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Background: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC)., Methods: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test., Results: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20)., Conclusion: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: We sought to develop Artificial Intelligence (AI) based models to predict non-transplantable recurrence (NTR) of hepatocellular carcinoma (HCC) following hepatic resection (HR)., Methods: HCC patients who underwent HR between 2000-2020 were identified from a multi-institutional database. NTR was defined as recurrence beyond Milan Criteria. Different machine learning (ML) and deep learning (DL) techniques were used to develop and validate two prediction models for NTR, one using only preoperative factors and a second using both preoperative and postoperative factors., Results: Overall, 1763 HCC patients were included. Among 877 patients with recurrence, 364 (41.5%) patients developed NTR. An ensemble AI model demonstrated the highest area under ROC curves (AUC) of 0.751 (95% CI: 0.719-0.782) and 0.717 (95% CI:0.653-0.782) in the training and testing cohorts, respectively which improved to 0.858 (95% CI: 0.835-0.884) and 0.764 (95% CI: 0.704-0.826), respectively after incorporation of postoperative pathologic factors. Radiologic tumor burden score and pathological microvascular invasion were the most important preoperative and postoperative factors, respectively to predict NTR. Patients predicted to develop NTR had overall 1- and 5-year survival of 75.6% and 28.2%, versus 93.4% and 55.9%, respectively, among patients predicted to not develop NTR (p < 0.0001)., Conclusion: The AI preoperative model may help inform decision of HR versus LT for HCC, while the combined AI model can frame individualized postoperative care (https://altaf-pawlik-hcc-ntr-calculator.streamlit.app/)., Competing Interests: Conflicts of 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 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Antimicrobial treatment disrupts human microbiota. The effects of lascufloxacin (LSFX), a new fluoroquinolone, on human microbiota remains unknown. Therefore, in this study, we aimed to evaluate the effects of LSFX administration on the gut and salivary microbiota of healthy participants and those with pneumonia., Methods: LSFX (75 mg, once a day, orally) was administered to healthy adults (healthy group) and adult patients with pneumonia (pneumonia group), and fecal and saliva samples were collected at five time points (Days 0, 3, 7, 14, and 28). Using the collected samples, α- and β-diversity indices, as well as bacterial composition of the gut microbiota and salivary microbiota were analyzed using next-generation sequencing., Results: In the healthy group, α-diversity indices of the gut and salivary microbiota were reduced and the lowest values on Day 3. For the gut microbiota, the Chao1 index (richness) recovered on Day 28, whereas the Shannon index (evenness) did not. In the salivary microbiota, the Chao1 and Shannon indices did not recover within the 28 day period. The β-diversity indices changed after LSFX administration and subsequently recovered on Day 28. After LSFX administration, the abundance of the Lachnospiraceae family decreased in the gut microbiota, and the abundance of Granulicatella, Streptococcus, Prevotella, Absconditabacteriales(SR1), and Saccharimonadales decreased in the salivary microbiota. In the pneumonia group, the α-diversity indices were lowest on Day 14 after LSFX administration., Conclusions: We elucidated that LSFX administration differentially affected the gut and salivary microbiota; however, the richness and beta diversity recovered within 28 days., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: We sought to assess the impact of various perioperative factors on the risk of severe complications and post-surgical mortality using a novel maching learning technique., Methods: Data on patients undergoing resection for HCC were obtained from an international, multi-institutional database between 2000 and 2020. Gradient boosted trees were utilized to construct predictive models., Results: Among 962 patients who underwent HCC resection, the incidence of severe postoperative complications was 12.7% (n = 122); in-hospital mortality was 2.9% (n = 28). Models that exclusively used preoperative data achieved AUC values of 0.89 (95%CI 0.85 to 0.92) and 0.90 (95%CI 0.84 to 0.96) to predict severe complications and mortality, respectively. Models that combined preoperative and postoperative data achieved AUC values of 0.93 (95%CI 0.91 to 0.96) and 0.92 (95%CI 0.86 to 0.97) for severe morbidity and mortality, respectively. The SHAP algorithm demonstrated that the factor most strongly predictive of severe morbidity and mortality was postoperative day 1 and 3 albumin-bilirubin (ALBI) scores., Conclusion: Incorporation of perioperative data including ALBI scores using ML techniques can help risk-stratify patients undergoing resection of HCC., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Accurate prediction of patients at risk for early recurrence (ER) among patients with colorectal liver metastases (CRLM) following preoperative chemotherapy and hepatectomy remains limited., Methods: Patients with CRLM who received chemotherapy prior to undergoing curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Multivariable Cox regression analysis was used to assess clinicopathological factors associated with ER, and an online calculator was developed and validated., Results: Among 768 patients undergoing preoperative chemotherapy and curative-intent resection, 128 (16.7 %) patients had ER. Multivariable Cox analysis demonstrated that Eastern Cooperative Oncology Group Performance status ≥1 (HR 2.09, 95%CI 1.46-2.98), rectal cancer (HR 1.95, 95%CI 1.35-2.83), lymph node metastases (HR 2.39, 95%CI 1.60-3.56), mutated Kirsten rat sarcoma oncogene status (HR 1.95, 95%CI 1.25-3.02), increase in tumor burden score during chemotherapy (HR 1.51, 95%CI 1.03-2.24), and bilateral metastases (HR 1.94, 95%CI 1.35-2.79) were independent predictors of ER in the preoperative setting. In the postoperative model, in addition to the aforementioned factors, tumor regression grade was associated with higher hazards of ER (HR 1.91, 95%CI 1.32-2.75), while receipt of adjuvant chemotherapy was associated with lower likelihood of ER (HR 0.44, 95%CI 0.30-0.63). The discriminative accuracy of the preoperative (training: c-index: 0.77, 95%CI 0.72-0.81; internal validation: c-index: 0.79, 95%CI 0.75-0.82) and postoperative (training: c-index: 0.79, 95%CI 0.75-0.83; internal validation: c-index: 0.81, 95%CI 0.77-0.84) models was favorable (https://junkawashima.shinyapps.io/CRLMfollwingchemotherapy/)., Conclusions: Patient-, tumor- and treatment-related characteristics in the preoperative and postoperative setting were utilized to develop an online, easy-to-use risk calculator for ER following resection of CRLM., 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. No funding was received for this study., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background and Aims: High density lipoprotein (HDL) exerts an anti-atherosclerotic effect via reverse cholesterol transport (RCT). Several phases of RCT are transcriptionally controlled by Liver X receptors (Lxrs). Although macrophage Lxrs reportedly promote RCT, it is still uncertain whether hepatic Lxrs affect RCT in vivo., Methods: To inhibit Lxr-dependent pathways in mouse livers, we performed hepatic overexpression of sulfotransferase family cytosolic 2B member 1 (Sult2b1) using adenoviral vector (Ad-Sult2b1). Ad-Sult2b1 or the control virus was intravenously injected into wild type mice and Lxrα/β double knockout mice, under a normal or high-cholesterol diet. A macrophage RCT assay and an HDL kinetic study were performed., Results: Hepatic Sult2b1 overexpression resulted in reduced expression of Lxr-target genes - ATP-binding cassette transporter G5/G8, cholesterol 7α hydroxylase and Lxrα itself - respectively reducing or increasing cholesterol levels in HDL and apolipoprotein B-containing lipoproteins (apoB-L). A macrophage RCT assay revealed that Sult2b1 overexpression inhibited fecal excretion of macrophage-derived 3 H-cholesterol only under a high-cholesterol diet. In an HDL kinetic study, Ad-Sult2b1 promoted catabolism/hepatic uptake of HDL-derived cholesterol, thereby reducing fecal excretion. Finally, in Lxrα/β double knockout mice, hepatic Sult2b1 overexpression increased apoB-L levels, but there were no differences in HDL levels or RCT compared to the control, indicating that Sult2b1-mediated effects on HDL/RCT and apoB-L were distinct: the former was Lxr-dependent, but not the latter., Conclusions: Hepatic Lxr inhibition negatively regulates circulating HDL levels and RCT by reducing Lxr-target gene expression., 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 Elsevier B.V. All rights reserved.)

