bluuebunny/crossref_metadata_2025 huggingface dataset:
Emulation of a Target Trial From Observational Data to Compare Effectiveness of Casirivimab/Imdevimab and Bamlanivimab/Etesevimab for Early Treatment of Non-Hospitalized Patients With COVID-19
Authors: Mazzotta Valentina , Cozzi-Lepri Alessandro , Colavita Francesca , Lanini Simone , Rosati Silvia , Lalle Eleonora , Mastrorosa Ilaria , Cimaglia Claudia , Vergori Alessandra , Bevilacqua Nazario , Lapa Daniele , Mariano Andrea , Bettini Aurora , Agrati Chiara , Piselli Pierluca , Girardi Enrico , Castilletti Concetta , Garbuglia Anna Rosa , Vaia Francesco , Nicastri Emanuele , Antinori Andrea
Published: April 2022

Objectives

Comparative analysis between different monoclonal antibodies (mAbs) against SARS-CoV-2 are lacking. We present an emulation trial from observational data to compare effectiveness of Bamlanivimab/Etesevimab (BAM/ETE) and Casirivimab/Imdevimab (CAS/IMD) in outpatients with early mild-to-moderate COVID-19 in a real-world scenario of variants of concern (VoCs) from Alpha to Delta.

Methods

Allocation to treatment was subject to mAbs availability, and the measured factors were not used to determine which combination to use. Patients were followed through day 30. Viral load was measured by cycle threshold (CT) on D1 (baseline) and D7.

Primary outcome was time to COVID-19-related hospitalization or death from any cause over days 0-30. Weighted pooled logistic regression and marginal structural Cox model by inverse probability weights were used to compare BAM/ETE vs. CAS/IMD. ANCOVA was used to compare mean D7 CT values by intervention. Models were adjusted for calendar month, MASS score and VoCs. We evaluated effect measure modification by VoCs, vaccination, D1 CT levels and enrolment period.

Results

COVID19-related hospitalization or death from any cause occurred in 15 of 237 patients in the BAM/ETE group (6.3%) and in 4 of 196 patients in the CAS/IMD group (2.0%) (relative risk reduction [1 minus the relative risk] 72%; p=0.024). Subset analysis carried no evidence that the effect of the intervention was different across stratification factors. There was no evidence in viral load reduction from baseline through day 7 across the two groups (+0.17, 95% -1.41;+1.74, p=0.83). Among patients who experienced primary outcome, none showed a negative RT-PCR test in nasopharyngeal swab (p=0.009) and 82.4% showed still high viral load (p<0.001) on D7.

Conclusions

In a pre-Omicron epidemiologic scenario, CAS/IMD reduced risk of clinical progression of COVID-19 compared to BAM/ETE. This effect was not associated with a concomitant difference in virological response.
Association of Online Search Trends With Vaccination in the United States: June 2020 Through May 2021
Authors: Berning Philipp , Huang Leu , Razavi Alexander C. , Boakye Ellen , Osuji Ngozi , Stokes Andrew C. , Martin Seth S. , Ayers John W. , Blaha Michael J. , Dzaye Omar
Published: April 2022

Stagnating COVID-19 vaccination rates and vaccine hesitancy remain a threat to public health. Improved strategies for real-time tracking and estimation of population-level behavior regarding vaccinations are needed. The aim of this study was to evaluate whether online search trends for COIVD-19 and influenza mirror vaccination rates. State-level weekly fraction of online searches for top vaccination-related search terms and CDC vaccination data were obtained from June 1, 2020, to May 31, 2021. Next, trends in online search and vaccination data for COVID-19 and influenza were analyzed for visual and quantitative correlation patterns using Spearman’s rank correlation analysis. Online searches in the US for COVID-19 vaccinations increased 2.71-fold (95% CI: 1.98-3.45) in the 4 weeks after the FDA emergency authorization compared to the precedent 4 weeks. In March-April 2021, US online searches reached a plateau that was followed by a decline of 83.3% (95% CI: 31.2%-135.3%) until May 31, 2021. The timing of peaks in online searches varied across US states. Online searches were strongly correlated with vaccination rates (r=0.71, 95% CI: 0.45 - 0.87), preceding actual reported vaccination rates in 44 of 51 states. Online search trends preceded vaccination trends by a median of 3.0 weeks (95% CI: 2.0-4.0 weeks) across all states. For influenza vaccination searches, seasonal peaks in September-October between 2016-2020 were noted. Influenza search trends highly correlated with the timing of actual vaccinations for the 2019-2020 (r=0.82, 95% CI: 0.64 – 0.93) and 2020-2021 season (r=0.91, 95% CI: 0.78 – 0.97). Search trends and real-world vaccination rates are highly correlated. Temporal alignment and correlation levels were higher for influenza vaccinations; however, only online searches for COVID-19 vaccination preceded vaccination trends. These findings indicate that US online search data can potentially guide public health efforts, including policy changes and identifying geographical areas to expand vaccination campaigns.
Chronic Exposure to the Combination of Cigarette Smoke and Morphine Decreases CD4+ Regulatory T Cell Numbers by Reprogramming the Treg Cell Transcriptome
Authors: Shao Ying , Cornwell William , Xu Keman , Kirchhoff Aaron , Saasoud Fatma , Lu Yifan , Jiang Xiaohua , Criner Gerard J. , Wang Hong , Rogers Thomas J. , Yang Xiaofeng
Published: April 2022

