bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-administration of combretastatin A4 nanoparticles and anti-PD-L1 for synergistic therapy of hepatocellular carcinoma
Authors: Zhao Bonan , Dong Zhipeng , Liu Weixing , Lou Fangning , Wang Qiyan , Hong Hao , Wang Yue 
Published: May 2021

Abstract
Background
According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC.

Results
In this study, the use of poly(l-Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects—enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models.

Conclusions
We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment.

Graphic abstract
Conceptual framework for task shifting and task sharing: an international Delphi study
Authors: Orkin Aaron M. , Rao Sampreeth , Venugopal Jeyasakthi , Kithulegoda Natasha , Wegier Pete , Ritchie Stephen D. , VanderBurgh David , Martiniuk Alexandra , Salamanca-Buentello Fabio , Upshur Ross 
Published: May 2021

AbstractBackgroundTask shifting and sharing (TS/S) involves the redistribution of health tasks within workforces and communities. Conceptual frameworks lay out the key factors, constructs, and variables involved in a given phenomenon, as well as the relationships between those factors. Though TS/S is a leading strategy to address health worker shortages and improve access to services worldwide, a conceptual framework for this approach is lacking.MethodsWe used an online Delphi process to engage an international panel of scholars with experience in knowledge synthesis concerning TS/S and develop a conceptual framework for TS/S. We invited 55 prospective panelists to participate in a series of questionnaires exploring the purpose of TS/S and the characteristics of contexts amenable to TS/S programmes. Panelist responses were analysed and integrated through an iterative process to achieve consensus on the elements included in the conceptual framework.ResultsThe panel achieved consensus concerning the included concepts after three Delphi rounds among 15 panelists. The COATS Framework (Concepts and Opportunities to Advance Task Shifting and Task Sharing) offers a refined definition of TS/S and a general purpose statement to guide TS/S programmes. COATS describes that opportunities for health system improvement arising from TS/S programmes depending on the implementation context, and enumerates eight necessary conditions and important considerations for implementing TS/S programmes.ConclusionThe COATS Framework offers a conceptual model for TS/S programmes. The COATS Framework is comprehensive and adaptable, and can guide refinements in policy, programme development, evaluation, and research to improve TS/S globally.
The roles and mechanisms of hypoxia in liver fibrosis
Authors: Cai Jingyao , Hu Min , Chen Zhiyang , Ling Zeng 
Published: May 2021

AbstractLiver fibrosis occurs in response to any etiology of chronic liver injury. Lack of appropriate clinical intervention will lead to liver cirrhosis or hepatocellular carcinoma (HCC), seriously affecting the quality of life of patients, but the current clinical treatments of liver fibrosis have not been developed yet. Recent studies have shown that hypoxia is a key factor promoting the progression of liver fibrosis. Hypoxia can cause liver fibrosis. Liver fibrosis can, in turn, profoundly further deepen the degree of hypoxia. Therefore, exploring the role of hypoxia in liver fibrosis will help to further understand the process of liver fibrosis, and provide the theoretical basis for its diagnosis and treatment, which is of great significance to avoid further deterioration of liver diseases and protect the life and health of patients. This review highlights the recent advances in cellular and molecular mechanisms of hypoxia in developments of liver fibrosis.
Absence of the CXCR4 antagonist EPI-X4 from pharmaceutical human serum albumin preparations
Authors: Gilg Andrea , Harms Mirja , Olari Lia-Raluca , Urbanowitz Ann-Kathrin , Bonig Halvard , Münch Jan 
Published: May 2021

Abstract
Background
Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) is a natural antagonist of the CXC chemokine receptor 4 (CXCR4). EPI-X4 is a 16-mer peptide that is released from human serum albumin (HSA) by acidic aspartic proteases such as Cathepsin D and E. Since human serum albumin (HSA) is an important medicinal substance we asked whether different pharmaceutical HSA products contain EPI-X4 which could have been generated during manufacturing and whether HSA can serve as a substrate for cathepsins despite of the presence of stabilizers like caprylate.

Methods
Eight pharmaceutical HSA preparations representing all currently used fractionation technologies were analyzed. The previously described specific EPI-X4 ELISA was used for quantification; in vitro EPI-X4 generation by acidification in the presence or absence of cathepsins was followed by quantification with ELISA.

