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Background: The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events., Methods: Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events., Results: Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common grade ≥ 3 treatment-related adverse events., Conclusion: Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively., Methods: For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs)., Results: Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%)., Conclusion: Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations., 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 © 2024 Wang, Lin, Kuang and Cao.)

Objective: Whether the efficacy of combined stent retriever and contact aspiration (S + A) is superior to stent retriever (S) alone for revascularisation in patients with large vessel occlusive stroke remains uncertain. The aim of this meta-analysis was to assess the safety and efficacy of combined stent retriever and contact aspiration for the treatment of acute ischaemic stroke with large vessel occlusion by comparing it with stent retriever alone., Methods: We systematically searched the PubMed, Embase, Web of Science, and The Cochrane Library databases for randomised controlled trials and observational studies (case-control and cohort studies) published before 1 October 2023 comparing the efficacy of combined stent retriever and contact aspiration versus tent retriever alone in patients with large vessel occlusive stroke. The end point of the primary efficacy observed in this meta-analysis study was the rate of first pass nearly complete or complete recanalisation (mTICI 2c-3). Secondary effectiveness nodes were: rate of first pass successful recanalisation (mTICI 2b-3), rate of near-complete or complete recanalisation of the postoperative vessel, rate of successful recanalisation of the postoperative vessel, and MRS 0-2 within 90 days. Safety endpoints were interoperative embolism, symptomatic intracranial haemorrhage, and mortality within 90 days., Results: A total of 16 studies were included in the literature for this meta-analysis, with a total of 7,320 patients (S + C group: 3,406, S group: 3,914). A comprehensive analysis of the included literature showed that combined stent retriever and contact aspiration had a higher rate of near-complete or complete recanalisation of the postoperative vessel [OR = 1.53, 95% CI (1.24, 1.88), p  < 0.0001] and rate of successful recanalisation of the postoperative vessel compared to stent retriever alone [OR = 1.83, 95% CI (1.55, 2.17), p  < 0.00001]; there were no statistically significant differences between the two groups in terms of the rate of first pass nearly complete or complete recanalisation [OR = 1.00, 95% CI (0.83, 1.19), p  = 0.96], rate of first pass successful recanalisation [OR = 1.02, 95% CI (0.85, 1.24), p  = 0.81], interoperative embolism [OR = 0.93, 95% CI (0.72, 1.20), p  = 0.56], symptomatic intracranial haemorrhage [OR = 1.14, 95% CI (0.87, 1.48), p  = 0.33], MRS 0-2 within 90 days [OR = 0.89, 95% CI (0.76, 1.04), p  = 0.14] and mortality within 90 days [OR = 1.11, 95% CI (0.94, 1.31), p  = 0.22]., Conclusion: Combined stent retriever and contact aspiration has a higher rate of postprocedural revascularisation (mTICI 2c-3/mTICI 2b-3) compared with stent retriever alone in patients with large vessel occlusion stroke. In addition, it was not superior to stenting alone in terms of the rate of first pass recanalisation (mTICI 2c-3/mTICI 2b-3), interoperative embolisation, symptomatic intracranial haemorrhage, good functional prognosis within 90 days and mortality within 90 days., 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 © 2024 Li, Lin, Li, Zhou, Chen, Sun and Chen.)

Background: Few studies have studied the efficacy of using immersive virtual reality (iVR) to teach surgical skills, especially by using real-world iVR recordings rather than simulations. This study aimed to investigate whether viewing 360° iVR instructional recordings produces greater improvements in basic suturing skills of students without prior medical training, beyond traditional methods like reading written manuals or watching 2D instructional videos., Materials and Methods: This was a partially blinded randomized cohort study. 44 pre-university students (aged 17) were randomized equally to either the written instruction manual, 2D instructional video, or iVR recordings. All students first watched a silent 2D demonstration video of the suturing task, before attempting to place three simple interrupted sutures on a piece of meat as a baseline. The time taken for the first attempt was recorded. Students were then given an hour to train using their allocated modality. They attempted the suturing task again, and timings were re-recorded. Four blinded surgically-trained judges independently assessed the quality of the stitches placed both pre and post-intervention. One-way analysis of variance tests (ANOVAs) and independent two-sample t-tests were used to determine the effect of training modality on improvements in suturing scores and time taken to complete suturing from pre to post-training., Results: For suturing scores, the iVR group showed significantly larger score improvements than the Written Manual group ( p  = 0.031, Cohen's D = 0.92), while this iVR advantage was less pronounced when compared with the 2D Video group ( p  = 0.16, Cohen's D = 0.65). Similarly for time taken to complete suturing, the iVR group had significantly larger time improvements than the Written Manual group ( p  = 0.045), although this difference was less robust compared to the 2D Instructional Video group ( p  = 0.34)., Conclusion: This study demonstrates that iVR training using real-world 360° instructional recordings produced significantly greater training gains in suturing scores and efficiency compared to reading written text. iVR training also led to larger training gains in both outcome measures than viewing 2D instructional videos, although the differences between them did not reach statistical significance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Acinetobacter baumannii is a major cause of nosocomial infections, and its highly adaptive nature and broad range of antibiotic resistance enable it to persist in hospital environments. A. baumannii often employs two-component systems (TCSs) to regulate adaptive responses and virulence-related traits. This study describes a previously uncharacterized TCS in the A. baumannii ATCC19606 strain, consisting of a transcriptional sensor, DJ41&#95;1407, and its regulator, DJ41&#95;1408, located adjacent to GacA of the GacSA TCS. Markerless mutagenesis was performed to construct DJ41&#95;1407 and DJ41&#95;1408 single and double mutants. DJ41&#95;1408 was found to upregulate 49 genes and downregulate 43 genes, most of which were associated with carbon metabolism and other metabolic pathways, such as benzoate degradation. MEME analysis revealed a putative binding box for DJ41&#95;1408, 5'TGTAAATRATTAYCAWTWAT3'. Colony size, motility, biofilm-forming ability, virulence, and antibiotic resistance of DJ41&#95;1407 and DJ41&#95;1408 single and double mutant strains were assessed against wild type. DJ41&#95;1407 was found to enhance motility, while DJ41&#95;1408 was found to upregulate biofilm-forming ability, and may also modulate antibiotic response. Both DJ41&#95;1407 and DJ41&#95;1408 suppressed virulence, based on results from a G. mellonella infection assay. These results showcase a novel A. baumannii TCS involved in metabolism, with effects on motility, biofilm-forming ability, virulence, and antibiotic response.

Background: Tyrosine kinase inhibitors (TKIs) contribute to the treatment of patients with anaplastic thyroid cancer (ATC). Although prospective clinical studies of TKIs exhibit limited efficacy, whether ATC patients benefit from TKI treatment in real-world clinical practice may enlighten future explorations. Therefore, we conducted this effective analysis based on real-world retrospective studies to illustrate the efficacy of TKI treatment in ATC patients., Methods: We systematically searched the online databases on September 03, 2023. Survival curves were collected and reconstructed to summarize the pooled curves. Responses were analyzed by using the "meta" package. The primary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR)., Results: 12 studies involving 227 patients were enrolled in the study. Therapeutic strategies included: anlotinib, lenvatinib, dabrafenib plus trametinib, vemurafenib, pembrolizumab plus dabrafenib and trametinib, pembrolizumab plus lenvatinib, pembrolizumab plus trametinib, and sorafenib. The pooled median OS and PFS were 6.37 months (95% CI 4.19-10.33) and 5.50 months (95% CI 2.17-12.03). The integrated ORR and DCR were 32% (95% CI 23%-41%) and 40% (95% CI 12%-74%)., Conclusion: In real-world clinical practice, ATC patients could benefit from TKI therapy. In future studies, more basic experiments and clinical explorations are needed to enhance the effects of TKIs in the treatment of patients with ATC., 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 © 2024 Kuang, Zhang, Lin, Fu, Cao and Wang.)

