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Backgrounds: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the standard of care for first-line therapy in metastatic non-small cell lung cancer (NSCLC) patients without actionable mutations. The safety ranking of different ICI and CT combination regimens has not been investigated. This study was aimed to provide a toxicity profile and safety ranking of different ICI and CT combination regimens., Methods: We performed comprehensive searches of phase 2 and 3 randomized clinical trials (RCTs) comparing different ICI regimens (alone or combination) or CT for the first-line treatment of advanced NSCLC. Outcomes of interest were the cumulative incidence of any treatment-related adverse events (TRAEs), grade 3-5 TRAEs (grade 3-5), any immune-related adverse events (irAEs), and grade 3-5 irAEs (grade 3-5). Odds ratios and 95% credible intervals were calculated as summary statistics to quantify the effect of different ICI combination regimens., Results: We included 21 RCTs from 2016 to 2021 with a total of 12,626 patients. The incidence of any TRAEs and grade 3-5 TRAEs ranked from high to low were ICI-CT (probability: 88.3% and 87.1%), ICI-ICI-CT (66.2% and 73.9%), CT alone (77.7% and 86.6%), ICI-ICI (98.9% and 99.2%), and ICI monotherapy (99.7% and 100%). Adding CT to ICI regimens resulted in a higher incidence of any grade or grade 3-5 TRAEs compared to ICI-ICI combinations or ICI monotherapy. However, ICI-ICI-CT combinations did not result in a higher incidence of TRAEs than ICI-CT combinations. For any irAEs and grade 3-5 irAEs, the ranking was ICI-ICI (probability: 97.6% and 99.8%), ICI monotherapy (97.2% and 99.8%), ICI-CT (99.5% and 99.9%), and CT alone (99.9% and 100%). Notably, the incidence of any grade and grade 3-5 irAEs was lower when adding CT to ICI monotherapy., Conclusion: Lack of head-to-head comparisons, these findings provide evidence for clinical decision-making when considering different ICI combination regimens for advanced NSCLC patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The investigation and research on the application status of Hepatic Venous Pressure Gradient (HVPG) is very important to understand the real situation and future development of this technology in China. Methods: This study comprehensively investigated the basic situation of HVPG technology in China, including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications and existing problems. Results: According to the survey, there were 70 hospitals in China carrying out HVPG technology in 2021, distributed in 28 provinces (autonomous regions and municipalities directly under the central Government). A total of 4 398 cases of HVPG were performed in all the surveyed hospitals in 2021, of which 2 291 cases (52.1%) were tested by HVPG alone. The average cost of HVPG detection was (5 617.2±2 079.4) yuan. 96.3% of the teams completed HVPG detection with balloon method, and most of the teams used thrombectomy balloon catheter (80.3%). Conclusion: Through this investigation, the status of domestic clinical application of HVPG has been clarified, and it has been confirmed that many domestic medical institutions have mastered this technology, but it still needs to continue to promote and popularize HVPG technology in the future.

Previous studies have reported that circular RNAs (circRNAs) play a key role in the pathogenesis and progression of various diseases. In the present study, we aimed to identify potential circRNAs associated with the progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (IRFA). A xenograft mouse IRFA model was initially established, and immunohistochemical staining (IHC) and polymerase chain reaction (PCR) were performed to confirm the expression of programmed cell death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor-1 (VEGFR-1). CircRNA expression alterations were screened by next-generation sequencing (RNA-seq). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to predict the function of genes coding differentially expressed circRNAs. The selected circRNAs were validated utilizing PCR and Sanger sequencing. The relationships between circRNAs, microRNAs, PD-L1, and VEGFR-1 were predicted by bioinformatics. Overall, a total of 612 circRNAs were differentially expressed in IRFA-treated subcutaneous tumorigenesis tissue. Among them, 435 circRNAs were significantly upregulated and 177 circRNAs were downregulated. GO and KEGG analyses were employed to predict the functions of these circRNAs. Thereafter, quantitative reverse transcription PCR (qRT-PCR) assays determined that these seven circRNAs were overexpressed in the IRFA group, which was consistent with the RNA-seq results. Based on the bioinformatic analysis, seven circRNAs confirmed by Sanger sequencing were predicted to likely regulate PD-L1 and VEGFR-1 expression levels by functioning as sponges for microRNAs (miRNAs) and forming a circRNA-miRNA-PD-L1/VEGFR-1 regulatory network. Finally, IHC and qRT-PCR of PD-L1 and VEGFR-1 confirmed the activation of this pathway. Taken together, we report that differentially expressed circRNAs might simultaneously regulate PD-L1 and VEGFR-1 in the IRFA tissues, which provides a novel view of circRNAs in HCC progression after the IRFA procedure.

During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute around the world. Here, we designed and produced a recombinant spike (S)-Trimer that is maintained in a prefusion state and exhibits a high ACE2 binding affinity. Rodents received different doses of S-Trimer (0.5, 5, or 20 μg) antigen formulated with aluminum hydroxide (Alum) or an emulsion-type adjuvant (SWE), or no adjuvant. After two vaccinations, the antibody response, T-cell responses, and number of follicular helper T-cells (Tfh) or germinal center (GC) B cells were assessed in mice; the protective efficacy was evaluated on a Syrian hamster infection model. The mouse studies demonstrated that adjuvating the S-Trimer with SWE induced a potent humoral immune response and Th1-biased cellular immune responses (in low dose) that were superior to those induced by Alum. In the Syrian hamster studies, when S-Trimer was adjuvanted with SWE, higher levels of neutralizing antibodies were induced against live SARS-CoV-2 from the original lineage and against the emergence of variants (Beta or Delta) with a slightly decreased potency. In addition, the SWE adjuvant demonstrated a dose-sparing effect; thus, a lower dose of S-Trimer as an antigen (0.5 μg) can induce comparable antisera and provide complete protection from viral infection. These data support the utility of SWE as an adjuvant to enhance the immunogenicity of the S-Trimer vaccine, which is feasible for further clinical testing.

Sickle cell disease (SCD) is an inherited disorder of hemoglobin (Hb); approximately 300,000 babies are born worldwide with SCD each year. In SCD, fibers of polymerized sickle Hb (HbS) form in red blood cells (RBCs), which cause RBCs to develop their characteristic "sickled" shape, resulting in hemolytic anemia and numerous vascular complications including vaso-occlusive crises. The development of novel antisickling compounds will provide new therapeutic options for patients with SCD. We developed a high-throughput "sickling assay" that is based on an automated high-content imaging system to quantify the effects of hypoxia on the shape and size of RBCs from HbSS SCD patients (SS RBCs). We used this assay to screen thousands of compounds for their ability to inhibit sickling. In the assay, voxelotor (an FDA-approved medication used to treat SCD) prevented sickling with a z '-factor > 0.4, suggesting that the assay is capable of identifying compounds that inhibit sickling. We screened the Broad Repurposing Library of 5393 compounds for their ability to prevent sickling in 4% oxygen/96% nitrogen. We identified two compounds, SNS-314 mesylate and voxelotor itself, that successfully prevented sickling. SNS-314 mesylate prevented sickling in the absence of oxygen, while voxelotor did not, suggesting that SNS-314 mesylate acts by a mechanism that is different from that of voxelotor. The sickling assay described in this study will permit the identification of additional, novel antisickling compounds, which will potentially expand the therapeutic options for SCD., Competing Interests: The authors declare the following competing financial interest(s): Massachusetts General Hospital has filed a patent related to SNS-314 mesylate., (© 2022 The Authors. Published by American Chemical Society.)