Background: The efficacy of immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs), trans-arterial chemoembolization (TACE), and radiotherapy to treat hepatocellular carcinoma (HCC) has not been well-defined. We performed a meta-analysis to characterize tumor response and survival associated with multimodal treatment of HCC., Methods: PubMed, Embase, Medline, Scopus, and CINAHL databases were searched (1990-2022). Random-effect meta-analysis was conducted to compare efficacy of treatment modalities. Odds ratios (OR) and standardized mean difference (SMD) were reported., Results: Thirty studies (4170 patients) met inclusion criteria. Triple therapy regimen (ICI + TKI + TACE) had the highest overall disease control rate (DCR) (87%, 95% CI 83-91), while ICI + radiotherapy had the highest objective response rate (ORR) (72%, 95% CI 54%-89%). Triple therapy had a higher DCR than ICI + TACE (OR 4.49, 95% CI 2.09-9.63), ICI + TKI (OR 3.08, 95% CI 1.63-5.82), and TKI + TACE (OR 2.90, 95% CI 1.61-5.20). Triple therapy demonstrated improved overall survival versus ICI + TKI (SMD 0.72, 95% CI 0.37-1.07) and TKI + TACE (SMD 1.13, 95% CI 0.70-1.48) (both p < 0.05). Triple therapy had a greater incidence of adverse events (AEs) compared with ICI + TKI (OR 0.59, 95% CI 0.29-0.91; p = 0.02), but no difference in AEs versus ICI + TACE or TKI + TACE (both p > 0.05)., Conclusion: The combination of ICIs, TKIs and TACE demonstrated superior tumor response and survival and should be considered for select patients with advanced HCC., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The aMAP score is a proposed model to predict the development of hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis. The role of the aMAP score to predict long-term survival among patients following resection of HCC has not been determined., Methods: Patients undergoing resection for HCC between 2000 and 2020 were identified using a multi-institutional database. The impact of the aMAP score on long-term outcomes following HCC resection was assessed., Results: Among 1377 patients undergoing resection for HCC, a total of 972 (70.6 %) patients had a low aMAP score (≤63), whereas 405 (29.4 %) individuals had a high aMAP score (≥64). aMAP score was associated with 5-year OS in the entire cohort (low vs high aMAP score:66.5 % vs. 54.3 %, p < 0.001). aMAP score predicted 5-year OS following resection among patients with HBV-HCC (low vs. high aMAP:68.8 % vs. 55.6 %, p = 0.01) and NASH/other-HCC (64.7 % vs. 53.7, p = 0.04). aMAP score could sub-stratify 5-year OS among patients undergoing HCC resection within (low vs. high aMAP:81.5 % vs. 67.4 %, p < 0.001) and beyond (55.9 % vs. 38.8 %, p < 0.001) Milan criteria., Discussion: The aMAP score predicted postoperative outcomes following resection of HCC within and beyond Milan criteria. Apart from a surveillance tool, the aMAP score can also be used as a prognostic tool among patients undergoing resection of HCC., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: A preoperative predictive score for hepatocellular carcinoma (HCC) can help stratify patients who undergo resection relative to long-term outcomes and tailor treatment strategies., Methods: Patients who underwent curative-intent hepatectomy for HCC between 2000 and 2020 were identified from an international multi-institutional database. A risk score (mFIBA) was developed using an Eastern cohort and then validated using a Western cohort., Results: Among 957 patients, 443 and 514 patients were included from the Eastern and Western cohorts, respectively. On multivariable analysis, alpha-feto protein (HR1.97, 95%CI 1.42-2.72), neutrophil-to-lymphocyte ratio (HR1.74, 95%CI 1.28-2.38), albumin-bilirubin grade (HR1.66, 95%CI 1.21-2.28), and imaging tumor burden score (HR1.25, 95%CI 1.12-1.40) were associated with OS. The c-index in the Eastern test and Western validation cohorts were 0.69 and 0.67, respectively. Notably, mFIBA score outperformed previous HCC staging systems. 5-year OS incrementally decreased with an increase in mFIBA. On multivariable Cox regression analysis, the mFIBA score was associated with worse OS (HR1.18, 95%CI 1.13-1.23) and higher risk of recurrence (HR1.16, 95%CI 1.11-1.20). An easy-to-use calculator of the mFIBA score was made available online (https://yutaka-endo.shinyapps.io/mFIBA&#95;score/)., Discussion: The online mFIBA calculator may help surgeons with clinical decision-making to individualize perioperative treatment strategies for patients undergoing resection of HCC., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Despite being one of the most reliable procedures in orthopedic surgery, complications can occur after total hip arthroplasty, and radiology plays an essential role in their evaluation. This article will review the various types of hip arthroplasty and their normal appearances on imaging, followed by mechanisms and imaging appearances of component wear and fracture., Competing Interests: Declaration of competing interest None to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The therapeutic role of lymphadenectomy (LND) for intrahepatic cholangiocarcinoma (ICC) patients remains ill-defined. We sought to analyze the therapeutic value of LND relative to tumor location and preoperative lymph node metastasis (LNM) risk., Methods: Patients who underwent curative-intent hepatic resection of ICC between 1990 and 2020 were included from a multi-institutional database. Therapeutic LND (tLND) was defined as LND that harvested ≥3 lymph nodes., Results: Among 662 patients, 178 (26.9%) individuals received tLND. Patients were categorized into central type ICC (n = 156, 23.6%) and peripheral type ICC (n = 506, 76.4%). Central type harbored multiple adverse clinicopathologic factors and worse overall survival (OS) compared with peripheral type (5-year OS, central: 27.0% vs. peripheral: 47.2%, p < 0.001). After consideration of preoperative LNM risk, patients with central type and high-risk LNM who underwent tLND survived longer than individuals who did not (5-year