participants, 32% reported experiencing VIMS, and 40% of those experiencing VIMS agreed that this could negatively impact their learning through a VR anatomy instruction video. Adjusting the screen size from large to small significantly delayed the onset of VIMS. In conclusion, the VR anatomy instruction video strategy is feasible and helpful for large classes, but educators should consider VIMS when planning their use of this teaching approach., (© 2024 The Authors. Anatomical Sciences Education published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Background: Ultra-low contrast administration during coronary angiography has been previously shown to be feasible and safe among patients with stable chronic kidney disease. In the present study, we investigate the safety of ultra-low contrast coronary angiography in patients with pre-existing acute kidney injury (AKI)., Methods: The study was a retrospective single-center evaluation of hospitalized patients who had AKI and required coronary angiography. Ultra-low contrast use was defined as ≤18 mL of contrast media., Results: The cohort consisted of a case series of eight inpatients with AKI who required coronary angiography. The mean age was 57 (±16) years and half were females. All patients had chronic kidney disease with a mean baseline estimated glomerular filtration rate of 34 (±17) mL/min/1.73 m 2 . The mean creatinine before angiography was 3 (±1) mg/dL and volume of contrast administered was 14 (±4) mL. One patient had a 0.1 mg/dL increase in creatinine during admission, and no patients had further AKI up to 1-week postprocedure., Conclusions: The current data suggest that ultra-low contrast coronary angiography can be safely performed in patients with pre-existing AKI The study should be viewed as hypothesis-generating due to its small sample size. A larger cohort is required to validate the results., (© 2024 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Artificial intelligence (AI) edge devices prefer employing high-capacity nonvolatile compute-in-memory (CIM) to achieve high energy efficiency and rapid wakeup-to-response with sufficient accuracy. Most previous works are based on either memristor-based CIMs, which suffer from accuracy loss and do not support training as a result of limited endurance, or digital static random-access memory (SRAM)-based CIMs, which suffer from large area requirements and volatile storage. We report an AI edge processor that uses a memristor-SRAM CIM-fusion scheme to simultaneously exploit the high accuracy of the digital SRAM CIM and the high energy-efficiency and storage density of the resistive random-access memory memristor CIM. This also enables adaptive local training to accommodate personalized characterization and user environment. The fusion processor achieved high CIM capacity, short wakeup-to-response latency (392 microseconds), high peak energy efficiency (77.64 teraoperations per second per watt), and robust accuracy (<0.5% accuracy loss). This work demonstrates that memristor technology has moved beyond in-lab development stages and now has manufacturability for AI edge processors.

Artificial Intelligence (AI) is currently experiencing a bloom driven by deep learning (DL) techniques, which rely on networks of connected simple computing units operating in parallel. The low communication bandwidth between memory and processing units in conventional von Neumann machines does not support the requirements of emerging applications that rely extensively on large sets of data. More recent computing paradigms, such as high parallelization and near-memory computing, help alleviate the data communication bottleneck to some extent, but paradigm- shifting concepts are required. Memristors, a novel beyond-complementary metal-oxide-semiconductor (CMOS) technology, are a promising choice for memory devices due to their unique intrinsic device-level properties, enabling both storing and computing with a small, massively-parallel footprint at low power. Theoretically, this directly translates to a major boost in energy efficiency and computational throughput, but various practical challenges remain. In this work we review the latest efforts for achieving hardware-based memristive artificial neural networks (ANNs), describing with detail the working principia of each block and the different design alternatives with their own advantages and disadvantages, as well as the tools required for accurate estimation of performance metrics. Ultimately, we aim to provide a comprehensive protocol of the materials and methods involved in memristive neural networks to those aiming to start working in this field and the experts looking for a holistic approach., (© 2024. The Author(s).)

The role of heat shock protein 27 (HSP27), a chaperone, in neuropathic pain after nerve injury has not been systematically surveyed despite its neuroprotective and regeneration-promoting effects. In this study, we found that HSP27 expression in sensory neurons of the dorsal root ganglia (DRG) mediated nerve injury-induced neuropathic pain. Neuropathic pain behaviors were alleviated by silencing HSP27 in the DRG of a rat spinal nerve ligation (SNL) model. Local injection of an HSP27-overexpression construct into the DRG of naïve rats elicited neuropathic pain behaviors. HSP27 interacted with a purinergic receptor, P2X3, and their expression patterns corroborated the induction and reversal of neuropathic pain according to two lines of evidence: colocalization immunohistochemically and immunoprecipitation biochemically. In a cell model cotransfected with HSP27 and P2X3, the degradation rate of P2X3 was reduced in the presence of HSP27. Such an alteration was mediated by reducing P2X3 ubiquitination in SNL rats and was reversed after silencing HSP27 in the DRGs of SNL rats. In summary, the interaction of HSP27 with P2X3 provides a new mechanism of injury-induced neuropathic pain that could serve as an alternative therapeutic target., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatitis D virus (HDV), which co-infects or superinfects patients with hepatitis B virus, is estimated to affect 74 million people worldwide. Chronic hepatitis D is the most severe form of viral hepatitis and can result in liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Currently, there are no efficient HDV-specific drugs. Therefore, there is an urgent need for novel HDV therapies that can achieve a functional cure or even eliminate the viral infection. In the HDV life cycle, agents targeting the entry step of HDV infection preemptively reduce the intrahepatic viral RNA. Human sodium taurocholate co-transporting polypeptide (hNTCP), a transporter of bile acids on the plasma membrane of hepatocytes, is an essential entry receptor of HDV and is a promising molecular target against HDV infection. Here, we investigated the effect of ergosterol peroxide (EP) on HDV infection in vitro and in vivo. EP inhibited HDV infection of hNTCP-expressing dHuS-E/2 hepatocytes by interrupting the early fusion/endocytosis step of HDV entry. Furthermore, molecular modeling suggested that EP hinders LHBsAg binding to hNTCP by blocking access to S267 and V263. In addition, we generated hNTCP-expressing transgenic (Tg) C57BL/6 mice using the Cre/loxP system for in vivo study. EP reduced the liver HDV RNA level of HDV-challenged hNTCP-Cre Tg mice. Intriguingly, EP downregulated the mRNA level of liver IFN-γ. We demonstrate that EP is a bona fide HDV entry inhibitor that acts on hNTCP and has the potential for use in HDV therapies., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Physical limitations may hinder older adults with physical disabilities' capability to perform various activities, which can affect their quality of life (QOL). Accomplishing meaningful activities may mitigate the impact of limited activity performance on their QOL. This longitudinal study aims to investigate how activity meaning mediates the relationship between activity performance and QOL among older adults with disabilities., Methods: Data for this longitudinal study was collected from 813 community-dwelling older adults aged 60 and above who had physical disabilities, over a two year interval. Path analysis was used to examine the cross-sectional and longitudinal mediation effects from activity performance, through activity meaning, to QOL., Results: At the same wave, high IADL performance or social activity performance, and high QOL was indirectly associated through high IADL meaning or social meaning. As for longitudinal association, high T1 IADL performance was associated with better T2 QOL through high T1 and T2 IADL meaning. Similarly, high T1 social activity performance also contributed to T2 QOL through high T1 and T2 social activity meaning. Additionally, social activity performance exhibited higher influence on QOL than that of IADL., Conclusions: Both IADL and social activities have distinct impacts on the QOL of older adults with disabilities. To improve the current and future QOL of older adults with disabilities, professionals must prioritize their involvement in the most meaningful activities while being sensitive to and supportive of their preferences and valued lifestyles., (© 2023. The Author(s).)