Background: Previous studies have confirmed the involvement of EmaSR (ethanol metabolism a sensor/regulator) in the regulation of Acinetobacter baumannii ATCC 19606 ethanol and acetate metabolism. RNA-seq analysis further revealed that DJ41&#95;568-571 , DJ41&#95;2796 , DJ41&#95;3218 , and DJ41&#95;3568 regulatory gene clusters potentially participate in ethanol and acetate metabolism under the control of EmaSR., Methods: This study fused the EmaSR regulon promoter segments with reporter genes and used fluorescence expression levels to determine whether EmaSR influences regulon expression in ethanol or acetate salt environments. The enzymatic function and kinetics of significantly regulated regulons were also studied., Results: The EmaSR regulons P 2796 and P 3218 exhibited > 2-fold increase in fluorescence expression in wild type compared to mutant strains in both ethanol and acetate environments, and P emaR demonstrated a comparable trend. Moreover, increases in DJ41&#95;2796 concentration enhanced the conversion of acetate and succinyl-CoA into acetyl-CoA and succinate, suggesting that DJ41&#95;2796 possesses acetate: succinyl-CoA transferase (ASCT) activity. The k cat /K M values for DJ41&#95;2796 with potassium acetate, sodium acetate, and succinyl-CoA were 0.2131, 0.4547, and 20.4623 mM -1 s -1 , respectively., Conclusions: In A. baumannii , EmaSR controls genes involved in ethanol and acetate metabolism, and the EmaSR regulon DJ41&#95;2796 was found to possess ASCT activity.

Background: Novel-fosfamides (NFOs) belong to active metabolites of ifosfamide that bypass the generation of toxic byproducts. In this analysis, we aimed to comprehensively assess the benefits and risks of NFO monotherapy or in combination with doxorubicin (DOX) versus single-drug DOX in previously untreated patients with advanced soft-tissue sarcoma (ASTS)., Methods: Online PubMed, Web of Science, Embase, and Cochrane CENTRAL databases were systematically searched on April 26, 2022. Objective response rate and disease control rate were primary outcomes. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events were secondary outcomes., Results: In all, 3 randomized clinical trials with a total of 1207 ASTS patients were eligible. DOX plus NFO combination therapy showed higher risk ratios of objective response rate (1.50, 95% CI 1.20-1.68, P = .0003) and disease control rate (1.15, 95% CI 1.05-1.27, P = .0030) compared with DOX monotherapy. Nevertheless, NFO-based monotherapy and combination therapy were found no improvements on OS (hazard ratio 0.93, 95% CI 0.52-1.65, P = .8050) and PFS (hazard ratio 0.88, 95% CI 0.54-1.43, P = .6088) against DOX. More incidences of grade 3 or worse anemia, thrombocytopenia, stomatitis, diarrhea, constipation, and febrile neutropenia were observed in NFO-based treatments., Conclusion: Adding NFO to DOX as first-line therapy improved the responses in ASTS patients but did not prolong OS and PFS. Grade 3 or worse treatment-related adverse events should be treated with caution during the NFO-based therapies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate that targets the human trophoblast cell-surface antigen 2 to deliver SN-38 to cancer cells. In this study, we assessed the efficacy and safety of SG in patients with relapsed or refractory metastatic triple-negative breast cancer (RM-TNBC)., Methods: For this integrated analysis, from inception to January 2, 2023, we searched PubMed, Web of Science, Embase, and Cochrane library databases for prospective studies that evaluated SC in RM-TNBC patients. Primary endpoints were survival outcomes and responses. Secondary endpoints were all grade and grade ≥ 3 toxicities., Results: Six hundred potentially relevant records were screened. Our analysis included 3 trials (412 patients). Median overall survival was 12.9 months (95% confidence interval [CI], 11.5-14.4), progression-free survival was 5.7 months (5% CI, 5.1-6.3), and duration of objective response was 7.4 months (5% CI, 5.8-9.0). The objective response rate was 34%, and the disease control rate was 71%. Key grade ≥ 3 toxicities (in over 10% of the patients) included neutropenia (46%), leukopenia (12%), febrile neutropenia (11%), diarrhea (11%), and anemia (10%). Four treatment-related deaths were reported., Conclusion: SG was associated with effectiveness in patients with RM-TNBC. Myelosuppression and diarrhea were the primary treatment-related adverse events., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: The authors have no conflicts of interest relevant to this article.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal curvature deformity that appears in the adolescent period. In this study, we performed whole-exome sequencing on 11 unrelated Taiwanese patients with a Cobb's angle greater than 40 degrees. Our results identified more than 200 potential pathogenic rare variants, however, most of which were carried only by one individual. By in silico pathogenicity annotation studies, we found that TTN , CLCN1 , and SOX8 were the most important genes, as multiple pathogenic variants were within these genes. Furthermore, biological functional annotation indicated critical roles of these AIS candidate genes in the skeletal muscle. Importantly, a pathogenic variant on SOX8 was shared by over 35% of the patients. These results highlighted TTN , CLCN1 , and SOX8 as the most likely susceptibility genes for severe AIS.

To retrospectively analyze local and systemic factors that resulted in the short-term tooth loss of teeth that were previously assigned a favorable prognosis in patients who were seen and treated over an observational five-year period. This retrospective study included the records of patients who had a minimum of two dental exams at least twelve months apart over a 5-year period. This study investigated extracted teeth with an initially favorable periodontal prognosis that were then divided into one of four categories based on the reason for extraction: caries, periodontal disease, endodontic reasons, or fracture. Patient- and tooth-related factors associated with the extracted teeth were recorded: crown-to-root ratio, initial pocket depth, initial periodontal diagnosis, maintenance interval, presence of existing restoration, furcation involvement, and systemic conditions. Data analysis was performed using a linear mixed model. A total of 50 patients with 111 teeth met the inclusion criteria for this study. A higher odds ratio (OR) for tooth loss due to caries, endodontic reasons, and fracture were found in teeth with a history of root canal treatment with an OR of 3.61, 3.86, and 2.52, respectively. For tooth loss due to periodontal disease, higher ORs were found in patients who were on anti-depressants (OR = 4.28) and patients who had an initial diagnosis of Stage III/IV periodontitis (OR = 2.66). In addition, teeth with initial probing depths ≥5 mm (OR = 4.32) and with furcation involvement (OR = 1.93) showed a higher OR for tooth loss due to periodontal disease. Within the limitations of this study, previously root-canal-treated teeth present a higher OR for early loss due to caries, recurrent endodontic lesions, or fracture. In addition, patients with anti-depressant medication use, sporadic maintenance, initial probing depths ≥5 mm, and furcation involvement represent a significantly higher OR of tooth loss due to periodontal disease even for initially favorable teeth.