OS, tLND: 27.9% vs. non-tLND: 9.0%, p = 0.001), whereas tLND was not associated with better survival among patients with peripheral type ICC or low-risk LNM. The therapeutic index of hepatoduodenal ligament (HDL) and other regions was higher in central type than in peripheral type, which was more pronounced among high-risk LNM patients., Conclusions: Central type ICC with high-risk LNM should undergo LND involving regions beyond the HDL., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Animals' sensory systems adjust their responsiveness to environmental stimuli that vary greatly in their intensity. Here we report the neural mechanism of experience-dependent sensory adjustment, especially gain control, in the ASH nociceptive neurons in Caenorhabditis elegans. Using calcium imaging under gradual changes in stimulus intensity, we find that the ASH neurons of naive animals respond to concentration increases in a repulsive odor 2-nonanone regardless of the magnitude of the concentration increase. However, after preexposure to the odor, the ASH neurons exhibit significantly weak responses to a small gradual increase in odor concentration while their responses to a large gradual increase remain strong. Thus, preexposure changes the slope of stimulus-response relationships (i.e., gain control). Behavioral analysis suggests that this gain control contributes to the preexposure-dependent enhancement of odor avoidance behavior. Mathematical analysis reveals that the ASH response consists of fast and slow components, and that the fast component is specifically suppressed by preexposure for the gain control. In addition, genetic analysis suggests that G protein signaling may be required for the regulation of fast component. We propose how prior experience dynamically and specifically modulates stimulus-response relationships in sensory neurons, eventually leading to adaptive modulation of behavior., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Lentivirus is an efficient gene transfer system that is widely used in basic science. We aimed to improve viral titer by applying an ultra-expression vectors to lentiviral packaging. Application of the ultra-expression vectors increased biological titer 4 times for standard preparation. We also evaluated the efficacy of the ultra-expression vectors to relatively longer insert fragments, such as CSII-CMV-CNROE containing 5 genes in multiple cloning sites. Packaging of the ultra-expression vectors showed 3.5 times higher biological titer compared with the original method. Our improved packaging system could be applied to lentivirus to produce higher titers., Competing Interests: Declaration of competing interest All authors do not have any conflict of interest and competing interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: This study aimed to develop a holistic risk score incorporating preoperative tumor, liver, nutritional, and inflammatory markers to predict overall survival (OS) after hepatectomy for hepatocellular carcinoma (HCC)., Methods: Patients who underwent curative-intent surgery for HCC between 2000 and 2020 were identified using an international multi-institutional database. Preoperative predictors associated with OS were selected and a prognostic risk score model (PreopScore) was developed and validated using cross-validation., Results: A total of 1676 patients were included. On multivariable analysis, preoperative parameters associated with OS included α-feto protein (hazard ratio [HR]1.17, 95%CI 1.03-1.34), neutrophil-to-lymphocyte ratio (HR2.62, 95%CI 1.30-5.30), albumin (HR0.49, 95%CI 0.34-0.70), gamma-glutamyl transpeptidase (HR1.00, 95%CI 1.00-1.00), as well as vascular involvement (HR3.52, 95%CI 2.10-5.89) and tumor burden score (medium, HR3.49, 95%CI 1.62-7.58; high, HR3.21, 95%CI 1.40-7.35) on preoperative imaging. A weighted PreopScore was devised and made available online (https://yutaka-endo.shinyapps.io/PrepoScore&#95;Shiny/). Patients with a PreopScore 0-2, 2-3.5, and >3.5 had incrementally worse 5-year OS of 85.8%, 70.7%, and 52.4%, respectively (p < 0.001). The c-index of the test and validation cohort were 0.75 and 0.71, respectively. The PreopScore outperformed individual parameters and previous HCC staging systems., Discussion: The PreopScore can be used as a better guide to preoperatively identify patients and individualize pre-/post-operative strategies., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Defining patterns and risk of recurrence can help inform surveillance strategies and patient counselling. We sought to characterize peak hazard rates (pHR) and peak time of recurrence among patients who underwent resection of hepatocellular carcinoma (HCC)., Methods: 1434 patients who underwent curative-intent resection of HCC were identified from a multi-institutional database. Hazard, patterns, and peak rates of recurrence were characterized., Results: The overall hazard of recurrence peaked at 2.4 months (pHR: 0.0384), yet varied markedly. The incidence of recurrence increased with Barcelona Clinic Liver Cancer (BCLC) stage 0 (29%), A (54%), and B (64%). While the hazard function curve for BCLC 0 patients was relatively flat (pHR: <0.0177), BCLC A patients recurred with a peak at 2.4 months (pHR: 0.0365). Patients with BCLC B had a bimodal recurrence with a peak rate at 4.2 months (pHR: 0.0565) and another at 22.8 months. The incidence of recurrence also varied according to AFP level (≤400 ng/mL: 52.6% vs. >400 ng/mL: 36.3%) and Tumor Burden Score (low: 73.7% vs. medium: 50.6% vs. high: 24.2%) (both p < 0.001)., Conclusion: Recurrence hazard rates for HCC varied substantially relative to both time and intensity/peak rates. TBS and AFP markedly impacted patterns of hazard risk of recurrence., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to develop a predictive model to identify individuals most likely to derive overall survival (OS) benefit from adjuvant chemotherapy (AC) after hepatic resection of intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent hepatic resection of