bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of antisecretory factor, given as a food supplement to adult patients with severe traumatic brain injury (SASAT): protocol for an exploratory randomized double blind placebo-controlled trial
Authors: Cederberg David , Harrington Bradley M. , Vlok Adriaan Johannes , Siesjö Peter 
Published: April 2022

Abstract
Background
Traumatic brain injury (TBI) constitutes a global epidemic. Overall outcome is poor, with mortality ranging from 10 to 70% and significant long-term morbidity. Several experimental reports have claimed effect on traumatic edema, but no clinical trials have shown effect on edema or outcome. Antisecretory factor, an endogenous protein, is commercially available as Salovum®, which is classified as a medical food by the European Union and has shown effect in experimental trauma models and feasibility with signs of effect in 2 pilot case series. The aim of this study is to assess the effect of antisecretory factor in adult patients with severe traumatic brain injury as measured by 30-day mortality, treatment intensity level (TIL), and intracranial pressure (ICP).

Methods/design
This is a single-center, double-blind, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement to adults with severe TBI (GCS < 9), presenting to the trauma unit at Tygerberg University Hospital, Cape Town, South Africa, that are planned for invasive ICP monitoring and neurointensive care, will be screened for eligibility, and assigned to either treatment group (n = 50) or placebo group (n = 50). In both groups, the primary outcome will be 30-day mortality, recorded via hospital charts, follow-up phone calls, and the population registry. Secondary outcomes will be treatment intensity level (TIL), scored from hospital charts, and ICP registered from hospital data monitoring.

Trial registration
ClinicalTrials.gov NCT03339505. Registered on September 17, 2017.
Protocol version 3.0 from November 13, 2020
Quality problems of clinical trials in China: evidence from quality related studies
Authors: Fan Jin , Liu Xiaobo , Li Yuxi , Xia Haisha , Yang Rong , Li Juan , Zhang Yonggang 
Published: April 2022

Abstract
Background
Recently, the quality of clinical trials conducted in China has made considerable progress. However, clinical trials conducted in China still fall below the global average standard. The aim of this systematic review was to assess studies that investigated the quality of clinical trials conducted in China, summarize the issues, and provide suggestions for conducting high-quality clinical trials in China.

Methods
We comprehensively searched studies that investigated the quality of clinical trials conducted in China in the following databases from inception to December 1, 2021: National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database, WanFang Data, China Biology Medicine, PubMed, and Embase. We then analyzed the issues in clinical trial registration, ethics review, implementation, and reporting. SPSS 25.0 software was used for data analysis. The data synthesis was conducted using summary statistics and a narrative format.

Results
A total of 90 studies were analyzed, there were 50 studies with 0–5 citation counts (55.56%), 18 studies with 5–10 citation counts (20%), 9 studies with 10–15 citation counts (10%), and 13 studies with more than 15 citation counts (14.44%). Eight (8.89%) studies were conducted by a supervision department, 38 (42.22%) by organizations with GCP qualification, and 44 (48.89%) by third parties. Additionally, there were some problems in the ethical review process of clinical trials, clinical trial registration process, clinical trial implementation process, and clinical trial reporting process.

Conclusions
The current study shows that the quality problems of clinical trials in China still exist. The reported problems are related to the process of clinical trials, including ethical review, registration, implementation, reporting. Due to the limited quantity and quality of included studies, the conclusions of this study need to be verified by high-quality studies.

Review registration
Not registerated in PROSPERO.
Effect of Automated Closed-loop ventilation versus convenTional VEntilation on duration and quality of ventilation in critically ill patients (ACTiVE) – study protocol of a randomized clinical trial
Authors: Botta Michela , Tsonas Anissa M. , Sinnige Jante S. , De Bie Ashley J. R. , Bindels Alexander J. G. H. , Ball Lorenzo , Battaglini Denise , Brunetti Iole , Buiteman–Kruizinga Laura A. , van der Heiden Pim L. J. , de Jonge Evert , Mojoli Francesco , Robba Chiara , Schoe Abraham , Paulus Frederique , Pelosi Paolo , Neto Ary Serpa , Horn Janneke , Schultz Marcus J. ,   The ACTiVE collaborative group, Botta Michela , Tsonas Anissa M. , Sinnige Jante S. , De Bie Ashley J. R. , Bindels Alexander J. G. H. , Ball Lorenzo , Battaglini Denise , Brunetti Iole , Buiteman–Kruizinga Laura A. , van der Heiden Pim L. J. , de Jonge Evert , Mojoli Francesco , Robba Chiara , Schoe Abraham , Paulus Frederique , Pelosi Paolo , Neto Ary Serpa , Horn Janneke , Schultz Marcus J. 
Published: April 2022