Introduction: Modified teaching strategies (MTS), asynchronous online teaching and smaller dissection groups, were applied to a gross anatomy course for dental students in the National Taiwan University in April 2020 in response to the COVID-19 pandemic. This study aimed to investigate the effects and perceptions of MTS on dental students., Materials and Methods: Scores for anatomy examinations for 2018-2019 (without MTS) and 2019-2020 (with MTS) cohorts were compared to explore the effect on academic performance. Moreover, questionnaire from the 2019-2020 cohort was analysed to determine dental students' perceptions about MTS., Results: The lecture performance in the final examination of the second semester for the 2019-2020 cohort was significantly higher than that of the first semester (pre-COVID-19) and that for the 2018-2019 cohort. However, the laboratory performance in the midterm examination of the second semester for the 2019-2020 cohort was significantly lower than that for the 2018-2019 cohort and showed no difference in the final examination of the first semester. The questionnaires revealed that the majority of students displayed positive attitudes towards MTS and agreed with the importance of peer discussion during laboratory dissection., Conclusions: Asynchronous online learning for anatomy lecture may be beneficial for dental students; however, a smaller dissection group accompanied by reduced peer discussion may temporarily exert negative effects on their laboratory performance at the beginning of the application. Furthermore, more dental students exhibited positive perceptions towards smaller dissection groups. These findings could illuminate the learning condition of dental students in anatomy education., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background Aims: This study aimed to evaluate quarterly trends in process and health outcomes among Veterans with cirrhosis and assess the factors associated with cirrhosis outcomes before and during the COVID-19 pandemic., Approach Results: US Veterans with cirrhosis were identified using the Veterans Health Administration Corporate Data Warehouse. Quarterly measures were evaluated from September 30, 2018, through March 31, 2022, including twice yearly screening for hepatocellular carcinoma (HCC-6), new HCC, surveillance for or treatment of esophageal varices, variceal bleeding, all-cause hospitalization, and mortality. Joinpoint analyses were used to assess the changes in trends over time. Logistic regression models were used to identify the demographic and medical factors associated with each outcome over time. Among 111,558 Veterans with cirrhosis with a mean Model for End-stage Liver Disease-Sodium of 11±5, rates of HCC-6 sharply declined from a prepandemic peak of 41%, to a nadir of 28%, and rebounded to 36% by March 2022. All-cause mortality did not significantly change over the pandemic, but new HCC diagnosis, EVST, variceal bleeding, and all-cause hospitalization significantly declined over follow-up. Quarterly HCC diagnosis declined from 0.49% to 0.38%, EVST from 50% to 41%, variceal bleeding from 0.15% to 0.11%, and hospitalization from 9% to 5%. Rurality became newly, significantly associated with nonscreening over the pandemic (aOR for HCC-6=0.80, 95% CI 0.74 to 0.86; aOR for EVST=0.95, 95% CI 0.90 to 0.997)., Conclusions: The pandemic continues to impact cirrhosis care. Identifying populations at the highest risk of care disruptions may help to address ongoing areas of need., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks have constituted a public health issue with drastic mortality higher than 34%, necessitating the development of an effective vaccine. During MERS-CoV infection, the trimeric spike protein on the viral envelope is primarily responsible for attachment to host cellular receptor, dipeptidyl peptidase 4 (DPP4). With the goal of generating a protein-based prophylactic, we designed a subunit vaccine comprising the recombinant S1 protein with a trimerization motif (S1-Fd) and examined its immunogenicity and protective immune responses in combination with various adjuvants. We found that sera from immunized wild-type and human DPP4 transgenic mice contained S1-specific antibodies that can neutralize MERS-CoV infection in susceptible cells. Vaccination with S1-Fd protein in combination with a saponin-based QS-21 adjuvant provided long-term humoral as well as cellular immunity in mice. Our findings highlight the significance of the trimeric S1 protein in the development of MERS-CoV vaccines and offer a suitable adjuvant, QS-21, to induce robust and prolonged memory T cell response., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ming-Fu Chang reports financial support was provided by Ministry of Science & Technology of Taiwan. Ming-Fu Chang reports a relationship with Ministry of Science & Technology of Taiwan that includes: funding grants. Ming-Fu Chang has patent NA pending to NA. 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With growing environmental concerns and the exploitation of ubiquitous big data, smart transportation is transforming logistics business and operations into a more sustainable approach. To answer questions in intelligent transportation planning, such as which data are feasible, which methods are applicable for intelligent prediction of such data, and what are the available operations for prediction, this paper offers a new deep learning approach called bi-directional isometric-gated recurrent unit (BDIGRU). It is merged to the deep learning framework of neural networks for predictive analysis of travel time and business adoption for route planning. The proposed new method directly learns high-level features from big traffic data and reconstructs them by its own attention mechanism drawn by temporal orders to complete the learning process recursively in an end-to-end manner. After deriving the computational algorithm with stochastic gradient descent, we use the proposed method to perform predictive analysis of stochastic travel time under various traffic conditions (especially for congestions) and then determine the optimal vehicle route with the shortest travel time under future uncertainty. Based on empirical results with big traffic data, we show that the proposed BDIGRU method can (1) significantly improve the predictive accuracy of one-step 30 min ahead travel time compared to several conventional (data-driven, model-driven, hybrid, and heuristics) methods measured with several performance criteria, and (2) efficiently determine the optimal vehicle route in relation to the predictive variability under uncertainty., Competing Interests: Conflicts of interestAuthors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: Successful application of deep machine learning could reduce time-consuming and labor-intensive clinical work of calculating the amount of radiographic bone loss (RBL) in diagnosing and treatment planning for periodontitis. This study aimed to test the accuracy of RBL classification by machine learning., Materials and Methods: A total of 236 patients with standardized full mouth radiographs were included. Each tooth from the periapical films was evaluated by three calibrated periodontists for categorization of RBL and radiographic defect morphology. Each image was pre-processed and augmented to ensure proper data balancing without data pollution, then a novel multitasking InceptionV3 model was applied., Results: The model demonstrated an average accuracy of 0.87 ± 0.01 in the categorization of mild (< 15%) or severe (≥ 15%) bone loss with fivefold cross-validation. Sensitivity, specificity, positive predictive, and negative predictive values of the model were 0.86 ± 0.03, 0.88 ± 0.03, 0.88 ± 0.03, and 0.86 ± 0.02, respectively., Conclusions: Application of deep machine learning for the detection of alveolar bone loss yielded promising results in this study. Additional data would be beneficial to enhance model construction and enable better machine learning performance for clinical implementation., Clinical Relevance: Higher accuracy of radiographic bone loss classification by machine learning can be achieved with more clinical data and proper model construction for valuable clinical application., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background & Aims: Patients with decompensated liver disease have been categorized by disease severity. This analysis sought to classify patients with end-stage liver disease based on symptoms rather than disease state and to identify distinct severity classes of physical and psychological symptoms., Methods: Patients with a model for end-stage liver disease-sodium score of 15 or higher were recruited from liver clinics in 2 health care organizations. They completed the Condensed Memorial Symptom Assessment Scale, Revised Ways of Coping Checklist, Patient Health Questionnaire, Life Orientation Test-Revised, and the Short-Form Health Survey. Cross-sectional data were analyzed using latent class mixture modeling., Results: The sample (N = 191; age, 56.6 ± 11.1 y; 33.5% ETOH; 28.3% nonalcoholic fatty liver disease; 13.1% autoimmune/primary biliary cholangitis/primary sclerosing cholangitis) was predominantly male (64.2%), Child-Turcotte-Pugh class C (49.5%), with an average model for end-stage liver disease-sodium score of 18.7 ± 4.9. Three distinct classes of symptoms were identified, as follows: mild (26.7%), moderate (41.4%), or severe (31.9%) symptoms. Symptom classes were independent of disease severity and demographic characteristics, except age. All Condensed Memorial Symptom Assessment Scale symptoms and Patient Health Questionnaire scores were significantly different across the 3 classes (P &lt; .05). The symptom classes also differed significantly in physical and mental quality of life, optimism, and avoidance coping behaviors (all P &lt; .001)., Conclusions: Patient-reported symptom severity occurred independent of disease severity, contrary to common assumptions. Focusing on the moderate and severe symptom classes as well as patient history of end-stage liver disease complications may enhance providers' ability to improve symptom management for this population., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Hepatitis delta virus (HDV), a satellite virus of hepatitis B virus (HBV), is a small, defective RNA virus strongly associated with the most severe form of hepatitis and progressive chronic liver disease and cirrhosis. Chronic hepatitis D, resulting from HBV/HDV coinfection, is considered to be the most severe form of viral hepatitis and affects 12-20 million people worldwide. Involved in the endocytosis and exocytosis of cellular and viral proteins, clathrin contributes to the pathogenesis and morphogenesis of HDV. Previously, we demonstrated that HDV-I and -II large hepatitis delta antigens (HDAg-L) possess a putative clathrin box that interacts with clathrin heavy chain (CHC) and supports HDV assembly., Methods: Virus assembly and vesicular trafficking of HDV virus-like particles (VLPs) were evaluated in Huh7 cells expressing HDV-I, -II and -III HDAg-L and hepatitis B surface antigen (HBsAg). To elucidate the interaction motif between HDAg-L and CHC, site-directed mutagenesis was performed to introduce mutations into HDAg-L and CHC and analyzed using coimmunoprecipitation or pull-down assays., Results: Comparable to HDV-I virus-like particles (VLPs), HDV-III VLPs were produced at a similar level and secreted into the medium via clathrin-mediated post-Golgi vesicular trafficking. Mutation at F27 or E33 of CHC abolished the binding of CHC to the C-terminus of HDV-III HDAg-L. Mutation at W207 of HDV-III HDAg-L inhibited its association with CHC and interfered with HDV-III VLP formation. We elucidated mechanism of the binding of HDV-III HDAg-L to CHC and confirmed the pivotal role of clathrin binding in the assembly of genotype III HDV., Conclusions: A novel W box which was identified at the C terminus of HDV-III HDAg-L is known to differ from the conventional clathrin box but also interacts with CHC. The novel W box of HDAg-L constitutes a new molecular target for anti-HDV-III therapeutics., (© 2022. The Author(s).)

