bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial
Authors: Wehmeyer Malte H. , Horvatits Thomas , Buchholz Anika , Krause Linda , Walter Sarah , Zapf Antonia , Lohse Ansgar W. , Kluwe Johannes ,   the STOPPIT-trial group
Published: April 2022

Abstract
Background
Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication.

Methods
The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021.

Discussion
The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis.

Trial registration
EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). ClinicalTrials.gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).
Evaluations of candidate markers of dihydroartemisinin-piperaquine resistance in Plasmodium falciparum isolates from the China–Myanmar, Thailand–Myanmar, and Thailand–Cambodia borders
Authors: Ye Run , Zhang Yilong , Zhang Dongmei 
Published: April 2022

Abstract
Background
The fast-declining clinical efficacy of dihydroartemisinin-piperaquine (DHA-PPQ) in Cambodia is a warning of the underlying westward dissemination of piperaquine resistance in the Greater Mekong Subregion (GMS). Mutations in the Plasmodium falciparum Kelch 13-propeller (PfK13) and the P. falciparum chloroquine resistance transporter (PfCRT), as well as plasmepsin 2/3 gene amplification, have been discovered as molecular markers for predicting DHA-PPQ treatment failure. Determining whether these genetic variations of P. falciparum are linked to DHA-PPQ resistance is critical, especially along the China–Myanmar (CM) border, where PPQ has been utilized for decades.

Methods
A total of 173 P. falciparum samples of dried blood spots (DBS) were collected along the CM border between 2007 and 2010, the Thailand–Cambodia (TC) border between 2009 and 2013, and the Thailand–Myanmar (TM) border between 2012 and 2014. PCR and sequencing were used to identified PfCRT mutations, while qPCR was used to determine the copy number of plasmepsin 2/3. The prevalence of DHA-PPQ resistance in three locations was investigated using data paired with K13 mutations.

Results
Three fragments of the pfcrt gene were amplified for all 173 samples, and seven SNPs were identified (M74I, N75E/D, K76T, H97L, I218F, A220S, I356L). No new PfCRT mutations conferring resistance to PPQ (T93S, H97Y, F145I, M343L, and G353V) were discovered, except for one mutant I218F identified in the TM border (2.27%, 1/44). Additionally, mutant H97L was found in the TC, TM, and CM borders at 3.57% (1/28), 6.82% (3/44), and 1% (1/101), respectively. A substantial K13 C580Y variant prevalence was found in the TC and TM border, accounting for 64.29% (18/28) and 43.18% (19/44), respectively, while only 1% (1/101) was found in the CM border. The K13 F446I variant was only identified and found to reach a high level (28.71%, 29/101) in the CM border. Furthermore, 10.71% (3/28) of TC isolates and 2.27% (1/44) of TM isolates carried more than one copy of plasmepsin 2/3 and K13 C580Y variant, while no plasmepsin 2/3 amplification was identified in the CM isolates.

Conclusions
Compared with the P. falciparum samples collected from the TC and TM borders, fewer parasites carried plasmepsin 2/3 amplification and novel PfCRT variants, while more parasites carried predominant K13 mutations at position F446I, in the CM border. Clear evidence of DHA-PPQ resistance associated with candidate markers was not found in this border region suggesting a further evaluation of these markers and continuous surveillance is warranted.

Graphical Abstract
Albuminuria but not low eGFR is closely associated with atherosclerosis in patients with type 2 diabetes: an observational study
Authors: Wang Jun-Wei , Ke Jiang-Feng , Zhang Zhi-Hui , Lu Jun-Xi , Li Lian-Xi 
Published: April 2022

Abstract
Background
There is still controversy regarding the associations of urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) with atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Therefore, it is necessary to explore the correlation between them in T2DM patients.

Methods
We conducted a survey involving 2565 T2DM patients from a single center. The study cohort was classified into three groups based on the levels of albuminuria: normal UAE (UAE < 30 mg/24 h), moderate UAE (UAE between 30 and 299 mg/24 h) and high UAE (UAE ≥ 300 mg/24 h). Additionally, the patients were divided into three separate groups according to eGFR levels, including low eGFR (eGFR < 60 ml/min/1.73 m2), intermediate eGFR (eGFR 60–89 ml/min/1.73 m2) and normal eGFR (eGFR ≥ 90 ml/min/1.73 m2) groups. Atherosclerotic lesions were compared among the three UAE and eGFR groups. Regression analyses were used to assess the associations of atherosclerotic lesions with UAE and eGFR in T2DM.