Importance: Baseline global cognitive function may affect cognitive and functional outcomes during combined physical and cognitive training; however, how it influences the effects of combined training remains uncertain., Objective: To determine the impact of baseline global cognitive function on cognitive and functional outcomes after combined physical and cognitive training among older adults with cognitive decline., Design: Observational., Setting: Local communities and senior centers., Participants: Older adults with mild cognitive decline (MCD; n = 51) and moderate to severe cognitive decline (MSCD; n = 40)., Intervention: Participants received 45 to 55 min of physical exercise training followed by 45 to 55 min of cognitive training in one session per week for 12 wk. Outcomes and Measures: Montreal Cognitive Assessment (MoCA), Lawton-Brody Instrumental Activities of Daily Living Scale (Lawton-Brody IADL), Word Recall Test (WRT), Stroop Color and Word Test (SCWT), Digital Symbol Substitution Test (DSST), and Trail Making Test (TMT) scores were assessed and compared between the MCD and MSCD groups., Results: Significant interaction effects were found for the WRT, SCWT, MoCA, and Lawton-Brody IADL. WRT and SCWT scores significantly improved in the MCD group, whereas MoCA and Lawton-Brody IADL scores significantly improved in the MSCD group. DSST scores increased among all participants, but TMT scores improved only in the MCD group., Conclusions and Relevance: Older adults' baseline global cognitive function affected cognitive and instrumental activities of daily living (IADL) outcomes regarding combined training. High-level cognitive function, including inhibition and shifting abilities and working memory capacity, improved among older adults with MCD, whereas general cognitive function and IADLs improved among older adults with MSCD. What This Article Adds: Findings revealed domain-specific changes with respect to baseline cognitive function, which may help to refine current combined training protocols and facilitate development of personalized combined training programs for older adults with cognitive impairments., (Copyright © 2022 by the American Occupational Therapy Association, Inc.)

DNA N6-methyladenine (6 mA) is a new type of DNA methylation identified in various eukaryotic cells. However, its alteration and genomic distribution features in hepatocellular carcinoma (HCC) remain elusive. In this study, we found that N6AMT1 overexpression increased HCC cell viability, suppressed apoptosis, and enhanced migration and invasion, whereas ALKBH1 overexpression induced the opposite effects. Further, 23,779 gain-of-6 mA regions and 11,240 loss-of-6 mA regions were differentially identified in HCC tissues. The differential gain and loss of 6 mA regions were considerably enriched in intergenic regions. Moreover, 7% of the differential 6 mA modifications were associated with tumors, with 60 associated with oncogenes and 57 with tumor suppressor genes (TSGs), and 17 were common to oncogenes and TSGs. The candidate genes affected by 6 mA were filtered by gene ontology (GO) and RNA-seq. Using quantitative polymerase chain reaction (qPCR), BCL2 and PARTICL were found to be correlated with DNA 6 mA in certain HCC processes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Premature atrial complexes (PACs) have been reported to increase the risk of adverse cardiovascular outcomes. Beta blockers at low dosages may help to reduce PAC symptoms, but it is unclear whether they can improve long-term outcomes., Methods: Patients enrolled from a Holter cohort in a medical referral center were stratified into high-burden (≥100 beats/24 h) and low-burden (<100 beats/24 h) sub-cohorts, and propensity score matching between treatment groups and non-treatment groups was conducted for each sub-cohort., Results: In the high-burden sub-cohort, after propensity score matching, the treatment group and non-treatment group respectively had 208 and 832 patients. The treatment group had significantly lower mortality rates than the non-treatment group [hazard ratio (HR) = 0.521, 95% confidence interval (CI) = 0.294-0.923, p = 0.025], but there was no difference in new stroke (HR = 0.830, 95% CI = 0.341-2.020, p = 0.681), and new atrial fibrillation (HR = 1.410, 95% CI = 0.867-2.292, p = 0.167) events. In the low-burden sub-cohort, after propensity score matching, there were 614 patients in the treatment group and 1,228 patients in the non-treatment group. Compared to the non-treatment group, up to 40% risk reduction in mortality was found in the treatment group (HR = 0.601, 95% CI = 0.396-0.913, p = 0.017), but no differences in new stroke (HR =0.969, 95% CI = 0.562-1.670, p = 0.910) or atrial fibrillation (HR = 1.074, 95% CI = 0.619-1.863, p = 0.800) were found., Conclusions: Beta blockers consistently decreased long-term mortality in high-burden and low-burden patients. Interestingly, this effect was not achieved through reduction of new-onset stroke or AF, and further research is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Lee, Huang, Chiu, Su and Liu.)

Change of water environment is strongly associated with mosquito breeding. Because of long-term effectiveness, low cost and high environmental compatibility, ecological pollution control systems have been widely used in water pollution control projects. However, the potential effects of mosquito breeding are likely to cause expansion of mosquito populations and an increase in the risk of transmission of vector-borne diseases, which may become an urgent problem to be solved during the water environment "post-remediation" period. This review summarizes the physical, chemical and biological factors affecting mosquito breeding caused by water environment changes and analyzes the effects of water pollution control approaches on mosquito breeding and the underlying mechanisms, so as to promote the interdisciplinary connections between water pollution control and vector control, and avoid secondary disasters caused by ecological environment restoration, such as mosquito infestation. This review may provide insights into the use of technology combinations and water pollution control approaches in vector control.

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is overexpressed and activated in many cancer types. FAK regulates diverse cellular processes, including growth factor signaling, cell cycle progression, cell survival, cell motility, angiogenesis, and the establishment of immunosuppressive tumor microenvironments through kinase-dependent and kinase-independent scaffolding functions in the cytoplasm and nucleus. Mounting evidence has indicated that targeting FAK, either alone or in combination with other agents, may represent a promising therapeutic strategy for various cancers. In this review, we summarize the mechanisms underlying FAK-mediated signaling networks during tumor development. We also summarize the recent progress of FAK-targeted small-molecule compounds for anticancer activity from preclinical and clinical evidence.

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Ion channels and pumps not only regulate membrane potential, ion homeostasis, and electric signaling in excitable cells but also contribute to cell proliferation, migration, apoptosis, and differentiation. Channel proteins and ion pumps can form macromolecular complexes with signaling molecules, including growth factors and cell adhesion molecules. Serotonin (5-hydroxytryptamine (5-HT)) promotes the proliferation of various cancer cell types mediated through the activation of the 5-HT receptor (HTR). Only HTR3 is a ligand-gated ion channel. However, the role of the HTR3 family of HTRs in lung cancer has not been adequately evaluated. We evaluated the relationship between the HTR3 family of HTRs and lung cancer patients' survival using Kaplan-Meier analyses and examined the expression levels of target proteins using immunohistochemistry. In this study, we found that HTR3C was amplified with high frequency in lung cancer patients, and HTR3C protein expression levels were significantly associated with lymph node metastasis and distant metastasis in lung cancer tissues. Survival analysis using the log-rank test demonstrated a decrease in disease-free survival (DFS) and overall survival (OS) rates among the high-level HTR3C expression group compared with the low-level HTR3C expression group. We also evaluated the risk factors associated with lung cancer. The univariate and multivariate analyses of DFS and OS showed that HTR3C expression was a significant predictor of patient outcomes. Taken together, these data demonstrated that HTR3C expression levels were associated with poor DFS and OS in lung cancer patients, indicating that HTR3C can serve as a useful predictive biomarker for lung cancer., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Jiun-Rung Chen et al.)