There is a high incidence of tobacco use among intravenous opioid drug users. It is well established that opioids and tobacco smoke induce a degree of immune activation, and recent work suggests that the combination of these drugs promotes further activation of the immune system. Our approach involved the treatment of wild-type mice with cigarette smoke (SM) for a period of eight weeks, and the chronic continuous administration of morphine (M) via mini-pumps for the final four weeks. In an effort to examine the responses of CD4+CD25highCD127low regulatory T (Treg) cells, the major immune suppressive cell type, to the combined chronic administration of SM and M, we determined the frequency of these cells in the spleen, lymph nodes and lungs. Flow cytometric analyses showed that SM and M individually, and the combination (SM + M) have differential effects on the numbers of Treg in the spleen, lymph node, and lung. Either SM or M alone increased Treg cell numbers in the spleen, but SM+M did not. Furthermore, SM + M decreased Treg cell numbers in the lymph node and lung. We then performed RNA-Seq on Treg cells from mice treated with SM, M, or SM + M, and we found that the S + M induced a number of significant changes in the transcriptome, that were not as apparent following treatment with either SM or M alone. This included an activation of TWEAK, PI3K/AKT and OXPHOS pathways and a shift to Th17 immunity. Our results have provided novel insights on tissue Treg cell changes, which we suggest are the result of transcriptomic reprogramming induced by SM, M, and SM + M, respectively. We believe these results may lead to the identification of novel therapeutic targets for suppressing smoke and opioid induced Treg cell impairment.
Subsurface Microbial Community Composition in Anchialine Environments Is Influenced by Original Organic Carbon Source at Time of Deposition
Authors: Risley Catherine A. , Tamalavage Anne E. , van Hengstum Peter J. , Labonté Jessica M.
Published: April 2022

Prokaryotes constitute the majority of sedimentary biomass, where they cycle organic carbon and regulate organic matter transformation. The microbes inhabiting sediment are diverse and the factors controlling microbial community composition are not fully understood. Here, we characterized the prokaryotic community using 16S rRNA gene sequencing in 24 stratigraphic layers within a 89 cm (dated to ~1900 years old) sediment core from an anchialine sinkhole in the Bahamas with a stratified water column and anoxic bottom water. The microbial community was dominated by members of the Alphaproteobacteria, Dehalococcoidia, Gammaproteobacteria, Bathyarchaeota, and Campylobacter classes. Most interestingly, subsurface microbial community structure could be correlated to previous evidence for timewise changes in the main source of organic matter that was supplied to the sediment accumulating during the last 2000 years, which itself was caused by regional terrestrial vegetation changes. The C:N ratio was correlated to the relative abundance of the microbial classes, and the microbial communities followed three previously determined time periods based on the source of organic matter, which suggests that the carbon source at time of deposition influences the resultant subsurface microbial community composition. These results show that carbon source is a driver of the microbial community composition inhabiting anoxic sediment, which could have implications for improving understanding of carbon cycling in coastal sedimentary basins.
Metabolic Response in the Gill of Portunus trituberculatus Under Short-Term Low Salinity Stress Based on GC-MS Technique
Authors: Wang Jiali , Liu Qi , Zhang Xinni , Gao Gao , Niu Mingming , Wang Huan , Chen Lizhi , Wang Chunlin , Mu Changkao , Wang Fangfang
Published: April 2022

Salinity is an important factor affecting the survival, growth, and metabolism of marine crustaceans. Low-salt stress will result in the death of swimming crabs. This paper investigates the metabolic response in the gills of Portunus trituberculatus under short-term low-salt stress by comparing the metabolic molecules in the four salinity treatment groups (24‰, 16‰, 12‰, and 8‰) by GC-MS technique. In this study, nine common differential metabolites such as pyruvate, malic acid, and phosphoethanolamine were found in the gill tissues of crabs. KEGG enrichment analysis revealed that six metabolic pathways, including the citric acid cycle, pyruvate metabolism, and the HIF-1 signaling system, were significantly impacted by low salt stimulation. According to the findings, salinity 12‰ is a critical node in crab adaptation to low salinity. In the process of adaptation to short-term low-salinity environment, amino acids participated in osmotic regulation, and organic acids such as pyruvate and malic acid were involved in energy metabolism to ensure their energy supply. This research further enriched the theory of osmotic regulation and metabolic mechanism of adaptation to low salt in crustaceans, with the goal of providing guidance for the improvement of culture technique in Portunus trituberculatus.
Ulcerative Colitis: Novel Epithelial Insights Provided by Single Cell RNA Sequencing
Authors: Serigado Joao M. , Foulke-Abel Jennifer , Hines William C. , Hanson Joshua A , In Julie , Kovbasnjuk Olga
Published: April 2022