ICC between 1990 and 2020 were identified from a multi-institutional database. Factors associated with worse OS were identified and incorporated into an online predictive model to identify patients most likely to benefit from AC., Results: Among 726 patients, 189 (26.0%) individuals received AC. Factors associated with OS on multivariable analysis included CA19-9 (Hazard Ratio [HR]1.17, 95%CI 1.04-1.31), tumor burden score (HR1.09, 95%CI 1.04-1.15), T-category (T2/3/4, HR1.73, 95%CI 1.73-2.64), nodal disease (N1, HR3.80, 95%CI 2.02-7.15), tumor grade (HR1.88, 95%CI 1.00-3.55), and morphological subtype (HR2.19, 95%CI 1.08-4.46). A weighted predictive score was devised and made available online (https://yutaka-endo.shinyapps.io/ICCrisk&#95;model&#95;for&#95;AC/). Receipt of AC was associated with a survival benefit among patients at high/medium-risk (high: no AC, 0% vs. AC, 20.6%; medium: no AC, 36.4% vs. 40.8%; both p < 0.05) but not low-risk (low: no AC, 65.1% vs. AC, 65.1%; p = 0.73) tumors., Conclusion: An online predictive model based on tumor characteristics may help identify which patients may benefit the most from AC following resection of ICC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

The cellular repressor of adenovirus early region 1A-stimulated gene 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and energy metabolism. It also binds to insulin-like growth factor 2 receptor (IGF2R), a protein implicated in muscle regeneration. However, whether CREG1 regulates the regeneration and metabolism of skeletal muscles via IGF2R remains unclear. This study investigates the role of CREG1 in skeletal muscle regeneration and glucose uptake in C2C12 myotubes and a cardiotoxin (CTX)-induced mouse skeletal muscle regeneration model. CTX-treated skeletal muscle showed significantly higher levels of IGF2R, CREG1, phospho-AMPKα Thr 172 , and GLUT4 proteins. Similarly, treatment of myotubes with CREG1 also stimulated AMPKα phosphorylation and GLUT4 expression. CREG1-induced AMPKα phosphorylation and 2DG uptake in myotubes were suppressed by IGF2R knockdown and Compound C, an AMPK inhibitor. These results suggest that CREG1 stimulates glucose uptake in skeletal muscles partially through AMPK activation. Hence, CREG1 plays an essential role in muscle regeneration by affecting glucose metabolism in skeletal muscles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/objectives: In the Philippines, treatment success rates for drug-resistant tuberculosis (DR-TB) remains low and little is known about the quality of DR-TB services. This study aimed to explore clinician's perspectives of DR-TB care services., Methods: We conducted semi-structured in-depth interviews from January-March 2018 with 11 providers selected purposively to explore the barriers associated with DR-TB care service delivery, best practices, and recommendations for enhancing patient care. Emerging themes were organized according to the socio-ecological framework., Results: Five major themes were identified: (1) nurses do not feel empowered; (2) particular patients are left behind and more vulnerable than others; (3) infection control practices, fear, and limited capacity in rural health centers; (4) financial insecurity due to program reimbursement mechanisms; and (5) local government support is limited and requires more involvement in support of DR-TB elimination activities. Best practices focused on tailored approaches that eliminated structural, economic, and motivational barriers for patients. Participants recommended financial support from local government units, nutritional assistance for patients, and refresher training for healthcare workers., Conclusion: The findings provide additional understanding regarding the barriers that limit successful DR-TB care delivery and provide critical information to improve clinical practice and develop public health interventions for frontline staff including nurses in the Philippines. These strategies could ultimately reduce disparities associated with access to care and treatment adherence, if implemented., Competing Interests: Conflicts of interest The authors have none to declare., (Copyright © 2022. Published by Elsevier B.V.)

COVID-19 control measures influenced education and training environments and profoundly impacted nursing students' career prospects and academic lives. This study intends to elucidate the impact of the COVID-19 pandemic on nursing students' academic experience and career choices. A qualitative descriptive study was conducted at a 4-year university in Japan, using semi-structured interviews with 14 nursing students. Sandelowski's qualitative descriptive analysis was conducted. We identified 11 categories that summarize COVID-19's influence on students' academic experience and career choices: "Forced change to a new learning system," "Difficult learning thoroughly with restricted face-to-face interactions," "Worries regarding teacher evaluations when face-to-face interactions are restricted," "Adapting to changes in the learning environment," "Finding new ways to learn due to the different learning environment," "Worries regarding career decision-making after losing opportunities to obtain career information," "Fully utilizing limited information resources in deciding where to work while being influenced by others," "Coping with a confusing new job hunting system," "Worries about becoming a nurse without enough practical experience," "Conscious of working as a nurse while facing infections," and "Support from those around me is helpful in an unfamiliar environment." The categories comprised four elements: academic impact, employment/career impact, future impact on working as a nurse, and environmental support. Building an online education/training program, ensuring the availability of regular psychological support, providing abundant information on employment, installing an information desk, and providing regular feedback were considered imperative for supporting nursing students., Competing Interests: None., (© 2022 The Authors.)