Results
After controlling for age, sex and diabetes duration, the prevalence of atherosclerotic plaque and stenosis were significantly increased from the normal to high UAE groups (plaque: 72.2%, 78.6% and 87.3%, respectively, p = 0.016 for trend; stenosis: 14.0%, 25.5% and 37.3%, respectively, p < 0.001 for trend). Likewise, the values of carotid intima-media thickness (CIMT) and femoral intima-media thickness (FIMT) were also obviously increased from the normal to high UAE groups (CIMT: p < 0.001 for trend; FIMT: p = 0.001 for trend). Conversely, only the FIMT value was clearly increased from the low to normal eGFR groups (p = 0.001 for trend). Fully adjusted regression analyses revealed that UAE was closely associated with the presence of atherosclerotic plaque (OR 1.20, 95% CI 1.03–1.40, p = 0.020) and stenosis (OR 1.17, 95% CI 1.01–1.35, p = 0.036), and with the values of CIMT (β 0.05, 95% CI 0.01–0.10, p = 0.029) and FIMT (β 0.07, 95% CI 0.03–0.11, p = 0.001) in T2DM patients. However, there was no significant association between eGFR levels and atherosclerotic lesions in T2DM after adjustment for multiple confounding factors.

Conclusions
Overall, albuminuria rather than low eGFR is closely associated with atherosclerotic lesions in T2DM patients. Albuminuria is an independent risk factor for carotid and femoral atherosclerotic lesions in T2DM. Therefore, albuminuria may be a potential early marker to predict the development of atherosclerosis in patients with T2DM.
LINC00114 stimulates growth and glycolysis of esophageal cancer cells by recruiting EZH2 to enhance H3K27me3 of DLC1
Authors: Qin Jianzhang , Li Yishuai , Li Zhe , Qin Xuebo , Zhou Xuetao , Zhang Hao , Li Shujun 
Published: April 2022

Abstract
Objective
LINC00114 could promote the development of colorectal cancer, but its mechanism has been rarely discussed in esophageal cancer (EC). Herein, we explored the molecular mechanism of LINC00114 via mediating enhancer of zeste homolog 2/deleted in liver cancer 1 (EZH2/DLC1) axis in EC.

Methods
LINC00114, EZH2 and DLC1 expression in EC tissues and cells were tested. LINC00114, EZH2 and DLC1 expression were altered in EC cells through transfection with different constructs, and cell proliferation, migration, invasion, apoptosis and glycolysis were subsequently observed. The interaction between LINC00114 and EZH2 and that between EZH2 and DLC1 were explored. Tumor formation was also conducted to confirm the in vitro results.

Results
The expression levels of LINC00114 and EZH2 were elevated while those of DLC1 were reduced in EC. Inhibiting LINC00114 or reducing EZH2 blocked cell proliferation, migration, invasion and glycolysis and induce cell apoptosis in EC. LINC00114 promoted H3K27 trimethylation of DLC1 by recruiting EZH2. Knockdown of DLC1 stimulated cell growth and glycolysis in EC and even mitigated the role of LINC00114 inhibition in EC. In vivo experiment further confirmed the anti-tumor effect of LINC00114 inhibition in EC.

Conclusion
The data indicate that LINC00114 promotes the development of EC by recruiting EZH2 to enhance H3K27me3 of DLC1.
Acute myeloid leukemia causing acute thrombosis of the coronary arteries: a case report
Authors: Ferrel Meganne N. , Ryan John J. , Han Frederick T. 
Published: April 2022

Abstract
Background
This case report demonstrates acute myeloid leukemia causing acute thrombosis of coronary arteries with anterolateral ST elevation myocardial infarction and ventricular tachycardia in an otherwise healthy woman. Few case reports have been documented on patients with concomitant conditions of acute myeloid leukemia and acute myocardial infarction, and it is important to note that prognosis for patients with both is worse than that of either condition. While both conditions together are rare, other non-atherosclerotic causes of acute coronary syndromes are likewise important considerations in the context of myocardial ischemia.