Background: Taxane chemotherapy represents the standard of care in the second-line setting for non-small cell lung cancer (NSCLC) patients, but immunotherapy agents pose great challenges. Whether immunotherapy/chemotherapy alone or combination therapy has more benefits remains controversial. In this study, we provided comparisons to integrate the efficacy of immunotherapy and taxane chemotherapy as second- or later-line treatments in advanced NSCLC., Methods: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to September 1, 2020. Randomized controlled trials comparing immunotherapy and taxane chemotherapy were enrolled in the Bayesian network analysis. Overall survival (OS) and progression-free survival (PFS) with hazard ratios (HRs) were investigated., Results: Eight trials in 13 studies with 4398 patients comparing seven treatments were identified. Pembrolizumab 10 mg/kg was associated with the best improved OS, with significant differences versus docetaxel (HR 0.81, 95% credible interval [CrI] 0.74-0.88), avelumab (HR 0.84, 95% CrI 0.75-0.95), and pembrolizumab 200 mg plus docetaxel (HR 0.75, 95% CrI 0.56-1.00). Although pembrolizumab 200 mg plus docetaxel ranked the last in terms of OS, the combination therapy showed the most favorable PFS. Additionally, the anti-programmed death-ligand 1 (PD-L1) agent, avelumab, was associated with the least improvement in PFS., Conclusion: As second- or later-line therapeutic strategies, pembrolizumab 10 mg/kg provided the largest OS benefits and pembrolizumab 200 mg plus docetaxel improved PFS to the greatest extent. Considering that immunotherapy has been recommended to the first-line setting of NSCLC, advanced patients who have not received immunotherapy previously might be the suitable population for our findings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Non-small-cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) exon 20 mutant occurs in 3% of NSCLCs. Targeted agents for this population remain an unmet need. In this analysis, we pooled-analyzed the efficacy and safety of poziotinib, a novel tyrosine kinase inhibitor, in HER2 exon 20 mutant NSCLC., Methods: PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were systematically searched on March 9, 2022. The primary endpoints were objective response rate (ORR) and disease control rate. The secondary endpoint was treatment-related adverse events., Results: Three prospective clinical trials, involving 126 patients, were identified. The pooled ORR and disease control rate of poziotinib in HER2 exon 20 mutant NSCLC were 27% (95% CI, 19-35) and 72% (95% CI, 64-80), respectively. Patients with G778&#95;P780dupGSP had the highest ORR (88%; 95% CI, 33-100; n = 12), followed by Y772&#95;A775dupYVMA (20%; 95% CI, 12-30; n = 88) and G776delinsVC (19%; 95% CI, 0-50; n = 13). The most common grade 3 to 4 treatment-related adverse events were skin rash (36%), diarrhea (23%), and oral mucositis (13%)., Conclusion: Poziotinib demonstrates moderate antitumor activity in previously treated HER2 exon 20 mutant NSCLC patients with a manageable safety profile. In addition, different subgroup mutations show various benefits of poziotinib treatment. Large-scale and multiarm clinical trials are warranted to confirm a suitable population and therapeutic strategies., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Acinetobacter baumannii is a well-known nosocomial pathogen that can survive in different environments through the use of intricate networks to regulate gene expression. Two-component systems (TCS) form an important part of such regulatory networks, and in this study, we describe the identification and characterization of a novel EmaSR TCS in A. baumannii . We constructed a Tn 5 -tagged mutagenesis library, from which an emaS sensor kinase gene and emaR response regulator gene were identified. We found that emaS / emaR single-mutants and double-mutants were unable to replicate in M9 medium with 1% ethanol as the single carbon source. Motility and biofilm formation were negatively affected in double-mutants, and transcriptomic analysis showed that mutation of emaSR dysregulated genes required for carbon metabolism. In addition, emaS / emaR single-mutants and double-mutants were unable to survive in acetic acid- and sodium acetate-containing medium, indicating that the EmaSR TCS is also important for acetate metabolism. Furthermore, virulence against Galleria mellonella was diminished in emaS / emaR single- and double-mutants. Taken together, these results show that this novel EmaSR TCS is involved in the regulation of A. baumannii ethanol metabolism and acetate metabolism, with important implications on motility, biofilm formation, and virulence if mutated. Further research on the underlying mechanisms is warranted.

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy is the standard of care in treating advanced non-small cell lung cancer (NSCLC). Nevertheless, whether adding pemetrexed-based chemotherapy to EGFR-TKI targeted therapy furtherly prolongs survival outcomes and improves responses remains controversial. Therefore, we conducted this pooled analysis to compare the efficacy and tolerability between gefitinib plus pemetrexed-based chemotherapy and gefitinib alone in the first-line treatment of advanced NSCLC patients with mutated EGFR., Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane CENTRAL on June 23, 2022. Eligible studies were registered randomized clinical trials comparing gefitinib plus pemetrexed-based chemotherapy with gefitinib alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR), disease control rate (DCR), and discontinuation rate (DR) were explored as secondary outcomes., Results: Eight studies within five randomized clinical trials were eligible. Gefitinib combined with pemetrexed-based chemotherapy significantly prolonged OS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.37-0.89, p = 0.0125) and PFS (HR 0.52, 95% CI 0.39-0.70, p < 0.0001) versus gefitinib alone. In subgroup analysis, patients with EGFR exon 19 deletion and exon 21 L858R could benefit from the addition of pemetrexed-based chemotherapy to gefitinib in terms of PFS (EGFR exon 19 deletion: HR 0.50, 95% CI 0.34-0.75, p = 0.0008; EGFR exon 21 L858R: HR 0.46, 95% CI 0.26-0.82, p = 0.0079) but not OS. In addition, ORR was improved after the administration of gefitinib plus pemetrexed-based chemotherapy against gefitinib (odds ratio [OR] 1.91, 95% CI 1.44-2.55, p < 0.0001). Both strategies showed comparable DCRs (OR 1.46, 95% CI 0.94-2.26, p = 0.0952) and DRs (risk ratio [RR] 2.80, 95% CI 0.69-11.44, p = 0.1509)., Conclusion: Compared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation., Competing Interests: The authors have declared that no competing interests exist.

Background: Immunotherapy has revolutionized the treatment of advanced lung cancer. Nevertheless, it remains unclear whether adding stereotactic body radiotherapy (SBRT) to immunotherapy (IT) further improves responses and survival outcomes. Therefore, in this pooled analysis, we comprehensively compared IT plus SBRT with IT alone in patients with advanced lung cancer., Methods: Online databases, including PubMed, Web of Science, Embase, and Cochrane CENTRAL, were systematically searched on April 24, 2022. Eligible studies were randomized clinical trials comparing IT plus SBRT to IT. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR). Progression-free survival (PFS) and overall survival (OS) were explored as secondary outcomes., Results: Overall, three phase 2 randomized clinical trials with a total of 146 previously treated lung cancer patients were enrolled. The median PFS and OS were 3.8 months and 9.5 months for IT plus SBRT versus 2.4 months and 6.1 months for IT. Comparing IT plus SBRT with IT alone, pooled risk ratios for ORR and DCR were 1.95 (95% confidence interval 1.07-3.53, p  = 0.03) and 1.28 (0.94-1.73, p  = 0.12). While pooled hazard ratios were 0.77 (0.25-2.42, p  = 0.66) for PFS and 0.71 (0.16-3.21, p  = 0.65) for OS, respectively. No publication bias was found across the trials., Conclusion: Compared to IT alone, the addition of SBRT improved the best response but failed to prolong the survival outcomes in treating advanced lung cancer patients. Future studies are necessary to explore new modalities of the combination of IT and SBRT., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Bi-Cheng Wang et al.)