Results
None of the pharmaceutical HSA preparations tested contained EPI-X4. Acidification of HSA did not generate EPI-X4. Addition of cathepsins D and E to acidified HSA yielded high concentrations of EPI-X4 in all HSA preparations, indistinguishable between individual products.

Conclusion
Medicinal HSA preparations per se do not contain EPI-X4, but will replenish its precursor which can be cleaved to EPI-X4 in vivo, environmental conditions permitting.
A new approach of inducing proprioceptive illusion by transcutaneous electrical stimulation
Authors: Rangwani Rohit , Park Hangue 
Published: May 2021

Abstract
Background
Neurotraumas or neurodegenerative diseases often result in proprioceptive deficits, which makes it challenging for the nervous system to adapt to the compromised sensorimotor conditions. Also, in human machine interactions, such as prosthesis control and teleoperation, proprioceptive mismatch limits accuracy and intuitiveness of controlling active joints in robotic agents. To address these proprioceptive deficits, several invasive and non-invasive approaches like vibration, electrical nerve stimulation, and skin stretch have been introduced. However, proprioceptive modulation is still challenging as the current solutions have limitations in terms of effectiveness, usability, and consistency. In this paper, we propose a new way of modulating proprioception using transcutaneous electrical stimulation. We hypothesized that transcutaneous electrical stimulation on elbow flexor muscles will induce illusion of elbow joint extension.

Method
Eight healthy human subjects participated in the study to test the hypothesis. Transcutaneous electrodes were placed on different locations targeting elbow flexor muscles on human subjects and experiments were conducted to identify the best locations for electrode placement, and best electrical stimulation parameters, to maximize induced proprioceptive effect. Arm matching experiments and Pinocchio illusion test were performed for quantitative and qualitative analysis of the observed effects. One-way repeated ANOVA test was performed on the data collected in arm matching experiment for statistical analysis.

Results
We identified the best location for transcutaneous electrodes to induce the proprioceptive illusion, as one electrode on the muscle belly of biceps brachii short head and the other on the distal myotendinous junction of brachioradialis. The results for arm-matching and Pinocchio illusion tests showed that transcutaneous electrical stimulation using identified electrode location and electrical stimulation parameters evoked the illusion of elbow joint extension for all eight subjects, which supports our hypothesis. On average, subjects reported 6.81° angular illusion of elbow joint extension in arm-matching tests and nose elongated to 1.78 × height in Pinocchio illusion test.

Conclusions
Transcutaneous electrical stimulation, applied between the the synergistic elbow flexor muscles, consistently modulated elbow joint proprioception with the illusion of elbow joint extension, which has immense potential to be translated into various real-world applications, including neuroprosthesis, rehabilitation, teleoperation, mixed reality, and etc.
Leaf area index estimation model for UAV image hyperspectral data based on wavelength variable selection and machine learning methods
Authors: Zhang Juanjuan , Cheng Tao , Guo Wei , Xu Xin , Qiao Hongbo , Xie Yimin , Ma Xinming 
Published: May 2021

Abstract
Background
To accurately estimate winter wheat leaf area index (LAI) using unmanned aerial vehicle (UAV) hyperspectral imagery is crucial for crop growth monitoring, fertilization management, and development of precision agriculture.

Methods
The UAV hyperspectral imaging data, Analytical Spectral Devices (ASD) data, and LAI were simultaneously obtained at main growth stages (jointing stage, booting stage, and filling stage) of various winter wheat varieties under various nitrogen fertilizer treatments. The characteristic bands related to LAI were extracted from UAV hyperspectral data with different algorithms including first derivative (FD), successive projections algorithm (SPA), competitive adaptive reweighed sampling (CARS), and competitive adaptive reweighed sampling combined with successive projections algorithm (CARS_SPA). Furthermore, three modeling machine learning methods including partial least squares regression (PLSR), support vector machine regression (SVR), and extreme gradient boosting (Xgboost) were used to build LAI estimation models.

Results
The results show that the correlation coefficient between UAV and ASD hyperspectral data is greater than 0.99, indicating the UAV data can be used for estimation of wheat growth information. The LAI bands selected by using different algorithms were slightly different among the 15 models built in this study. The Xgboost model using nine consecutive characteristic bands selected by CARS_SPA algorithm as input was proved to have the best performance. This model yielded identical results of coefficient of determination (0.89) for both calibration set and validation set, indicating a high accuracy of this model.