Background: We aim to investigate prognostic effects of carotid strain (CS) and strain rate (CSR) in hypertension., Methods: We prospectively recruited 120 patients being treated for hypertension (65.8 ± 11.8 years, 58% male) in this observational study. Peak circumferential CS and peak CSR after ejection were identified using two-dimensional speckle tracking ultrasound. Major cardiovascular events were any admission for stroke, acute coronary syndrome, and heart failure., Results: After a mean follow-up period of 63.6 ± 14.5 months, 14 (12%) patients had cardiovascular events. Age (75.3 ± 9.2 vs 64.6 ± 11.6 years; p = 0.001), systolic blood pressure (131.8 ± 15.5 vs 143.1 ± 16.6 mm Hg; p = 0.021), diastolic blood pressure (74.6 ±11.4 vs 82.1 ± 12.2 mm Hg; p = 0.039), use of diuretics (71 vs 92%; p = 0.014), carotid CS (2.17 ± 1.02 vs 3.28 ± 1.14 %; p = 0.001), and CSR (.28 ± .17 vs .51 ± .18 1/s; p < 0.001) were significantly different between the patients who did and did not reach the end-points. Multivariate Cox regression analysis controlling for age, systolic blood pressure, diastolic blood pressure, and use of diuretics showed that CS (HR .425, 95%CI .223-.811, p = 0.009) and CSR (HR .001, 95%CI .000-.072, p = 0.001) were independent predictors for cardiovascular events., Conclusion: In conclusions, decreased CS and CSR were associated with cardiovascular events in hypertension., (© 2021 Wiley Periodicals LLC.)

Objective: High-intensity focused ultrasound (HIFU) therapy is a noninvasive alternative to conventional abdominal surgery in obstetrics and gynecology. The aim of this study is to evaluate the reduction of pain intensity with bowel manipulation before ultrasound-guided HIFU treatment in women with posterior wall uterine fibroids and/or adenomyosis., Materials and Methods: This is a multicenter retrospective observational study. Data from all patients who underwent HIFU therapy at three HIFU clinics (Sichuan Maternal and Child Health Hospital, Xiangya Hospital of Central South University, and Kuo General Hospital) between January 2019 and December 2019 were analyzed. We compared pain intensity with and without bowel manipulation during the HIFU treatment and evaluated tolerability without intravenous sedation. The presence of discomfort or pain during the HIFU procedure was evaluated using the visual analog scale (VAS)., Results: A total of 86 women were included in this study. All women underwent HIFU therapy with the PRO-2008 system in the supine position for posterior wall uterine fibroids and/or adenomyosis. Thirty-seven women received pretreatment anal catheterization with a condom and 49 women were not subjected to bowel manipulation. All patients received pretreatment condom-catheter device were well tolerated during the procedure of bowel manipulation. During the HIFU procedure, the women who had received bowel manipulation experienced lower pain intensity, especially less sacrococcygeal pain (VAS score 1.56 ± 1.46 vs 2.89 ± 1.61), target region pain (1.54 ± 1.30 vs 2.53 ± 1.29), and radiating pain (0.13 ± 0.34 vs 0.41 ± 0.54), compared with the women without bowel manipulation., Conclusion: Bowel manipulation with anal catheterization before HIFU therapy for posterior wall uterine masses can be safely performed and is effective as a low risk intervention to aid in reducing potential HIFU complications related to nerve involvement., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Human pluripotent stem cells have emerged as a promising in vitro model system for studying the brain. Two-dimensional and three-dimensional cell culture paradigms have provided valuable insights into the pathogenesis of neuropsychiatric disorders, but they remain limited in their capacity to model certain features of human neural development. Specifically, current models do not efficiently incorporate extracellular matrix-derived biochemical and biophysical cues, facilitate multicellular spatio-temporal patterning, or achieve advanced functional maturation. Engineered biomaterials have the capacity to create increasingly biomimetic neural microenvironments, yet further refinement is needed before these approaches are widely implemented. This Review therefore highlights how continued progression and increased integration of engineered biomaterials may be well poised to address intractable challenges in recapitulating human neural development., (© 2021. Springer Nature Limited.)

Objectives: Lung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1 ) and its ligands, programmed death ligand 1 ( CD274 ) and 2 ( PDCD1LG2 ), associated with lung cancer risk in never-smoking women., Materials and Methods: During September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs., Results: A total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 ( p < 0.001), rs12237624 ( p = 0.019), and rs78096119 ( p = 0.019) were associated with the expression levels of programed death ligand 2., Conclusions: Novel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening., Competing Interests: S-KL received honoraria for speech from Roche, AstraZeneca, Pfizer, Merck Sharp & Dohme, Novartis, and Boehringer Ingelheim. K-YC received honoraria for speech from Pfizer, Novartis, Merck Sharp & Dohme, AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Chugai Pharmaceutical, and Bristol-Myers Squibb, as well as travel/accommodation/meeting expenses from Merck Sharp & Dohme, Chugai Pharmaceutical, and Boehringer Ingelheim. Y-MC served on advisory boards of Merck Sharp & Dohme, Ono Pharmaceutical, Astra-Zeneca, Roche, Boehringer Ingelheim, and Bristol-Myers Squibb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liang, Chien, Chang, Tsai, Su, Chen, Huang, Lin, Fang, Hung, Jiang, Chen, Chen, Chang, Hsiung, Chen, Yang and the GELAC Study Group.)

The new generation, i.e., second- and third-generation, drug-eluting stents (DESs) remain a risk of in-stent restenosis (ISR). We evaluated the power of a genetic risk score (GRS) model to identify high-risk populations for new generation DES ISR. We enrolled patients with coronary artery disease (CAD) treated with new generations DESs by a single-center cohort study in Taiwan and evaluated their genetic profile. After propensity score matching, there were 343 patients and 153 patients in the derivation and validation cohorts, respectively. Five selected single-nucleotide polymorphisms (SNPs), i.e., SNPs in CAMLG , GALNT2 , C11orf84 , THOC5 , and S AMD11 , were included to calculate the GRS for new generation DES ISR. In the derivation and the validation cohorts, patients with a GRS greater than or equal to 3 had significantly higher new generation DES ISR rates. We provide biological information for interventional cardiologists prior to percutaneous coronary intervention by specific five SNP-derived GRS., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

