bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: A Nation-Wide Multicenter Epidemiological Study in China
Authors: Wu Yun , Han Yiqun , Yu Pei , Ouyang Quchang , Yan Min , Wang Xiaojia , Hu Xichun , Jiang Zefei , Huang Tao , Tong Zhongsheng , Wang Shusen , Yin Yongmei , Li Hui , Yang Runxiang , Yang Huawei , Teng Yuee , Sun Tao , Cai Li , Li Hongyuan , Chen Xi , He Jianjun , Liu Xinlan , Yang Shune , Qiao Youlin , Fan Jinhu , Wang Jiayu , Xu Binghe
Published: February 2021

Background

Clinical guidelines generally recommend endocrine therapy (ET) as first-line treatment of hormone receptor-positive advanced breast cancer (HR+ ABC) whereas chemotherapy (CT) should be considered in the presence of life-threatening disease or limited clinical benefit after three sequential ET regimens. However, it is unclear if real-world clinical practice is in accordance with the current guidelines. This study was to present the real-world treatment patterns and ET regimens among HR+ ABC patients in China.

Methods

Using data from the Nation-wide Multicenter Retrospective Clinical Epidemiology Study of Female Advanced Breast Cancer in China (ClinicalTrials.gov identifier: NCT03047889), we investigated the clinicopathological characteristics, clinical profiles, and treatment patterns of HR+ ABC patients from January 2012 to December 2014.

Results

A total of 2,342 patients with HR+ ABC were included in this study. Our findings revealed that, in comparisons with those receiving initial CT (n = 1445), patients initiated ET (n =402) were significantly older, later recurrent after adjuvant treatment, with a lower rate of visceral involvement and a decreasing quantity of metastatic sites. A total of 1,308 patients received palliative ET while only 18.9% patients (n = 247) reached three lines of ET. Among patients completing more than one line of ET, the median treatment duration was 8 months for the first line, 6 months for the second line, and 3 months for the third line for patients receiving ET. In the advanced setting, the choices of palliative ET regimens were diverse, yet aromatase inhibitor (AI) monotherapy was still the overall mainstay of ET; in contrast, patients were less accessible to everolimus plus AI regimen in this population.

Conclusions

Less than one quarter of patients initiated palliative ET for HR+ ABC in routine clinical practice. Patients who received multi-lines of ET experienced successive shorter durations following each line of therapy. This real-life data provides a solid overview of ET for HR+ ABC from China, indicating unmet need for treatment options that improve the effectiveness of endocrine therapy.
Radiomics Features Predict Telomerase Reverse Transcriptase Promoter Mutations in World Health Organization Grade II Gliomas via a Machine-Learning Approach
Authors: Fang Shengyu , Fan Ziwen , Sun Zhiyan , Li Yiming , Liu Xing , Liang Yuchao , Liu Yukun , Zhou Chunyao , Zhu Qiang , Zhang Hong , Li Tianshi , Li Shaowu , Jiang Tao , Wang Yinyan , Wang Lei
Published: February 2021

The detection of mutations in telomerase reverse transcriptase promoter (pTERT) is important since preoperative diagnosis of pTERT status helps with evaluating prognosis and determining the surgical strategy. Here, we aimed to establish a radiomics-based machine-learning algorithm and evaluated its performance with regard to the prediction of mutations in pTERT in patients with World Health Organization (WHO) grade II gliomas. In total, 164 patients with WHO grade II gliomas were enrolled in this retrospective study. We extracted a total of 1,293 radiomics features from multi-parametric magnetic resonance imaging scans. Elastic net (used for feature selection) and support vector machine with linear kernel were applied in nested 10-fold cross-validation loops. The predictive model was evaluated by receiver operating characteristic and precision-recall analyses. We performed an unpaired t-test to compare the posterior predictive probabilities among patients with differing pTERT statuses. We selected 12 valuable radiomics features using nested 10-fold cross-validation loops. The area under the curve (AUC) was 0.8446 (95% confidence interval [CI], 0.7735–0.9065) with an optimal summed value of sensitivity of 0.9355 (95% CI, 0.8802–0.9788) and specificity of 0.6197 (95% CI, 0.5071–0.7371). The overall accuracy was 0.7988 (95% CI, 0.7378–0.8598). The F1-score was 0.8406 (95% CI, 0.7684–0.902) with an optimal precision of 0.7632 (95% CI, 0.6818–0.8364) and recall of 0.9355 (95% CI, 0.8802–0.9788). Posterior probabilities of pTERT mutations were significantly different between patients with wild-type and mutant TERT promoters. Our findings suggest that a radiomics analysis with a machine-learning algorithm can be useful for predicting pTERT status in patients with WHO grade II glioma and may aid in glioma management.
Knockdown of circRNA circ_0087378 Represses the Tumorigenesis and Progression of Esophageal Squamous Cell Carcinoma Through Modulating the miR-140-3p/E2F3 Axis
Authors: Wang Jing , Wang Qiushuang , Gong Yi , Hu Qiu , Zhang Haoliang , Ke Shaobo , Chen Yongshun
Published: February 2021

Background

We aimed to investigate the function and underlying mechanisms of circ_0087378 in esophageal squamous cell carcinoma (ESCC).

Methods

We verified higher circ_0087378 expression in ESCC tissues by performing qRT-PCR assays. We further confirmed the oncogenic roles of circ_0087378 in ESCC cells through a series of biological function assays. Then, we used an RNA pull-down assay and luciferase reporter assay to identify miR-140-3p that directly interacts with circ_0087378. Subsequent studies were performed to demonstrate that the circ_0087378/miR-140-3p/E2F3 axis promotes ESCC development.

