bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomized, Double‐Blind, Placebo‐ and Positive‐Controlled, Three‐Way Crossover Study in Healthy Participants to Investigate the Effect of Savolitinib on the QTc Interval
Authors: Sahota Tarjinder , Dota Corina D. , Vik Torbjörn , Yan Weili , Verheijen Remy B. , Walker Stephen , Li Yan , Goldwater Ronald , Ghiorghiu Dana , Mellemgaard Anders , Ahmed Ghada F. 
Published: January 2021

AbstractSavolitinib (AZD6094, HMPL‐504, volitinib) is an oral, bioavailable, selective MET‐tyrosine kinase inhibitor. This randomized, double‐blind, 3‐way, crossover phase 1 study of savolitinib versus moxifloxacin (positive control) and placebo‐evaluated effects on the QT interval after a single savolitinib dose. Healthy non‐Japanese men were randomized to 1 of 6 treatment sequences, receiving single doses of savolitinib 600 mg, moxifloxacin 400 mg, and placebo. The primary end point was time‐matched, placebo‐adjusted change from baseline in the QT interval corrected for the time between corresponding points on 2 consecutive R waves on electrocardiogram (RR) by the Fridericia formula (ΔΔQTcF). Secondary end points included 12‐lead electrocardiogram (ECG) variables, pharmacokinetics, and safety. All 3 treatment periods were completed by 44 of 45 participants (98%). Baseline demographics were balanced across treatment groups. After a single savolitinib 600‐mg dose, the highest least‐squares mean ΔΔQTcF of 12 milliseconds was observed 5 hours postdose. Upper limits of the 2‐sided 90% confidence interval for ΔΔQTcF exceeded 10 milliseconds (the prespecified International Council for Harmonisation limit) 3‐6 hours postsavolitinib but otherwise remained less than the threshold. Savolitinib showed no additional effect on PR, QRS, QT, or RR intervals. A positive ΔΔQTcF signal from the moxifloxacin group confirmed study validity. Savolitinib was well tolerated, with a low incidence of adverse events. In this thorough QT/QTc study, QTcF prolongation was observed with a single savolitinib 600‐mg dose. ECG monitoring will be implemented in ongoing and future studies of savolitinib to assess the clinical relevance of the observed QT changes from this study.
Stochastic dominance algorithms with application to mutual fund performance evaluation
Authors: Venkataraman Sree Vinutha , Rao S. V. D. Nageswara 
Published: January 2021

AbstractWhile the possibility for investment A to dominate investment B under the first‐ and second‐order stochastic dominance framework can be tested only at the points of jumps in the probabilities of the distributions, the comparison at interior points is also essential under third‐order, due to the non‐linearity in the difference in the third‐order stochastic dominance integral. Furthermore, it was established that the quantile approach used to test for the first‐ and second‐order dominance does not work under the third‐order. If these points are overlooked, it is possible to conclude that an investment is third‐order inefficient when it is actually efficient. Also, an inefficient investment may not be relegated to the inefficient set. In this work, to test for third‐order efficiency, we derive the expressions for the functions essential for testing the possibility of third‐order stochastic dominance at the interior points and arrive at their restrictions on the common grid of the pairwise investments under consideration. We also develop a program to determine the efficient funds and the funds superior and inferior to the benchmark indices at a fast pace. We find that the size of the efficient set reduces drastically under third‐order. Also, several funds are found to be superior to the indices under second‐ and third‐order.
IL‐37‐induced activation of glycogen synthase kinase 3β promotes IL‐1R8/Sigirr phosphorylation, internalization, and degradation in lung epithelial cells
Authors: Li Lian , Wei Jianxin , Suber Tomeka L. , Ye Qinmao , Miao Jiaxing , Li Shuang , Taleb Sarah J. , Tran Kevin C. , Tamaskar Arya S. , Zhao Jing , Zhao Yutong 
Published: January 2021