Ulcerative Colitis (UC) is a chronic inflammatory disease of the intestinal tract for which a definitive etiology is yet unknown. Both genetic and environmental factors have been implicated in the development of UC. Recently, single cell RNA sequencing (scRNA-seq) technology revealed cell subpopulations contributing to the pathogenesis of UC and brought new insight into the pathways that connect genome to pathology. This review describes key scRNA-seq findings in two major studies by Broad Institute and University of Oxford, investigating the transcriptomic landscape of epithelial cells in UC. We focus on five major findings: (1) the identification of BEST4 + cells, (2) colonic microfold (M) cells, (3) detailed comparison of the transcriptomes of goblet cells, and (4) colonocytes and (5) stem cells in health and disease. In analyzing the two studies, we identify the commonalities and differences in methodologies, results, and conclusions, offering possible explanations, and validated several cell cluster markers. In systematizing the results, we hope to offer a framework that the broad scientific GI community and GI clinicians can use to replicate or corroborate the extensive new findings that RNA-seq offers.
Ferroptosis Biology and Implication in Cancers
Authors: Qu Chi , Peng Yang , Liu Shengchun
Published: April 2022

Ferroptosis, a novel form of regulated cell death (RCD), has garnered increasing attention in studies on numerous human diseases in the last decade. Emerging evidence has indicated that the pathological process of ferroptosis involves the overloaded production of reactive oxygen species (ROS), followed by aberrant accumulation of lipid peroxidation in an iron-dependent manner, accompanied with an increased uptake of polyunsaturated fatty acids into the cellular membrane, further unfolding an ancient vulnerability in multiple context. The unique nature of ferroptosis differentiates it from other forms of RCD, as it is intricately associated with several biological processes, including the metabolism of iron, amino acids, synthesis of ROS and lipid peroxidation. Accordingly, inducers and inhibitors designed to target the key processes of ferroptosis have been extensively studied. Characterized by its distinct properties as mentioned above and its inducible nature, ferroptosis has been widely implicated in several diseases, and numerous studies have focused on identifying effective therapeutic targets for multiple human diseases, including in cancer, by targeting this process. In the present review, recent studies on the involvement of ferroptosis in several types of cancer are summarized and the findings discussed, highlighting the need for increased contemplation of its involvement in the study of cancer, particularly in the clinical setting. A comprehensive summary of the biological mechanisms underlying ferroptosis, the implications of the multiple inducers of ferroptosis, as well as immunotherapy targeting ferroptosis in different types of cancer is provided in this review to highlight the pathophysiological role of ferroptosis in carcinogenesis, to serve as an aid in future studies on the role of ferroptosis in cancer.
Comprehensive Molecular Profiling of Colorectal Cancer With Situs Inversus Totalis by Next-Generation Sequencing
Authors: Li Hongsen , Gong Liu , Cheng Huanqing , Wang Huina , Zhang Xiaochen , Rao Chuangzhou , Song Zhangfa , Wang Da , Lou Haizhou , Lou Feng , Cao Shanbo , Pan Hongming , Fang Yong
Published: April 2022

Background

Colorectal cancer (CRC) is one of the most prevalent malignances worldwide. However, CRC with situs inversus totalis (SCRC) is extremely rare, and molecular characterization of this disease has never been investigated.

Methods

Tumor tissue samples from 8 patients with SCRC and 33 CRC patients without situs inversus totalis (NSCRC) were subjected to multigene next-generation sequencing.

Results

The most frequently mutated genes in SCRC were APC, TP53, CHEK2, MDC1, GNAQ, KRAS, and SMAD4. A high frequency of SCRC tumors had mutations in DNA damage repair genes. Single amino acid substitutions in the DNA damage repair genes caused by continuous double base substitution was identified in the majority of this population. Furthermore, mutational profiles showed notable differences between the SCRC and NSCRC groups. In particular, CHEK2, MDC1, GNAQ, SMAD4, BRCA1, HLA-B, LATS2, and NLRC5 mutations were more frequently observed in SCRC patients. The mutation loci distributions of KRAS in the SCRC cohort differed from that of the NSCRC cohort. Additionally, differences in the targeted genomic profiles and base substitution patterns were observed between the two groups.

Conclusions

These findings comprehensively revealed a molecular characterization of SCRC, which will contribute to the development of personalized therapy and improved clinical management of SCRC patients.
Cost-Effectiveness of Nivolumab Plus Chemotherapy vs. Chemotherapy as First-Line Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer/Esophagel Adenocarcinoma in China
Authors: Shu Yamin , Ding Yufeng , Zhang Qilin
Published: April 2022

Objective

The purpose of this study was to evaluate the cost-effectiveness of nivolumab plus chemotherapy vs. chemotherapy as first-line therapy in patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma from the perspective of the Chinese healthcare system.

Methods

This economic evaluation used a state-transition Markov model to assess the cost and effectiveness of nivolumab plus chemotherapy vs. chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma. The characteristics of patients in the model came from a phase 3 open-label randomized clinical trial (CheckMate 649). Key clinical data were based on the CheckMate 649 trial conducted from March 2017 to April 2019, and costs and utilities were collected from the published literature. The total cost of treatment per patient, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated for the two treatment strategies. Deterministic sensitivity analysis and probabilistic sensitivity analysis were performed.

Results

In the baseline analysis, the incremental effectiveness and cost of nivolumab plus chemotherapy vs. chemotherapy were 0.28 QALYs and $78,626.53, resulting in an ICER of $278,658.71/QALY, higher than the willingness-to-pay (WTP) threshold of China ($31,498.70/QALY). The model was sensitive to the duration of progression-free survival (PFS) for the nivolumab plus chemotherapy group, the cost of nivolumab per 100 mg, and the utility of PFS.