This study aimed to analyze the association between elevated gamma-glutamyl transpeptidase (GGT) and metabolic syndrome (MetS), hepatic steatosis, and fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). From August 2013 to August 2018, a community-based study was conducted in the northeastern part of Taiwan. Patients who underwent abdominal ultrasonography (US) and had no history of alcoholic liver disease were included. According to a US examination showing fatty liver degree, 1566 patients with NAFLD were divided into four groups: normal GGT, isolated GGT elevation, isolated alanine aminotransferase (ALT) elevation, and both GGT and ALT elevation groups. Further 1147 participants with normal serum ALT, GGT, and the abdominal US were included as the control group. GGT levels were associated with high sensitivity C-reactive protein, lower adiponectin, diabetes mellitus, and chronic kidney disease. A stepwise increase in odds ratio (OR) for MetS was found in the normal GGT group (OR = 1.71), isolated GGT elevation group (OR = 3.06), isolated ALT elevation (OR = 4.00), and both GGT + ALT elevation group (OR = 4.17) than the control group. Linear regression analysis revealed a positive association between GGT/ALT value and hepatic steatosis degree, GGT value, and degree of hepatic fibrosis. Hence, GGT elevation is associated with MetS, hepatic steatosis, and fibrosis in patients with NAFLD., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Oral squamous cell carcinoma (OSCC) is among the most prevalent cancers of the head and neck. This study revealed that isoorientin attenuates OSCC cell stemness and epithelial-mesenchymal transition potential through the inhibition of JAK/signal transducer and activator of transcription 3 (STAT3) and Wnt/β-catenin signaling in cell lines. Our findings indicated that isoorientin is a potential inhibitor of β-catenin/STAT3 in vitro and in vivo. We analyzed possible synergism between isoorientin and cisplatin in OSCC. A sulforhodamine B assay, colony formation assay, tumorsphere-formation assay, and Wnt reporter activity assay were used for determining cell invasion, cell migration, drug cytotoxicity, and cell viability with potential molecular mechanisms in vitro. Isoorientin reduced the expression of p-STAT3, β-catenin, and p-GSK3 as well as downstream effectors TCF1/TCF7 and LEF1 and significantly reduced β-catenin colocalization in the nucleus. Isoorientin markedly strengthened the cytotoxic effects of cisplatin against SAS and SCC-25. Therefore, combining isoorientin and cisplatin treatments can potentially improve the anticancer effect of cisplatin. Isoorientin inhibited the tumorigenicity and growth of OSCC through the abrogation of Wnt/β-catenin/STAT3 signaling in vivo. Thus, isoorientin disrupted the β-catenin signaling pathway through the inactivation of STAT3 signaling. In conclusion, targeting OSCC-SC-mediated stemness with isoorientin to eradicate OSCC-SCs may be an effective strategy for preventing relapse and metastasis of OSCC and providing long-term survival benefits., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Study Objective: To evaluate the associations among race/ethnicity, route of surgery, and perioperative outcomes for women undergoing hysterectomy for uterine leiomyomas., Design: Retrospective cohort study., Setting: Multistate., Patients: Women who underwent hysterectomies for leiomyomas from the American College of Surgeons National Surgical Quality Improvement Program database, 2014 to 2017., Interventions: None. Exposures of interest were race/ethnicity and route of surgery., Measurements and Main Results: Racial/ethnic variation in route of surgery and perioperative outcomes. Propensity score matching was employed to control for possible confounders. We identified 20 133 women who underwent nonemergent abdominal hysterectomy (AH), laparoscopic hysterectomy (LH), or vaginal hysterectomy (VH) for leiomyomas. We defined minimally invasive hysterectomy (MIH) as LH or VH. Black women were more likely to have open surgery (AH vs MIH adjusted odds ratio [aOR], 2.22; 95% confidence interval [CI], 2.07-2.38; AH vs VH aOR, 1.79; 95% CI, 1.54-2.08; AH vs LH aOR, 2.27; 95% CI, 2.13-2.44) than white women. Likewise, Hispanic women were more likely to have open surgery (AH vs MIH aOR, 1.76; 95% CI, 1.58-1.96; AH vs LH aOR, 1.82; 95% CI, 1.61-2.00) than white women. Black women were more likely to experience any complication after hysterectomy (AH aOR, 1.54; 95% CI, 1.31-1.80; VH aOR, 1.65; 95% CI, 1.02-2.68; LH aOR, 1.37; 95% CI, 1.13-1.66) than white women. Hispanic women were less likely than white women to experience major complications after VH (aOR, 0.28; 95% CI, 0.08-0.98). Compared with white women, the mean length of stay was longer for black women who underwent AH or LH. The mean total operation time was higher for all minority groups (except for Asian/other undergoing AH) regardless of surgical approach., Conclusion: Women of minority race/ethnicity were more likely to undergo abdominal rather than MIH for leiomyomas. Even when controlling for route of surgery, they were more likely to experience perioperative complications., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)

Premature atrial complexes (PACs) have been suggested to increase the risk of adverse events. The distribution of PAC burden and its dose-response effects on all-cause mortality and cardiovascular death had not been elucidated clearly. We analyzed 15,893 patients in a medical referral center from July 1st, 2011, to December 31st, 2018. Multivariate regression driven by ln PAC (beats per 24 h plus 1) or quartiles of PAC burden were examined. Older group had higher PAC burden than younger group (p for trend < 0.001), and both genders shared similar PACs distribution. In Cox model, ln PAC remained an independent risk factor for all-cause mortality (hazard ratio (HR) = 1.09 per ln PAC increase, 95% CI = 1.06‒1.12, p < 0.001). PACs were a significant risk factor in cause-specific model (HR = 1.13, 95% CI = 1.05‒1.22, p = 0.001) or sub-distribution model (HR = 1.12, 95% CI = 1.04‒1.21, p = 0.004). In ordinal PAC model, 4th quartile group had significantly higher risk of all-cause mortality than those in 1st quartile group (HR = 1.47, 95% CI = 1.13‒1.94, p = 0.005), but no difference in cardiovascular death were found in competing risk analysis. In subgroup analysis, the risk of high PAC burden was consistently higher than in low-burden group across pre-specified subgroups. In conclusion, PAC burden has a dose response effect on all-cause mortality and cardiovascular death.