Results

We demonstrated that upregulated circ_0087378 expression was positively associated with tumor size, histological grade, tumor stage, the presence of metastasis, and worse survival in patients with ESCC. Our results further revealed that knockdown of circ_0087378 suppressed the proliferation, migration, and invasion of ESCC cells and reduced tumor growth in vivo. Mechanistically, we showed that circ_0087378 could directly bind to miR-miR-140-3p and relieve the suppression for target E2F3, which accelerated cell proliferation, migration, and invasion. Correlation analysis in ESCC specimens supported the involvement of the circ_0087378/miR-140-3p/E2F3 axis in ESCC progression.

Conclusions

This study demonstrated that circ_0087378 might act as a competing endogenous RNA for miR-140-3p, which could inhibit the tumorigenesis and progression of ESCC through upregulating E2F3 expression.
Deep Neural Networks Outperform the CAPRA Score in Predicting Biochemical Recurrence After Prostatectomy
Authors: Sargos Paul , Leduc Nicolas , Giraud Nicolas , Gandaglia Giorgio , Roumiguié Mathieu , Ploussard Guillaume , Rozet Francois , Soulié Michel , Mathieu Romain , Artus Pierre Mongiat , Niazi Tamim , Vinh-Hung Vincent , Beauval Jean-Baptiste
Published: February 2021

Background

Use of predictive models for the prediction of biochemical recurrence (BCR) is gaining attention for prostate cancer (PCa). Specifically, BCR occurs in approximately 20–40% of patients five years after radical prostatectomy (RP) and the ability to predict BCR may help clinicians to make better treatment decisions. We aim to investigate the accuracy of CAPRA score compared to others models in predicting the 3-year BCR of PCa patients.

Material and Methods

A total of 5043 men who underwent RP were analyzed retrospectively. The accuracy of CAPRA score, Cox regression analysis, logistic regression, K-nearest neighbor (KNN), random forest (RF) and a densely connected feed-forward neural network (DNN) classifier were compared in terms of 3-year BCR predictive value. The area under the receiver operating characteristic curve was mainly used to assess the performance of the predictive models in predicting the 3 years BCR of PCa patients. Pre-operative data such as PSA level, Gleason grade, and T stage were included in the multivariate analysis. To measure potential improvements to the model performance due to additional data, each model was trained once more with an additional set of post-operative surgical data from definitive pathology.

Results

Using the CAPRA score variables, DNN predictive model showed the highest AUC value of 0.7 comparing to the CAPRA score, logistic regression, KNN, RF, and cox regression with 0.63, 0.63, 0.55, 0.64, and 0.64, respectively. After including the post-operative variables to the model, the AUC values based on KNN, RF, and cox regression and DNN were improved to 0.77, 0.74, 0.75, and 0.84, respectively.

Conclusions

Our results showed that the DNN has the potential to predict the 3-year BCR and outperformed the CAPRA score and other predictive models.
Changing Trends in Melanoma Incidence and Decreasing Melanoma Mortality in Hungary Between 2011 and 2019: A Nationwide Epidemiological Study
Authors: Liszkay Gabriella , Kiss Zoltan , Gyulai Roland , Oláh Judit , Holló Péter , Emri Gabriella , Csejtei András , Kenessey István , Benedek Angela , Polányi Zoltán , Nagy-Erdei Zsófia , Daniel Andrea , Knollmajer Kata , Várnai Máté , Vokó Zoltán , Nagy Balázs , Rokszin György , Fábián Ibolya , Barcza Zsófia , Polgár Csaba
Published: February 2021

Background

The incidence of malignant melanoma has continually increased during the past few decades, however, certain reports suggest a recent change in trends. The aim of our study was to examine the epidemiology of melanoma in Hungary.

Methods

This nationwide, retrospective, longitudinal study included melanoma patients diagnosed between 1 January 2009 and 31 December 2019 using the databases of the National Health Insurance Fund (NHIF) and Central Statistical Office (CSO) of Hungary. Age-standardized incidence and cause-specific mortality rates were calculated.

Results

We identified 2,426 and 2,414 new melanoma cases in 2011 and in 2019. Age-standardized incidence rates were higher in males and varied between 28.28 and 34.57/100,000 person-years (PYs), and between 22.63 and 26.72/100,000 PYs in females. We found 16.14 and 18.82% increases in male and female incidence rates from 2011 to 2015 (p=0.067 and p<0.001, respectively), and 12.77 and 11.35% decreases from 2015 to 2019 (p=0.062 and p=0.004, respectively). The change of incidence trends (2011–2015 vs. 2015–2019) was significant in females (p=0.002) and in the total melanoma population (p=0.011), but not in the male population (p=0.063). A 16.55% (95% CI: −27.07 to −4.59; p=0.013) decrease in mortality rates was found in the overall melanoma population.

Conclusions

We observed a significant trend change in melanoma incidence in the female and total melanoma population, and a significant decrease in mortality in the total melanoma population. These changes may be attributed to intensive melanoma awareness campaigns as well as to the increase in screening and access to modern therapies.
A Prognostic Model Based on RNA Binding Protein Predicts Clinical Outcomes in Hepatocellular Carcinoma Patients
Authors: Man Zhongsong , Chen Yongqiang , Gao Lu , Xei Guowei , Li Quanfu , Lu Qian , Yan Jun
Published: February 2021