AbstractInterleukin (IL)‐37 diminishes a variety of inflammatory responses through ligation to its receptor IL‐1R8/Sigirr. Sigirr is a Toll like receptor/IL‐1R family member. We have shown that Sigirr is not stable in response to IL‐37 treatment. IL‐37‐induced Sigirr degradation is mediated by the ubiquitin‐proteasome system, and the process is reversed by a deubiquitinase, USP13. However, the molecular mechanisms by which USP13 regulates Sigirr stability have not been revealed. In this study, we investigate the roles of glycogen synthesis kinase 3β (GSK3β) in Sigirr phosphorylation and stability. IL‐37 stimulation induced Sigirr phosphorylation and degradation, as well as activation of GSK3β. Inhibition of GSK3β attenuated IL‐37‐induced Sigirr phosphorylation, while exogenous expressed GSK3β promoted Sigirr phosphorylation at threonine (T)372 residue. Sigirr association with GSK3β was detected. Amino acid residues 51–101 in GSK3β were identified as the Sigirr binding domain. These data indicate that GSK3β mediates IL‐37‐induced threonine phosphorylation of Sigirr. Further, we investigated the role of GSK3β‐mediated phosphorylation of Sigirr in Sigirr degradation. Inhibition of GSK3β attenuated IL‐37‐induced Sigirr degradation, while T372 mutant of Sigirr was resistant to IL‐37‐mediated degradation. Furthermore, inhibition of Sigirr phosphorylation prevented Sigirr internalization and association with USP13, suggesting GSK3β promotes Sigirr degradation through disrupting Sigirr association with USP13.
Isoniazid Therapeutic Drug Monitoring in Tunisian Patients With Tuberculosis
Authors: Alshaikheid Mohammed , Romdhane Haifa Ben , Fredj Nadia Ben , Fadhel Najah Ben , Aouam Abir , Chadli Zohra , Boughattas Naceur , Chaabane Amel , Aouam Karim 
Published: January 2021

AbstractA regular therapeutic drug monitoring (TDM) of isoniazid could be useful to predict the acetylation profile and to prescribe doses associated with optimal efficacy and safety. We aimed to assess the usefulness of isoniazid TDM in the Tunisian population, to describe the acetylation profile distribution in this population, and to investigate the influence of certain parameters on acetylation phenotype. We performed a retrospective study including Tunisian patients with tuberculosis underwent an isoniazid TDM. Isoniazid concentrations were measured 3 hours after drug intake (C3). Subsequent isoniazid doses were adjusted to maintain the C3 within the recommended target (1‐2 µg/mL). Patients were qualified as slow acetylators (SAs) or rapid acetylators (RAs) according to their acetylation index. Among the 255 patients, 58% were SAs and 42% were RAs. Of all patients, only 30.6% had a C3 value within the target range. A dose adjustment has been performed for patients with C3 outside the target range. C3 was controlled in 77 patients. It became within the target range in 39 patients (50.6%). The median recommended isoniazid weight doses for SAs and RAs were 2.1 ± 0.7 mg/kg and 4.2 ± 1.4 mg/kg, respectively. The multivariate analysis showed that body weight, C3, and C3/isoniazid dose were found to be significantly different between the 2 acetylation groups. In the pediatric group, only 9 had a C3 value within the target range, and all of them were RAs. The irrevocable interest of isoniazid TDM has been shown in Tunisian patients with tuberculosis, in both adult and pediatric patients, as isoniazid demonstrates an unpredictable pharmacokinetic profile.
Concurrent lymphovascular and perineural invasion after preoperative therapy for gastric adenocarcinoma is associated with decreased survival
Authors: Blumenthaler Alisa N. , Newhook Timothy E. , Ikoma Naruhiko , Estrella Jeannelyn S. , Blum Murphy Mariela , Das Prajnan , Minsky Bruce D. , Ajani Jaffer A. , Mansfield Paul F. , Badgwell Brian D. 
Published: January 2021

AbstractBackground and ObjectivesWe sought to evaluate the impact of lymphovascular invasion (LVI) and perineural invasion (PNI) on survival outcomes in gastric cancer patients treated with preoperative therapy.MethodsPatients with gastric cancer treated with preoperative therapy and potentially curative resection were stratified according to the presence of LVI, PNI, or both. Kaplan–Meier and Cox regression analyses were used to evaluate the impact on overall survival (OS) and disease‐free survival (DFS).ResultsThe study included 281 patients, of whom 93 (33%) had LVI, 69 (25%) had PNI, 51 (18%) had both LVI and PNI, and 170 (61%) had neither. LVI and PNI were each associated with higher ypT and ypN categories and more positive lymph nodes (all p < .001), associations that were emphasized with both factors present. On multivariable analyses, ypN (p < .001) and concurrent LVI/PNI (hazard ratio [HR]: 2.62; 95% confidence interval [CI]: 1.55–4.45; p = .001) were predictive of OS and DFS (ypN: p < .001; both LVI/PNI: HR: 2.27; 95% CI: 1.34–3.82; p = .002).ConclusionsGastric cancer patients with concurrent LVI and PNI after preoperative therapy have more advanced disease and worse survival outcomes than patients with neither or only one of these factors.
Identification and determination of chemical constituents from Yinchen Qingjin granules by ultra high‐performance liquid chromatography coupled with linear ion trap‐Orbitrap mass spectrometry
Authors: Lu Jie , Liang Kun , Chen Ying , Zhao Cheng , Wang Xinhong , An Rui 
Published: January 2021