Purpose: For patients with symptomatic middle cerebral artery (MCA) atherosclerotic stenosis, identifying the potential stroke mechanisms may contribute to secondary prevention. The purpose of the study is to explore the relationship between stroke mechanisms and the characteristics of culprit plaques in patients with atherosclerotic ischemic stroke in the M1 segment of the middle cerebral artery (MCA) based on high-resolution vessel wall imaging (HR-VWI)., Methods: We recruited 61 patients with acute ischemic stroke due to MCA atherosclerotic stenosis from Shenzhen Bao'an District People's Hospital. According to prespecified criteria based on infarct topography and magnetic resonance angiography, possible stroke mechanisms were divided into parent artery atherosclerosis occluding penetrating artery (P), artery-to-artery embolism (A), hypoperfusion (H), and mixed mechanisms (M). The correlation between the characteristics of MCA M1 culprit plaque and different stroke mechanisms was analyzed using HR-VWI. The indicators included plaque surface irregularity, T1 hyperintensity, location, plaque burden (PB), remodeling index (RI), enhancement rate, and stenosis rate., Results: Parental artery atherosclerosis occluding penetrating artery was the most common mechanism (37.7%). The proposed criteria showed substantial to excellent interrater reproducibility (κ, 0.728; 0.593-0.863). Compared with the P group, the surface irregularity, T1 hyperintensity, and obvious enhancement of the culprit plaque in the A group were more common ( p < 0.0125). Compared with the other stroke mechanisms, positive remodeling of culprit plaques was more common ( p < 0.0125), the RI was greater ( p < 0.05), and the PB was the smallest ( p < 0.05) in the P group. The enhancement ratio (ER) was smaller in the P group ( p < 0.05). Compared with the A group, T1 hyperintensity of the culprit plaque was more common in the H group ( p < 0.0125), and the stenosis rate was greater ( p < 0.05). After adjustment for clinical demographic factors in the binary logistic regression analysis, the enhancement level (odds ratio [ OR ] 0.213, 95% CI (0.05-0.91), p = 0.037) and PB of culprit plaque ( OR 0, 95% CI (0-0.477), p = 0.034) were negatively associated with P groups., Conclusion: The culprit plaque characteristics of patients with symptomatic MCA atherosclerotic in different stroke mechanisms may be evaluated using HR-VWI. The plaque characteristics of different stroke mechanisms may have clinical value for the selection of treatment strategies and prevention of stroke recurrence., Clinical Trial Registration: Identifier: ChiCTR1900028533., 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 Lin, Song, Huang, Fu and Zhong.)

Background: Herpes zoster presents as clustered blisters on one side of the body, accompanied by nerve pain. This is caused by reactivation of the varicella zoster virus, and it occurs primarily in people with weakened immunity. Tumor and chemotherapy drugs can impair the patient's immune function, induce herpes zoster and prolong the course of disease.In these patients, skin changes can last for months and blisters can recur and cause serious complications such as postherpetic neuralgia.Acupuncture is a common alternative therapy for herpes zoster in East Asia., Case Presentation: We report a case of an elderly male patient with widespread herpes zoster in the trunk after non-Hodgkin's lymphoma chemotherapy. The patient had received conventional treatment with valaciclovir and mecobalamin within 24 hours of symptom onset. Because neither the clustered blisters nor the nerve pain were improved a week later, acupuncture and related techniques were applied. These included electro-acupuncture, surrounding acupuncture, fire acupuncture, and cupping. The patient recovered 20 days after the herpes zoster attack, and there were no adverse reactions during the treatment process., Conclusions: This case suggests that acupuncture and related techniques are effective interventions for this condition.This case report is innovative because it shows that acupuncture as an adjuvant treatment can improve the skin lesions in patients with HZ after tumour chemotherapy, relieve pain, and shorten the course of HZ., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rodents' lifestyles vary in different environments, and to adapt to various lifestyles specific digestion strategies have been developed. Among these strategies, the morphology of the digestive tracts and the gut microbiota are considered to play the most important roles in such adaptations. However, how subterranean rodents adapt to extreme environments through regulating gut microbial diversity and morphology of the digestive tract has yet to be fully studied. Here, we conducted the comparisons of the gastrointestinal morphology, food intake, food assimilation, food digestibility and gut microbiota of plateau zokor Eospalax baileyi in Qinghai-Tibet Plateau and laboratory rats Rattus norvegicus to further understand the survival strategy in a typical subterranean rodent species endemic to the Qinghai-Tibet Plateau. Our results revealed that plateau zokor evolved an efficient foraging strategy with low food intake, high food digestibility, and ultimately achieved a similar amount of food assimilation to laboratory rats. The length and weight of the digestive tract of the plateau zokor was significantly higher than the laboratory rat. Particularly, the weight and length of the large intestine and cecum in plateau zokor is three times greater than that of the laboratory rat. Microbiome analysis showed that genus (i.e., Prevotella , Oscillospira , CF231, Ruminococcus and Bacteroides ), which are usually associated with cellulose degradation, were significantly enriched in laboratory rats, compared to plateau zokor. However, prediction of metagenomic function revealed that both plateau zokor and laboratory rats shared the same functions in carbohydrate metabolism and energy metabolism. The higher digestibility of crude fiber in plateau zokor was mainly driven by the sizes of cecum and cecum tract, as well as those gut microbiota which associated with cellulose degradation. Altogether, our results highlight that both gut microbiota and the morphology of the digestive tract are vital to the digestion in wild rodents.

Background: Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) has been defined as an oncogene in tumor cells. However, the role of UHRF1 in mediating metastasis in thyroid cancer remains unexplored. In this study, we aimed to investigate the metastatic function and the potential mechanisms of UHRF1 in thyroid cancer., Methods: Transwell assays were used to detect the metastatic capability of thyroid cancer. Dual-luciferase reporter assays were applied to examine the activation of transcription factors. Coimmunoprecipitation assays and immunofluorescence staining assays were used to elucidate the potential mechanisms of UHRF1 in promoting the metastasis of thyroid cancer., Results: In this study, we found that overexpression of UHRF1 promoted the metastasis of papillary thyroid cancer cells, and suppression of UHRF1 decreased the metastasis of anaplastic thyroid cancer cells. Regarding the signaling pathway in regulating metastasis, UHRF1 directly combined and activated the transcription factor c-Jun/AP-1 in the nucleus, subsequently increasing the transcription of IL-6 and MIF., Conclusion: Our results suggest that UHRF1 could induce the metastasis of thyroid cancer, and the potential signaling pathway might be that UHRF1 activates c-Jun/AP-1 to increase the expression of IL-6 and MIF. These findings provide a novel mechanism of UHRF1 and illustrate that UHRF1/AP-1 complex could be a potential therapeutic target for patients with thyroid cancer., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Bo-Hua Kuang et al.)

Background: Adding induction chemotherapy to concurrent platinum-based chemoradiotherapy has significantly prolonged the survival time of patients with locoregionally advanced nasopharyngeal carcinoma. In this study, we intend to evaluate the survival outcomes, responses, and incidences of toxicities of induction chemotherapy and the differences between different strategies., Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science, and Cochrane CENTRAL on August 10, 2021. Single-arm or multi-arm prospective clinical trials on induction chemotherapy without targeted therapies or immune checkpoint inhibitors were included. Primary outcomes included survival outcomes, objective response rate, and disease control rate, and the secondary outcome was the rates of grade 3 or higher treatment-related adverse events., Results: The 39 studies included in the systematic review and meta-analysis comprised 36 clinical trials and 5389 patients. The estimates for 3-year overall and fail-free survival rates were 87% and 77%. The estimates for 5-year rates of overall and fail-free survival were 81% and 73%. Gemcitabine plus platinum and docetaxel combined with 5-fluorouracil plus platinum strategies were associated with the highest rates of 3-year and 5-year overall survival. The objective response and disease control rates were 85% and 98% after the completion of induction chemotherapy. Neutropenia (27%) and nausea/vomiting (7%) were the most common grade 3 or higher treatment-related hematological and non-hematological adverse events during the induction phase., Conclusions: Different induction chemotherapeutic strategies appear to have varying effects and risks; a comprehensive summary of the survival outcomes, responses, and toxicities in clinical trials may provide a crucial guide for clinicians., 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 Wang, Kuang, Liu, Lin and Liu.)