Dysregulation of RNA binding proteins (RBPs) is closely associated with tumor events. However, the function of RBPs in hepatocellular carcinoma (HCC) has not been fully elucidated. The RNA sequences and relevant clinical data of HCC were retrieved from the The Cancer Genome Atlas (TCGA) database to identify distinct RBPs. Subsequently, univariate and multivariate cox regression analysis was performed to evaluate the overall survival (OS)-associated RBPs. The expression levels of prognostic RBP genes and survival information were analyzed using a series of bioinformatics tool. A total of 365 samples with 1,542 RBPs were included in this study. One hundred and eighty-seven differently RBPs were screened, including 175 up-regulated and 12 down-regulated. The independent OS-associated RBPs of NHP2, UPF3B, and SMG5 were used to develop a prognostic model. Survival analysis showed that low-risk patients had a significantly longer OS and disease-free survival (DFS) when compared to high-risk patients (HR: 2.577, 95% CI: 1.793–3.704, P < 0.001 and HR: 1.599, 95% CI: 1.185–2.159, P = 0.001, respectively). The International Cancer Genome Consortium (ICGC) database was used to externally validate the model, and the OS of low-risk patients were found to be longer than that of high-risk patients (P < 0.001). The Nomograms of OS and DFS were plotted to help in clinical decision making. These results showed that the model was effective and may help in prognostic stratification of HCC patients. The prognostic prediction model based on RBPs provides new insights for HCC diagnosis and personalized treatment.
Chaperone Mediated Autophagy Substrates and Components in Cancer
Authors: Rios Javiera , Sequeida Alvaro , Albornoz Amelina , Budini Mauricio
Published: February 2021

Chaperone-mediated autophagy (CMA) represents a specific way of lysosomal protein degradation and contrary to macro and microautophagy is independent of vesicles formation. The role of CMA in different physiopathological processes has been studied for several years. In cancer, alterations of the CMA principal components, Hsc70 and Lamp2A protein and mRNA levels, have been described in malignant cells. However, changes in the expression levels of these CMA components are not always associated with changes in CMA activity and their biological significance must be carefully interpreted case by case. The objective of this review is to discuss whether altering the CMA activity, CMA substrates or CMA components is accurate to avoid cancer progression. In particular, this review will discuss about the evidences in which alterations CMA components Lamp2A and Hsc70 are associated or not with changes in CMA activity in different cancer types. This analysis will help to better understand the role of CMA activity in cancer and to elucidate whether CMA can be considered as target for therapeutics. Further, it will help to define whether the attention of the investigation should be focused on Lamp2A and Hsc70 because they can have an independent role in cancer progression beyond of their participation in altered CMA activity.
Global Research Trends on Prostate Diseases and Erectile Dysfunction: A Bibliometric and Visualized Study
Authors: Ma Chengquan , Su Hao , Li Hongjun
Published: February 2021

Objectives

To identify the cooperation of authors, countries, institutions and explore the hot topics’ prospects regarding research of prostate diseases and erectile dysfunction (ED).

Methods

Publications on research of prostate diseases and ED were retrieved from the Web of Science Core Collection (WoSCC). Bibliometric analyses were performed using VOSviewer and CiteSpace software. Network maps were generated to evaluate the collaborations between different authors, countries, institutions, and keywords.

Results

A total of 2,599 articles related to study of prostate diseases and ED were identified. We observed gradually increasing in the number of publications from 1998 to 2016, and the trend was to be relatively stable in the past 3 years. Journal of Sexual Medicine (243 papers) owned the highest number of publications and Journal of Urology was the most co-cited journal. Mulhall John P (52 papers) was the top most productive authors and Mcvary Kebin T with the largest numbers of citations (1,589 co-citations) during the past decades. There were active collaborations among the top authors. The USA was the leading contributor in this field with 1,078 papers. Active cooperation between countries and between institutions was observed. The main hot topics included matters related to erectile dysfunction, prostate cancer, quality-of-life, radical prostatectomy, sexual function, and BPH.

Conclusion

Bibliometric analysis provides a comprehensive overview of the development of scientific literature, allowing relevant authors and research teams to recognize the current research status in this field and at the same time provide a reference for formulating future research directions.
Comparison of Growth Velocity Among School Age Children With Different Body Mass Index From Childhood Into Early Adolescence in Hualien County, Taiwan: A Retrospective Cohort Study
Authors: Hsiao Yu-Chao , Wang Jen-Hung , Chu Chia-Hsiang , Chang Yu-Hsun , Chen Jui-Shia , Jan Rong-Hwa , Yang Shang-Hsien , Chen Ming-Chun , Chou Wei-Chih , Chu Shao-Yin , Lai Pei-Chun , Cheng Ching-Feng , Chiu Pin-Yun , Liu Yu-Hsuan , Chang Yung-Chieh
Published: February 2021

Objective: This study aimed to investigate the contribution of high body mass index (BMI) to growth velocity among school-aged children who remained in the same BMI categories for a 6-year period.

Methods: This retrospective cohort study included children who enrolled in the school year 2009 and remained in the same BMI categories during their 1st, 4th, and 7th grades (6–7, 9–10, 12–13 years of age). Annual linear growth velocity and weight gain were calculated and compared between sexes, BMI groups, and different times. Risk analysis and repeated measures analysis of variance were performed to identify the impact of BMI on growth velocity.

Results: Of the 1,637 subjects, 53.0% were male, and 2.5% and 10.9% belonged to BMI groups of overweight and obese, respectively. In students between 6 and 13 years of age, obesity was associated with higher annual weight gain and height gain. Risk analysis showed that obese subjects had higher linear growth velocity than normal BMI groups of both sexes between 6 and 9 years of age. Unexpectedly, overweight and obese girls between 9 and 13 years of age had less linear growth velocity than underweight girls at the same interval. Repeated measures analysis of variance in both sexes showed a significant statistical association between BMI and different times of growth. However, the effect was less in girls between 9 and 13 years of age.