Conclusions
The Xgboost modeling method in combine with CARS_SPA algorithm can reduce input variables and improve the efficiency of model operation. The results provide reference and technical support for nondestructive and rapid estimation of winter wheat LAI by using UAV.
Delayed embolization associated with increased mortality in pelvic fracture with hemodynamic stability at hospital arrival
Authors: Aoki Makoto , Abe Toshikazu , Matsumoto Shokei , Hagiwara Shuichi , Saitoh Daizoh , Oshima Kiyohiro 
Published: May 2021

Abstract
Background
Embolization is widely used for controlling arterial hemorrhage associated with pelvic fracture. However, the effect of a delay in embolization among hemodynamically stable patients at hospital arrival with a pelvic fracture is unknown. Therefore, our aim was to investigate the association between the time to embolization and mortality in hemodynamically stable patients at hospital arrival with a pelvic fracture.

Methods
A multicenter, retrospective cohort study was undertaken using data from the Japan Trauma Data Bank between 2004 and 2018. Hemodynamically, stable patients with a pelvic fracture who underwent an embolization within 3 h were divided into six groups of 30-min blocks of time until pelvic embolization (0–30, 30–60, 60–90, 90–120, 120–150, and 150–180 min). We compared the adjusted 30-day mortality rate according to time to embolization.

Results
We studied 620 hemodynamically stable patients with a pelvic fracture who underwent pelvic embolization within 3 h of hemorrhage. The median age was 68 (48–79) years and 55% were male. The median injury severity score was 26 (18–38). Thirty-day mortality was 8.9% (55/620) and 24-h mortality was 4.2% (26/619). A Cochran–Armitage test showed that a 30-min delay for embolization was associated with increased 30-day (p = 0.0186) and 24-hour (p = 0.033) mortality. Mortality within 0–30 min to embolization was 0%. The adjusted 30-day mortality rate increased with delayed embolization and was up to 17.0% (10.2–23.9) for the 150–180 min group.

Conclusion
Delayed embolization was associated with increased mortality in pelvic fracture with hemodynamic stability at hospital arrival. When you decide to embolize pelvic fracture patients, the earlier embolization may be desirable to promote improved survival regardless of hemodynamics.
Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China
Authors: Zhang Min , Chen Tianhui 
Published: May 2021

AbstractDNA mismatch repair (MMR) genes play an important role in maintaining genome stability. Germline mutations in MMR genes disrupt the mismatch repair function and cause genome instability. Carriers with MMR germline mutations are more likely to have MMR deficiency and microsatellite instability (MSI) than non-carriers and are prone to develop colorectal cancer (CRC) and extracolorectal malignancies, known as Lynch syndrome (LS). MMR gene testing for suspected mutation carriers is a reliable method to identify the mutation types and to discover mutation carriers. Given that carriers of MMR germline mutations have a higher risk of LS-related cancers (LS-RC) and a younger age at onset than non-carriers, early surveillance and regular screening of relevant organs of carriers are very important for early detection of related cancers. This review mainly focuses on the general status of MMR carriers, the approaches for early detection and screening, and the surveillance of MMR mutation carriers in China. Population screening of MMR germline mutation carriers in China will be helpful for early detection, early diagnosis and treatment of MMR mutation carriers, which may improve the 5-year survival, and reduce mortality and incidence rate in the long term.
Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for status epilepticus: study protocol for a multicenter non-inferiority designed randomized control trial
Authors: Nakamura Kensuke , Marushima Aiki , Takahashi Yuji , Kimura Akio , Asami Masahiro , Egawa Satoshi , Kaneko Junya , Kondo Yutaka , Yonekawa Chikara , Hoshiyama Eisei , Yamada Takeshi , Maruo Kazushi , Inoue Yoshiaki ,   IENE ECT with the LIFE study group
Published: May 2021

Abstract
Background
Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE.

Methods
This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is “continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance.” In both groups, diazepam is initially administered at 1–20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000–3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes.

Discussion
The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application.