Objective: To develop a model combined with dual-energy CT quantitative parameters and conventional CT features for evaluating the expression level of Ki-67 in invasive breast cancer. Methods: A total of 191 patients with histologically confirmed invasive breast cancer in Lishui Central Hospital from March 2019 to December 2020, were retrospectively enrolled, all of them were females, aged from 25 to 77 (53.2±11.3) years. All patients underwent preoperative non-contrast chest and contrast-enhanced Dual energy CT scans, and the normalized iodine concentration (NIC) of lesions on arterial and venous phase, spectral curve slope (λ HU ), and normalized effective atomic number (nZ eff ) were measured and calculated, and their conventional CT characteristics were assessed. According to the results of immunohistochemistry (IHC), the patients were divided into Ki-67 high expression group ( n =129 patients) and low expression group ( n =62 patients) level. The differences in clinical data, conventional CT characteristics and dual-energy CT quantitative parameters between the two groups were analyzed. The receiver operating characteristic curve (ROC) curve was conducted to assess the efficacy of each individual model and joint model in evaluating Ki-67 expression levels, and the area under the curve (AUC), sensitivity, specificity, and accuracy were calculated, respectively. Results: In the analysis of CT features, the longest diameter, shape and enhancement pattern of the tumor were significantly difference between the two groups (all P <0.05). The NIC, nZ eff on the arterial phase and NIC, nZ eff and λ HU [ M ( Q 1 , Q 3 )] on the venous phase were higher in the high Ki-67 expression group compared to the low expression group [0.13 (0.12, 0.16) vs 0.11 (0.08, 0.14), 0.71 (0.70, 0.75) vs 0.70 (0.67, 0.72), 0.40 (0.32, 0.48) vs 0.23 (0.17, 0.32), 3.10 (2.58, 3.63) vs 2.86 (2.19, 3.48), 0.88 (0.85, 0.92) vs 0.85 (0.84, 0.86), all P <0.05]. The logistic regression model, which integrated significant conventional CT features and dual-energy CT quantitative parameters, demonstrated the highest diagnostic performance for assessing Ki-67 expression levels, with an AUC of 0.924, sensitivity of 88.37%, specificity of 83.87%, and accuracy of 86.91%; the AUC of the dual-energy CT parameter model was 0.908, sensitivity of 82.17%, specificity of 88.71%, and accuracy of 84.29%. Though the diagnostic efficacy was no significant difference ( P =0.238), both models showed superior to the conventional CT feature model (all P <0.001). Conclusion: A dual-energy CT quantitative parameter combined with a conventional CT feature model was successfully constructed, which has a good evaluation performance on the expression level of Ki-67 in invasive breast cancer.

Background: Sublingual immunotherapy (SLIT) has been proved to be an effective and safe treatment for allergic asthma (AS) in children. Nonetheless, several issues regarding SLIT remain to be resolved, including the information about optimal administration timing., Methods: A total of 163 AS children aged 4-13 years were enrolled and randomized into the morning dosing (MD) group and the evening dosing (ED) group. Participants received SLIT with Dermatophagoides farinae drops between 7:00 a. m. and 9:00 a.m. (for the MD group) or between 8:00 p. m. and 10:00 p.m. (for the ED group). The total asthma symptom score (TASS), total asthma medicine score (TAMS), Asthma Control Questionnaire (ACQ), forced expiratory volume in one second (FEV 1 ), FEV 1 /forced volume vital capacity (FVC), fractional exhaled nitric oxide (FeNO) and adverse events (AEs) were assessed at baseline, 0.5 and 1 year during the 1-year SLIT., Results: After 1 year, 62 patients in the MD group and 63 patients in the ED group completed the entire study. The clinical efficacy, pulmonary function and FeNO in both groups improved significantly at 0.5 and 1 year ( p < 0.001). Compared to the MD group, the ED group showed significant lower ACQ score at 0.5 year ( p < 0.001) and lower FeNO at 1 year ( p < 0.05). No significant difference between two groups was observed in AE rate ( p > 0.05). All AEs occurred in the first month, with no systemic AEs reported., Conclusion: 1-year house dust mite (HDM) SLIT is effective and well-tolerated in AS children regardless of administration time. SLIT dosing in the evening might enhance the asthma control level and reduce FeNO level compared with SLIT dosing in the morning., 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 Liao, Chen, Wang, Quan, Chen and Lin.)

Genomic integration of genes and pathway-sized DNA cassettes is often an indispensable way to construct robust and productive microbial cell factories. For some uncommon microbial hosts, such as Mycolicibacterium and Mycobacterium species, however, it is a challenge. Here, we present a multiplexed integrase-assisted site-specific recombination (miSSR) method to precisely and iteratively integrate genes/pathways with controllable copies in the chromosomes of Mycolicibacteria for the purpose of developing cell factories. First, a single-step multi-copy integration method was established in M. neoaurum by a combination application of mycobacteriophage L5 integrase and two-step allelic exchange strategy, the efficiencies of which were ∼100% for no more than three-copy integration events and decreased sharply to ∼20% for five-copy integration events. Second, the R4, Bxb1 and ΦC31 bacteriophage Att/Int systems were selected to extend the available integration toolbox for multiplexed gene integration events. Third, a reconstructed mycolicibacterial Xer recombinases (Xer-cise) system was employed to recycle the selection marker of gene recombination to facilitate the iterative gene manipulation. As a proof of concept, the biosynthetic pathway of ergothioneine (EGT) in Mycolicibacterium neoaurum ATCC 25795 was achieved by remodeling its metabolic pathway with a miSSR system. With six copies of the biosynthetic gene clusters (BGCs) of EGT and pentose phosphate isomerase (PRT), the titer of EGT in the resulting strain in a 30 mL shake flask within 5 days was enhanced to 66 mg/L, which was 3.77 times of that in the wild strain. The improvements indicated that the miSSR system was an effective, flexible, and convenient tool to engineer the genomes of Mycolicibacteria as well as other strains in the Mycobacteriaceae due to their proximate evolutionary relationships., Competing Interests: The authors declare that they have no conflicts of interest., (© 2022 The Authors.)