Conclusion: Puberty may dominate over BMI as the main contributor to high growth velocity in girls with underweight BMI emerging into pubertal age.
Clinical Pharmacokinetics of Enalapril and Enalaprilat in Pediatric Patients—A Systematic Review
Authors: Faisal Muhammad , Cawello Willi , Laeer Stephanie ,   The LENA Consortium
Published: February 2021

Purpose: Enalapril has an established safety and efficacy in adults and is used in hypertension, heart failure, and renal failure. In pediatric patients, enalapril is labeled for children with hypertension and used off label in children with heart failure. The systematic literature search aims to assess the current knowledge about enalapril and its active metabolite enalaprilat pharmacokinetics in children as a basis for dose delineation for pediatric patients with heart failure.

Methods: A systematic literature review was performed in the PubMed database using relevant keywords. Dose normalization of relevant pharmacokinetic parameters of the identified studies was done for comparison between different diseases and pediatric age groups.

Results: The literature search has resulted in three pediatric pharmacokinetic studies of enalapril out of which Wells et al. reported about children with hypertension and Nakamura et al., and Llyod et al. presented data for pediatric heart failure patients. The area under the curve values of enalaprilat in hypertensive pediatric patients increased with respect to the age groups and showed maturation of body functions with increasing age. Dose normalized comparison with the heart failure studies revealed that although the pediatric heart failure patients of > 20 days of age showed the area under the curve a similar to that of hypertensive patients, two pediatric patients of very early age (<20 days) were presented with 5–6-fold higher area under the curve values.

Conclusion: Data related to the pharmacokinetics of enalapril and enalaprilat in hypertensive patients and few data for young heart failure children are available. Comparison of dose normalized exposition of the active metabolite enalaprilat indicated similarities between heart failure and hypertensive patients and a potentially high exposition of premature patients but substantially more pharmacokinetic studies are required to have reliable and robust enalapril as well as enalaprilat exposures especially in pediatric patients with heart failure as a basis for any dose delineation.
Simulation-Based Education in the Training of Newborn Care Providers—A Malaysian Perspective
Authors: Pong Kwai-Meng , Teo Jerrold Tze-Ren , Cheah Fook-Choe
Published: February 2021

Simulation-based education (SBE) is increasingly used as an education tool to improve learning for healthcare providers. In newborn care practice, SBE is used in the Neonatal Resuscitation Program (NRP) and training in procedural skills. The NRP is a mandatory course in Malaysia for all house officers (interns) and medical officers (residents) during their pediatric rotation. Almost 30,000 of NRP providers have been trained over the last 5 years. The recent establishment of the Allied Healthcare Center of Excellence (AHCoE), an organization dedicated to promoting SBE, and Malaysian Society for Simulation in Healthcare (MaSSH) aims to enhance the integration of SBE into the healthcare training curriculum and set up a local healthcare simulation educator training program. Our experience in implementing SBE necessitated that we made several important choices. As there was no strong evidence to favor high-fidelity over low-fidelity simulation, and because simulation centers can be very costly to set up with limited resources, we chose SBE mainly in the form of low-fidelity andin situsimulation. We also identified an important developmental goal to train Malaysian instructors on structured debriefing, a critical activity for learning in SBE. Currently, debriefing is often carried out in our centers at anad hocbasis because of time limitation and the lack of personnel trained. Finally, we aim to implement SBE further in Malaysia, with two axes: (1) the credentialing and recertification of physicians and nurses, and (2) the education of lay caregivers of high-risk infants before discharge from the neonatal intensive care unit.
Plasma Amino Acid Concentrations at Birth and Patent Ductus Arteriosus in Very and Extremely Preterm Infants
Authors: Huizing Maurice J. , Borges-Luján Moreyba , Cavallaro Giacomo , González-Luis Gema E. , Raffaeli Genny , Bas-Suárez Pilar , Bakker Jaap A. , Moonen Rob M. , Villamor Eduardo
Published: February 2021

Background: Amino acids are increasingly recognized as bioactive molecules in numerous physiological and pathophysiological pathways. The non-essential amino acid glutamate is vasoactive in the rat ductus arteriosus (DA) and a decrease in its levels within the 1st days of life has been associated with the presence of patent DA (PDA) in extremely preterm infants. However, these findings have not been confirmed in other studies.

Objective: To investigate the possible association between amino acid concentrations in the 1st day of life and the presence of PDA in a cohort of 121 newborns with gestational age (GA) below 30 weeks and birth weight (BW) below 1,500 g.

Methods: Plasma samples were collected 6–12 h after birth and amino acid concentrations were determined by tandem mass spectrometry. Besides PDA, we analyzed the potential association of amino acid concentrations with infant sex, small for GA (SGA, defined as BW < third percentile), antenatal corticosteroids, chorioamnionitis, and preeclampsia. Group differences were analyzed by ANOVA adjusted for GA and BW. A Bonferroni significance threshold of P < 0.0024 was used to correct for multiple testing.

Results: PDA was found in 48 of the 121 infants examined. We observed higher mean levels of glutamate in infants with PDA (147.0 μmol/L, SD 84.0) as compared with those without (106.7 μmol/L, SD 49.1, P = 0.0006). None of the other amino acid concentrations in the PDA group reached the level of statistical significance that was pre-set to correct for multiple comparisons. Glutamate levels were not significantly affected by infant sex, being SGA, or by exposure to antenatal corticosteroids, clinical chorioamnionitis, or preeclampsia.