Conclusion

Nivolumab plus chemotherapy was clearly not a cost-effective treatment strategy compared with chemotherapy as first-line therapy for patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma in China. Reducing the price of nivolumab may improve its cost-effectiveness.
Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis
Authors: Heatley Susan L. , Page Elyse C. , Eadie Laura N. , McClure Barbara J. , Rehn Jacqueline , Yeung David T. , Osborn Michael , Revesz Tamas , Kirby Maria , White Deborah L.
Published: April 2022

Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop B-cell acute lymphoblastic leukemia (B-ALL). Through in-vitro modeling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signaling, indicative of leukemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.
Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter
Authors: Thornton Jessica , Chhabra Gagan , Singh Chandra K. , Guzmán-Pérez Glorimar , Shirley Carl A. , Ahmad Nihal
Published: April 2022

Melanoma is one of the seven most common cancers in the United States, and its incidence is still increasing. Since 2011, developments in targeted therapies and immunotherapies have been essential for significantly improving overall survival rates. Prior to the advent of targeted and immunotherapies, metastatic melanoma was considered a death sentence, with less than 5% of patients surviving more than 5 years. With the implementation of immunotherapies, approximately half of patients with metastatic melanoma now survive more than 5 years. Unfortunately, this also means that half of the patients with melanoma do not respond to current therapies and live less than 5 years after diagnosis. One major factor that contributes to lower response in this population is acquired or primary resistance to immunotherapies via tumor immune evasion. To improve the overall survival of melanoma patients new treatment strategies must be designed to minimize the risk of acquired resistance and overcome existing primary resistance. In recent years, many advances have been made in identifying and understanding the pathways that contribute to tumor immune evasion throughout the course of immunotherapy treatment. In addition, results from clinical trials focusing on treating patients with immunotherapy-resistant melanoma have reported some initial findings. In this review, we summarize important mechanisms that drive resistance to immunotherapies in patients with cutaneous melanoma. We have focused on tumor intrinsic characteristics of resistance, altered immune function, and systemic factors that contribute to immunotherapy resistance in melanoma. Exploring these pathways will hopefully yield novel strategies to prevent acquired resistance and overcome existing resistance to immunotherapy treatment in patients with cutaneous melanoma.
Angiotensin II Receptor Blocker Associated With Less Outcome Risk in Patients With Acute Kidney Disease
Authors: Wu Vin-Cent , Lin Yu-Feng , Teng Nai-Chi , Yang Shao-Yu , Chou Nai-Kuan , Tsao Chun-Hao , Chen Yung-Ming , Chueh Jeff S , Chen Likwang
Published: April 2022

Objective: The aim of this study was to explore the respective use of angiotensin-converting-enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) on the outcomes of patients who could be weaned from dialysis-requiring acute kidney injury (AKI-D).

Methods: This case–control study enrolled 41,731 patients who were weaned from AKI-D for at least 7 days from Taiwan’s National Health Insurance Administration. We further grouped AKI-D patients according to ACEi and ARB use to evaluate subsequent risks of all-cause mortality and re-dialysis. The outcomes included the all-cause mortality and new-onset of end-stage kidney disease (ESKD; re-dialysis) following withdraw from AKI-D.

Results: A total of 17,141 (41.1%) patients surviving AKI-D could be weaned from dialysis for at least 7 days. The overall events of mortality were 366 (48.9%) in ACEi users, 659 (52.1%) in ARB users, and 6,261 (41.3%) in ACEi/ARB nonusers, during a mean follow-up period of 1.01 years after weaning from AKI-D. In regard to all-cause of mortality, pre-dialysis ARB users had lower incidence than ACEi users [hazard ratio (HR 0.82), p = 0.017]. Compared with ACEi/ARB nonusers, continuing ARB users had a significantly low risk of long-term all-cause mortality (adjusted hazard ratio 0.51, p = 0.013) after propensity score matching. However, new users of ACEi at the acute kidney disease (AKD) period had a higher risk of re-dialysis after weaning than ACEi/ARB nonusers (aHR 1.82, p < 0.001), whereas neither ACEi nor ARB users confronted significantly increased risks of hyperkalemia after weaning.

Conclusions: Compared with patients without ACEi/ARB, those continuing to use ARB before the event and after weaning had low all-cause mortality, while new users of ACEi at AKD had increased risk of re-dialysis. AKI-D patients continuing to use ACEi or ARB did not have higher risk of hyperkalemia. Future prospective randomized trials are expected to confirm these findings.
Xuedan Sustained Release Pellets Ameliorate Dextran Sulfate Sodium–Induced Ulcerative Colitis in Rats by Targeting Gut Microbiota and MAPK Signaling Pathways
Authors: Zhang Yingchun , Feng Dan , Zeng Yue , Zhang Hanyu , Du Xiaohong , Fu Yang , Wang Xinhui , Lian Dingyue , Wang Ruikang , Xiao Hongyu , Wei Ning , Zhai Fuqiang , Liu Hanru
Published: April 2022