Abstract
Background
INTELLiVENT–Adaptive Support Ventilation (ASV) is a fully automated closed-loop mode of ventilation for use in critically ill patients. Evidence for benefit of INTELLiVENT–ASV in comparison to ventilation that is not fully automated with regard to duration of ventilation and quality of breathing is largely lacking. We test the hypothesis that INTELLiVENT–ASV shortens time spent on a ventilator and improves the quality of breathing.

Methods
The “Effects of Automated Closed–loop VenTilation versus Conventional Ventilation on Duration and Quality of Ventilation” (ACTiVE) study is an international, multicenter, two-group randomized clinical superiority trial. In total, 1200 intensive care unit (ICU) patients with an anticipated duration of ventilation of > 24 h will be randomly assigned to one of the two ventilation strategies. Investigators screen patients aged 18 years or older at start of invasive ventilation in the ICU. Patients either receive automated ventilation by means of INTELLiVENT–ASV, or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is the number of days free from ventilation and alive at day 28; secondary endpoints are quality of breathing using granular breath-by-breath analysis of ventilation parameters and variables in a time frame of 24 h early after the start of invasive ventilation, duration of ventilation in survivors, ICU and hospital length of stay (LOS), and mortality rates in the ICU and hospital, and at 28 and 90 days.

Discussion
ACTiVE is one of the first randomized clinical trials that is adequately powered to compare the effects of automated closed-loop ventilation versus conventional ventilation on duration of ventilation and quality of breathing in invasively ventilated critically ill patients. The results of ACTiVE will support intensivist in their choices regarding the use of automated ventilation.

Trial registration
ACTiVE is registered in clinicaltrials.gov (study identifier: NCT04593810) on 20 October 2020.
Acute glycemic variability and risk of mortality in patients with sepsis: a meta-analysis
Authors: Li Xiaofei , Zhang Daofu , Chen Yongxin , Ye Weiwei , Wu Shuang , Lou Lianqing , Zhu Yanshuang 
Published: April 2022

Abstract
Background
Acute glycemic variability (GV) has been correlated with the severity of sepsis. The aim of the study was to evaluate the potential association between acute GV and mortality risk in patients with sepsis.

Methods
Cohort studies comparing the risk of death within 3 months between septic patients with higher versus lower acute GV were retrieved by systematic search of Medline, Embase, Web of Science, Wanfang and CNKI databases. We used a random-effect model to pool the data by incorporating the between-study heterogeneity. Sensitivity analyses were performed to evaluate the stability of the findings.

Results
Ten studies including 4296 patients were available for the meta-analysis. Pooled results showed that septic patients with higher acute GV had significantly increased mortality risk compared to those with lower acute GV, as evidenced by results using different parameters including standard deviation of blood glucose (SDBG, risk ratio [RR]: 1.74, 95% confidence interval [CI] 1.36–2.24, p < 0.001; I2 = 0%), coefficient of variation of blood glucose (RR: 1.91, 95% CI 1.57–2.31, p < 0.001; I2 = 0%), mean amplitude of glycemic excursion (RR: 1.81. 95% CI 1.36–2.40, p < 0.001; I2 = 0%), and glycemic lability index (RR: 2.52, 95% CI 1.72–3.68, p < 0.001; I2 = 0%). Sensitivity analyses by excluding one study at a time did not significantly affect the results (p all < 0.05).