Background: Studies assessing multiple symptoms and the distress of these symptoms in decompensated cirrhosis are lacking., Aims: The aims of this study were to assess symptom prevalence and distress among patients with decompensated cirrhosis and to describe medical management of the most prevalent symptoms., Methods: Patients were recruited from hepatology clinics within two health-care systems. Eligibility criteria included a model for end-stage liver disease (MELD-Na) score ≥15. Patients completed the Condensed Memorial Symptom Assessment Scale and Patient Health Questionnaire. Comparative statistics were used to analyze the cross-sectional survey data., Results: Of the sample (n = 146), most patients were Child-Turcotte-Pugh (CTP) class B (49.7%) and C (46.2%). Mean age was 56.5 years, 65.1% were male, and 88.4% were white. Average MELD-Na score was 19.1 ± 4.5. The most prevalent symptoms were lack of energy and feeling drowsy while the most distressing were lack of energy and difficulty sleeping. Only 24 patients (16.4%) were treated for their difficulty sleeping with sleep medication. Importantly, those prescribed sleep medications had similar distress (3.9 ± 1.2 vs. 3.5 ± 1.2, p = 0.229) compared with patients not prescribed sleep medications. Opioids were prescribed to 57 (39.0%) patients; antidepressants to 34 (23.3%). Forty patients (27.4%) who reported moderate or greater depression were not prescribed an antidepressant., Conclusions: The study highlights the multiple symptoms and distress experienced by patients with decompensated cirrhosis, and the need for improved medical management by health-care providers through enhanced awareness and attention to these complex symptoms. Future research should focus on improvements in symptom management., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A physically unclonable function (PUF) is a creditable and lightweight solution to the mistrust in billions of Internet of Things devices. Because of this remarkable importance, PUF need to be immune to multifarious attack means. Making the PUF concealable is considered an effective countermeasure but it is not feasible for existing PUF designs. The bottleneck is finding a reproducible randomness source that supports repeatable concealment and accurate recovery of the PUF data. In this work, we experimentally demonstrate a concealable PUF at the chip level with an integrated memristor array and peripherals. The correlated filamentary switching characteristic of the hafnium oxide (HfO x )-based memristor is used to achieve PUF concealment/recovery with SET/RESET operations efficiently. PUF recovery with a zero-bit error rate and remarkable attack resistance are achieved simultaneously with negligible circuit overhead. This concealable PUF provides a promising opportunity to build memristive hardware systems with effective security in the near future.