Trial registration
Japan Registry of Clinical Trials jRCTs031190160. Registered on December 13, 2019
Can we decrease the duration of basal thumb joint distraction for early osteoarthritis from 8 to 6 weeks? Study protocol for a non-inferiority randomized controlled trial
Authors: Ottenhoff Janna S. E. , Teunis Teun , Braakenburg Assa , Mink van der Molen Aebele B. 
Published: May 2021

Abstract
Background
To our knowledge, to date, 52 patients with thumb carpometacarpal osteoarthritis (CMC1 OA) were treated with joint distraction. So far, most patients experienced improved physical function and less pain. After 2 years, only 1 patient proceeded to trapeziectomy. This study assesses if we can safely lower the distraction duration from 8 to 6 weeks for CMC1 joint distraction, maintaining the improvement in physical function and pain.

Methods
This is a monocenter randomized controlled non-inferiority trial that includes patients younger than 65 years of age with ongoing symptoms of CMC1 OA and an established indication for surgery. All patients will be treated with CMC1 joint distraction. The primary outcome is to assess whether 6 weeks of joint distraction is not inferior to 8 weeks in terms of physical function at 1 year after surgery. Secondary outcomes will identify differences between groups at 1 year in pain intensity, patient satisfaction, hand health status, adverse event rates, treatment failure, differences in thumb strength and range of motion, and radiographic changes.

Discussion
If safe, the duration of basal thumb joint distraction can be reduced to 6 weeks, reducing patient burden. Because this is a relatively new treatment, this trial will provide greater knowledge of potential adverse events. This knowledge allows for more informed decision making for patients considering CMC1 distraction treatment. Future studies can directly compare joint distraction to other treatments of CMC1 joint arthritis like splinting and trapeziectomy.

Trial registration
Central Committee on Research Involving Human Subjects (CCMO), NL68225.100.18; registered on 9 August 2019. Medical Research Ethics Committees United (MEC-U), R19.003; registered on 9 August 2019. Netherlands Trial Register, NL8016; registered on 15 September 2019.
Connecting the Dots: a cluster-randomized clinical trial integrating standardized autism spectrum disorders screening, high-quality treatment, and long-term outcomes
Authors: McClure Leslie A. , Lee Nora L. , Sand Katherine , Vivanti Giacomo , Fein Deborah , Stahmer Aubyn , Robins Diana L. 
Published: May 2021

Abstract
Background
Autism spectrum disorder (ASD) affects one in 54 children in the United States of America, and supporting people with ASD across the lifespan presents challenges that impact individuals, families, and communities and can be quite costly. The American Academy of Pediatrics has issued recommendations for routine ASD screening at 18 and 24 months, but some research suggests that few pediatricians perform high-fidelity, standardized screening universally. Furthermore, the United States Preventive Services Task Force (USPSTF) found insufficient evidence to recommend for or against universal ASD screening. The objective of this study is to test the hypothesis that children with ASD who have high fidelity; standardized screening will achieve superior outcomes at 5 years of age compared to children receiving usual care ASD detection strategies.

Methods
This is a cluster-randomized, controlled clinical trial in 3 sites in the USA. Pediatric practices will be randomized to implement universal, standardized, high-fidelity toddler screening or usual care, with randomization stratified by the practice size. The study will enroll 3450 children, approximately half in each group. From this sample, we anticipate 100 children to be diagnosed with ASD. Children in both groups receiving an ASD diagnosis will be administered the Early Start Denver Model, an evidence-based early intervention addressing social, communication, and cognitive functioning. Treatment will last for 1 year, with up to 20 h per week of therapy for children with ASD.

Results
Primary outcomes measured at baseline, following treatment, and at 4 and 5 years of age include ASD symptom severity (Brief Observation of Social Communication Change (BOSCC)) and cognitive functioning (Mullen Scales of Early Learning (MSEL) and Differential Abilities Scale-II (DAS-II)). Secondary outcomes in children include measures of adaptive functioning, ASD symptoms, and kindergarten readiness; secondary analyses will also examine stress and empowerment among parents. Several novel exploratory measures will be included as well. The study will utilize a modified intention-to-treat analysis.

Conclusions
This trial will evaluate the impact of universal, standardized, high-fidelity screening for ASD among children at 18 months of age, with a goal of providing evidence to support this strategy to detect ASD in toddlers in order to start treatment as young as possible and maximize outcomes.

Ethics and dissemination
This study was approved by the Institutional Review Board at Drexel University (IRB protocol: 1607004653). All findings will be provided by the principal investigator via email; data will be available through the NIMH Data Archive (https://nda.nih.gov/).

Trial registration
ClinicalTrials.gov NCT03333629. Registered on November 7, 2017