Cucurbitacins have a variety of bioactivities, such as anticancer, anti-inflammatory, antidepressant-like, and antiviral effects, but their pharmacological effect in ulcerative colitis (UC) has not been reported until now. Thus, this study aims to investigate the preventive effects of Xuedan sustained release pellets (XSPs) on UC rats and the underlying mechanisms. XSPs were prepared by extracting cucurbitacins from Hemsleya. Experimental UC rats were induced by the intake of 4% dextran sulfate sodium (DSS) for a week and treated with different doses of XSP (0.95, 1.90, and 3.8 mg/kg). The body weight, colon length, disease activity index (DAI), and histological changes of colonic tissue were measured. In addition, the expressions of pro-inflammatory cytokines were detected by using the enzyme-linked immunosorbent assay. Pathways involved in the intestinal inflammation were targeted by RNA-sequencing. Moreover, the changes of gut microbial diversity and composition were analyzed by the 16SrNA analysis and the contents of short-chain fatty acids (SCFAs) were detected by GC-MS. The results revealed that XSP intervention greatly restored the weight loss and colonic shortening (p < 0.05) and reduced the raised DAI scores, myeloperoxidase, and nitric oxide activities in UC in rats (p < 0.05). XSP administration also downregulated the protein levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α. Notably, it was found that XSP considerably suppressed the activation of the MAPK signaling pathway. In addition, XSP treatment improved the balance of gut microbiota that was disturbed by DSS. The beneficial bacteria Lachnospiraceae_NK4A136 group and Lactobacillus at the genus level significantly increased in the XSP group, which had decreased with the use of DSS (p < 0.05). Pathogenic bacteria including Escherichia–Shigella and Bacteroides in UC in rats were reduced by XSP intervention. Furthermore, XSP significantly elevated the production of SCFAs in UC in rats (p < 0.05). These alterations in inflammatory status were accompanied with changes in gut microbiota diversity and SCFA production. In conclusion, XSP exhibited protective effects against DSS-induced UC in rats. XSP treatment decreased inflammation via modulation of gut microbiota composition and SCFA production.
Observation of Voriconazole in the Treatment of Liver Failure Complicated With Invasive Pulmonary Fungal Infection Induced by Chinese Patent Medicine in Teenagers: 2 Case Reports
Authors: Su Qian , Pan Jinjin , Zhang Li , Xia Lingling , Gao Yufeng , Li Jiabin
Published: April 2022

Background: Drug-induced liver injury (DILI) caused by Chinese patent medicines is increasing in China. The incidence of invasive fungal infections (IFIs) is increasing due to the suppression of the immune function in greater numbers of patients. Invasive procedures such as deep vein catheterization and the use of glucocorticoids are also predisposing factors to IFIs. The clinical presentation of IFI in teenagers is often atypical, challenging to diagnose, difficult to treat, and associated with a high fatality rate.

Case presentation: Herein, we report 2 teenagers with liver failure after receiving oral Chinese patent medicines. Case 1 was a 14-year-old boy who presented with subacute liver failure who had been administered a Chinese patent medicine that included acetaminophen. Administration of glucocorticoids and non-bioartificial liver treatment improved his condition. Subsequently, invasive pulmonary Aspergillus (IPA) was diagnosed and was successfully treated with voriconazole for 85 days. Case 2 was a 17-year-old girl who presented with acute liver failure after taking the Chinese patent medicine QubaiBabuqi tablets for vitiligo. Chest computed tomography (CT) revealed multiple pulmonary nodules with an intermittent low-grade fever, and she was diagnosed with IPA. She was initially treated with caspofungin (23 days) and then voriconazole (406 days) for 429 days. Her liver function returned to normal, and lung lesions were absorbed in 2 patients. At the same time, two to three histopathological examinations of the liver biopsy showed that the drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy.

Conclusion: To the best of our knowledge, this is the first report of the successful treatment of 2 cases of liver failure (Child–Pugh class C) caused by Chinese patent medicines complicated with IPA in teenagers. Drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy.
A Novel Epithelial-Mesenchymal Transition Gene Signature Correlated With Prognosis, and Immune Infiltration in Hepatocellular Carcinoma
Authors: Kong Weihao , Mao Zhongxiang , Han Chen , Ding Zhenxing , Yuan Qianqian , Zhang Gaosong , Li Chong , Wu Xuesheng , Chen Jia , Guo Manyu , Hong Shaocheng , Yu Feng , Liu Rongqiang , Wang Xingyu , Zhang Jianlin
Published: April 2022

Background: Although many genes related to epithelial-mesenchymal transition (EMT) have been explored in hepatocellular carcinoma (HCC), their prognostic significance still needs further analysis.

Methods: Differentially expressed EMT-related genes were obtained through the integrated analysis of 4 Gene expression omnibus (GEO) datasets. The univariate Cox regression and Lasso Cox regression models are utilized to determine the EMT-related gene signature. Based on the results of multivariate Cox regression, a predictive nomogram is established. Time-dependent ROC curve and calibration curve are used to show the distinguishing ability and consistency of the nomogram. Finally, we explored the correlation between EMT risk score and immune immunity.

Results: We identified a nine EMT-related gene signature to predict the survival outcome of HCC patients. Based on the EMT risk score’s median, HCC patients in each dataset were divided into high and low-risk groups. The survival outcomes of HCC patients in the high-risk group were significantly worse than those in the low-risk group. The prediction nomogram based on the EMT risk score has better distinguishing ability and consistency. High EMT risk score was related to immune infiltration.