Memristive devices, which combine a resistor with memory functions such that voltage pulses can change their resistance (and hence their memory state) in a nonvolatile manner, are beginning to be implemented in integrated circuits for memory applications. However, memristive devices could have applications in many other technologies, such as non-von Neumann in-memory computing in crossbar arrays, random number generation for data security, and radio-frequency switches for mobile communications. Progress toward the integration of memristive devices in commercial solid-state electronic circuits and other potential applications will depend on performance and reliability challenges that still need to be addressed, as described here.

Objective: Although the microenvironment for peripheral nerve regeneration is permissive, such a mechanism is defective in diabetes, and the molecular mediators remain elusive. [Correction added on May 11, 2022, after first online publication: In the preceding sentence, "is ok" was changed to "is defective".] This study aimed to (1) investigate the relationship between skin innervation and collagen pathology in diabetic neuropathy and to (2) clarify the molecular alterations that occur in response to hyperglycemia and their effects on axon regeneration., Methods: We addressed this issue using two complementary systems: (1) human skin from patients with diabetic neuropathy and to (2) a coculture model of human dermal fibroblasts (HDFs) with rat dorsal root ganglia neurons in the context of intrinsic neuronal factor and extrinsic microenvironmental collagen and its biosynthetic pathways., Results: In diabetic neuropathy, the skin innervation of intraepidermal nerve fiber density (IENFd), a measure of sensory nerve degeneration, was reduced with similar expression of a growth associated protein 43, a marker of nerve regeneration. In contrast, the content and packing of collagen in the diabetic skin became more rigid than the control skin. Sec31a, a protein that regulates the collagen biosynthetic pathway, was upregulated and inversely correlated with IENFd. In the cell model, activated HDFs exposed to high-glucose medium enhanced the expression of Sec31a and collagen I through the activation of transforming growth factor β, a profibrotic molecule. Sec31a upregulation impaired neurite outgrowth. This effect was reversed by silencing Sec31a expression and neurite outgrowth was resumed., Interpretation: The current study provides evidence that Sec31a plays a key role in inhibiting nerve regeneration in diabetic neuropathy. ANN NEUROL 2022;91:821-833., (© 2022 American Neurological Association.)

Background: Registered nurses are required for high-quality healthcare. Thus, the anatomy course is essential regarding professional knowledge of the human body during the nursing training process. However, previous studies have indicated that anatomy teaching time and anatomy teachers were reduced and insufficient. Therefore, to improve the learning of practical anatomy in response to these difficulties, a bilingual National Taiwan University web-based anatomy atlas (NTU-WAA) was created as a cross-platform application and its feasibility was evaluated., Methods: The comparison of anatomy examination scores between nursing students of two cohorts (66 from the 2018-2019 cohort, whom was without NTU-WAA application; 54 from the 2019-2020 cohort, to whom NTU-WAA was offered) and the evaluation of questionnaires collected from nursing students of the 2019-2020 cohort and 4 anatomy teachers were carried out to define the feasibility of this strategy., Results: Results obtained by nursing students for the 2019-2020 cohort showed a significant increase in anatomy learning performance compared with that of the 2018-2019 cohort with reference to the laboratory midterm [2018-2019 cohort vs. 2019-2020 cohort, mean (standard deviation, SD): 77.20 (16.14) vs. 81.80 (12.03); p = 0.043], the laboratory final examination [59.68 (15.28) vs. 80.35 (13.74); p < 0.001] and the theory final examination [80.85 (10.10) vs. 84.33 (6.925); p = 0.017]. Moreover, results of the questionnaires indicated that the new bilingual cross-platform atlas was highly accepted by students and teachers., Conclusions: The NTU-WAA, a bilingual web-based atlas, was evaluated as a beneficial anatomy-learning tool that may enhance self-study of nursing students with consequent amelioration of their anatomy-related performance in both theoretical and laboratory examinations. This reflection suggests the future implementation of the bilingual web-based atlas on a large scale., (© 2022. The Author(s).)

Due to the Covid-19 pandemic, National Taiwan University anatomy teachers adopted asynchronous online video teaching and reduced the size of anatomy laboratory groups in April 2020. The aim of this study was to investigate the impact of these changes on medical students' learning. Before Covid-19, the performance of the 2019-2020 cohort was significantly better than that of the 2018-2019 cohort. However, the implementation of modified teaching strategies significantly lowered the laboratory midterm score of the 2019-2020 cohort in the second semester. Conversely, the final laboratory examination score of the 2019-2020 cohort was significantly higher than that of the 2018-2019 cohort. Through correlation analysis, lecture and laboratory examination scores were highly correlated. Additionally, the difference in lecture and laboratory z-scores between two cohorts, the Likert scale survey and free-text feedback of the 2019-2020 cohort, were conducted to show the impact of modified teaching strategies. There were several important findings in this study. First, the change in teaching strategies may temporarily negatively influence medical students to learn anatomy. Besides, analyzing the performance of laboratory assessments could be a complementary strategy to evaluate online assessments. Applying lecture examination scores to predict laboratory performance was a feasible way to identify students who may have difficulty in learning practical dissection. Finally, reducing group size together with reduced peer discussion may have a negative effect on learning cadaver dissection for students with low academic performance. These findings should be taken into consideration when anatomy teachers apply new teaching strategies in anatomy courses., (© 2022 American Association for Anatomy.)