Conclusion: Our study not only does not confirm the previous findings of low glutamate levels in preterm infants with PDA, but we have even found elevated glutamate concentrations associated with PDA. Nevertheless, despite the high statistical significance, the difference in glutamate levels may lack clinical significance or may be an epiphenomenon associated with the particular clinical condition of infants with PDA.
The Combination of Scutellaria baicalensis Georgi and Sophora japonica L. ameliorate Renal Function by Regulating Gut Microbiota in Spontaneously Hypertensive Rats
Authors: Guan Yiqing , Chen Kai , Quan Dongling , Kang Liangqi , Yang Danni , Wu Huanxian , Yan Mengqiu , Wu Shaoyu , Lv Lin , Zhang Guohua
Published: February 2021

Chronic kidney disease (CKD) is becoming a notable health concern globally. The combination of Scutellaria baicalensis Georgi (SB) and Sophora japonica L. (SJ) has been demonstrated to have anti-hypertensive effects and improve kidney injury clinically. This study aimed to explore the renal protective effect of the combination of SB and SJ against CKD and clarify the potential mechanisms. Male spontaneously hypertensive rats (SHR) were used to induce hypertensive nephropathy and were treated with SB or SJ separately or in combination for 15 weeks, and an antibiotic group was used for a rescue experiment. Blood pressure, serum or urine biochemical markers, serum inflammation factors, short-chain fatty acids (SCFAs), indoxyl sulfate (IS), and oxidative stress indicators were assessed. Western blot analysis was performed to determine the expression of intestinal tight junction proteins, including occludin and ZO-1. The mRNA expression of the SCFAs receptors olfactory 78 (Olfr78) and G protein-coupled receptor 41 (GPR41) was determined by quantitative real-time PCR. Gut microbiota profiles were established via high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene. SB and SJ significantly ameliorated the severity of renal injury induced by hypertension. The combination also decreased the ratio of Firmicutes/Bacteroidetes, increased the relative abundance of Lactobacillus, and reduced that of Clostridiaceae. The intestinal barrier was improved, and the change in dominant bacteria reduced IS accumulation and further inhibited oxidative stress activation in kidneys. SB and SJ increased SCFAs production, inhibited inflammatory factor release, and regulated blood pressure by decreasing the expression of Olfr78 and increasing that of GPR41, then alleviated kidney damage. This research demonstrated the positive effects of SB and SJ in a rat model of hypertensive nephropathy, indicated that the treatment of SB and SJ by improving the intestinal barrier function, increasing SCFAs, reducing inflammation, decreasing IS, and inhibiting oxidative stress reactions.
Feasibility of De-Escalation Implementation for Positive Blood Cultures in Patients With Sepsis: A Prospective Cohort Study
Authors: Pedroso José Victor de Miranda , Motter Fabiane Raquel , Koba Sonia Tiemi , Camargo Mayara Costa , Toledo Maria Inês de , Del Fiol Fernando de Sá , Silva Marcus Tolentino , Lopes Luciane Cruz
Published: February 2021

Purpose: The aim of the present study was to determine whether de-escalation guided by blood cultures for patients with a diagnosis of sepsis, severe sepsis or septic shock reduces mortality, and antimicrobial drug resistance (ADR).

Methods: A prospective, single-center, cohort study was conducted with adults admitted to the ICU with a diagnosis of sepsis, severe sepsis, or septic shock at a public hospital in Sorocaba, State of São Paulo, Brazil, from January 2013 to December 2013. We excluded patients who had negative blood cultures. Patients who had replaced the initial empirical broad-spectrum antibiotic therapy (EAT) by the antibiotic therapy guided by blood cultures were compared with those who continued receiving EAT. The outcome included mortality and antimicrobial drug resistance. We used the Cox regression (proportional hazards regression) and the Poisson regression to analyze the association between antibiotic therapy guided by blood cultures (ATGBC) and outcomes. The statistical adjustment in all models included the following variables: sex, age, APACHE II (Acute Physiology And Chronic Health Evaluation II) score and SOFA (Sequential Organ Failure Assessment) score.

Results: Among the 686 patients who were admitted to the intensive care unit, 91 were included in this study. The mean age of the patients was 52.7 years (standard deviation = 18.5 years) and 70.3% were male. EAT was replaced by ATGBC in 33 patients (36.3%) while 58 patients (63.7%) continued receiving EAT. Overall hospital mortality decreased from 56.9% in patients who received EAT to 48.5% in patients who received ATGBC [Hazard ratio- HR 0.44 (95% CI 0.24–0.82), p = 0.009]. There was no association between ATGBC and ADR [HR 0.90 (95% CI 0.78 – 1.03) p = 0.15].

Conclusions: Although the early and appropriate empirical EAT is undoubtedly an important factor prognostic, ATGBC can reduce the mortality in these patients.
Molecular Mechanism of Action of Repurposed Drugs and Traditional Chinese Medicine Used for the Treatment of Patients Infected With COVID-19: A Systematic Scoping Review
Authors: Lem Fui Fui , Opook Fernandes , Lee Dexter Jiunn Herng , Chee Fong Tyng , Lawson Fahcina P. , Chin Su Na
Published: February 2021

Background: The emergence of COVID-19 as a pandemic has resulted in the need for urgent development of vaccines and drugs and the conduction of clinical trials to fight the outbreak. Because of the time constraints associated with the development of vaccines and effective drugs, drug repurposing and other alternative treatment methods have been used to treat patients that have been infected by the SARS-CoV-2 virus and have acquired COVID-19.

Objective: The objective of this systematic scoping review is to provide an overview of the molecular mechanism of action of repurposed drugs or alternative treatment medicines used to attenuate COVID-19 disease.