While infections by enterovirus A71 (EV-A71) are generally self-limiting, they can occasionally lead to serious neurological complications and death. No licensed therapies against EV-A71 currently exist. Using anti-virus-induced cytopathic effect assays, 3,4-dicaffeoylquinic acid (3,4-DCQA) from Ilex kaushue extracts was found to exert significant anti-EV-A71 activity, with a broad inhibitory spectrum against different EV-A71 genotypes. Time-of-drug-addition assays revealed that 3,4-DCQA affects the initial phase (entry step) of EV-A71 infection by directly targeting viral particles and disrupting viral attachment to host cells. Using resistant virus selection experiments, we found that 3,4-DCQA targets the glutamic acid residue at position 98 (E98) and the proline residue at position 246 (P246) in the 5-fold axis located within the VP1 structural protein. Recombinant viruses harboring the two mutations were resistant to 3,4-DCQA-elicited inhibition of virus attachment and penetration into human rhabdomyosarcoma (RD) cells. Finally, we showed that 3,4-DCQA specifically inhibited the attachment of EV-A71 to the host receptor heparan sulfate (HS), but not to the scavenger receptor class B member 2 (SCARB2) and P-selectin glycoprotein ligand-1 (PSGL1). Molecular docking analysis confirmed that 3,4-DCQA targets the 5-fold axis to form a stable structure with the E98 and P246 residues through noncovalent and van der Waals interactions. The targeting of E98 and P246 by 3,4-DCQA was found to be specific; accordingly, HS binding of viruses carrying the K242A or K244A mutations in the 5-fold axis was successfully inhibited by 3,4-DCQA.The clinical utility of 3,4-DCQA in the prevention or treatment of EV-A71 infections warrants further scrutiny. IMPORTANCE The canyon region and the 5-fold axis of the EV-A71 viral particle located within the VP1 protein mediate the interaction of the virus with host surface receptors. The three most extensively investigated cellular receptors for EV-A71 include SCARB2, PSGL1, and cell surface heparan sulfate. In the current study, a RD cell-based anti-cytopathic effect assay was used to investigate the potential broad spectrum inhibitory activity of 3,4-DCQA against different EV-A71 strains. Mechanistically, we demonstrate that 3,4-DCQA disrupts the interaction between the 5-fold axis of EV-A71 and its heparan sulfate receptor; however, no effect was seen on the SCARB2 or PSGL1 receptors. Taken together, our findings show that this natural product may pave the way to novel anti-EV-A71 therapeutic strategies.

Esophageal motility disorders account for a large proportion of nonobstructive dysphagia cases, which constitute a heterogeneous group of diagnoses that commonly result in peristaltic derangement and impaired relaxation of the lower esophageal sphincter. We performed a single-institution retrospective study enrolling consecutive patients with chief complaints of dysphagia who underwent HRIM from December 2014 to December 2019, and analyzed demographic, clinical, and manometric data using descriptive statistics. In total, 277 identified patients were included in the final analysis. Ineffective esophageal motility ( n = 152, 24.5%) was the most common diagnosis by HRIM, followed by absent contractility, EGJ outflow obstruction, type II achalasia, and type I achalasia. Furthermore, surgery including exploratory, laparoscopic, and robotic myotomy, as well as POEM, is considered the most effective treatment for patients with non-spastic achalasia and EGJOO, due to its effective symptom palliation and prevention of disease progression; surgery also contributes to an obvious improvement of dysphagia compared with slightly less efficacy for other related symptoms. Our study aimed to elaborate the clinical characteristics of patients with nonobstructive dysphagia based on HRIM in a Taiwanese population, and to analyze the therapeutic outcomes of such patients who ultimately underwent surgical interventions.

Background: The prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma., Methods: PubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities., Results: Six retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31-58) for objective response and 66% (55-77) for disease control. Grade 3-4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3-16), 7% (3-11), and 8% (5-10) of chemotherapeutic cycles, respectively. 18% (7-32) and 6% (2-11) of patients suffered grade 3-4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment., Conclusion: Irinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results., (© 2022. The Author(s).)

Background: The major aim of this Bayesian network analysis was to determine the optimal treatment strategy for locoregionally advanced nasopharyngeal carcinoma (LANPC)., Method: We systematically searched databases and extracted data from randomized clinical trials involving LANPC patients randomly assigned to receive induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT), CCRT followed by adjuvant chemotherapy (CCRT+AC), or CCRT., Results: In the network analysis, IC+CCRT was significantly better than CCRT alone for 5-year FFS (odds ratio [OR]: 1.63, 95% credible interval [CrI] 1.16-2.29), DMFS (OR: 1.56, 95% CrI 1.08-2.22), and LFRS (OR: 1.62, 95% CrI 1.02-2.59), but not OS (OR: 1.35, 95% CrI 0.92-2.00). Rank probabilities showed that IC+CCRT was ranked the best followed by CCRT+AC and CCRT for all 5-year outcomes. Although compared to IC+CCRT and CCRT, CCRT+AC did not significantly improve survival but had the highest 5-year survival rates., Conclusions: IC+CCRT could be recommended as a front-preferred primary definitive therapy for patients with LANPC., Competing Interests: The authors have declared that no competing interests exist.

Overweight and obese are risk factors for various diseases. In Taiwan, the combined prevalence of overweight and obesity has increased dramatically. Here, we conducted a genome-wide association study (GWAS) on four adiposity traits, including body-mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-hip ratio (WHR), using the data for more than 21,000 subjects in Taiwan Biobank. Associations were evaluated between 6,546,460 single-nucleotide polymorphisms (SNPs) and adiposity traits, yielding 13 genome-wide significant (GWS) adiposity-associated trait-loci pairs. A known gene, FTO, as well as two BF%-associated loci (GNPDA2-GABRG1 [4p12] and RNU6-2-PIAS1 [15q23]) were identified as pleiotropic effects. Moreover, RALGAPA1 was found as a specific genetic predisposing factor to high BMI in a Taiwanese population. Compared to other populations, a slightly lower heritability of the four adiposity traits was found in our cohort. Surprisingly, we uncovered the importance of neural pathways that might influence BF%, WC and WHR in the Taiwanese (East Asian) population. Additionally, a moderate genetic correlation between the WHR and BMI (γg = 0.52; p = 2.37×10-9) was detected, suggesting different genetic determinants exist for abdominal adiposity and overall adiposity. In conclusion, the obesity-related genetic loci identified here provide new insights into the genetic underpinnings of adiposity in the Taiwanese population., Competing Interests: The authors have declared that no competing interests exist.

The CO 2 absorption rate by using a Monoethanolamide (MEA) solution through the spiral wired channel in concentric circular membrane contactors under both concurrent-flow and countercurrent-flow operations was investigated experimentally and theoretically. The one-dimensional mathematical modeling equation developed for predicting the absorption rate and concentration distributions was solved numerically using the fourth Runge-Kutta method under various absorbent flow rate, CO 2 feed flow rate and inlet CO 2 concentration in the gas feed. An economical viewpoint of the spiral wired module was examined by assessing both absorption flux improvement and power consumption increment. Meanwhile, the correlated average Sherwood number to predict the mass-transfer coefficient of the CO 2 absorption mechanisms in a concentric circular membrane contactor with the spiral wired annulus channel is also obtained in a generalized and simplified expression. The theoretical predictions of absorption flux improvement were validated by experimental results in good agreements. The amine solution flowing through the annulus of a concentric circular tube, which was inserted in a tight-fitting spiral wire in a small annular spacing, could enhance the CO 2 absorption flux improvement due to reduction of the concentration polarization effect. A larger concentration polarization coefficient (CPC) was achieved in the countercurrent-flow operations than that in concurrent-flow operations for various operations conditions and spiral-wire pitches. The absorption flux improvement for inserting spiral wire in the concentric circular module could provide the maximum relative increment up to 46.45%.

Background: Doxorubicin/Adriamycin (ADM) alone or combined with ifosfamide (IFO) (AI) is available for previously untreated advanced soft tissue sarcoma (ASTS). However, the clinical choice between them remains controversial. In this pooled analysis, we comprehensively compared the efficacy and tolerability of AI versus ADM in patients with ASTS., Methods: PubMed, Web of Science, EMBASE, and Cochrane Library were systematically searched from inception to April 14, 2021. Eligible studies were randomized clinical trials comparing AI to ADM. The primary outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Discontinuation rate (DR) and toxic death (TD) were explored as secondary outcomes., Results: Overall, three open-label randomized phase 2/3 clinical trials with a total of 1108 newly diagnosed ASTS patients were enrolled. Between AI and ADM, pooled hazard ratios were 0.93 (95% confidence interval 0.58-1.50, p = 0.78) for OS and 0.85 (0.57-1.25, p = 0.41) for PFS. While pooled risk ratios for ORR, DR, and TD were 1.37 (0.94-1.99, p = 0.10), 1.04 (0.74-1.46, p = 0.82), and 0.68 (0.19-2.36, p = 0.54) respectively. No publication bias was observed across the studies., Conclusion: In the first-line setting, adding IFO to ADM failed to benefit ASTS patients against ADM alone, even with comparable tolerability., 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 Wang, Kuang, Xiao and Lin.)