Introduction: The Veteran Integrated Service Network (VISN) 20 Veterans Affairs-Extension for Community Healthcare Outcomes (VA-ECHO) program connects specialty and primary care providers (PCPs) across large geographic areas, utilizing video-teleconferencing with the intention of increasing access to care among underserved and isolated populations. No previously published work describes participation patterns of a multispecialty ECHO program. We describe the development of VISN 20 VA-ECHO program to inform the design and evaluation of ECHO programs. Methods: The participant cohort included VA-affiliated licensed health care professionals, including trainees, who attended at least one VISN 20 VA-ECHO session between April 2012 and December 2018. Participant characteristics reported include gender, clinical location, clinical specialty, discipline, and rurality. Results: Over the 6-year time frame, VISN 20 VA-ECHO offered 945 sessions in 14 clinical specialties and recorded 17,893 hours of attendance. The cohort included 1,346 participants, 74.3% of whom were female, 85.2% employed in medical centers, and 40.7% affiliated with primary care. Most participants (62.3%) attended one specialty exclusively; among all participants, 40% attended five or more sessions. Discussion: Although VA-ECHO was implemented to develop single specialty expertise among PCPs, our participant cohort represented a more diverse audience from a range of disciplines and specialties. Our experience may be valuable to other teams implementing ECHO programs. Conclusions: Through adaptability and strategies that actively promoted inclusion of a diverse audience, VISN 20 VA-ECHO expanded to include multiple clinical specialties and successfully engaged an audience across a large geographic area and beyond PCPs.

Vibration-controlled transient elastography (VCTE) is a non-invasive method of evaluating liver fibrosis and steatosis. It can easily be performed in the outpatient setting and has been suggested as an alternative to liver biopsy. However, VCTE and biopsy discrepancies commonly occur. Patient characteristics, procedure performance, and liver features can impact the reliability of VCTE results. We identified 82 patients who received VCTE and biopsy within one month to assess how frequently major discrepancies occur and to determine the role of the liver biopsy in this workup. In our study, 35.4% of patients had a major fibrosis discrepancy, which was defined as advanced fibrosis or cirrhosis by VCTE and no to minimal fibrosis on biopsy. This was significantly associated with increased BMI, and liver features including steatohepatitis, inflammation, congestion, and cholestasis were important contributors to discrepancies. All patients with advanced fibrosis or cirrhosis on liver biopsy were appropriately detected by VCTE (n = 28). Detection of steatosis was less sensitive as 19% (n = 4 of 21) of patients with moderate to severe steatosis on biopsy were missed by VCTE. Liver biopsy has been traditionally performed for diagnosis, but with the emergence of non-invasive tools to evaluate for liver fibrosis and steatosis, biopsies are now additionally being performed to confirm findings from noninvasive procedures. Although VCTE is a highly sensitive tool for liver fibrosis, it is not as specific, and therefore, the liver biopsy remains the gold standard for accurate fibrosis assessment., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Sleep VA-ECHO (Veterans Affairs-Extension for Community Healthcare Outcomes) is a national telementorship program intended to improve knowledge about sleep disorders among non-specialty providers. The project goal was to describe the characteristics of Sleep VA-ECHO participants from primary care and their use of program-obtained knowledge in practice. Sleep VA-ECHO consisted of 10 voluntary, 75-min teleconference sessions combining didactics and case discussion. Out of 86 participants, 21 self-identified as primary care team members and completed a program evaluation. Participants self-reported their application of knowledge gained, including changes to practice as a result of program participation. These 21 participants represented 18 sites in 11 states and attended a median of 5.0 sessions. They included physicians (29%), nurse practitioners (24%), and registered nurses (24%). Nearly all participants (95%) reported using acquired knowledge to care for their own patients at least once a month; 67% shared knowledge with colleagues at least once a month. Eighty-five percent reported improved quality of sleep care for their patients, and 76% reported an expanded clinical skillset. The greatest self-reported change in practice occurred in patient education about sleep disorders (95%) and non-pharmacologic management of insomnia (81%).

Background: To investigate all-cause and cause-specific mortality in Taiwanese patients with type 1 diabetes., Methods: A cohort of 17,203 patients with type 1 diabetes were identified from Taiwan's National Health Insurance claims in the period of 1998-2014. Person-years were accumulated for each individual from date of type 1 diabetes registration to date of death or the last day of 2014. Age, sex, and calendar year standardized mortality ratios (SMRs) were calculated with reference to the general population., Results: In up to 17 years of follow-up, 4,916 patients died from 182,523 person-years. Diabetes (30.15%), cancer (20.48%), circulatory diseases (13.14%), and renal diseases (11.45%) were the leading underlying causes of death. Mortality rate (26.93 per 1,000 person-years) from type 1 diabetes in Taiwan was high, the cause of death with the highest mortality rate was diabetes (8.12 per 1,000 person-years), followed by cancer (5.52 per 1,000 person-years), and circulatory diseases (3.54 per 1,000 person-years). The all-cause SMR was significantly elevated at 4.16 (95% confidence interval, 4.04-4.28), with a greater all-cause SMR noted in females than in males (4.62 vs 3.79). The cause-specific SMR was highly elevated for diabetes (SMR, 16.45), followed by renal disease (SMR, 14.48), chronic hepatitis and liver cirrhosis (SMR, 4.91) and infection (SMR, 4.59). All-cause SMRs were also significantly increased for all ages, with the greatest figure noted for 15-24 years (SMR, 8.46)., Conclusions: Type 1 diabetes in both genders and all ages was associated with significantly elevated SMRs for all-cause and mostly for diabetes per se and renal disease.