Method: The research articles or gray literature, including theses, government reports, and official news online, were identified from four databases and one search engine. The full content of a total of 160 articles that fulfilled our inclusion criteria was analyzed and information about six drugs (ritonavir, lopinavir, oseltamivir, remdesivir, favipiravir, and chloroquine) and four Traditional Chinese Medicines (Shuang Huang Lian Kou Fu Ye, TCM combination of Bu Huan Jin Zheng Qi San and Da Yuan Yin, Xue Bi Jing Injection, and Qing Fei Pai Du Tang) was extracted.

Results: All of the repurposed drugs and complementary medicine that have been used for the treatment of COVID-19 depend on the ability of the drug to inhibit the proliferation of the SARS-CoV-2 virus by binding to enzyme active sites, viral chain termination, or triggering of the molecular pathway, whereas Traditional Chinese Medicine plays a pivotal role in triggering the inflammation pathway, such as the neuraminidase blocker, to fight the SARS-CoV-2 virus.
Ethnobotanical Survey of Natural Galactagogues Prescribed in Traditional Chinese Medicine Pharmacies in Taiwan
Authors: Chao Jung , Ko Chien-Yu , Lin Chin-Yu , Tomoji Maeda , Huang Chia-Hung , Chiang Hung-Che , Yang Jeng-Jer , Huang Shyh-Shyun , Su Shan-Yu
Published: February 2021

Natural medicinal materials have been used to promote breast milk secretion. Here, we investigated the natural medicinal materials prescribed in traditional Chinese medicine (TCM) pharmacies across Taiwan to induce lactation. We collected medicinal materials from 87 TCM pharmacies, identified them in the prescriptions, and analyzed their drug contents. We examined their botanical origins, biological classifications, traditional usage, and modern pharmacological properties. We used the TCM Inheritance Support System to identify core medicinal materials in galactogenous prescriptions. We collected 81 medicinal materials from 90 galactogenous prescriptions. Leguminosae accounted for 12%, whereas Apiaceae accounted for 7% of all materials examined. The primary medicinal plant parts used were roots and seeds. Nineteen frequently used medicinal materials had a relative frequency of citation of greater than or equal to 0.2. According to their efficacy, 58% were warm, 54% were sweet, and 63% were tonifying; 74% of the frequently used medicinal materials have been showed efficacy against breast cancer. The primary core medicinal material was Angelica sinensis (Oliv.) Diels, whereas the secondary core medicinal materials were Tetrapanax papyrifer (Hook.) K. Koch and Hedysarum polybotrys Hand.-Mazz. Most galactogenous prescriptions consisted of multiple materials from Leguminosae and Apiaceae. The mechanisms underlying galactogenous efficacy warrant further investigations.
Isorhynchophylline Ameliorates Cerebral Ischemia/Reperfusion Injury by Inhibiting CX3CR1-Mediated Microglial Activation and Neuroinflammation
Authors: Deng Yuanyuan , Tan Ruirong , Li Fei , Liu Yuangui , Shi Jingshan , Gong Qihai
Published: February 2021

Reperfusion therapy is an effective way to rescue cerebral ischemic injury, but this therapy also shows the detrimental risk of devastating disorders and death due to the possible inflammatory responses involved in the pathologies. Hence, the therapy of ischemia/reperfusion (I/R) injury is a great challenge currently. Isorhynchophylline (IRN), a tetracyclic oxindole alkaloid extracted from Uncaria rhynchophylla, has previously shown neuroprotective and anti-inflammatory effects in microglial cells. This study systematically investigates the effect of IRN on I/R injury and its underlying mechanism. The effects of IRN on neuronal injury and microglia-mediated inflammatory response were assessed on a rat model with middle cerebral artery occlusion (MCAO) and reperfusion-induced injury. We found that IRN treatment attenuated the infarct volume and improved the neurological function in I/R injury rats. IRN treatment also reduced the neuronal death rate, brain water content, and aquaporin-4 expression in the ischemic penumbra of I/R injury rats’ brains. Besides, IRN treatment could inhibit the following process, including IκB-α degradation, NF-κB p65 activation, and CX3CR1 expression, as well as the microglial activation and inflammatory response. These findings suggest that IRN is a promising candidate to treat the cerebral I/R injury via inhibiting microglia activation and neuroinflammation.
Phytochemistry, Pharmacology and Medicinal Uses of Plants of the Genus Salix: An Updated Review
Authors: Tawfeek Nora , Mahmoud Mona F. , Hamdan Dalia I , Sobeh Mansour , Farrag Nawaal , Wink Michael , El-Shazly Assem M.
Published: February 2021

The Willows (genus Salix), with more than 330–500 species and 200 hybrids, are trees, shrubs or prostrate plants that are widely distributed in Africa, North America, Europe, and Asia. The genus is traditionally used in folk medicine and represents a valuable source of biologically active compounds among them salicin, a prodrug for salicylic acid. Altogether, 322 secondary metabolites were characterized in the genus including flavonoids 94) (flavonols, flavones, flavanones, isoflavones, flavan-3-ols (catechins and procyanidins), chalcones, dihydrochalcone, anthocyanins, dihydroflavonols), phenolic glycosides (76), organic acids (28), and non-phenolic glycosides (17), sterols and terpenes (17), simple phenolics 13) and lignans 7) in addition to volatiles and fatty acids (69). Furthermore, willows exert analgesic, anti-inflammatory, antioxidant, anticancer, cytotoxic, antidiabetic, antimicrobial, antiobesity, neuroprotective and hepatoprotective activities. The current review provides an updated summary of the importance of willows, their chemical composition and pharmacological activities.
Cardiotoxicity Induced by Immune Checkpoint Inhibitors: A Pharmacovigilance Study From 2014 to 2019 Based on FAERS
Authors: Chen Chenxin , Chen Ting , Liang Jizhou , Guo Xiaojing , Xu Jinfang , Zheng Yi , Guo Zhijian , Chi Lijie , Wei Lianhui , Chen Xiao , Ye Xiaofei , He Jia
Published: February 2021