AbstractAn ultra high‐performance liquid chromatography coupled with linear ion trap‐Orbitrap mass spectrometry method had been used to identify chemical constituents in Yinchen Qingjin Granules. A total of 117 chemical constituents were tentatively identified based on the molecular weight, the mass fragmentation behavior, and the comparison with retention time and accurate mass of reference standards. Meanwhile, an ultra high‐performance liquid chromatography coupled with triple quadrupole mass spectrometry method has been developed to evaluate the quality of Yinchen Qingjin Granules through a simultaneous determination of ten components, namely gallic acid, shanzhiside, neochlorogenic acid, chlorogenic acid, caffeic acid, geniposide, liquirition, isoliquirition, glycyrrhizic acid, and rhein. Altogether, content levels of each compound ranged from 0.228 to 8.712 mg/g. At the same time, a hydrophilic interaction liquid chromatography combined with UV for the quantification of sarmentosin in Yinchen Qingjin Granules is presented and its content was from 5.608 to 6.200 mg/g. The linearity, accuracy, and precision of these two validation methods were satisfactory. The both determination methods were successfully used for the analysis of six batches of Yinchen Qingjin Granules samples made in China and could be as suitable analytical method for quality control.
Hymenoptera venom immunotherapy without human serum albumin as a stabilizer in a canine patient
Authors: Apostolopoulos Neoklis , Mayer Ursula 
Published: January 2021

AbstractA four‐month‐old female Beagle, with a history of repeated anaphylactic reactions, was managed with venom immunotherapy (VIT), based on the results of a blood allergy test. Because there is a lack of VIT for dogs, a product from human medicine was used, which requires human serum albumin (HSA) in the solvent as a stabilizer. HSA has been described to cause sensitization and anaphylactic reactions, as well as other adverse effects in dogs. To avoid such adverse effects, water for injection was used as a solvent. VIT was initiated with a one‐day ultra‐rush induction scheme, followed by a conventional protocol as maintenance. The dog was stung by a bee after 11 months of VIT, presenting only mild lip edema. VIT is performed for the last 35 months. To the authors’ knowledge, this is the first report of a successful VIT using water for injection as a solvent, without HSA.
Pore‐scale modeling of microbial activity: What we have and what we need
Authors: Golparvar Amir , Kästner Matthias , Thullner Martin 
Published: January 2021

AbstractUnder water‐unsaturated conditions, environmental factors (e.g., substrate, nutrients, O2, water activity, and porous structure) controlling microbial activity are highly variable in space and time. The physical structure of porous media (pore size distribution and pore arrangements) has been considered to have a significant role in nutrient (either substrate and/or its reaction partners like O2) fluxes. Understanding what eventually controls microbial activity thus requires a sound description of the physical and chemical conditions in the pore space down to the microscale, as well as knowledge on how microorganisms respond to the energy and matter fluxes in their microscale environment. Microscale modeling has the advantage to resolve the processes down to their fundamental level. In recent years, microscale models describing the physical setting in unsaturated porous media such as soils, as well as growth and functional performance of microorganisms, have become increasingly established and are supported by new experimental techniques resolving the distribution of solid, liquid, and gaseous phases at microscale resolution. Still, integration of these components for simulation of microbial activities in a soil system at the microscale is scarce. This mini‐review highlights the available approaches for pore‐scale modeling of flow and transport processes in both saturated and unsaturated porous media, and for modeling the dynamics of microbial activity constrained by different soil boundary conditions. Further, it is discussed what is required in terms of model development and improved modeling concepts to achieve a holistic reactive transport modeling approach describing microbial activity at the pore scale.
Real-world outcome of immune checkpoint inhibitors for advanced hepatocellular carcinoma with macrovascular tumor thrombosis
Authors: Tsai Hong-Ming , Han Meng-Zhi , Lin Yih-Jyh , Chang Ting-Tsung , Chen Chiung-Yu , Cheng Pin-Nan , Chuang Chiao-Hsiung , Wu I-Chin , Chen Po-Jun , Kang Jui-Wen , Chiu Yen-Cheng , Chiu Hung-Chih , Chien Shih-Chieh , Kuo Hsin-Yu 
Published: January 2021