LMBD1 was previously demonstrated to regulate the endocytosis of insulin receptor on the cell surface and to mediate the export of cobalamin from the lysosomes to the cytosol, but little is known about its function in mitosis. In this study, interactome analysis data indicate that LMBD1 is involved in cytoskeleton regulation. Both immunoprecipitation and GST pulldown assays demonstrated the association of LMBD1 with tubulin. Immunofluorescence staining also showed the colocalization of LMBD1 with microtubule in both interphase and mitotic cells. LMBD1 specifically accelerates microtubule assembly dynamics in vitro and antagonizes the microtubule-disruptive effect of vinblastine. In addition, LMBRD1-knockdown impairs mitotic spindle formation, inhibits tubulin polymerization, and diminishes the mitosis-associated tubulin acetylation. The reduced acetylation can be reversed by ectopic expression of LMBD1 protein. These results suggest that LMBD1 protein stabilizes microtubule intermediates. Furthermore, embryonic fibroblasts derived from Lmbrd1 heterozygous knockout mice showed abnormality in microtubule formation, mitosis, and cell growth. Taken together, LMBD1 plays a pivotal role in regulating microtubule assembly that is essential for the process of cell mitosis., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background & Aims: Management of end-stage liver disease (ESLD) has implications for not only patients' quality of life (QOL), but also their caregivers'. We aimed to identify characteristics of patients with ESLD and their caregivers that are associated with QOL., Methods: We obtained cross-sectional baseline data from patients and their caregivers (132 dyads; 62% were married or partners), recruited from outpatient hepatology clinics within 2 healthcare centers. Patients were included if their model for end-stage liver disease score was 15 or more; caregivers were identified by the patient as the primary informal caregiver. QOL was measured by the SF-36 and relationship quality using the mutuality scale. We measured uncertainty using the uncertainty in illness scales for patients and caregivers. Multilevel modeling was used to analyze the data., Results: Refractory ascites was associated with worse physical QOL for patients (unstandardized beta [B], -9.19; standard error [SE], 2.28) and caregivers (B, -5.41; SE, 2.33); history of hepatic encephalopathy was associated with worse patient physical QOL (B, -3.86; SE, 1.65). High levels of uncertainty were associated with worse physical and mental QOL for both members of the dyads; relationship quality was significantly associated with patient mental QOL (B, 2.73; SE, 1.19)., Conclusions: Clinicians and researchers should consider the effects of ESLD on caregivers as well as their patients to optimize the QOL for both., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Type I and type III interferons (IFNs) are the frontline of antiviral defense mechanisms that trigger hundreds of downstream antiviral genes. In this study, we observed that MERS-CoV nucleocapsid (N) protein suppresses type I and type III IFN gene expression. The N protein suppresses Sendai virus-induced IFN-β and IFN-λ1 by reducing their promoter activity and mRNA levels, as well as downstream IFN-stimulated genes (ISGs). Retinoic acid-inducible gene I (RIG-I) is known to recognize viral RNA and induce IFN expression through tripartite motif-containing protein 25 (TRIM25)-mediated ubiquitination of RIG-I caspase activation and recruitment domains (CARDs). We discovered that MERS-CoV N protein suppresses RIG-I-CARD-induced, but not MDA5-CARD-induced, IFN-β and IFN-λ1 promoter activity. By interacting with TRIM25, N protein impedes RIG-I ubiquitination and activation and inhibits the phosphorylation of transcription factors IFN-regulatory factor 3 (IRF3) and NF-κB that are known to be important for IFN gene activation. By employing a recombinant Sindbis virus-EGFP replication system, we showed that viral N protein downregulated the production of not only IFN mRNA but also bioactive IFN proteins. Taken together, MERS-CoV N protein functions as an IFN antagonist. It suppresses RIG-I-induced type I and type III IFN production by interfering with TRIM25-mediated RIG-I ubiquitination. Our study sheds light on the pathogenic mechanism of how MERS-CoV causes disease. IMPORTANCE MERS-CoV causes death of about 35% of patients. Published studies showed that some coronaviruses are capable of suppressing interferon (IFN) expression in the early phase of infection and MERS-CoV proteins can modulate host immune response. In this study, we demonstrated that MERS-CoV nucleocapsid (N) protein suppresses the production of both type I and type III IFNs via sequestering TRIM25, an E3 ubiquitin ligase that is essential for activating the RIG-I signaling pathway. Ectopic expression of TRIM25 rescues the suppressive effect of the N protein. In addition, the C-terminal domain of the viral N protein plays a pivotal role in the suppression of IFN-β promoter activity. Our findings reveal how MERS-CoV evades innate immunity and provide insights into the interplay between host immune response and viral pathogenicity., (Copyright © 2020 American Society for Microbiology.)

Context.—: Disease guidelines specify universal alanine aminotransferase (ALT) thresholds for clinical decision-making, yet the effect of variability among ALT analyzers remains unclear., Objective.—: To compare ALT results from different analyzers from 2012-2017., Design.—: Veterans Health Administration (VHA) laboratories perform external ALT proficiency testing using standardized College of American Pathologists (CAP) samples in analyzers by 5 manufacturers. In this operational analysis, we evaluated 22 950 ALT values from 80 independent CAP samples tested at 223 laboratories. Using mixed effects modeling, we estimated the association between analyzer manufacturer and CAP outcome, adjusting for manufacturer, facility, and calendar year. We performed subgroup analyses on CAP samples with overall means near clinical guideline-specified thresholds, including less than 50 U/L (n = 10) and less than 35 U/L (n = 5)., Results.—: The VHA used Abbott Laboratories (n = 3175; 14%), Beckman Coulter Diagnostics (n = 8723; 38%), Roche Diagnostics (n = 2595; 11%), Siemens Healthineers USA (n = 5713; 25%), and Vitros/Ortho Clinical Diagnostics (n = 2744; 12%) analyzers. The CAP samples (n = 80 samples, n = 22 950 tests) covered a wide range of mean ALT values (21-268 U/L). The average difference in mean ALT value per sample between the highest-reading and lowest-reading manufacturers was 15.4 U/L (SD = 1.8) for the 10 samples with mean ALT less than 50 U/L, and it was 10.4 U/L (SD = 3.6) overall (n = 80). In linear mixed effects modeling, we found statistically significant differences in ALT values between the different manufacturers in each year., Conclusions.—: We found statistically and clinically meaningful differences between analyzers across the ALT spectrum in each year, including at ALT levels lower than 50 U/L and lower than 35 U/L. Universal ALT thresholds should be avoided as a trigger for clinical action until differences between analyzers can be resolved.