Abstract: Although dental treatment with sedation is performed increasingly in special needs patients, data on adding midazolam to intravenous propofol sedation are very limited for this group. The purpose of this study was to identify the factors and procedure time associated with the use of intravenous sedation with propofol alone or propofol combined with midazolam in dental patients with special needs.This was a retrospective data analysis. The sedation medications and relevant covariates, including demographic parameters, disability levels, oral health conditions, dental procedures, treatment time, and side effects, of 718 patients with special needs were collected between April 2013 and September 2014. The unfavorable side effects by sedation types were reported. Factors associated with procedure time and the sedation medications were assessed with multiple logistic regression analyses.Of 718 patients, 8 patients experienced unfavorable side effects (vomiting, sleepiness, or emotional disturbance) after the dental procedures; the rate was 0.6% in the 509 patients who received propofol only. In 209 patients who received propofol and midazolam, 2.4% experienced the side effects. Sedation time was associated with body mass index (BMI) < 25 (adjusted odds ratio [aOR] = 1.45, 95% confidence interval [CI]: 1.04-2.04) and the performance of multiple dental procedures (aOR = 1.44, 95% CI: 1.06-1.97) but not associated with the sedation types. A significant odds ratio for the combined use of propofol and midazolam was shown for adolescents (aOR = 2.22, 95% CI: 1.28-3.86), men (aOR = 2.05, 95% CI: 1.41-2.98), patients with cognitive impairment (aOR = 1.99, 95% CI: 1.21-3.29), and patients undergoing scaling procedures (aOR = 1.64, 95% CI: 1.13-2.39).With the acceptable side effects of the use of propofol alone and propofol combined with midazolam, multiple dental procedures increase the sedation time and the factors associated with the combined use of propofol and midazolam are younger age, male sex, recognition problems, and the type dental procedure in the dental treatment of patients with special needs., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: DCBLD2 is highly expressed in various cancers, including colorectal cancer. DCBLD2 overexpression promotes tumor occurrence, development, and metastasis. However, DCBLD2 sensitivity to chemotherapy drugs and its mechanism on tumor development are unknown. Methods: DCBLD2 expression differences in cancer and normal tissues were obtained from GEO and TCGA databases. DCBLD2 influence on prognosis was also compared, and the database analysis results were verified via the analysis of clinical samples. GDSC database was used to analyze the effect of DCBLD2 expression difference on 5-FU drug sensitivity on tumor cells. CCK-8, clone formation, scratch, Transwell invasion and migration assays were used to assess DCBLD2 effects on the proliferation, metastasis, and 5-FU drug sensitivity on HCT116 and Caco-2 colorectal cancer cells. Angiogenesis and Matrigel plug assays were used to study the effect of DCBLD2 on angiogenesis. Q-RCR and Western Blot were used to analyze DCBLD2 impact on the EMT signaling pathway, and TAP-MS assay with Co-IP verification was used to identify the downstream target proteins binding to DCBLD2. Results: Both database and clinical sample validation results showed that the expression of DCBLD2 in colorectal cancer tissues was significantly higher than that in normal tissues, leading to poor prognosis of patients. GDSC database analysis showed that DCBLD2 overexpression caused tumor cell resistance to 5-FU. The results of in vitro and in vivo experiments showed that the inhibition of DCBLD2 reduced the proliferation, migration and invasion of colorectal cancer cells, inhibited the angiogenesis of endothelial cells, and enhanced the drug sensitivity to 5-FU. The results of q-RCR and Western Blot experiments showed that the inhibition of DCBLD2 can suppress the EMT signal. The results of TAP-MS assay showed that the proteins bound to DCBLD2 were enriched to the Focal adhesion pathway. The results of Co-IP assay show that DCBLD2 can combine with ITGB1, the key factor of Focal adhesion pathway. Conclusion: DCBLD2 may affect the development of colorectal cancer by regulating cell proliferation and motility, and modulate 5-FU resistance. Down-regulation of DCBLD2 can inhibit EMT signal and angiogenesis. DCBLD2 can combine with ITGB1, the key signal factor of the Focal adhesion pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xie, Yuan, Huang, Zhang, Zhou, Li and Liu.)

Background: Afatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib., Methods: We designed a retrospective study, enrolling all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg daily afatinib as their initial treatment in three Kaohsiung Medical University-affiliated hospitals in Taiwan., Results: A total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (75% vs. 83%, p = 0.1672), median PFS (14.5 vs. 14.8 months, log-rank p = 0.4649), and median OS (34.0 vs. 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients initially receiving 30 mg afatinib daily had fewer ADRs compared with those using 40 mg daily. The overall incidence of moderate and severe ADRs was significantly lower in patients receiving 30 mg afatinib daily compared with those using 40 mg daily (49% vs. 77%, p = 0.002); similar findings was observed in terms of severe ADRs (7% vs. 24%, p < 0.0001)., Conclusion: Patients receiving 30 mg afatinib daily as their initial treatment had similar RR, PFS, OS, but significantly fewer serious ADRs, as compared with those using 40 mg as their starting dose.

This paper investigates the expression of the CREB1 gene in ovarian cancer (OV) by deeply excavating the gene information in the multiple databases and the mechanism thereof. In short, we found that the expression of the CREB1 gene in ovarian cancer tissue was significantly higher than that of normal ovarian tissue. Kaplan-Meier survival analysis showed that the overall survival was significantly shorter in patients with high expression of the CREB1 gene than those in patients with low expression of the CREB1 gene, and the prognosis of patients with low expression of the CREB1 gene was better. The CREB1 gene may play a role in the occurrence and development of ovarian cancer by regulating the process of protein. Based on differentially expressed genes, 20 small-molecule drugs that potentially target CREB1 with abnormal expression in OV were obtained from the CMap database. Among these compounds, we found that naloxone has the greatest therapeutic value for OV. The high expression of the CREB1 gene may be an indicator of poor prognosis in ovarian cancer patients. Targeting CREB1 may be a potential tool for the diagnosis and treatment of OV.

The aim of this study was to analyze and provide an in-depth improvement priority for medication adverse events. Thus, the Human Factor Analysis and Classification System with subfactors was used in this study to analyze the adverse events. Subsequently, the improvement priority for the subfactors was determined using the hybrid approach in terms of the Analytical Hierarchy Process and the fuzzy Technique for Order of Preference by Similarity to Ideal Solution. In Of the 157 medical adverse events selected from the Taiwan Patient-safety Reporting system, 25 cases were identified as medication adverse events. The Human Factor Analysis and Classification System and root cause analysis were used to analyze the error factors and subfactors that existed in the medication adverse events. Following the analysis, the Analytical Hierarchy Process and the fuzzy Technique for Order of Preference by Similarity to Ideal Solution were used to determine the improvement priority for subfactors. The results showed that the decision errors, crew resource management, inadequate supervision, and organizational climate contained more types of subfactors than other error factors in each category. In the current study, 16 improvement priorities were identified. According to the results, the improvement priorities can assist medical staff, researchers, and decisionmakers in improving medication process deficiencies efficiently.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

Whether reduced-dose prasugrel has a better efficacy or safety than standard-dose clopidogrel remains unknown in patients undergoing percutaneous coronary intervention (PCI).A systematic search of PubMed, EMBASE, Google Scholar, and Cochrane Library from database inception to May 1, 2020 was performed to compare the clinical outcomes in patients with acute coronary syndrome or stable coronary artery disease undergoing PCI between those treated with reduced-dose prasugrel and clopidogrel. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using the fixed-effect or random-effect model if significant heterogeneity was observed. The primary efficacy endpoint was major adverse cardiovascular events (MACE), including cardiovascular (CV) death, myocardial infarction (MI), or ischemic stroke. The primary safety endpoint was all bleeding events.Overall, seven studies with 32,951 patients with PCI were included in the analysis. Reduced-dose prasugrel was associated with a lower risk of MACE than clopidogrel (OR 0.80, 95% CI 0.67-0.97). Except for MI (OR 0.74, 95% CI 0.56-0.98), the secondary efficacy endpoints of CV death, ischemic stroke, all-cause death, and stent thrombosis were similar. For the primary safety endpoint of all bleeding events, there was no significant difference between reduced-dose prasugrel and clopidogrel (OR 1.31, 95% CI 0.87-1.98), but the risk of minor bleeding was significantly higher in reduced-dose prasugrel (OR 1.73, 95% CI 1.25-2.41).In patients undergoing PCI, a lower risk of MACE was found in patients receiving reduced-dose prasugrel than in those with clopidogrel, but a higher risk of minor bleeding events was noted.