AbstractProgrammed cell death protein-1 (PD-1) inhibitors have shown promising results for treating advanced hepatocellular carcinoma (HCC). However, the clinical utility of such inhibitors in HCC patients with vascular tumor thrombosis remains unclear. This study investigated PD-1 inhibitor efficacy in advanced HCC with macrovascular invasion in a clinical setting. Among the 110 patients with unresectable HCC treated with PD-1 inhibitors, 34 patients with vascular metastases in the portal vein and inferior vena cava were retrospectively compared with 34 patients without tumor thrombi. The vascular response and its effect on survival were assessed. Predictors of survival were identified using multivariate analysis. Among patients achieving objective response, those with and without thrombi exhibited similar response to immunotherapy and comparable survival. Among the 34 patients with tumor thrombi, including 13 receiving PD-1 inhibitors alone and 21 receiving it in combination with tyrosine kinase inhibitors, the median overall survival was 8.9 months (95% confidence interval 3.2–12.6). The objective response rate of vascular metastasis was 52.9%, and vascular responders had a significantly longer survival than did non-responders (11.1 vs 3.9 months). Failure to obtain a vascular response correlated significantly with increased post-treatment Child–Pugh score or class. Multivariate analysis showed that vascular response was a significant positive factor for longer overall survival. Treatment-related grade 3/4 adverse events occurred in 3 (8.8%) of the patients with tumor thrombi. Immunotherapy with PD-1 inhibitors may be a feasible treatment option for HCC with tumor thrombi owing to the high response rate of tumor thrombi and favorable survival outcomes.
The impact of bronchial artery embolisation on the quality of life of patients with haemoptysis: a prospective observational study
Authors: Omachi Naoki , Ishikawa Hideo , Hara Masahiko , Nishihara Takashi , Yamaguchi Yu , Yamamoto Yumiko , Youmoto Mihoko , Hattori Tomoaki , Kitaguchi Kazushi , Yamamoto Shota , Kawaguchi Tomoya , Fukuzawa Masahiro 
Published: January 2021

Abstract
Objectives
Patients with haemoptysis often experience daily physical and mental impairment. Bronchial artery embolisation is among the first-line treatment options used worldwide; however, no evidence exists regarding the health-related quality of life (HRQoL) after bronchial artery embolisation. Therefore, this study aimed to evaluate the effects of bronchial artery embolisation on the HRQoL of patients with haemoptysis.

Methods
We prospectively enrolled 61 consecutive patients who visited our hospital from July 2017 to August 2018 and received bronchial artery embolisation for haemoptysis. The primary outcome was the HRQoL evaluated using the Short Form Health Survey, which contains physical and mental components, before and after bronchial artery embolisation. The secondary outcomes were procedural success, complications, and recurrence-free survival rate at 6 months.

Results
The mean age of the patients was 69 years (range, 31–87 years). The procedural success rate was 98%. No major complications occurred. The recurrence-free survival rate estimated using the Kaplan-Meier analysis at 6 months after bronchial artery embolisation was 91.8% (95% confidence interval, 91.1–92.5%). Compared with the pre-treatment scores, the physical and mental scores were significantly improved at 6 months after bronchial artery embolisation (p < 0.05).

Conclusion
Bronchial artery embolisation improved the HRQoL of patients with haemoptysis.

Key Points
• Bronchial artery embolisation improved the HRQoL of patients with haemoptysis.
• Vessel dilation on computed tomography and systemic artery-pulmonary artery direct shunting on angiography were the most common abnormalities.
• The recurrence-free survival rate estimated using the Kaplan-Meier analysis at 6 months after bronchial artery embolisation was 91.8%.
Magnetic resonance colonography with intestine-absorbable nanoparticle contrast agents in evaluation of colorectal inflammation
Authors: Dong Xue , Luo Jingfeng , Lan Pengxun , Guo Xiuyu , Zhao Xin , Wang Xiaoyan , Zhou Fei , Wang Qiangfeng , Yuan Hong , Sun Jihong 
Published: January 2021

Abstract
Objectives
To develop a nanoparticle-based MRI protocol based on transrectal administration of intestine-absorbable nanoparticle contrast agents to evaluate ulcerative colitis (UC).