Conclusion: The nomogram based on the EMT risk score can reliably predict the survival outcome of HCC patients, thereby providing benefits for medical decisions.
Single and Repeated Doses of EGb 761® do not Affect Pharmacokinetics or Pharmacodynamics of Rivaroxaban in Healthy Subjects
Authors: Hoerr Robert , Zimmermann Andrea , Seitz Friedeborg , Dienel Angelika
Published: April 2022

The present drug-drug interaction study investigates whether single or repeated doses of 240 mg Ginkgo biloba extract EGb 761® alter the pharmacokinetics or pharmacodynamics of rivaroxaban in healthy subjects. This was a single-centre, two-period, fixed-sequence trial. In Period 1, rivaroxaban was taken alone. In Period 2, rivaroxaban was given on the first and last of 8 days of EGb 761® treatment. Plasma concentrations of rivaroxaban and anti-Factor Xa activity were determined until 48 h after each rivaroxaban intake. The data of forty-one healthy subjects (25 males, 16 females) aged 21–70 years were evaluable. Geometric mean ratios (90% confidence intervals) for rivaroxaban administered concomitantly with a single or multiple doses of EGb 761® vs. rivaroxaban administered alone were 97.97 (91.78, 104.58) and 96.78 (90.67, 103.31) for maximum concentration (Cmax), 98.55 (94.43, 102.84) and 97.82 (93.73, 102.08) for area under the concentration-time curve (AUC0-∞) of rivaroxaban in plasma (primary endpoints), 98.19 (92.00, 104.80) and 99.78 (93.43, 106.55) for maximum effect (Emax), 99.46 (93.63, 105.66) and 99.12 (93.25, 105.35) for area under the effect curve (AUEC0-48). All 90% confidence intervals were within the prespecified range of 80%–125%. Neither adverse events related to haemorrhages nor clinically significant findings in haematology or coagulation parameters were observed. The treatments were safe and well-tolerated. Single and repeated doses of EGb 761® neither affect plasma concentrations of rivaroxaban nor anti-Factor Xa activity in healthy subjects.
Elastoresistivity of Heavily Hole-Doped 122 Iron Pnictide Superconductors
Authors: Hong Xiaochen , Sykora Steffen , Caglieris Federico , Behnami Mahdi , Morozov Igor , Aswartham Saicharan , Grinenko Vadim , Kihou Kunihiro , Lee Chul-Ho , Büchner Bernd , Hess Christian
Published: April 2022

Nematicity in heavily hole-doped iron pnictide superconductors remains controversial. Sizeable nematic fluctuations and even nematic orders far from magnetic instability were declared in RbFe2As2and its sister compounds. Here, we report a systematic elastoresistance study of a series of isovalent- and electron-doped KFe2As2crystals. We found divergent elastoresistance on cooling for all the crystals along their [110] direction. The amplitude of elastoresistivity diverges if K is substituted with larger ions or if the system is driven toward a Lifshitz transition. However, we conclude that none of them necessarily indicates an independent nematic critical point. Instead, the increased nematicity can be associated with another electronic criticality. In particular, we propose a mechanism for how elastoresistivity is enhanced at a Lifshitz transition.
Low-Intensity Resistance Exercise Combined With Blood Flow Restriction is More Conducive to Regulate Blood Pressure and Autonomic Nervous System in Hypertension Patients—Compared With High-Intensity and Low-Intensity Resistance Exercise
Authors: Zhao Yan , Zheng Yuchan , Ma Xiaohuan , Qiang Lili , Lin Aicui , Zhou Mo
Published: April 2022

Background: The effect of resistance exercise on the autonomic nervous system of patients with hypertension has not been identified.

Objective: To explore a suitable resistance training method for hypertension patients to regulate blood pressure (BP) and autonomic nervous system function.

Method: Forty-five hypertension patients aged between 55 and 70 years were randomly equally divided into three groups: the high-intensity resistance exercise (HE) group, the low-intensity resistance exercise combined with blood flow restriction (LE-BFR) group, and the low-intensity resistance exercise (LE) group. All patients performed quadriceps femoris resistance exercise. The exercise intensity of HE, LE-BFR and LE group was 65, 30 and 30% of one repetition maximum (1RM), respectively. The LE-BFR group used pressure cuffs to provide 130% of systolic pressure to the patient’s thighs during resistance exercise. The training program was 20 times/min/set with a 1-min break after each set, and was conducted five sets/day and 3 days/week, lasting for 12 weeks. The heart rate (HR), BP, root-mean-square of difference-value of adjacent RR intervals (RMSSD), low frequency (LF) and high frequency (HF) were evaluated before and after the first training and the last training.

Result: Significant differences in HR were observed in both recovery states after the first and last training (p < 0.01). After 12 weeks of training, the recovery speed of HR in the LE-BFR group increased significantly (p < 0.01). The systolic blood pressures in the HE and LE-BFR group were significantly reduced (p < 0.05 and p < 0.01), and the differences among groups were significant (p < 0.01). In the last recovery state, the RMSSD of the LE group was significantly lower than that in the first recovery state (p < 0.01). The LF/HF ratios of the HE and LE groups in the resting and recovery states were increased significantly (all p < 0.01). LF/HF ratios in the LE-BFR group in the resting and recovery state were decreased significantly (both p < 0.01).