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease caused by the SFTS virus (SFTSV). SFTSV causes severe symptoms both in humans and cats. In this study, we report the clinical and pathological findings of 4 fatal cases of cats with high SFTS viremia levels. These cats showed an acute onset of fever, leukopenia, thrombocytopenia, and increased serum amyloid A and pro-inflammatory cytokine levels. A high viral copy number was detected in the blood, oral swabs, rectal swabs, conjunctiva swabs, and urine. Histopathologically, necrotizing lymphadenitis, splenitis with lymphoblastoid cell proliferation, and hemophagocytosis were observed in all 4 cats. Immunohistochemistry revealed the presence of SFTSV antigen on lymphoblastoid B cells. SFTSV-RNA was detected in systemic tissues, including the brain. The present findings provide useful information for understanding the features of fatal SFTS in cats. To elucidate the mechanisms of severe progress of SFTS cats, as well as its role as a source of human infection, further research is needed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Activated monocytes/macrophages promote glomerular injury, including crescent formation, in anti-glomerular basement membrane (GBM) glomerulonephritis. Disulfiram, an alcohol-aversion drug, inhibits monocyte/macrophage migration by inhibiting FROUNT, a cytosolic protein that enhances chemokine receptor signaling. Our study found that disulfiram at a human equivalent dose successfully blocked albuminuria and crescent formation with podocyte loss, and later stage kidney fibrotic lesions, in a rat model of anti-GBM glomerulonephritis. A disulfiram derivative, DSF-41, with more potent FROUNT inhibition activity, inhibited glomerulonephritis at a lower dose than disulfiram. Disulfiram markedly reduced the number of monocytes or macrophages at the early stage of glomerulonephritis and that of CD3 + and CD8 + lymphocytes at the established stage. Impaired pseudopodia formation was observed in the glomerular monocytes/macrophages of the disulfiram group; consistent with the in vitro observation that disulfiram blocked chemokine-dependent pseudopodia formation and chemotaxis of bone marrow-derived monocytes/macrophages. Furthermore, disulfiram suppressed macrophage activation as revealed by reduced expression of inflammatory cytokines and chemokines (TNF-α, CCL2, and CXCL9) and reduced CD86 and MHC class II expressions in monocytes/macrophages during glomerulonephritis. The dramatic reduction in monocyte/macrophage number might have resulted from disulfiram suppression of both the chemotactic response of monocytes/macrophages and their subsequent activation to produce cytokines and chemokines, which further recruit monocytes. Additionally, FROUNT was expressed in CD68 + monocytes/macrophages infiltrating the crescentic glomeruli in human anti-GBM glomerulonephritis. Thus, disulfiram can be a highly effective and safe drug for the treatment of glomerulonephritis by blocking the chemotactic responses of monocytes/macrophages and their activation status in the glomerulus., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Despite the remarkable success of total hip arthroplasty as treatment of arthritis of the hip, complications can still occur, and imaging plays a crucial role for both diagnosis and guiding management. Component dislocation in total hip arthroplasty is usually diagnosed on radiographs, but cross-sectional imaging is necessary to quantitatively assess component orientation which may have predisposed to the dislocation. The definitive sign of component loosening on radiography is progressive motion of the component, but CT will provide more osseous detail and recent studies have shown the role of MRI in assessing component loosening as well. Infection is a devastating complication for which early diagnosis is crucial. Radiographs are not sensitive for infection, but there are certain MRI features that can suggest infection, and ultrasound and fluoroscopy are useful for guiding arthrocenteses to diagnose infection. Tendon and neurovascular injuries can be a source of long-term disability after total hip arthroplasty, and radiological studies, particularly advanced cross-sectional imaging such as MRI and ultrasound, often play an important role in their diagnoses., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Technique for preserving limited number of human spermatozoa is important for successful treatment of patients with azoospermia and cryptozoospermia. This study determined whether the non-biological devices (Cryotop and Cell Sleeper) efficiently vitrify small numbers of human spermatozoa. From December 2011 to December 2018, 10 males with very low sperm numbers managed with a single sperm vitrification method. Post-warmed sperm recovery was similar with both devices. Post-warmed sperm motility and fertilization after intracytoplasmic sperm injection were significantly higher in Cryotop group than in Cell Sleeper group (40.0% vs. 22.0%, P < 0.01 and 50.7% vs. 21.7%, P < 0.01, respectively). The pregnancy rate was 15.4% and 2 healthy babies were born in the Cryotop, while 14.3% and 1 baby in the Cell Sleeper, which did not differ between the groups. Both devices have clinical advantages in terms of easy use and safety, and would be performed more efficiently by using devices with different properties., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The rotational spectrum (4-40 GHz and 50-330 GHz) has been measured and analyzed for trifluoroacetaldehyde, also known as fluoral (CF 3 CHO), which is one of the degradation products of the fluorinated contaminants emitted into the atmosphere. The complexity of the spectroscopic analysis of this molecule arises from the strong coupling between the internal rotation motion of CF 3 group and the overall rotation of the molecule. The value obtained for its coupling constant (ρ = 0.91723481(49)) is comparable to the corresponding value of methanol (CH 3 OH, ρ = 0.81), which is known for its complex spectrum. A total of 12,322 transitions of the ground, the first and second excited torsional states (ΔE 1υt  = 62.0183(13)cm -1 ; ΔE 2υt  = 120.3315(13)cm -1 ) with J ≤ 50 were included in the analysis that was performed employing the rho-axis-method (RAM), and the RAM36 code. A fit within experimental error (root mean square deviation equals to 35 kHz) has been achieved for this dataset using 47 parameters of the RAM torsion-rotation Hamiltonian. In the course of the analysis, it became evident that for such high ρ value, as it is determined for fluoral, a larger than usual torsional basis set at the first diagonalization step of the two-step diagonalization procedure is required for achieving a fit within experimental error., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Obesity is a major risk factor for developing various respiratory diseases. Patients with anti-aminoacyl tRNA synthetase (ARS) antibodies often have interstitial lung disease (ILD). The present study was conducted to evaluate the association between obesity and outcomes of anti-ARS antibody-related ILD (ARS-ILD)., Methods: We retrospectively investigated 58 patients with ARS-ILD and compared the clinical characteristics, treatment, and prognoses between obese (body mass index [BMI] ≥25 kg/m 2 ) and nonobese (BMI <25 kg/m 2 ) patients. Chest fat was quantified via computed tomography (CT). Thoracic subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured at diagnosis and first relapse of ILD., Results: Sixteen patients were obese. Obese patients had lower percentages of predicted diffusing capacity of the lungs for carbon monoxide and higher high-resolution CT scores and SAT and VAT indexes than did nonobese patients. The ILD relapse rate was higher in obese patients (P < 0.01), especially among those with high SAT indexes (P < 0.01). The SAT and VAT indexes increased significantly from diagnosis until first relapse. Among clinical parameters at first relapse, SAT and VAT indexes were correlated with serum Krebs von den Lungen-6 levels (r = 0.720, P = 0.008) and