This study was to scientifically and systematically explore the association between cardiotoxicity and immune checkpoint inhibitors (ICIs) and also to characterize the spectrum of ICI-related cardiac complications. From the first quarter of 2014 to the fourth quarter of 2019, data from the FDA Adverse Event Reporting System database were selected to conduct the disproportionality analysis. Reporting odds ratios and information components were used to evaluate the signal after statistical shrinkage transformation. In total, 7,443,137 cases and 36,326,611 drug-adverse event pairs were collected, among which 9,271 cases were identified to be related to ICI-induced cardiotoxicities. The number of male patients was much higher than that of females (5,579 vs. 3,031) and males presented a slightly higher reporting frequency than females in general, which was statistically significant (ROR = 1.04, 95%CI: 0.99–1.09, p < 0.001). Simultaneously, the proportion of serious or life-threatening outcomes in males was significantly higher than in females (ROR = 1.05, 95%CI: 0.96–1.15, p < 0.001). Importantly, ICIs were associated with over-reporting frequencies of cardiotoxicities in general (ROR025 = 1.06, IC025 = 0.08). PD-1 and PD-L1 were found to be related to cardiac adverse events, corresponding to ROR025 = 1.06, IC025 = 0.08, and ROR025 = 1.06, IC025 = 0.08, respectively, while anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) was significantly associated with some specific adverse events rather than common adverse events. The spectrum of cardiotoxicities induced by ICIs mostly differed among individual agents, but also demonstrated some common features. Dyspnea (N = 2,527, 21.25%), myocarditis (N = 614, 5.16%), atrial fibrillation (N = 576, 4.84%), cardiac failure (N = 476, 4.00%), and pericardial effusion (N = 423, 3.56%) were the top five cardiac adverse events reported in the database. Among them, myocarditis was the only one caused by all ICIs with strong signal value and high risk, warranting further attention. Overall, this investigation mainly showed the profile of cardiotoxicities caused by ICIs, which varied between different ICI therapies, but also shared some similarities in specific symptoms such as myocarditis. Therefore, it is vital and urgent to recognize and manage ICI-related cardiotoxicities, known to frequently occur in clinical practice, at the earliest point.
Effectiveness of Benralizumab in Improving the Quality of Life of Severe Eosinophilic Asthmatic Patients: Our Real-Life Experience
Authors: Scioscia Giulia , Carpagnano Giovanna Elisiana , Quarato Carla Maria Irene , Lacedonia Donato , Santamaria Sonia , Soccio Piera , Depalo Annarita , Fuso Paolo , Foschino Barbaro Maria Pia
Published: February 2021

Background: Severe eosinophilic asthma decreases lung function and causes worsen symptoms, often forcing recurrent maintenance corticosteroid use. The aim of our real-life study was to evaluate the effectiveness of an add-on treatment with benralizumab in patients with severe eosinophilic asthma, paying particular attention to the impact on their quality of life (QoL).

Materials and methods: In this prospective study, 10 outpatients with severe eosinophilic asthma were added-on with benralizumab and followed-up in our severe asthma clinic after 12 and 24 weeks. At each patient visit, pre-bronchodilator FEV1 and inflammatory markers were recorded. Variations in asthma symptoms control and QoL perception was assessed by validated questionnaires.

Results: All the subjects experienced a marked reduction of nocturnal and diurnal symptoms over time and were able to stop using OCS, as documented by the improvement in Asthma control test (ACT) and Asthma Control Questionnaire score. Similarly, we recorded a statistically significant increase in patient’s QoL perception in EQ-VAS, EQ-5D-3L and Asthma Quality of Life Questionnaire (AQLQ) assessment (p < 0.05). Simultaneously we recorded a significant reduction in eosinophilic inflammation, an improvement in pre-bronchodilator FEV1. These results appear to be in line with those already obtained in the previous randomized controlled trials (RCTs).

Conclusion: Our 24-weeks real life experience supports the effectiveness of an add-on treatment with benralizumab in reducing eosinophilic inflammation and OCS-use, increasing lung function and improving control of nocturnal and diurnal symptoms, as well as restoring severe asthma patients to a better QoL.
Impedimetric Analysis of Trabecular Bone Based on Cole and Linear Discriminant Analysis
Authors: Wei Wenzuo , Shi Fukun , Kolb Juergen F.
Published: February 2021

A spatially unambiguous characterization of electrical properties of osseous tissues is important for the therapy of osteopathy via electrical stimulation. Accordingly, the study aimed to characterize the highly inhomogeneous composition and structures of different anatomical regions of trabecular bone based on their electrical properties. The electrical properties of 64 porcine trabecular bone samples were analyzed in a parallel plate electrode configuration and compared with published results. Therefore, a novel method, combining traditional Cole model with a linear discriminant analysis (LDA), was developed to discriminate the different regions, i.e., femur head, greater trochanter, and femur neck. Possible mechanisms behind the distinction for different regions could be interpreted from both methods. Respective adjacent regions with similar structure and composition could be distinguished from statistically significant differences of Cole parameters, i.e., α (p < 0.01) and R∞ (p < 0.05). The latter was correlated especially with water content, indicating an association of individual differences in microstructures in particular with conductivity. Conversely, different regions were unambiguously discriminated with LDA based on permittivity or conductivity. Contributions to the discrimination were explicitly reflected by the coefficients of the derived LDA features. A clear distinction was obtained especially for a frequency response at 950 kHz. Moreover, predictions for the classification of unspecified samples assigned them correctly to their origin with a success of 92.9%. The combination of both methods offers the possibility for a spatially resolved and eventually patient specific discrimination and evaluation of bone tissues and their response to therapies, notably electrical stimulation.
External Counterpulsation Attenuates Hypertensive Vascular Injury Through Enhancing the Function of Endothelial Progenitor Cells
Authors: Liang Jianwen , Shi Jian , Wei Wenbin , Wu Guifu
Published: February 2021

Background

Vascular injury is a landmark of hypertension and enhanced external counterpulsation (EECP) has been identified as a noninvasive treatment to restore the capacity of endothelial cells. However, the effect of EECP on blood pressure lowering in hypertension and the potential mechanism remain unknown.