Conclusion: Compared to HE and LE, LE-BFR could effectively decrease systolic pressure and regulate the autonomic nervous system function in hypertension patients.
Effect of an Ultra-Endurance Event on Cardiovascular Function and Cognitive Performance in Marathon Runners
Authors: Perrotta Andrew S. , Jeklin Andrew T. , Bredin Shannon S. D. , Shellington Erin M. , Kaufman Kai L. , de Faye Amanda , Miles Rosalin M. , Warburton Darren E. R.
Published: April 2022

Background

Ultra-marathon running participation has become increasingly more popular in recent years; however, there is inconclusive evidence concerning the effects of participation on cognition and cardiovascular function. The purpose of this study was to examine alterations in cardiovascular function and cognitive performance and their association in ultra-marathon runners prior to and following an ultra-endurance event.

Methods

In total, 24 runners (19 males and 5 females) participated in an ultra-marathon race (FatDog120) held in British Columbia, Canada. Participants competed in varying races distances [48 km (n = 2), 80 km (n = 7), 113 km (n = 3), and 193 km (n = 12)]. Cognition was assessed prior to and upon race completion using simple reaction time, choice reaction time, discrimination reaction time, and recognition memory (% correct). Cardiovascular function was assessed prior to and upon race completion using radial applanation tonometry for diastolic pulse contour examination.

Results

Cognitive performance displayed significantly (p < 0.001) slower reaction times post-race for simple (30.2%), discrimination (22.7%), and choice reaction time (30.5%), as well as a significant (p < 0.05) reduction in memory test performance (−8.2%). A significant association between systemic vascular resistance and choice reaction time was observed post-race (r = 0.41, p < 0.05). Significant changes in post-race cardiovascular function were observed in resting heart rate (31.5%), cardiac output (27.5%), mean arterial blood pressure (−5.6%), total systemic resistance (−17.6%), systolic blood pressure (−7.0%), pulse pressure (−11.2%), and rate pressure product (22.4%). There was evidence of enhanced cardiovascular function being associated with improved cognitive performance before and after the ultra-endurance event.

Conclusion

Ultra endurance running is associated with marked impairments in cognitive performance that are associated (at least in part) with changes in cardiovascular function in healthy adults.
GhSOC1s Evolve to Respond Differently to the Environmental Cues and Promote Flowering in Partially Independent Ways
Authors: Ma Limei , Yan Yuanyuan
Published: April 2022

Gossypium hirsutum is most broadly cultivated in the world due to its broader adaptation to the environment and successful breeding of early maturity varieties. However, how cotton responds to environmental cues to adjust flowering time to achieve reproductive success is largely unknown. SOC1 functions as an essential integrator for the endogenous and exogenous signals to maximize reproduction. Thus we identified six SOC1-like genes in Gossypium that clustered into two groups. GhSOC1-1 contained a large intron and clustered with monocot SOC1s, while GhSOC1-2/3 were close to dicot SOC1s. GhSOC1s expression gradually increased during seedling development suggesting their conserved function in promoting flowering, which was supported by the early flowering phenotype of 35S:GhSOC1-1 Arabidopsis lines and the delayed flowering of cotton silencing lines. Furthermore, GhSOC1-1 responded to short-day and high temperature conditions, while GhSOC1-2 responded to long-day conditions. GhSOC1-3 might function to promote flowering in response to low temperature and cold. Taken together, our results demonstrate that GhSOC1s respond differently to light and temperature and act cooperatively to activate GhLFY expression to promote floral transition and enlighten us in cotton adaptation to environment that is helpful in improvement of cotton maturity.
The Nexuses Between Social Media Marketing Activities and Consumers’ Engagement Behaviour: A Two-Wave Time-Lagged Study
Authors: Shang Yunfeng , Rehman Hina , Mehmood Khalid , Xu Aidi , Iftikhar Yaser , Wang Yifei , Sharma Ridhima
Published: April 2022

This study examined how social media marketing activities (SMMA) influence consumers’ engagement behaviour in developing countries. Based on the stimulus-organism-response theory, we examined the effect of SMMA on consumers’ engagement intention and further investigated the moderating effect of social media sales intensity. The study employed a time-lagged design with two waves to confirm the hypothesised framework. The study findings showed that SMMA positively influence consumers’ engagement intention and engagement behaviour. In addition, social media sales intensity strengthens the link between engagement intention and engagement behaviour. This study adds to the literature on social media and discusses its practical implications.
Perceptual Cue Weighting Is Influenced by the Listener's Gender and Subjective Evaluations of the Speaker: The Case of English Stop Voicing
Authors: Yu Alan C. L.
Published: April 2022

Speech categories are defined by multiple acoustic dimensions and their boundaries are generally fuzzy and ambiguous in part because listeners often give differential weighting to these cue dimensions during phonetic categorization. This study explored how a listener's perception of a speaker's socio-indexical and personality characteristics influences the listener's perceptual cue weighting. In a matched-guise study, three groups of listeners classified a series of gender-neutral /b/-/p/ continua that vary in VOT and F0 at the onset of the following vowel. Listeners were assigned to one of three prompt conditions (i.e., a visually male talker, a visually female talker, or audio-only) and rated the talker in terms of vocal (and facial, in the visual prompt conditions) gender prototypicality, attractiveness, friendliness, confidence, trustworthiness, and gayness. Male listeners and listeners who saw a male face showed less reliance on VOT compared to listeners in the other conditions. Listeners' visual evaluation of the talker also affected their weighting of VOT and onset F0 cues, although the effects of facial impressions differ depending on the gender of the listener. The results demonstrate that individual differences in perceptual cue weighting are modulated by the listener's gender and his/her subjective evaluation of the talker. These findings lend support for exemplar-based models of speech perception and production where socio-indexical features are encoded as a part of the episodic traces in the listeners' mental lexicon. This study also shed light on the relationship between individual variation in cue weighting and community-level sound change by demonstrating that VOT and onset F0 co-variation in North American English has acquired a certain degree of socio-indexical significance.
Design of Longitudinal-Bending Coupled Horn of a Giant Magnetostriction Transducer
Authors: Li Pengyang , Chen Yunshuai , Li Wei , Sun Jian , Li Jian , Wang Kai
Published: April 2022