Methods
Solid lipid nanoparticles (SLNs) were synthesized by loading gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and octadecylamine-fluorescein isothiocyanate to produce Gd-FITC-SLNs as T1 contrast agents. Twenty mice with acute UC were divided into four groups: enema with Gd-FITC-SLNs, intravenous injection of Gd-FITC-SLNs, enema with Gd-DTPA, and intravenous injection of Gd-DTPA. Five mice with chronic UC and five mice without UC underwent enema with Gd-FITC-SLNs. Axial T1- and T2-weighted MR images were obtained before and 20, 40, 60, 80,100, and 120 min after enema or intravenous injection of the contrast agent. The signal-to-noise ratios (SNRs) of the colorectal wall were measured in both groups. The MRI findings were correlated with subsequent histological confirmation.

Results
At 20 min after enema with Gd-FITC-SLNs, MRI showed the following contrast enhancement pattern: acute UC > normal intestinal wall > chronic UC. A continuous enhancement effect was observed in mice with acute UC, whereas a slight continuous enhancement of the colorectal wall was observed in mice with chronic UC. The normal intestinal wall rapidly metabolized the contrast agent, and the enhancement decreased on sequential scans. There was no significant difference between the SNRs of the intestinal wall at 20 min after intravenous Gd-DTPA and transrectal Gd-FITC-SLN administration.

Conclusions
Enema with Gd-FITC-SLNs may be helpful for the diagnosis and differential diagnosis of acute and chronic UC and can confer the same or better results than with intravenous Gd-DTPA.

Key Points
• Enema with Gd-FITC-SLNs may be helpful for the diagnosis and differential diagnosis of acute and chronic UC.
• Enema with Gd-FITC-SLNs can achieve the same or better result than that with intravenous Gd-DTPA.
• SLN-based MR colonography enhances the colorectal wall inflammation, based on the colonic absorption of the nanoparticle contrast agents.
Work-related physical and psychosocial risk factors cluster with obesity, smoking and physical inactivity
Authors: van den Berge Mandy , van der Beek Allard J. , Türkeli Rukiye , van Kalken Marike , Hulsegge Gerben 
Published: January 2021

Abstract
Objective
This study investigated associations between the co-existence of multiple types of work-related psychosocial and physical risk factors, and (1) obesity; (2) smoking; and (3) leisure-time physical inactivity. It also aimed to identify sociodemographic characteristics related to clustering of work-related risk factors and lifestyle factors.

Methods
Cross-sectional data on work-related risk factors (e.g., decision authority and repetitive movements) and lifestyle was measured using a standardized questionnaire among 52,563 Dutch workers in health care, services, manufacturing and public sector. Multiple-adjusted logistic regression models assessed associations between the co-existence of multiple types of psychosocial and physical risk factors and lifestyle factors. Additionally, logistic regression models related age, gender and educational level to clustering of risk factors and lifestyle factors.

Results
The co-existence of multiple types of work-related psychosocial risk factors was associated with higher odds of smoking and being physically inactive. For example, workers exposed to three psychosocial risk factors had a 1.55 times higher odds of being physically inactive (95%CI: 1.42–1.70) compared to unexposed workers. A higher number of physical risk factors was also significantly associated with higher odds of smoking and obesity. The co-existence of multiple types of physical risk factors was not associated with higher odds of physical inactivity. Clustering of work-related risk factors and at least one unhealthy lifestyle factor occurred in particular among workers with low educational level.

Conclusions
Results imply that interventions are needed that focus on workers with a low educational level and address work-related physical and psychosocial risk factors as well as lifestyle.
Everolimus als krankheitsspezifische Therapieoption bei mit tuberöser Sklerose assoziierter, therapierefraktärer Epilepsie – ein systematischer Überblick
Authors: Willems Laurent M. , Strzelczyk Adam , Rosenow Felix 
Published: January 2021

ZusammenfassungTuberöse Sklerose („tuberous sclerosis complex“ [TSC]) ist eine seltene genetische Erkrankung, die neben kutanen und viszeralen Organmanifestationen typischerweise bereits in einem sehr frühen Erkrankungsstadium mit einer schweren, meist therapierefraktären Epilepsie einhergeht. Aufgrund seiner direkten Wirkung am durch TSC dysregulierten mTOR-Signalweg sowie der synergistischen Effekte auf andere Organmanifestationen kommt das Rapamycin-Derivat Everolimus (EVE) zunehmend zur Anwendung. Ziel dieses systematischen Reviews ist, die Wirksamkeit, Sicherheit und Verträglichkeit von EVE bei Patienten mit TSC-assoziierter, therapierefraktärer Epilepsie aufzuarbeiten.