Methods

We measured the ambulatory blood pressure (AMBP) and flow-mediated endothelial dilation (FMD) in the essential hypertensive patients who were randomly assigned to the EECP group (n = 20) or control group (n = 20). We also evaluated in vitro function of endothelial progenitor cells (EPCs). Furthermore, multivariate analysis was performed to determine the actual correlation between EPC function and FMD.

Results

Compared with the control, EECP group exhibited decreased systolic [(133.2 ± 4.9) mmHg vs. (139.3 ± 6.4) mmHg, P < 0.05] and diastolic [(83.4 ± 4.5) mmHg vs. (89.5 ± 7.6) mmHg, P < 0.05] blood pressure and increased FMD value [(8.87 ± 2.46%) vs. (7.51 ± 2.32%), P < 0.01]. In addition, the migration [(47.3 ± 6.4)/hpf vs. (33.4 ± 5.1) hpf, P < 0.05] and adhesion [(45.1 ± 5.5)/hpf vs. (28.4 ± 3.9) hpf, P < 0.05] functions of EPCs in the EECP group were improved significantly, whereas no change was observed in the control. Both migration [odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.27–0.64, P < 0.05] and adhesion (OR = 0.44, 95% CI = −0.0034 to 0.0012, P < 0.05) of EPCs correlated with FMD. After multivariate analysis, the migration (β = 3.37, 95% CI = 1.67–5.33, P < 0.05) and adhesion (β = 3.98, 95% CI = 1.12–6.43, P < 0.05) functions still independently correlated to FMD.

Conclusion

The present study demonstrates for the first time that EECP decreases both systolic and diastolic blood pressure and increases FMD value in hypertension. The fall in endogenous EPCs repair capacity might be an important mechanism of hypertensive vascular injury and could be restored by EECP.
Association Between Intermittent Hypoxia and Left Ventricular Remodeling in Patients With Obstructive Sleep Apnea-Hypopnea Syndrome
Authors: Deng Ming , Huang Yi-teng , Xu Jian-qing , Ke Xiao , Dong Yi-fei , Cheng Xiao-shu
Published: February 2021

The present study was undertaken to examine the association between intermittent hypoxia and left ventricular (LV) remodeling and explore which parameter of intermittent hypoxia is most relevant to LV remodeling in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). Two hundred eighty six patients underwent polysomnographic examination were enrolled. Based on apnea-hypoxia index (AHI), patients were divided into no, mild, moderate and severe OSAHS groups. Between-group differences in LV remodeling and the association between parameters of intermittent hypoxia and LV remodeling was evaluated. Patients with severe OSAHS were more likely to have hypertension, and higher values of LV mass (LVM) and LVM index (LVMI). In univariate regression analysis, male, body mass index (BMI), systolic and diastolic blood pressure (BP), statins, antihypertensive drugs, creatinine, and parameters of intermittent hypoxia (AHI, obstructive apnea index [OAI], lowest oxygen saturation [LSpO2], oxygen desaturation index [ODI], time spent below oxygen saturation of 90% [TS90%], and mean nocturnal oxygen saturation [MSpO2]) were associated with LVMI. After multivariate regression analyses, only male gender, BMI, systolic BP, creatinine, and ODI remained significantly associated with LVMI. Compared to those without LV hypertrophy (LVH), patients with LVH had higher ODI. Compared to patients with normal LV, concentric remodeling and eccentric LVH, those with concentric LVH had higher ODI. In conclusion, intermittent hypoxia was significantly associated with left ventricular remodeling; and among various parameters of intermittent hypoxia, ODI was the most relevant to LV remodeling.
Time Lag Between Light and Heat Diurnal Cycles Modulates CIRCADIAN CLOCK ASSOCIATION 1 Rhythm and Growth in Arabidopsis thaliana
Authors: Masuda Kosaku , Yamada Tatsuya , Kagawa Yuya , Fukuda Hirokazu
Published: February 2021

Plant growth responses to cues such as light, temperature, and humidity enable the entrainment of the circadian rhythms with diurnal cycles. For example, the temperature variations between day and night affect plant growth and accompany the time lag to light cycle. Despite its importance, there has been no systematic investigation into time lags, and the mechanisms behind the entrainment of the circadian rhythms with multiple cycles remain unknown. Here, we investigated systemically the effects of the time lag on the circadian rhythm and growth in Arabidopsis thaliana. To investigate the entrainment status of the circadian clock, the rhythm of the clock gene CIRCADIAN CLOCK ASSOCIATION 1 (CCA1) was measured with a luciferase reporter assay. As a result, the rhythm was significantly modulated by the time lag with +10°C heating for 4 h every day but not −10°C cooling. A model based on coupled cellular oscillators successfully described these rhythm modulations. In addition, seedling growth depended on the time lag of the heating cycle but not that of the cooling cycle. Based on the relationship between the CCA1 rhythms and growth, we established an estimation method for the effects of the time lag. Our results found that plant growth relates to the CCA1 rhythm and provides a method by which to estimate the appropriate combination of light–dark and temperature cycles.