This article presents a design method of Longitudinal-Bending Coupled Horn (L-BCH) of a giant magnetostrictive transducer utilized in spinning ultrasonic machining. The structural parameters are initially determined by the design theory of the horn and thick disc. Then, the effect of the structural parameters of the rotating wheel on the vibration characteristics of the L-BCH are explored by the model and harmonic response analysis through the finite element method. Through continuous modification of the geometrical parameters of the rotary wheel, the L-BCH meeting the requirements of a giant magnetostrictive transducer is designed. Finally, the frequency and amplitude measurements are performed on the prototype by the impedance analyzer and the laser vibrometer. The finite element analysis and experimental results show that: the large diameter, small diameter, thickness, and fillet radius of the rotating wheel have different impacts on the dynamic characteristics of the L-BCH. Among them, the thickness of the rotary wheel has the most significant influence on the natural frequency and amplitude. In addition, the rotating wheel has a pitch circle when the longitudinal-bending coupled vibration occurs, and the structure itself also has the characteristic of amplifying amplitude.
An Inverse Dynamics-Based Control Approach for Compliant Control of Pneumatic Artificial Muscles
Authors: Baysal Cabbar Veysel
Published: April 2022

Rehabilitation is an area of robotics in which human–robot collaboration occurs, requiring adaptation and compliance. Pneumatic artificial muscles (PAM) are soft actuators that have built-in compliance making them usable for rehabilitation robots. Conversely, compliance arises from nonlinear characteristics and generates obstructions in modeling and controlling actions. It is a critical issue limiting the use of PAM. In this work, multi-input single-output (MISO) inverse modeling and inverse dynamics model learning approaches are combined to obtain a novel nonlinear adaptive control scheme for single PAM-actuated 1-DoF rehabilitation devices, for instance, continuous passive motion (CPM) devices. The objective of the proposed system is to bring an alternative solution to the compliant operation of PAM while performing exercise trajectories, to satisfy requirements such as larger range of motion (ROM) and adaptability to external load impedance variations. The control system combines the operation of a nonlinear autoregressive network with exogenous inputs (NARX)-based inverse dynamics estimator used as a global range controller and cascade PIDs for local position and pressure loops. Implementation results demonstrated the efficacy of the introduced method in terms of compliant operation for dynamic external load variations as well as a stable operation in case of impulsive disturbances. To summarize, a simple but efficient method is illustrated to facilitate the common use of PAM.
Bionic Design Method of a Non-Uniform Lattice Structure for a Landing Footpad
Authors: Deng Haoyu , Zhao Junpeng , Wang Chunjie
Published: April 2022

Due to its excellent performance and high design freedom, the lattice structure has shown excellent capabilities and considerable potential in aerospace and other fields. Inspired by the bamboo structure, a lattice cell configuration namely BCC4IZ is designed and a lattice alternative layout is obtained. Then, a design and modeling method for non-uniform lattice structures is proposed. Four designs of the landing footpad with different kinds of lattice cells are developed. A series of dynamic explicit finite element simulations were conducted to evaluate and compare the energy absorption and capacity of resisting impact deformation performance of different designs. The results show that the combination of the bionic design and the lattice structure can effectively improve the performance of the lattice-filled footpad. This study proves the feasibility and potential of application for bionic design in lattice structure.
Intercropping Practices in Mediterranean Mandarin Orchards from an Environmental and Economic Perspective
Authors: Martin-Gorriz Bernardo , Zabala José A. , Sánchez-Navarro Virginia , Gallego-Elvira Belén , Martínez-García Víctor , Alcon Francisco , Maestre-Valero José Francisco
Published: April 2022

Crop diversification is becoming increasingly important for preserving soil and ecosystems’ health and, subsequently, crop productivity and sustainability. Intercropping practices adopted in monocultural woody crops, with herbaceous crops covering the otherwise bare alleyways, foster ecological interactions and can provide both environmental and economic advantages. In this study, intercropping practices were implemented in a traditional mandarin orchard in south-eastern Spain, which was monitored for three years to assess their impact on the environmental footprint and profitability. The footprint was quantified with a cradle-to-gate life cycle assessment (LCA), while the costs and revenues assessment was based on materials, labor, and machinery used in the trial. The calculated LCA indicators evidenced that, although the cultivated surface area increases with the integration of the intercrops (fava bean, purslane, cowpea, and barley/vetch mix), this does not imply any additional detrimental effects (resource depletion, acidification, eutrophication, global warming). The economic analysis showed that while intercrops may involve additional production costs, the correct choice of intercrops, purslane, and fava bean, in this case, can reduce the market risks for farmers. Overall, this study shows that positive environmental and economic impacts are to be expected of co-integrated herbaceous crops within the same field as mandarin trees.