Conclusions
Higher acute GV may be a predictor of mortality risk in patients with sepsis.
Refractory flare-up of severe bronchial asthma controlled with mepolizumab due to Pneumocystis pneumonia: a case report
Authors: Takeda Kazuya , Sumi Toshiyuki , Nagahisa Yuta , Matsuura Keigo , Sekikawa Motoki , Watanabe Hiroki , Yamada Yuichi , Chiba Hirofumi 
Published: April 2022

Abstract
Background
Biologics dramatically improve symptoms of severe asthma; however, various exacerbating factors may induce flare-up. Pneumocystis spp. have not been reported as a cause of asthma exacerbation during biologic use, although patients with severe asthma have high levels of antibodies against Pneumocystis spp.

Case presentation
An 87-year-old female with severe asthma that was well-controlled with mepolizumab, who developed a steroid-resistant refractory flare-up. Chest computed tomography showed bilateral ground glass opacities, and results of polymerase chain reaction tests on induced sputum were positive for Pneumocystis DNA. Therefore, a diagnosis of Pneumocystis pneumonia was made. The clinical symptoms improved after treatment with sulfamethoxazole–trimethoprim.

Conclusion
Clinicians should be aware of Pneumocystis pneumonia as a cause of refractory exacerbation of bronchial asthma during use of interleukin-5 inhibitors.
Management of primary choroidal lymphoma presenting as extensive serous retinal detachment and salmon patch of bulbar conjunctiva: a case report
Authors: Mahdizad Zahra , Khalili Pour Elias , Mehrabi Bahar Mohammadreza , Esfandiari Amirreza , Masoomian Babak , Riazi-Esfahani Hamid , Mirshahi Ahmad , Ghassemi Fariba 
Published: April 2022

Abstract
Background
We describe the outcome of ultra-low-dose radiotherapy plus intravitreal methotrexate and rituximab injections for a patient with primary choroidal lymphoma who presented with nodular conjunctival salmon patches and extensive serous retinal detachment.

Case presentation
A 34-year-old Iranian man presented with a nodular patch of bulbar conjunctiva in the right eye, and 1+ vitritis. A nearly complete shallow serous retinal detachment, retinal folds, and multifocal yellow choroidal infiltrates were seen during a fundus examination of the right eye. Enhanced depth imaging optical coherence tomography revealed macular retinal folds and an uneven, undulating, “seasick” appearance of the choroidal surface with choriocapillaris compression, intraretinal and subretinal fluid, and clusters of optically dense material at the outer retinal level. An incisional biopsy of the conjunctival lesion confirmed the diagnosis of primary choroidal lymphoma with epibulbar involvement. The patient was treated with ultra-low-dose “boom-boom” radiation (4 Gy delivered in two fractions over two consecutive days) as well as intravitreal methotrexate and rituximab injections. After a year, the lesions had completely disappeared, with no adverse effects or recurrence.

Conclusion
Ultra-low-dose (boom-boom) radiotherapy combined with intravitreal chemotherapy and/or immunotherapy may be an effective treatment for primary choroidal lymphoma with anterior epibulbar extension and diffuse subretinal fluid with favorable response and minimal side effects.
PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury
Authors: Sarre Charlotte , Contreras-Lopez Rafael , Nernpermpisooth Nitirut , Barrere Christian , Bahraoui Sarah , Terraza Claudia , Tejedor Gautier , Vincent Anne , Luz-Crawford Patricia , Kongpol Kantapich , Kumphune Sarawut , Piot Christophe , Nargeot Joel , Jorgensen Christian , Djouad Farida , Barrere-Lemaire Stéphanie 
Published: April 2022

Abstract
Background
Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated.

Objectives
The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction.

Methods and results
Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H2O2. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 105 PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 105 naïve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects.