Purpose: We analyzed and compared the imaging characteristics of the vessel wall of the middle cerebral artery (MCA) in symptomatic and asymptomatic patients using a 3.0-T high-resolution magnetic resonance imaging (HR-MRI) protocol, including a 3-dimensional T1-sampling perfection with application-optimized contrasts using different flip angle evolutions sequence., Methods: Fifty-three patients with atherosclerotic stenosis of the MCA underwent 3.0-T HR-MRI examinations. The characteristics of atherosclerotic plaques in 53 patients (28 symptomatic, 25 asymptomatic) were analyzed, including plaque distribution and signal intensity. Plaque burden (PB), stenosis degree, and the remodeling index were measured and compared between symptomatic and asymptomatic patients., Results: The PB of the symptomatic group was significantly higher than that of the asymptomatic group ( P = .006), and moderate-severe stenosis was more common ( P = .01). The remodeling index of the symptomatic group was also lower ( P = .015) and negative remodeling (NR) was more common ( P = .043). Binary logistic regression analysis showed that stenosis degree was a risk factor in symptomatic patients (odds ratio = 135, P = .023)., Conclusion: There is a trend that some characteristics of plaques and vessels, including the moderate-severe stenosis, larger PB, and NR, were observed more frequently among patients with symptomatic atherosclerotic stenosis of the MCA than among asymptomatic patients.

Most bacteria possess alcohol dehydrogenase (ADH) genes ( Adh genes) to mitigate alcohol toxicity, but these genes have functions beyond alcohol degradation. Previous research has shown that ADH can modulate quorum sensing in Acinetobacter baumannii , a rising opportunistic pathogen. However, the number and nature of Adh genes in A. baumannii have not yet been fully characterized. We identified seven alcohol dehydrogenases (NAD + -ADHs) from A. baumannii ATCC 19606, and examined the roles of three iron-containing ADHs, ADH3, ADH4, and ADH6. Marker-less mutation was used to generate Adh3 , Adh4 , and Adh6 single, double, and triple mutants. Disrupted Adh4 mutants failed to grow in ethanol-, 1-butanol-, or 1-propanol-containing mediums, and recombinant ADH4 exhibited strongest activity against ethanol. Stress resistance assays with inorganic and organic hydroperoxides showed that Adh3 and Adh6 were key to oxidative stress resistance. Virulence assays performed on the Galleria mellonella model organism revealed that Adh4 mutants had comparable virulence to wild-type, while Adh3 and Adh6 mutants had reduced virulence. The results suggest that ADH4 is primarily involved in alcohol metabolism, while ADH3 and ADH6 are key to stress resistance and virulence. Further investigation into the roles of other ADHs in A. baumannii is warranted.

Background: Postpartum subinvolution of the uterus is a more common condition after cesarean section. Auricular acupressure (AA) is widely used for the treatment of postpartum diseases. However, few studies have explored the effects of AA as a treatment of uterine involution following cesarean section to date. This study aimed to assess the efficacy and safety of AA for uterine involution after cesarean section., Methods: A total of 109 women who underwent cesarean section participated in this study. They were randomly allocated to either real AA or sham AA in a 1:1 ratio by a computer program. For 3 days, the real AA and sham AA groups received treatment 3 times daily. A series of assessments at 42 days after cesarean section, namely on the uterine size, the incidence of hydrometra, the first anal exsufflation time, bleeding volume at 6 hours, bleeding volume at 6-24 hours along with other general assessments were carried out., Results: A total of 89 women completed the study. The uterine size at 42 days after a cesarean section was 6.3 cm smaller in the real AA group than in the sham AA group ( P  < 0.01). The incidence of hydrometra on day 42 postpartum was lower in the real AA group than in the sham AA group ( P  < 0.01). The lochia duration and the first anal exsufflation time after cesarean section were shorter in the real AA group than in the sham AA group ( P  < 0.05)., Conclusion: AA improves uterine involution after cesarean section., Trial Registration: ChiCTR1800015569., (© 2021 Published by Elsevier B.V. on behalf of Korea Institute of Oriental Medicine.)

Purpose: This systematic review compares the clinical and radiographic outcomes for patients who received only a corticotomy or periodontal accelerated osteogenic orthodontics (PAOO) with those who received a conventional orthodontic treatment., Methods: An electronic search of four databases and a hand search of peer-reviewed journals for relevant articles published in English between January 1980 and June 2021 were performed. Human clinical trials of ≥10 patients treated with a corticotomy or PAOO with radiographic and/or clinical outcomes were included. Meta-analyses were performed to analyze the weighted mean difference (WMD) and confidence interval (CI) for the recorded variables., Results: Twelve articles were included in the quantitative analysis. The meta-analysis revealed a localized corticotomy distal to the canine can significantly increase canine distalization (WMD = 1.15 mm, 95% CI = 0.18-2.12 mm, p = 0.02) compared to a conventional orthodontic treatment. In addition, PAOO also showed a significant gain of buccal bone thickness (WMD = 0.43 mm, 95% CI = 0.09-0.78 mm, p = 0.01) and an improvement of bone density (WMD = 32.86, 95% CI = 11.83-53.89, p = 0.002) compared to the corticotomy group., Conclusion: Based on the findings of the meta-analyses, the localized use of a corticotomy can significantly increase the amount of canine distalization during orthodontic treatment. Additionally, the use of a corticotomy as a part of a PAOO procedure significantly increases the rate of orthodontic tooth movement and it is accompanied by an increased buccal bone thickness and bone density compared to patients undergoing a conventional orthodontic treatment.