Case presentation
A 59-year-old Caucasian woman with no notable past medical history presented to her primary care provider with 2 weeks of severe fatigue, anorexia, and malaise, associated with chills, night sweats, and myalgias. Peripheral blood smear identified 92% blasts consistent with acute myeloid leukemia and computed tomography identified a right segmental pulmonary embolism and thrombotic infarcts in the spleen, bilateral kidneys, right lung, and liver. Laboratory testing also demonstrated disseminated intravascular coagulopathy. She was admitted to the intensive care unit for treatment and subsequently developed ventricular tachycardia, anterolateral ST segment elevation, acute dysarthria, and nonreactive pupils. Pulseless electrical activity developed with unsuccessful resuscitative measures. The patient died secondary to presumed cerebrovascular and coronary thromboses causing stroke and anterolateral infarct complicated by ventricular tachycardia and pulseless electrical activity.

Conclusion
This case is notable as a case of acute myeloid leukemia causing acute thrombosis of coronary arteries with anterolateral ST elevation myocardial infarction, ventricular tachycardia, and pulseless electrical activity. Prognosis of concomitant acute myeloid leukemia and acute myocardial infarction is poor. Management is challenging due to thrombocytopenia, platelet dysfunction, and systemic coagulopathy, and administration of thrombolytic agents can be fatal. This is an extreme presentation of a case of acute myocardial infarction with disseminated intravascular coagulopathy causing acute coronary thrombosis and sudden death with dramatic electrocardiogram and telemetry findings recorded with rapid progression from normal sinus rhythm to acute myocardial infarction to terminal rhythm.
Challenges to the broad application of allogeneic natural killer cell immunotherapy of cancer
Authors: Kennedy Philippa R. , Felices Martin , Miller Jeffrey S. 
Published: April 2022

AbstractNatural killer (NK) cells are innate immune cells that recognize malignant cells through a wide array of germline-encoded receptors. Triggering of activating receptors results in cytotoxicity and broad immune system activation. The former is achieved through release of cytotoxic granules and presentation of death receptor ligands, while the latter is mediated by inflammatory cytokines, such as interferon-γ and tumor necrosis factor α. Early success with ex vivo activation of NK cells and adoptive transfer suggest they are a safe therapeutic with promising responses in advanced hematologic malignancies. In particular, adoptive NK cell therapies can serve as a ‘bridge’ to potentially curative allogeneic stem cell transplantation. In addition, strategies are being developed that expand large numbers of cells from limited starting material and mature NK cells from precursors. Together, these make ‘off-the-shelf’ NK cells possible to treat a wide range of cancers. Research efforts have focused on creating a range of tools that increase targeting of therapeutic NK cells toward cancer—from therapeutic antibodies that drive antibody-dependent cellular cytotoxicity, to chimeric antigen receptors. As these novel therapies start to show promise in clinical trials, the field is rapidly moving toward addressing other challenges that limit NK cell therapeutics and the goal to treat solid tumors. This review describes the state of therapeutic NK cell targeting of tumors; discusses the challenges that need to be addressed before NK cells can be applied as a wide-ranging treatment for cancer; and points to some of the innovations that are being developed to surmount these challenges. Suppressive cells in the tumor microenvironment pose a direct threat to therapeutic NK cells, through presentation of inhibitory ligands and secretion of suppressive cytokines and metabolites. The nutrient- and oxygen-starved conditions under which NK cells must function necessitate an understanding of therapeutic NK cell metabolism that is still emerging. Prior to these challenges, NK cells must find their way into and persist in the tumor itself. Finally, the desirability of a ‘single-shot’ NK cell treatment and the problems and benefits of a short-lived rejection-prone NK cellular product are discussed.
Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes
Authors: Yang Shengnan , Liu Peipei , Gao Tingting , Song Dingyun , Zhao Xinyu , Li Yupeng , Wu Jun , Wang Liu , Wang Zai , Hao Jie , Wang Chen , Dai Huaping 
Published: April 2022

Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration.

Methods
To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations.

Results
IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-β.