total ground-glass attenuation scores (r = 0.620, P = 0.024), respectively., Conclusions: Obesity and high SAT indexes are risk factors for ILD relapse in patients positive for anti-ARS antibodies. Evaluating and quantifying patients' chest fat on CT is important for predicting ILD relapse., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The low sensitivity of NMR spectroscopy is of historical concern in the field, and various approaches have been developed to mitigate this limitation. On the shoulder of giants, today one can routinely implement, for example, the pulse/Fourier transform NMR with the cross polarization together with the ultra-low temperature MAS DNP under high-field conditions. We show in this work this current opportunity should further be augmented by combining them with the cryogenic signal amplification. Our presented MAS DNP probe operates with the closed-cycle helium MAS system, and cools the internal preamplifier-duplexer module with the "return" helium gas on its way back to the compressor in the loop. The signal-to-noise (S/N) gain relative to the room-temperature measurements of a factor of 4.6 and 2.4 was found for the measurement using the cold- and room-temperature preamplifier, respectively, at the sample temperature of T = 20 K at B 0  = 16.4 T. The ratio of these factors reveals ∼ two-fold sensitivity improvement that results purely from the introduction of the cold signal amplification, i.e., noise reduction. Together with the increase of the thermal Boltzmann polarization at low temperatures, the combined S/N gain of max. ∼70-fold is possible without DNP. The DNP enhancement factor of ∼40 as we found in this work for a microcrystalline MLF sample may be multiplied to this gain. We also demonstrated the sensitivity improvement with a 13 C-detected 2D NCaCx spectrum, illustrating the generality of the S/N gain from combining DNP with the cold signal amplification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Combination therapy with dexamethasone, remdesivir, and baricitinib has become a promising treatment for moderate or severe COVID-19; however, we have observed transient leukocytopenia in COVID-19 patients who received combination therapy., Methods: Twelve consecutive COVID-19 patients treated with combination therapy were included in this retrospective analysis. Blood cell counts collected at the following three time points were analyzed: before the start of therapy (period 1), within 24 h of starting therapy (period 2), and within 48 h of period 2 (period 3)., Results: The leukocyte count significantly decreased in period 2 compared to period 1 and then significantly increased in period 3 without withdrawal of baricitinib. The neutrophil count transiently decreased in period 2 and recovered in period 3., Conclusions: Clinicians should be aware of transient leukocytopenia in patients with COVID-19 during the early phase of combination therapy., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare in relation to this work., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The reaction system between the simplest Criegee intermediate, CH 2 OO, and the greenhouse gas CO 2 has been investigated by Fourier transform microwave spectroscopy. The CH 2 OO-CO 2 weakly bound complex was identified in the rotational spectrum, where inversion doublets due to the tunnelling motion between two equivalent configurations of the complex, with CO 2 located at one side or the other side of the CH 2 OO plane, were observed. Using a two-state torsion-rotation Hamiltonian, a complete set of rotational and centrifugal distortion constants for both tunneling states were derived. In addition, the torsional energy difference between both states could be accurately determined, being 23.9687 MHz. The non-observation of the cycloaddition reaction product is in agreement with our ab initio calculations and with previous results that concluded that the reactivity of CIs toward CO 2 is measured to be quite limited., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID) is involved in cartilage destruction via HA depolymerization in human knee osteoarthritis. However, the role of HYBID in the progression of osteoarthritis remain elusive. This study sought to examine whether genetic depletion of Hybid could suppress surgically induced osteoarthritis of mouse knee joints. In osteoarthritis induced by medial collateral ligament transection with meniscus removal, articular cartilage destruction and osteophyte formation at the medial femoral-tibial joint were significantly inhibited in Hybid-deficient (Hybid -/- ) mice compared with wild-type mice. Hybid was highly produced by synovial cells and articular chondrocytes in the osteoarthritis joints of wild-type mice. IL-1β, IL-6, and tumor necrosis factor-α were up-regulated in the osteoarthritis joint tissues of both wild-type and Hybid -/- mice. Vascular density at the synovial and periosteal junction was significantly reduced in Hybid -/- mice compared with wild-type mice. High-molecular-weight HA accumulated in osteoarthritis joint tissues of Hybid -/- mice. Injections of high-molecular-weight HA to knee joints attenuated the cartilage destruction and osteophyte formation in wild-type mouse osteoarthritis group. Inhibition of cartilage destruction and osteophyte formation in Hybid -/- mice was also observed in destabilization of the medial meniscus model. These data are the first to demonstrate that cartilage destruction and osteophyte formation are suppressed in Hybid -/- mice and suggest that Hybid-mediated HA depolymerization is implicated for the progression of mechanically-induced knee osteoarthritis., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

HER1-and HER2-targeted drugs are effective in cancer therapy, especially against lung, breast and colon malignancies; however, resistance of cancer cells to HER1-and HER2-targeted therapies is becoming a serious problem. The avidity/affinity constant (K A ) and growth inhibitory effect of anti-HER3 rat monoclonal antibodies (mAb, Ab1∼Ab6) in the presence of therapeutic mAb or low-molecular-weight inhibitors against HER family proteins were analyzed by flow cytometry-based Scatchard plots (Splot) and cell proliferation assay. The K A of Ab3 and Ab6, but not Ab1 or Ab4, split into dual (high and low) modes of K A , and Ab6 exhibited greater anti-proliferative effects against LS-174T colon cancer cells in the presence of Pertuzumab (anti-HER2 mAb). A high K A by Ab6 and Ab6-mediated increased growth inhibition were observed against NCI-H1838 lung or BT474 breast cancer cells, respectively, in the presence of Panitumumab (anti-HER1 mAb) or Perutuzumab. A high K A by Ab6 and Ab6-mediated increased anti-proliferative effects against NCI-H1838 or BT474 were also respectively observed in the presence of Erlotinib (HER1 inhibitor) or Lapatinib (HER1/HER2 inhibitor). In HER1-knockout (KO) NCI-H1838, the reactivity and K A of Ab4 increased compared with in parent NCI-H1838. In HER1-KO or HER3-KO SW1116 colon cancer cells, dual modes of K A with Pertuzumab were noted, and the combination Ab6 and Pertuzumab promoted growth inhibition of HER1-KO, but not of parent SW1116., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takashi Masuko reports financial support was provided by Healios KK., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Evocalcet is a recently approved calcimimetic agent for secondary hyperparathyroidism (SHPT). In this study, the efficacy and safety of once-daily oral evocalcet were evaluated in patients without prior cinacalcet use (nonusers) and previously treated patients (users)., Methods: This post hoc analysis of a previous phase III head-to-head comparison study included SHPT patients treated with evocalcet with or without prior cinacalcet use. Endpoints included trends in the median intact and whole parathyroid hormone (PTH), mean corrected calcium, phosphate, and bone metabolic markers, and whole-to-intact PTH ratios throughout the 30-week study period; proportions of patients achieving target intact PTH, corrected calcium, and phosphate at