Importance: The Stroke Impact Scale 3.0 appears to be a promising outcome measure of health-related quality of life (HRQOL) for clients with stroke. However, because the factorial validity of the Stroke Impact Scale 3.0 remains unclear, its validity is limited., Objective: To examine the underlying structure of the Stroke Impact Scale 3.0 by comparing the currently available eight- and four-domain structures simultaneously., Design: Secondary data analysis of responses to the Stroke Impact Scale 3.0 from a previous psychometric validation study., Setting: Five general hospitals in northern and southern Taiwan., Participants: Two hundred sixty-three patients with stroke from rehabilitation wards (inpatients) and neurology and rehabilitation clinics (outpatients)., Outcomes and Measures: Confirmatory factor analysis was used to examine the eight- and four-domain structures of the Stroke Impact Scale 3.0. Four fit indices were considered simultaneously to examine the model fits of both structures., Results: The eight- and four-domain structures of the Stroke Impact Scale 3.0 were not supported by all four indices (χ²/df = 2.7 and 5.0, comparative fit index = .79 and .86, root mean square error of approximation = .08 and .12, standardized root mean square residual = .08 and .08, respectively). The unidimensionality of each domain in the two structures was not supported., Conclusions and Relevance: Neither the eight- nor the four-domain structure of the Stroke Impact Scale 3.0 was supported, suggesting that scores may not provide valid assessments of HRQOL in clients with stroke. Further modification and validation of the Stroke Impact Scale 3.0 are warranted., What This Article Adds: Our findings suggest that the eight- and four-domain scores of the Stroke Impact Scale 3.0 may not be valid. Therefore, until more supporting evidence is developed, these scores should be interpreted cautiously in regard to clients' HRQOL; alternatively, other measures could be used., (Copyright © 2021 by the American Occupational Therapy Association, Inc.)

Locally advanced oral squamous cell carcinoma (OSCC) requires multimodal therapy, including surgery and concurrent chemoradiotherapy (CCRT). CCRT-resistant and recurrent cancer has a poor prognosis. We investigated the effects of Bruton's tyrosine kinase (BTK) on CCRT-resistant OSCC tissues. The effect of ibrutinib, a first-in-class BTK inhibitor, was tested on stem cell-like OSCC tumorspheres. A tissue array was constructed using tissue samples from 70 patients with OSCC. Human OSCC cell lines, SAS, TW2.6 and HSC-3, were examined. Wound healing, Matrigel invasion, and tumorsphere formation assays, as well as immunofluorescence analysis and flow cytometry, were used to investigate the effects of BTK knockdown (shBTK), ibrutinib, cisplatin, and ibrutinib/cisplatin combination on OSCC cells. We demonstrated that BTK was aberrantly highly expressed in the clinical CCRT-resistant OSCC tissue array, which resulted in poor overall survival in our local Tri-Service General Hospital and freely accessible TCGA OSCC cohorts. shBTK significantly downregulated the stemness markers Nanog, CD133, T cell immunoglobulin-3 (TIM-3), and Krüppel-like factor 4 (KLF4) in SAS tumorspheres and attenuated OSCC cell migration and colony formation. Ibrutinib reduced the number of aldehyde dehydrogenase (ALDH)-rich OSCC cells and reduced tumorsphere formation, migration, and invasion in a dose-dependent manner. Compared with ibrutinib or cisplatin monotherapy, the ibrutinib/cisplatin combination significantly reduced the formation of ALDH + OSCC tumorspheres and enhanced apoptosis. These results demonstrate that ibrutinib effectively inhibits the CSCs-like phenotype of OSCC cells through dysregulation of BTK/CD133 signaling. The ibrutinib/cisplatin combination may be considered for future clinical use.

In this paper, we present a copper(I)-catalyzed nitrile-addition/ N -arylation ring-closure cascade for the synthesis of 5,11-dihydro-6 H -indolo[3,2- c ]quinolin-6-ones from 2-(2-bromophenyl)- N -(2-cyanophenyl)acetamides. Using CuBr and t -BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6 H -[1,3]dioxolo[4',5':5,6]indolo[3,2- c ]quinolin-6-one ( 2k ), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6 H -indolo[3,2- c ]quinolin-6-ones as topoisomerase-I inhibitors.

Transarterial chemoembolization (TACE) induces a change in serum HIF-1α level in patients with hepatocellular carcinoma (HCC). This study investigated the prognostic value of change in serum HIF-1α following TACE treatment in HCC patients. A total of 61 hepatocellular carcinoma patients treated with TACE were included. Peripheral blood samples were collected within 1 week before and after TACE to determine the serum levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) by enzyme-linked immunosorbent assay (ELISA). Serum HIF-1α change was calculated as follows: ∆HIF-1α = (HIF-1α (pre-TACE) - HIF-1α (post-TACE))/HIF-1α (pre-TACE). Likewise, serum VEG-F change was calculated as follows: ∆VEG-F = (VEG-F (pre-TACE) - VEG-F(post-TACE))/VEG-F (pre-TACE). Based on the cutoffs (0.25) determined by the maximum Youden's index in receiver operating characteristic analysis, the patients were grouped into the low ∆HIF-1α group (< 0.25) and the high ∆HIF-1α group (> 0.25). After TACE treatment, HIF-1α was significantly decreased (pre-TACE 1901.62 vs. post-TACE 621.82 pg/ml, P < 0.01) but VEGF-A was significantly increased (pre-TACE 60.80 vs. post-TACE 143.81 pg/ml, P < 0.01). Multivariate logistic regression analysis demonstrated that ∆HIF-1α was a prognostic factor (OR = 58.09, 95% CI: 1.59-2127.32, P = 0.027) for the TACE treatment response. Furthermore, multivariate Cox regression analysis revealed that ∆HIF-1α was a prognostic factor for progression-free survival (PFS) (HR = 0.30, 95% CI: 0.14-0.66, P = 0.003) and overall survival (OS) (estimated HR = 0.38, 95% CI: 0.16-0.93, P = 0.034). Kaplan-Meier survival analysis showed that the high ∆HIF-1α group was more likely to have longer PFS (log-rank test, P = 0.004) and OS (log-rank test, P = 0.002) than the low ∆HIF-1α group. The change in serum HIF-1α level following TACE is a prognostic factor associated with the TACE treatment response, PFS, and OS in HCC patients following TACE.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10 - 26 ). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10 -3 ). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Patients with permanent pacemaker (PPM) implantation may have altered coronary perfusion patterns that may influence the accuracy of myocardial perfusion examination modalities, which was observed in previous studies but with limited statistic power. Our aim was to examine the performance of thallium-201 (TL-201) myocardial perfusion examination in patients with implanted PPM., Methods: Data of consecutive patients from our institution who had coronary angiography examination followed by TL-201 myocardial perfusion examination in pairs within 1 year were collected between January 2010 and December 2016 and were divided into PPM and control groups. Propensity score matching (PSM) was performed to compare the positive predictive value (PPV) of perfusion examinations., Results: A total of 934 pairs of studies were evaluated, with 81 in the PPM group and 853 controls. The PPV decreased significantly in the PPM group (28.2 vs. 62.9%, P < 0.001). The finding of large (>20%) ischemic areas correlated significantly with all-cause mortality in the control group (OR, 2.34; P = 0.001), but not in the PPM group (OR,1.05; P = 0.943). After PSM, the PPV was still significantly lower in the PPM group than in the non-PPM group (28.6 vs. 66.2%, P < 0.001)., Conclusion: Study results do not support the appropriateness of using TL-201 perfusion examinations for risk stratification in patients with implanted PPM.Video Abstract: http://links.lww.com/NMC/A181., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Treatment for pediatric ependymoma includes surgical resection followed by local radiotherapy (RT). Proton RT (PRT) enables superior sparing of critical structures compared with photons, with potential to reduce late effects. We report mature outcomes, patterns of failure, and predictors of outcomes in patients treated with PRT., Methods: One hundred fifty patients (<22 y) with World Health Organization grades II/III ependymoma were treated with PRT between January 2001 and January 2019 at Massachusetts General Hospital. Demographic, tumor, and treatment-related characteristics were analyzed. Event-free survival (EFS), overall survival (OS), and local control (LC) were assessed., Results: Median follow-up was 6.5 years. EFS, OS, and LC for the intracranial cohort (n = 145) at 7 years were 63.4%, 82.6%, and 76.1%. Fifty-one patients recurred: 26 (51.0%) local failures, 19 (37.3%) distant failures, and 6 (11.8%) synchronous failures. One hundred sixteen patients (77.3%) underwent gross total resection (GTR), 5 (3.3%) underwent near total resection (NTR), and 29 (19.3%) underwent subtotal resection (STR). EFS for the intracranial cohort at 7 years for GTR/NTR and STR was 70.3% and 35.2%. With multivariate analysis, the effect of tumor excision persisted after controlling for tumor location. There was no adverse effect on disease control if surgery to RT interval was within 9 weeks of GTR/NTR., Conclusion: PRT is effective and safe in pediatric ependymoma. Similar to previous studies, GTR/NTR was the most important prognostic factor. Intervals up to 9 weeks from surgery to PRT did not compromise disease outcomes. There was no LC benefit between patients treated with >54 Gray relative biological effectiveness (GyRBE) versus ≤54 GyRBE., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Effectively predicting and reducing readmission in long-term home care (LTHC) is challenging. We proposed, validated, and evaluated a risk management tool that stratifies LTHC patients by LACE predictive score for readmission risk, which can further help home care providers intervene with individualized preventive plans., Method: A before-and-after study was conducted by a LTHC unit in Taiwan. Patients with acute hospitalization within 30 days after discharge in the unit were enrolled as two cohorts (Pre-Implement cohort in 2017 and Post-Implement cohort in 2019). LACE score performance was evaluated by calibration and discrimination (AUC, area under receiver operator characteristic (ROC) curve). The clinical utility was evaluated by negative predictive value (NPV)., Results: There were 48 patients with 87 acute hospitalizations in Pre-Implement cohort, and 132 patients with 179 hospitalizations in Post-Implement cohort. These LTHC patients were of older age, mostly intubated, and had more comorbidities. There was a significant reduction in readmission rate by 44.7% (readmission rate 25.3% vs. 14.0% in both cohorts). Although LACE score predictive model still has room for improvement (AUC = 0.598), it showed the potential as a useful screening tool (NPV, 87.9%; 95% C.I., 74.2-94.8). The reduction effect is more pronounced in infection-related readmission., Conclusion: As real-world evidence, LACE score-based risk management tool significantly reduced readmission by 44.7% in this LTHC unit. Larger scale studies involving multiple homecare units are needed to assess the generalizability of this study.