Conclusion
IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different.
Galaxy workflows for fragment-based virtual screening: a case study on the SARS-CoV-2 main protease
Authors: Bray Simon , Dudgeon Tim , Skyner Rachael , Backofen Rolf , Grüning Björn , von Delft Frank 
Published: April 2022

AbstractWe present several workflows for protein-ligand docking and free energy calculation for use in the workflow management system Galaxy. The workflows are composed of several widely used open-source tools, including rDock and GROMACS, and can be executed on public infrastructure using either Galaxy’s graphical interface or the command line. We demonstrate the utility of the workflows by running a high-throughput virtual screening of around 50000 compounds against the SARS-CoV-2 main protease, a system which has been the subject of intense study in the last year.
Characterized source model of the 2013 Lushan earthquake (Mw 6.6) by the empirical Green’s function method
Authors: Wu Hao , Irikura Kojiro , Miyakoshi Ken , Somei Kazuhiro 
Published: April 2022

AbstractGround motions near the source area of the mainshock of the 2013 Lushan earthquake (Mw 6.6) in Sichuan Province in China were reproduced using the characterized source model and the empirical Green’s function method (EGFM). The best-fit characterized source model consisted of one strong motion generation area (SMGA) and a background area. The synthesized ground motions of the characterized source model were in fairly good agreement with the observed ground motions in the frequency range from 0.5 to 30.0 Hz at ten strong motion stations. For the 2013 Lushan earthquake (Mw 6.6), both the relationships between the SMGA and the seismic moment, and those between the flat amplitude of the acceleration source spectrum in the short period and the seismic moment almost followed the empirical scaling relationships of inner fault parameters developed for crustal earthquakes. The reasons for the largest peak ground acceleration (PGA) (> 1 g) in the strong-motion observation history of China recorded at the 51BXD strong motion station were investigated from the source and site effects. We found that the directivity effect did not contribute to the largest record by comparing the effect of different positions of the rupture starting point on the synthesized ground motions. The nonlinear effect of shallow layers was negligible, as indicated by the similarity of the earthquake H/V spectral ratios between the mainshock and EGF events. A large shear-wave velocity contrast might not exist in the shallow layers as the station was situated on the slope of a small rock hill. Finally, we agreed with previous studies that the hanging-wall effect and topographic effect might be the reasons for generating the largest record at Station 51BXD.
Graphical Abstract
An assessment of solvent residue contaminants related to cannabis-based products in the South African market
Authors: Viviers Hendrik Jacobus , Petzer Anél , Gordon Richard 
Published: April 2022

AbstractOrganic solvents are used for manufacturing herbal medicines and can be detected as residues of such processing in the final products. It is important for the safety of consumers to control these solvent residues. South African cannabis-based product samples were analysed for solvent residue contaminants as classified by the United States Pharmacopeia (USP), chapter 467. The origin of these samples ranged anywhere from crude extract, product development samples, and market ready final products. Samples were submitted to a contract laboratory over a period of 2 years from 2019 to 2021. To date, no data of this kind exist in South Africa specifically relating to cannabis-based medicinal, recreational, or complementary products. A total of 279 samples were analysed in duplicate by full evaporation headspace gas-chromatography mass-spectrometry and the results are reported in an anonymised format. The results showed an alarming 37% sample solvent residue failure rate with respect to adherence to USP 467 specification. It is important to ensure regulation is enforced to control product quality. The South African public need to be educated about the risks associated with cannabis-based products.
Metasurface with dynamic chiral meta-atoms for spin multiplexing hologram and low observable reflection
Authors: Wang He , Qin Zhe , Huang Lingling , Li Yongfeng , Zhao Ruizhe , Zhou Hongqiang , He Haoyang , Zhang Jieqiu , Qu Shaobo 
Published: April 2022

AbstractSpin light manipulation based on chiral metasurfaces is a striking hotspot that has intrigued huge attention. Circular dichroism, a unique phenomenon of chiral atoms/molecules, has been regarded as another auxiliary dimension for guiding electromagnetic waves, which has been explored in the field of artificial material sciences yet a challenging issue. Here, a generic strategy based on dynamic chiral meta-atom for revealing strong circular dichroism as well as applicable electromagnetic functionality is proposed in microwave regime. We demonstrate a dynamic metasurface that enables the fully independent holograms reconstruction for one circular polarization or the other at the active operating state. On the other hand, the electromagnetic scattering is realized for lowering observable backward reflection at the passive state. Numerical simulation and experimental verification are conducted to manifest the feasibility. It is expected that the proposed strategy can be applied to broaden the horizon for dynamic chiral meta-devices and may find applications in information encryption, anti-counterfeiting, and other dynamic systems.