weeks 28 to 30; and adverse drug reactions (ADRs)., Results: This study included 127 nonusers and 190 users with significant differences in age; duration of dialysis; use of intravenous vitamin D receptor activators; levels of intact PTH, corrected calcium, tartrate-resistant acid phosphatase 5b, procollagen type 1 N-terminal-propeptide; and largest parathyroid gland volume ( P  < 0.05 for all characteristics) between 2 groups at baseline. Users required higher evocalcet dosages than nonusers. Similar efficacy results were found in the 2 groups except for a significantly higher proportion of nonusers achieving the intact PTH target (81.6% vs 67.1%, difference [95% confidence interval], -14.5% [-24.59, -3.34]), and a significant reduction in largest parathyroid gland volume from week 0 to week 30 (-120.6 [567.2] mm 3 , P  = 0.043). No difference was found in ADRs between the 2 groups., Conclusion: Treatment with evocalcet is effective and safe irrespective of prior cinacalcet treatment in SHPT patients., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: T 2 -weighted, two-point Dixon fast-spin-echo (FSE) is an effective technique for magnetic resonance neurography (MRN) that can provide quantitative assessment of muscle denervation. Low signal-to-noise ratio and inadequate fat suppression, however, can impede accurate interpretation., Purpose: To quantify effects of principal component analysis (PCA) denoising on tissue signal intensities and fat fraction (FF) and to determine qualitative image quality improvements from both denoising and water-weighting (WW) algorithms to improve nerve conspicuity and fat suppression., Study Type: Prospective., Subjects: Twenty-one subjects undergoing MR neurography evaluation (11/10 male/female, mean age = 46.3±13.7 years) with 60 image volumes. Twelve subjects (23 image volumes) were determined to have muscle denervation based on diffusely elevated T 2 signal intensity., Field Strength/sequence: 3 T, 2D, two-point Dixon FSE., Assessment: Qualitative assessment included overall image quality, nerve conspicuity, fat suppression, pulsation and ringing artifacts by 3 radiologists separately on a three-point scale (1 = poor, 2 = average, 3 = excellent). Quantitative measurements for FF and signal intensity relative to normal muscle were made for nerve, abnormal muscle and subcutaneous fat., Statistical Tests: Linear and ordinal regression models were used for quantitative and qualitative comparisons, respectively; 95% confidence intervals (CIs) and p-values for pairwise comparisons were adjusted using the Holm-Bonferroni method. Inter-rater agreement was assessed using Gwet's agreement coefficient (AC 2 )., Results: Simulations showed PCA-denoising reduced FF error from 2.0% to 1.0%, and from 7.6% to 3.1% at noise levels of 10% and 30%, respectively. In human subjects, PCA-denoising did not change signal levels and FF quantitatively. WW decreased fat signal significantly (-83.6%, p < 0.001). Nerve conspicuity was improved by WW (odds ratio, OR = 5.8, p < 0.001). Fat suppression was improved by both PCA (OR = 3.6, p < 0.001) and WW (OR = 2.2, p < 0.001). Overall image quality was improved by PCA + WW (OR = 1.7, p = 0.04)., Conclusions: WW and PCA-denoising improved nerve conspicuity and fat suppression in MR neurography. Denoising can potentially provide improved accuracy of FF maps for assessing fat-infiltrated muscle., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Hyaluronan (HA) is an essential component of extracellular matrix in the skin, but its functions in the epidermis remain elusive., Objective: We examined the interaction of increased HA production mediated by 1-ethyl-β-N-acetylglucosaminide (β-NAG2), a newly developed highly selective inducer of HA production which is intracellularly converted to UDP-N-acetylglucosamine, a substrate of HA, with epidermal proliferation and differentiation., Methods: The amount, molecular size and epidermal tissue distribution of HA and expression of CD44, a cell surface receptor for HA, were analyzed in β-NAG2-treated organ cultured human skin, reconstructed human skin equivalents or cultured human skin keratinocytes. The relationship between HA and epidermal proliferation or differentiation was examined., Results: β-NAG2 significantly increased HA production in the epidermis of skin explants or skin equivalents without affecting molecular size of HA (>2000 kDa) or CD44 mRNA expression. Histochemical experiments revealed that β-NAG2 enhances HA signals in the basal to granular layers of the epidermis of skin equivalents, accompanying increased epidermal stratification. Immunohistochemical experiments demonstrated that signals of Ki67, transglutaminase 1 and filaggrin are increased in β-NAG2-treated skin equivalents, and these observations were confirmed by the data showing that mRNA expression of PCNA, transglutaminase 1 (TGM1) and filaggrin (FLG) is significantly up-regulated by β-NAG2 in skin equivalents. Importantly, blockade of HA production by inhibiting conversion of β-NAG2 to UDP-NAG abolished β-NAG2-mediated up-regulation of PCNA, TGM1 and FLG mRNA expression in cultured keratinocytes., Conclusion: These results suggest that increased epidermal HA production plays a key role in epidermal morphogenesis and homeostasis by accelerating keratinocyte proliferation and differentiation., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare, (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: This study was focused on the gait parameters of the knee extensor and hip abductor muscle groups, which are believed to contribute to knee joint function improvement in early postoperative TKA. The associations between patient-reported outcome measures (PROMs) 6 months after total knee arthroplasty (TKA) and the early postoperative internal knee extension moment, knee extension negative joint power, and internal hip abduction moment while walking were investigated., Methods: Twenty-one patients who underwent primary TKA for knee osteoarthritis were included. Three weeks after TKA, gait at a comfortable speed was measured by three-dimensional motion analysis. The lower limb joint angle, internal joint moment, and joint power parameters on the operated side while standing were calculated. The PROMs 6 months after TKA were assessed using the Japanese Knee Osteoarthritis Measure (JKOM). The relationship between each gait biomechanical parameter and the JKOM was determined., Results: The maximum internal knee extension moment and maximum knee extension negative joint power during the early stance showed moderate negative correlations with the JKOM scores. The maximum internal hip abduction moment was not correlated with the JKOM scores. The maximum internal hip extension moment during the early stance and internal hip flexion moment during the late stance showed moderate negative correlations with the total JKOM scores., Conclusion: The early postoperative internal knee extension moment, maximum knee extension negative joint power, and internal hip extension and flexion moment are associated with patient PROMs 6 months after TKA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: There has been no study elucidating whether cognitive impairment (CI) can provide additive prognostic information besides that provided by preexisting prognostic factors in elderly patients with heart failure. This study examined whether CI can provide additive prognostic information in elderly patients with heart failure., Methods: This multicenter retrospective study included 352 patients with heart failure aged ≥75 years. We administered the Mini-Mental State Examination (MMSE) and Mini-Cog test to assess CI. The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score was used as a model to incorporate the preexisting prognostic factors. All-cause mortality was considered the prognostic outcome., Results: The median age was 85 years old, 47.7% were male. According to MMSE and Mini-Cog, 167 (47.4%) and 159 (45.2%) patients had CI, respectively. The agreement between MMSE and Mini-Cog was fairly low (Cohen's kappa coefficient 0.37). During the follow-up period of median 346 days, 53 patients (15.1%) died. In multivariate Cox regression analysis, CI defined by MMSE and Mini-cog were individually associated with worse prognosis in older heart failure patients even after adjustment for MAGGIC risk model and log B-type natriuretic peptide levels [CI defined by MMSE, HR: 2.05 (95%CI: 1.16-3.61); and CI defined by Mini-Cog, HR:2.57 (95%CI: 1.46-4.53)]. The area under the curve of receiver operator characteristics curve was numerically greater for Mini-Cog than for MMSE (0.59 vs. 0.52, p = 0.109). Moreover, significant net reclassification improvement was observed when CI defined by Mini-Cog, but not on CI defined by MMSE, was added to the MAGGIC score, and when Mini-Cog, instead of MMSE, was used as a CI assessment tool (0.41, p = 0.004)., Conclusions: Among elderly hospitalized patients with heart failure, CI should be considered as a critical factor for prognosis prediction. Mini-Cog is a potentially preferable tool to assess CI in terms of providing prognostically relevant information compared to MMSE., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