Conventional methods for assessing the quality of components mass produced using injection molding are expensive and time-consuming or involve imprecise statistical process control parameters. A suitable alternative would be to employ machine learning to classify the quality of parts by using quality indices and quality grading. In this study, we used a multilayer perceptron (MLP) neural network along with a few quality indices to accurately predict the quality of "qualified" and "unqualified" geometric shapes of a finished product. These quality indices, which exhibited a strong correlation with part quality, were extracted from pressure curves and input into the MLP model for learning and prediction. By filtering outliers from the input data and converting the measured quality into quality grades used as output data, we increased the prediction accuracy of the MLP model and classified the quality of finished parts into various quality levels. The MLP model may misjudge datapoints in the "to-be-confirmed" area, which is located between the "qualified" and "unqualified" areas. We classified the "to-be-confirmed" area, and only the quality of products in this area were evaluated further, which reduced the cost of quality control considerably. An integrated circuit tray was manufactured to experimentally demonstrate the feasibility of the proposed method.

Background: Procalcitonin (PCT) has been widely investigated as an infection biomarker. The study aimed to prove that serum PCT, combining with other relevant variables, has an even better sepsis-detecting ability in critically ill patients., Methods: We conducted a retrospective cohort study in a regional teaching hospital enrolling eligible patients admitted to intensive care units (ICU) between July 1, 2016, and December 31, 2016, and followed them until March 31, 2017. The primary outcome measurement was the occurrence of sepsis. We used multivariate logistic regression analysis to determine the independent factors for sepsis and constructed a novel PCT-based score containing these factors. The area under the receiver operating characteristics curve (AUROC) was applied to evaluate sepsis-detecting abilities. Finally, we validated the score using a validation cohort., Results: A total of 258 critically ill patients (70.9±16.3 years; 55.4% man) were enrolled in the derivation cohort and further subgrouped into the sepsis group (n = 115) and the non-sepsis group (n = 143). By using the multivariate logistic regression analysis, we disclosed five independent factors for detecting sepsis, namely, "serum PCT level," "albumin level" and "neutrophil-lymphocyte ratio" at ICU admission, along with "diabetes mellitus," and "with vasopressor." We subsequently constructed a PCT-based score containing the five weighted factors. The PCT-based score performed well in detecting sepsis with the cut-points of 8 points (AUROC 0.80; 95% confidence interval (CI) 0.74-0.85; sensitivity 0.70; specificity 0.76), which was better than PCT alone, C-reactive protein and infection probability score. The findings were confirmed using an independent validation cohort (n = 72, 69.2±16.7 years, 62.5% men) (cut-point: 8 points; AUROC, 0.79; 95% CI 0.69-0.90; sensitivity 0.64; specificity 0.87)., Conclusions: We proposed a novel PCT-based score that performs better in detecting sepsis than serum PCT levels alone, C-reactive protein, and infection probability score., Competing Interests: The authors have declared that no competing interests exist.

Bony injuries lead to compromised skeletal functional ability which further increase in aging population due to decreased bone mineral density. Therefore, we aimed to investigate the therapeutic potential of platelet-derived biomaterials (PDB) against bone injury. Specifically, we assessed the impact of PDB on osteo-inductive characteristics and migration of mouse embryonic fibroblasts (MEFs). Osteogenic lineage, matrix mineralization and cell migration were determined by gene markers (RUNX2, OPN and OCN), alizarin Red S staining, and migration markers (FAK, pFAK and Src) and EMT markers, respectively. The therapeutic impact of TGF-β1, a key component of PDB, was confirmed by employing inhibitor of TGF-β receptor I (Ti). Molecular imaging-based in vivo cellular migration in mice was determined by establishing bone injury at right femurs. Results showed that PDB markedly increased expression of osteogenic markers, matrix mineralization, migration and EMT markers, revealing higher osteogenic and migratory potential of PDB-treated MEFs. In vivo cell migration was manifested by expression of migratory factors, SDF-1 and CXCR4. Compared to control, PDB-treated mice exhibited higher bone density and volume. Ti treatment inhibited both migration and osteogenic potential of MEFs, affirming impact of TGF-β1. Collectively, our study clearly indicated PDB-rescued bone injury through enhancing migratory potential of MEFs and osteogenesis.