Background: While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presents with mild or no symptoms in most cases, a significant number of patients become critically ill. Remdesivir has been approved for the treatment of coronavirus disease 2019 (COVID-19) in several countries, but its use as monotherapy has not substantially lowered mortality rates. Because agents from traditional Chinese medicine (TCM) have been successfully utilized to treat pandemic and endemic diseases, we designed the current study to identify novel anti-SARS-CoV-2 agents from TCM., Methods: We initially used an antivirus-induced cell death assay to screen a panel of herbal extracts. The inhibition of the viral infection step was investigated through a time-of-drug-addition assay, whereas a plaque reduction assay was carried out to validate the antiviral activity. Direct interaction of the candidate TCM compound with viral particles was assessed using a viral inactivation assay. Finally, the potential synergistic efficacy of remdesivir and the TCM compound was examined with a combination assay., Results: The herbal medicine Perilla leaf extract (PLE, approval number 022427 issued by the Ministry of Health and Welfare, Taiwan) had EC 50 of 0.12 ± 0.06 mg/mL against SARS-CoV-2 in Vero E6 cells - with a selectivity index of 40.65. Non-cytotoxic PLE concentrations were capable of blocking viral RNA and protein synthesis. In addition, they significantly decreased virus-induced cytokine release and viral protein/RNA levels in the human lung epithelial cell line Calu-3. PLE inhibited viral replication by inactivating the virion and showed additive-to-synergistic efficacy against SARS-CoV-2 when used in combination with remdesivir., Conclusion: Our results demonstrate for the first time that PLE is capable of inhibiting SARS-CoV-2 replication by inactivating the virion. Our data may prompt additional investigation on the clinical usefulness of PLE for preventing or treating COVID-19., Competing Interests: Conflicts of interest The authors declare they have no actual or potential competing financial interests., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Objective: The Fugl-Meyer motor scale (FM) is a well-validated measure for assessing upper extremity and lower extremity motor functions in people with stroke. The FM contains numerous items (50), which reduces its clinical usability. The purpose of this study was to develop a short form of the FM for people with stroke using a machine-learning methodology (FM-ML) and compare the efficiency (ie, number of items) and psychometric properties of the FM-ML with those of other FM versions, including the original FM, the 37-item FM, and the 12-item FM., Methods: This observational study with follow-up used secondary data analysis. For developing the FM-ML, the random lasso method of ML was used to select the 10 most informative items (in terms of index of importance). Next, the scores of the FM-ML were calculated using an artificial neural network. Finally, the concurrent validity, predictive validity, responsiveness, and test-retest reliability of all FM versions were examined., Results: The FM-ML used fewer items (80% fewer than the FM, 73% fewer than the 37-item FM, and 17% fewer than the 12-item FM) to achieve psychometric properties comparable with those of the other FM versions (concurrent validity: Pearson r = 0.95-0.99 vs 0.91-0.97; responsiveness: Pearson r = 0.78-0.91 vs 0.33-0.72; and test-retest reliability: intraclass correlation coefficient = 0.88-0.92 vs 0.93-0.98)., Conclusion: The findings preliminarily support the efficiency and psychometric properties of the 10-item FM-ML., Impact: The FM-ML has potential to substantially improve the efficiency of motor function assessments in patients with stroke., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In this study, we show that Acinetobacter baumannii ATCC 19606 harbors two sets of ohrR-ohr genes, respectively encoded in chromosomal DNA and a pMAC plasmid. We found no significant difference in organic hydroperoxide (OHP) resistance between strains with or without pMAC. However, a disk diffusion assay conducted by exposing wild-type, ∆ohrR-C , C represented gene on chromosome, or ∆ohr-C single mutants, or ∆ohrR - C∆ohr - C double mutants to tert -butyl hydroperoxide ( t BHP) found that the ohrR-p-ohr-p genes, p represented genes on pMAC plasmid, may be able to complement the function of their chromosomal counterparts. Interestingly, ∆ohr-C single mutants generated in A. baumannii ATCC 17978, which does not harbor pMAC, demonstrated delayed exponential growth and loss of viability following exposure to 135 μg of t BHP. In a survival assay conducted with Galleria mellonella larvae, these mutants demonstrated almost complete loss of virulence. Via an electrophoretic mobility shift assay (EMSA), we found that OhrR-C was able to bind to the promoter regions of both chromosomal and pMAC ohr - p genes, but with varying affinity. A gain-of-function assay conducted in Escherichia coli showed that OhrR-C was not only capable of suppressing transformed ohr-C genes but may also repress endogenous enzymes. Taken together, our findings suggest that chromosomal ohrR-C-ohr-C genes act as the major system in protecting A. baumannii ATCC 19606 from OHP stresses, but the ohrR-p-ohr-p genes on pMAC can provide a supplementary protective effect, and the interaction between these genes may affect other aspects of bacterial viability, such as growth and virulence.

Background: Adjuvant trastuzumab improves survival outcomes of human epidermal receptor 2 positive early breast cancer patients. Currently, administration of 12 months adjuvant trastuzumab is the standard therapy. However, whether 6 months treatment is non-inferior to the standard 12 months treatment remains controversial., Methods: Relevant records were searched in PubMed, Cochrane Library, Web of Science, and EMBASE through Jan 14, 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were meta-analyzed. The primary endpoint was DFS with a non-inferiority hazard margin of 1.2 and the second was OS with 1.43., Results: Three randomized clinical studies met the inclusion criteria, including 3974 patients in 6 months group and 3976 in 12 months group. HR for DFS was 1.18 (95% CI 0.97-1.44, P = .09), with the non-inferiority margin comprised in the 95% CI. HR for OS was 1.14 (95% CI 0.98-1.32, P= .08), whereas the upper limit of 95% CI did not exceed the non-inferiority hazard margin., Conclusion: Our analysis failed to show that 6 months treatment was non-inferior to 12 months treatment in improving the DFS. Although the non-inferiority of the 6-month adjuvant trastuzumab treatment was found for OS, considering that breast cancer patients should receive additional systematic therapies when disease progression or relapse happens, we suggest that 12 months adjuvant trastuzumab treatment should remain the standard therapeutic strategy for patients with early human epidermal receptor 2 positive breast cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV2 virus continues to pose a serious threat to public health worldwide. The development of rapid diagnostic kits can assist the Tzu Chi Foundation in supporting global volunteers working to provide relief during the current pandemic., Materials and Methods: In this study, nucleotide sequences derived from publicly available viral genome data for several domains of the SARS-CoV2 spike and nucleocapsid (N) proteins were chemically synthesized, with codon optimization for Escherichia coli protein expression. No actual viral particles were involved in these experiments. The synthesized sequences were cloned into an E. coli expression system based on pQE80L, and expressed viral proteins were subsequently purified using Ni-affinity chromatography. Western blotting was conducted using human antiviral sera to assess the response of codon-modified viral proteins to COVID-19 patient sera., Results: N protein was expressed in amounts large enough to support large-scale production. The N-terminal domain, receptor-binding domain (RBD), Region 3, and the S2 domain were expressed in small but sufficient amounts for experiments. Immunoblotting results showed that anti-N IgG and anti-N IgM antibodies were detected in most patient sera, but only 60% of samples reacted with the recombinant RBD and S2 domain expressed by E. coli ., Conclusion: The results indicated that codon-optimized SARS-CoV2 viral proteins can be expressed in E. coli and purified for rapid antibody detection kit preparation, with the codon-optimized N protein, RBD, and S2 protein demonstrating the most potential., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Tzu Chi Medical Journal.)

The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials, including dexamethasone, ritonavir, baricitinib, tofacitinib, naproxen, budesonide, ciclesonide and formoterol. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Enterovirus A71 (EV-A71), a positive-stranded RNA virus of the Picornaviridae family, may cause neurological complications or fatality in children. We examined specific factors responsible for this virulence using a chemical genetics approach. Known compounds from an anti-EV-A71 herbal medicine, Salvia miltiorrhiza (Danshen), were screened for anti-EV-A71. We identified a natural product, rosmarinic acid (RA), as a potential inhibitor of EV-A71 by cell-based antiviral assay and in vivo mouse model. Results also show that RA may affect the early stage of viral infection and may target viral particles directly, thereby interfering with virus-P-selectin glycoprotein ligand-1 (PSGL1) and virus-heparan sulfate interactions without abolishing the interaction between the virus and scavenger receptor B2 (SCARB2). Sequencing of the plaque-purified RA-resistant viruses revealed a N104K mutation in the five-fold axis of the structural protein VP1, which contains positively charged amino acids reportedly associated with virus-PSGL1 and virus-heparan sulfate interactions via electrostatic attraction. The plasmid-derived recombinant virus harbouring this mutation was confirmed to be refractory to RA inhibition. Receptor pull-down showed that this non-positively charged VP1-N104 is critical for virus binding to heparan sulfate. As the VP1-N104 residue is conserved among different EV-A71 strains, RA may be useful for inhibiting EV-A71 infection, even for emergent virus variants. Our study provides insight into the molecular mechanism of virus-host interactions and identifies a promising new class of inhibitors based on its antiviral activity and broad spectrum effects against a range of EV-A71.