Background & Aims: Military veterans have been reported to have higher odds of hepatitis B virus (HBV) exposure after adjustment for demographic factors, family income, and birthplace. It is not clear whether military-related exposures are associated with risk of HBV exposure in veterans., Methods: A random sample of veterans receiving care from 1998 through 2000 in the national Veterans' Health Administration system completed a risk factor survey and underwent phlebotomy analysis (N = 1146). Stored serum samples were reanalyzed to determine prevalence of HBV exposure (core antibody positive), infection (surface antigen or DNA positive), and immunity (surface antibody positive, surface antigen negative, and core antibody negative). Associations between military-related risk factors and HBV exposure were assessed using logistic regression., Results: The prevalence values for infection, exposure, and immunity were 0.7% (95% CI, 0.3-1.5), 13.6% (95% CI, 11.5-16.1), and 6.2% (95% CI, 4.7-8.2), respectively. Evidence of HBV exposure was highest among respondents with traditional risk factors (such as drug use or high-risk sexual practices). More than half the individuals with HBV exposure (53%) reported no history of traditional risk factors; of these, 59.5% reported a history of combat exposure. After adjustment for demographic and traditional risk factors, service in a combat zone (adjusted odds ratio, 1.56; 95% CI, 1.01-2.41) and being wounded in combat (adjusted odds ratio, 1.79; 95% CI, 1.04-3.08) were associated independently with exposure to HBV., Conclusions: In an analysis of US military veterans, we found the prevalence of exposure to HBV to be highest among veterans with traditional risk factors but also independently related to military combat or being wounded in combat. Studies are needed to determine whether veterans with combat exposure before the era of universal vaccination should be screened for HBV exposure., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatitis C virus (HCV) NS3 protein possesses protease and helicase activities and is considered an oncoprotein in virus-derived hepatocellular carcinoma. The NS3-associated oncogenesis has been studied but not fully understood. In this study, we have identified novel interactions of the NS3 protein with DNA repair factors, Werner syndrome protein (WRN) and Ku70, in both an HCV subgenomic replicon system and Huh7 cells expressing NS3. HCV NS3 protein inhibits WRN-mediated DNA repair and reduces the repair efficiency of nonhomologous end joining. It interferes with Ku70 recruitment to the double-strand break sites and alters the nuclear distribution of WRN-Ku repair complex. In addition, WRN is a substrate of the NS3/4A protease; the level of WRN protein is regulated by both the proteasome degradation pathway and HCV NS3/4A protease activity. The dual role of HCV NS3 and NS3/4A proteins in regulating the function and expression level of the WRN protein intensifies the effect of impairment on DNA repair. This may lead to an accumulation of DNA mutations and genome instability and, eventually, tumor development. IMPORTANCE HCV infection is a worldwide problem of public health and a major contributor to hepatocellular carcinoma. The single-stranded RNA virus with RNA-dependent RNA polymerase experiences a high error rate and develops strategies to escape the immune system and hepatocarcinogenesis. Studies have revealed the involvement of HCV proteins in the impairment of DNA repair. The present study aimed to further elucidate mechanisms by which the viral NS3 protein impairs the repair of DNA damage. Our results clearly indicate that HCV NS3/4A protease targets WRN for degradation, and, at the same time, diminishes the repair efficiency of nonhomologous end joining by interfering with the recruitment of Ku protein to the DNA double-strand break sites. The study describes a novel mechanism by which the NS3 protein influences DNA repair and provides new insight into the molecular mechanism of HCV pathogenesis., (Copyright © 2019 American Society for Microbiology.)

Leakage interference between memory cells is the primary obstacle for enlarging X-point memory arrays. Metal-filament threshold switches, possessing excellent selectivity and low leakage current, are developed in series with memory cells to reduce sneak path current and lower power consumption. However, these selectors typically have limited on-state currents (≤10 µA), which are insufficient for memory RESET operations. Here, a strategy is proposed to achieve sufficiently large RESET current (≈2.3 mA) by introducing highly ordered Ag nanodots to the threshold switch. Compared to the Ag thin film case, Ag nanodots as active electrode could avoid excessive Ag atoms migration into solid electrolyte during operations, which causes stable conductive filament growth. Furthermore, Ag nanodots with rapid thermal processing contribute to forming multiple weak Ag filaments at a lower voltage and then spontaneous rupture as the applied voltage reduced, according to quantized conductance and simulation analysis. Impressively, the Ag nanodots based threshold switch, which is bidirectional and truly electroforming-free, demonstrates extremely high selectivity >10 9 , ultralow leakage current <1 pA, very steep slope of 0.65 mV dec -1 , and good thermal stability up to 200 °C, and further represents significant suppression of leakage currents and excellent performances for SET/RESET operations in the one-selector-one-resistor configuration., Competing Interests: The authors declare no conflict of interest.

Nod-like receptor family, pyrin domain-containing 3 (NLRP3) regulates the secretion of proinflammatory cytokines interleukin 1 beta (IL-1β) and IL-18. We previously showed that influenza virus M2 or encephalomyocarditis virus (EMCV) 2B proteins stimulate IL-1β secretion following activation of the NLRP3 inflammasome. However, the mechanism by which severe acute respiratory syndrome coronavirus (SARS-CoV) activates the NLRP3 inflammasome remains unknown. Here, we provide direct evidence that SARS-CoV 3a protein activates the NLRP3 inflammasome in lipopolysaccharide-primed macrophages. SARS-CoV 3a was sufficient to cause the NLRP3 inflammasome activation. The ion channel activity of the 3a protein was essential for 3a-mediated IL-1β secretion. While cells uninfected or infected with a lentivirus expressing a 3a protein defective in ion channel activity expressed NLRP3 uniformly throughout the cytoplasm, NLRP3 was redistributed to the perinuclear space in cells infected with a lentivirus expressing the 3a protein. K + efflux and mitochondrial reactive oxygen species were important for SARS-CoV 3a-induced NLRP3 inflammasome activation. These results highlight the importance of viroporins, transmembrane pore-forming viral proteins, in virus-induced NLRP3 inflammasome activation.