In vertebrates, gap junctions and hemichannels consisting of connexins are important cell surface structures for communication with neighboring cells and for the regulation of various cell functions. To date, various gap-junction-related proteins have been found, including innexins in invertebrates and pannexins in vertebrates. Significant contributions of gap junctions by innexins and (hemi-)channels by pannexins to numerous functions have been reported. Verification of the presence and functional significance of innexin hemichannels, however, remains a gap in our knowledge in innexin physiology. In this study, we revealed the localization of an innexin protein (innexin 2) on the cell surface in mosquito tissues and cultured cells. Furthermore, we demonstrated the presence of functional hemichannels, as well as gap junctions, in mosquito cells using dye transfer assays. The inward uptake of fluorescent dye was inhibited by anti-innexin 2 antibody. These results suggest that innexin hemichannels are formed to function in cultured mosquito cells, in at least a partially innexin 2-dependent manner. Although only a few studies on insect hemichannels have been published, innexin-based hemichannels, as well as innexin gap junctions, could also significantly contribute to insect intercellular signal transduction., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Brown adipose tissue (BAT) plays a critical role in lipid metabolism and may protect from hyperlipidemia; however, its beneficial effect appears to depend on the ambient temperature of the environment. In this study, we investigated the effects of uncoupling protein 1 (UCP1) deficiency on lipid metabolism, including the pathophysiology of hyperlipidemia, in apolipoprotein E knockout (APOE-KO) mice at a normal (23 °C) and thermoneutral (30 °C) temperature. Unexpectedly, UCP1 deficiency caused improvements in hyperlipidemia, atherosclerosis, and glucose metabolism, regardless of an increase in hepatic lipid deposition, in Ucp1/Apoe double-knockout (DKO) mice fed a high-fat diet at 23 °C, with BAT hyperplasia and robust browning of inguinal white adipose tissue (IWAT) observed. Proteomics and gene expression analyses revealed significant increases in many proteins involved in energy metabolism and strong upregulation of brown/beige adipocyte-related genes and fatty acid metabolism-related genes in browned IWAT, suggesting an induction of beige fat formation and stimulation of lipid metabolism in DKO mice at 23 °C. Conversely, mRNA levels of fatty acid oxidation-related genes decreased in the liver of DKO mice. The favorable phenotypic changes were lost at 30 °C, with BAT whitening and disappearance of IWAT browning, while fatty liver further deteriorated in DKO mice compared with that in APOE-KO mice. Finally, longevity analysis revealed a significant lifespan extension of DKO mice compared with that of APOE-KO mice at 23 °C. Irrespective of the fundamental role of UCP1 thermogenesis, our results highlight the importance of beige fat for the improvement of hyperlipidemia and longevity under the atherogenic status at normal room temperature., 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 © 2020 Elsevier B.V. All rights reserved.)

Purpose: Early intervention is effective for developing motor ability and preventing contractures and deformities in patients with cerebral palsy (CP). Gait training using the newly developed Hybrid Assistive Limb (HAL) shows promise as an intervention to prevent deterioration in walking ability and deformities in pediatric CP patients. The purpose of this pilot study was to examine the safety and immediate effects on walking ability after gait training using the HAL in pediatric CP patients., Methods: Nineteen patients (six females, 13 males; mean age 8.5 years; mean height 120.5 cm; mean weight 23.2 kg) were enrolled. The Gross Motor Functional Classification Scale level was I in two patients, II in two, III in eight, and IV in seven. The HAL was used for a single session of gait training. The primary outcome was safety of the HAL for use in pediatric CP patients. The secondary outcome was the immediate effect after gait training with HAL, evaluated by passive range of motion (ROM) and gait parameters, including gait speed (m/s), step length (cm), and cadence (step/min)., Results: All 19 patients were able to carry out the gait training without any severe adverse events. Significant improvements were observed for mean internal/external rotation and abduction angles of the hip joint, and ankle dorsiflexion angles (n = 19). Significant improvements were observed for mean gait speed and step length based on expansion of the hip flexion-extension range (n = 11)., Conclusion: Gait training using the HAL is safe and can produce immediate improvements in ROM and walking ability in pediatric patients with CP., (Copyright © 2019. Published by Elsevier B.V.)

We designed and synthesized a celecoxib derivative UTX-121 to enhance its anti-tumor activity. Similar to celecoxib, this compound could also inhibit matrix metalloproteinase (MMP)-9 activity. In addition, UTX-121 suppressed membrane-type 1 MMP (MT1-MMP)-mediated pro-MMP-2 activation by disturbing the cell surface expression of MT1-MMP. UTX-121 also impeded the glycosylation of cell surface proteins, resulting in the suppression of cell attachment to fibronectin. This inhibition by UTX-121 caused the reduction of fibronectin-stimulated focal adhesion kinase activation, Akt activation, and cell migration. Consequently, UTX-121 treatment significantly inhibited fibronectin-induced HT1080 cell invasion into the Matrigel. UTX-121 may be a potent lead compound that can be used to develop a novel anti-tumor drug., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report a 38-year-old woman who presented with mild proximal dominant muscle weakness and fatigability that fluctuated during menstruation and treatment with ephedrine-containing medication. The patient had been diagnosed with "congenital myopathy with tubular aggregates" by muscle biopsy at age 19. Her revised diagnosis was congenital myasthenic syndrome (CMS) caused by a mutation in GFPT1 (2p13.3 [MIM 610542], c.722&#95;723insG homozygote, CMS-GFPT1) based on a screening gene analysis. Muscle CT revealed diffuse atrophy of proximal and axial muscles focused on the vastus lateralis, hamstrings, medial gastrocnemius and soleus muscles. Oral administration of pyridostigmine bromide clearly ameliorated weakness and fatigability. This is the first reported case of CMS-GFPT1 in Japan. Since CMS symptoms are reactive to treatment, it is important for clinicians to make an accurate diagnosis at an early stage to improve patient QOL. Tubular aggregates in muscle biopsy and day-to-day fluctuations are important features of the disorder. Quantitative muscle strength measurement was effective for evaluating treatment efficacy., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)