Larval mosquitoes have a more limited home range and lower resistance to adverse environment than adults, thus can be ideal targets for vector control in some cases. Coagulation-flocculation technology, which could be used for water treatment in breeding sites of several vector mosquito species, can significantly change both the distribution of organic particles and surface sediment characteristics in water environment. The aim of this study was to explore the effect, principle and possibility of using coagulation-flocculation technology in immature mosquitoes killing. In this study, dechlorinated water was treated with Poly Aluminum Chloride (PACl, sewage treatment using), and we observed the impacts of PACl treatment on the development and survival of immature Culex pipiens pallens mosquitoes. When exposed to PACl treatment, physical effect is believed to be a main reason of coagulation-flocculation caused high larvae mortality: Ⅰ) alum floc layer increases the difficulty of larvae foraging, leads larvae starving to death; (Ⅱ) the little floc particles could attach to the lateral hair of larvae, which impede floatation process and then surface respiration by larval mosquitoes. The alum floc layer had a good killing effect on the mosquito larvae, presented the half lethal time (LT 50 ) of 2d, the 90% lethal time (LT 90 ) of 8.7±7.3 ∼ 14±4.5 d, and the pupation rate of 0 ∼ (6.5±0.5)%, respectively. Our results indicates alum floc, produced by PACl coagulation-flocculation, was shown to be highly active against 1 st ∼2 nd instar larvae, the high mortality rate of immature mosquitoes as a result of physical effect. The observations suggest that coagulation-flocculation technology offers a novel potential approach to a sustainable and low-impact mosquito control method., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chaperonin-containing TCP-1 (CCT) is a chaperonin composed of eight subunits that participates in intracellular protein folding. Here, we showed that increased levels of subunits of CCT, particularly CCT-β, were significantly correlated with lower survival rates for cancer patients. Endogenously high expression of CCT-β was found in cancer cell lines, such as the triple-negative breast cancer cell line MDA-MB-231 and the highly metastatic non-small-cell lung cancer cell line CL1-5. Knocking down CCT-β in these cancer cells led to decreased levels of anti-apoptotic proteins, such as XIAP, as well as inhibited phosphorylation of Ser473-AKT and GSK3, resulting in decrease of the nucleus-entering form of β-catenin; these changes reduced the chemoresistance and migration/invasion of the cells. Conversely, overexpression of CCT-β recovered the chemoresistance and cell migration/invasion by promoting the AKT-GSK3β-β-catenin and XIAP-Survivin pathways. Coimmunoprecipitation data revealed that the CCT complex might directly bind and stabilize XIAP and β-catenin. This study not only elucidates the roles of CCT in chemoresistance and metastasis, which are two major obstacles for current cancer therapy, but also provides a possible therapeutic strategy against cancers with overexpressed CCT-β.

Introduction: In the prospective, observational, 16-week REACT study conducted between October 21, 2008 and May 12, 2011, we compared the real-world effectiveness of anti-inflammatory reliever and maintenance therapy with budesonide/formoterol (Symbicort ® Turbuhaler) and maintenance therapy with fixed-dose fluticasone/salmeterol (Seretide ® ) plus as-needed, short-acting β 2 agonists (SABAs) in Taiwanese patients with inadequate asthma control., Methods: Asthma control was assessed using the five-item Asthma Control Questionnaire (ACQ-5) and standardized pulmonary function testing. Assessments were performed at baseline and at weeks 4-5 and 12-16. Overall, we enrolled 842 patients at 11 clinics, 723 of whom were included in analyses (budesonide/formoterol, 563.3±1.3 μg/d, n=551; fluticasone/salmeterol, 1013.8±1.4 μg/d, n=172)., Results: At baseline, 72.5% and 27.5% of all patients had "partly" and "uncontrolled" asthma, respectively. Mean±SD ACQ-5 scores were 1.54±1.06 and 1.46±1.28 in the budesonide/formoterol and fluticasone/salmeterol groups, respectively. ACQ-5 scores significantly improved from baseline (ie, decreased) in both groups at weeks 4 and 16. ACQ-5 difference scores were significantly lower in the budesonide/formoterol group (-0.91±1.11) than the fluticasone/salmeterol group (-0.69±1.27) at the end of the study (p=0.027). Peak expiratory flow rate significantly improved from baseline in the budesonide/formoterol but not the fluticasone/salmeterol group at the end of the study. Severe exacerbation rates and medical resource utilization were comparable between the budesonide/formoterol and fluticasone/salmeterol groups., Conclusion: Collectively, results indicate the real-world effectiveness of budesonide/formoterol anti-inflammatory reliever and maintenance therapy is better than fixed-dose fluticasone/salmeterol plus as-needed SABA., Trial Registration: ClinicalTrials.gov registration number: NCT00784953., Competing Interests: The REACT study was supported by AstraZeneca Taiwan. The authors declare that there are no additional conflicts of interest., (© 2020 Cheng et al.)

Objective: The practice of parallel multiple jobs has increasingly become a global trend. However, the effects of parallel multiple jobs on physical and mental health have not been well understood., Method: Data come from China Health and Retirement Longitudinal Study published by CHARLS in 2015. The agricultural population aged 45 years old and above are selected through stratified random sampling (N = 10,118). Robust regression method is used to give robust estimation., Results: U-shape relations are found. The modest increase in the number of parallel multiple jobs can alleviate the difficulty in physical activities functioning and can reduce mental health problems. However, these beneficial effects could turn detrimental with the number of parallel multiple jobs beyond the modest level, leading to work overload., Conclusion: Parallel multiple jobs could be considered a double edge sword for physical and mental health.

Natural language processing (NLP) is widely applied in biological domains to retrieve information from publications. Systems to address numerous applications exist, such as biomedical named entity recognition (BNER), named entity normalization (NEN) and protein-protein interaction extraction (PPIE). High-quality datasets can assist the development of robust and reliable systems; however, due to the endless applications and evolving techniques, the annotations of benchmark datasets may become outdated and inappropriate. In this study, we first review commonlyused BNER datasets and their potential annotation problems such as inconsistency and low portability. Then, we introduce a revised version of the JNLPBA dataset that solves potential problems in the original and use state-of-the-art named entity recognition systems to evaluate its portability to different kinds of biomedical literature, including protein-protein interaction and biology events. Lastly, we introduce an ensembled biomedical entity dataset (EBED) by extending the revised JNLPBA dataset with PubMed Central full-text paragraphs, figure captions and patent abstracts. This EBED is a multi-task dataset that covers annotations including gene, disease and chemical entities. In total, it contains 85000 entity mentions, 25000 entity mentions with database identifiers and 5000 attribute tags. To demonstrate the usage of the EBED, we review the BNER track from the AI CUP Biomedical Paper Analysis challenge. Availability: The revised JNLPBA dataset is available at https://iasl-btm.iis.sinica.edu.tw/BNER/Content/Re vised&#95;JNLPBA.zip. The EBED dataset is available at https://iasl-btm.iis.sinica.edu.tw/BNER/Content/AICUP &#95;EBED&#95;dataset.rar. Contact: Email: thtsai@g.ncu.edu.tw, Tel. 886-3-4227151 ext. 35203, Fax: 886-3-422-2681 Email: hsu@iis.sinica.edu.tw, Tel. 886-2-2788-3799 ext. 2211, Fax: 886-2-2782-4814 Supplementary information: Supplementary data are available at Briefings in Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)