Dynamic voltage and frequency scaling (DVFS) is a well-known method for saving energy consumption. Several DVFS studies have applied learning-based methods to implement the DVFS prediction model instead of complicated mathematical models. This paper proposes a lightweight learning-directed DVFS method that involves using counter propagation networks to sense and classify the task behavior and predict the best voltage/frequency setting for the system. An intelligent adjustment mechanism for performance is also provided to users under various performance requirements. The comparative experimental results of the proposed algorithms and other competitive techniques are evaluated on the NVIDIA JETSON Tegra K1 multicore platform and Intel PXA270 embedded platforms. The results demonstrate that the learning-directed DVFS method can accurately predict the suitable central processing unit (CPU) frequency, given the runtime statistical information of a running program, and achieve an energy savings rate up to 42%. Through this method, users can easily achieve effective energy consumption and performance by specifying the factors of performance loss.

We present a system level description of a cavity-enhanced millimeter-wave spectrometer that is the first in its class to combine source and detection electronics constructed from architectures commonly deployed in the mobile phone industry and traditional pulsed Fourier transform techniques to realize a compact device capable of sensitive and specific in situ gas detections. The instrument, which has an operational bandwidth of 90-102 GHz, employs several unique components, including a custom-designed pair of millimeter-wave transmitter and heterodyne receiver integrated circuit chips constructed with 65 nm complementary metal-oxide semiconductor (CMOS) techniques. These elements are directly mated to a hybrid coupling structure that enables free-space interaction of the electronics with a small gas volume while also acting as a cavity end mirror. Instrument performance for sensing of volatile compounds is highlighted with experimental trials taken in bulk gas flows and seeded molecular beam environments.

Background/purpose: LMBD1 protein, a type IV-B plasma membrane protein possessing nine putative trans-membrane domains, was previously demonstrated at cellular level to play a critical part in the signaling cascade of insulin receptor through its involvement in regulating clathrin-mediated endocytosis. However, at physiological level, the significance of LMBD1 protein in cardiac development remains unclear., Methods: To understand the role of Lmbrd1 gene involved in the cardiac function, heterozygous knockout mice were used as an animal model system. The pathological outcomes were analyzed by micro-positron emission tomography, ECG acquisition, cardiac ultrasound, and immunohistochemistry., Results: By studying the heterozygous knockout of Lmbrd1 (Lmbrd1 +/- ), we discovered that lack of Lmbrd1 not only resulted in the increase of cardiac-glucose uptake, pathological consequences were also observed. Here, we have distinguished that Lmbrd1 +/- is sufficient in causing cardiac diseases through a pathway independent of the recessive vitamin B 12 cblF cobalamin transport defect. Lmbrd1 +/- mice exhibited an increase in myocardial glucose uptake and insulin receptor signaling that is insensitive to the administration of additional insulin. Pathological symptoms such as cardiac hypertrophy, ventricular tissue fibrosis, along with the increase of heart rate and cardiac muscle contractility were observed. As Lmbrd1 +/- mice aged, the decrease in ejection fraction and fraction shortening showed signs of ventricular function deterioration., Conclusion: The results suggested that Lmbrd1 gene not only plays a significant role in mediating the energy homeostasis in cardiac tissue, it may also be a key factor in the regulation of cardiac function in mice., (Copyright © 2017. Published by Elsevier B.V.)

Background: Middle East respiratory syndrome coronavirus (MERS-CoV) consists of a positive-sense, single-stranded RNA genome and four structural proteins: the spike, envelope, membrane, and nucleocapsid protein. The assembly of the viral genome into virus particles involves viral structural proteins and is believed to be mediated through recognition of specific sequences and RNA structures of the viral genome., Methods and Results: A culture system for the production of MERS coronavirus-like particles (MERS VLPs) was determined and established by electron microscopy and the detection of coexpressed viral structural proteins. Using the VLP system, a 258-nucleotide RNA fragment, which spans nucleotides 19,712 to 19,969 of the MERS-CoV genome (designated PS258(19712-19969) ME ), was identified to function as a packaging signal. Assembly of the RNA packaging signal into MERS VLPs is dependent on the viral nucleocapsid protein. In addition, a 45-nucleotide stable stem-loop substructure of the PS258(19712-19969) ME interacted with both the N-terminal domain and the C-terminal domain of the viral nucleocapsid protein. Furthermore, a functional SARS-CoV RNA packaging signal failed to assemble into the MERS VLPs, which indicated virus-specific assembly of the RNA genome., Conclusions: A MERS-oV RNA packaging signal was identified by the detection of GFP expression following an incubation of MERS VLPs carrying the heterologous mRNA GFP-PS258(19712-19969) ME with virus permissive Huh7 cells. The MERS VLP system could help us in understanding virus infection and morphogenesis.

Cirrhosis and portal hypertension can lead to the formation of a spontaneous splenorenal shunt (SSRS) that may divert portal blood flow to the systemic circulation and reduce hepatic perfusion. Our aims were to evaluate SSRSs as an independent prognostic marker for mortality in patients with decompensated cirrhosis and the influence of SSRSs on liver transplantation (LT) outcomes. We retrospectively analyzed adult patients with decompensated cirrhosis undergoing LT evaluation from January 2001 to February 2016 at a large U.S. center. All patients underwent liver cross-sectional imaging within 6 months of evaluation, and images were reviewed by two radiologists. Clinical variables were obtained by electronic health record review. The cohort was followed until death or receipt of LT, and the subset receiving LT was followed for death after LT or graft failure. Survival data were analyzed using multivariable competing risk and Cox proportional-hazards regression models. An SSRS was identified in 173 (23%) of 741 included patients. Patients with an SSRS more often had portal vein thrombosis and less often had ascites ( P < 0.01). An SSRS was independently associated with a nonsignificant trend for reduced mortality (adjusted subhazard ratio, 0.81; Gray's test P = 0.08) but had no association with receipt of LT (adjusted subhazard ratio, 1.02; Gray's test P = 0.99). Post-LT outcomes did not differ according to SSRS for either death (hazard ratio, 0.85; log-rank P = 0.71) or graft failure (hazard ratio, 0.71; log-rank P = 0.43). Conclusion : Presence of an SSRS does not predict mortality in patients with decompensated cirrhosis or in LT recipients. ( Hepatology Communications 2018;2:437-444).