Conclusion
Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.
Surge: a fast open-source chemical graph generator
Authors: McKay Brendan D. , Yirik Mehmet Aziz , Steinbeck Christoph 
Published: April 2022

AbstractChemical structure generators are used in cheminformatics to produce or enumerate virtual molecules based on a set of boundary conditions. The result can then be tested for properties of interest, such as adherence to measured data or for their suitability as drugs. The starting point can be a potentially fuzzy set of fragments or a molecular formula. In the latter case, the generator produces the set of constitutional isomers of the given input formula. Here we present the novel constitutional isomer generator based on the canonical generation path method. uses the package to compute automorphism groups of graphs. We outline the working principles of and present benchmarking results which show that is currently the fastest structure generator. is available under a liberal open-source license.
Prediction of multiple pH compartments by deep learning in magnetic resonance spectroscopy with hyperpolarized 13C-labelled zymonic acid
Authors: Fok Wai-Yan Ryana , Grashei Martin , Skinner Jason G. , Menze Bjoern H. , Schilling Franz 
Published: April 2022

Abstract
Background
Hyperpolarization enhances the sensitivity of nuclear magnetic resonance experiments by between four and five orders of magnitude. Several hyperpolarized sensor molecules have been introduced that enable high sensitivity detection of metabolism and physiological parameters. However, hyperpolarized magnetic resonance spectroscopy imaging (MRSI) often suffers from poor signal-to-noise ratio and spectral analysis is complicated by peak overlap. Here, we study measurements of extracellular pH (pHe) by hyperpolarized zymonic acid, where multiple pHe compartments, such as those observed in healthy kidney or other heterogeneous tissue, result in a cluster of spectrally overlapping peaks, which is hard to resolve with conventional spectroscopy analysis routines.

Methods
We investigate whether deep learning methods can yield improved pHe prediction in hyperpolarized zymonic acid spectra of multiple pHe compartments compared to conventional line fitting. As hyperpolarized 13C-MRSI data sets are often small, a convolutional neural network (CNN) and a multilayer perceptron (MLP) were trained with either a synthetic or a mixed (synthetic and augmented) data set of acquisitions from the kidneys of healthy mice.

Results
Comparing the networks’ performances compartment-wise on a synthetic test data set and eight real kidney data shows superior performance of CNN compared to MLP and equal or superior performance compared to conventional line fitting. For correct prediction of real kidney pHe values, training with a mixed data set containing only 0.5% real data shows a large improvement compared to training with synthetic data only. Using a manual segmentation approach, pH maps of kidney compartments can be improved by neural network predictions for voxels including three pH compartments.

Conclusion
The results of this study indicate that CNNs offer a reliable, accurate, fast and non-interactive method for analysis of hyperpolarized 13C MRS and MRSI data, where low amounts of acquired data can be complemented to achieve suitable network training.
Aryl hydrocarbon receptor activation ameliorates experimental colitis by modulating the tolerogenic dendritic and regulatory T cell formation
Authors: Cui Xiufang , Ye Ziping , Wang Di , Yang Yan , Jiao ChunHua , Ma Jingjing , Tang Nana , Zhang Hongjie 
Published: April 2022

Abstract
Background
Intestinal immune dysfunction is involved in the onset of Crohn’s disease (CD). Dendritic cells (DCs), antigen-presenting cells, play a key role in the maintenance of intestinal immune homeostasis. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor widely expressed in various immune cells, including DCs. Although AhR plays an important role in immune tolerance, its role in the DCs is unclear. The purpose of this study was to investigate whether the activation of AhR can induce tolerogenic DCs (tolDCs) and the differentiation of regulatory T (Treg) cells, as well as ameliorate experimental colitis.

Results
AhR activation in the DCs resulted in a lower expression of surface markers such as CD80, CD83, CD86, and pro-inflammatory cytokine production, and higher anti-inflammatory production (IL-1β, IL-23, and IL-12) compared to the control DCs. The surface dendrites in DCs were significantly reduced following AhR activation by 6-formylindolo [3,2-b]carbazole (FICZ). Such DCs with FICZ-mediated activation of AhR, namely tolDCs, promoted Treg cell differentiation. Adoptive transfer of tolDCs to a TNBS-induced colitis mouse model significantly alleviated the severity of inflammation by improving the colon length and decreasing the disease activity index (DAI) and histopathological score. Moreover, the transferred tolDCs decreased the frequency of Th17 cells and increased the frequency of Treg cells in the spleen and mesenteric lymph nodes (MLNs) in murine colitis models.

Conclusions
Activation of AhR in the DCs could induce tolDCs, and the transplantation of tolDCs may help in relieving intestinal inflammation and maintaining the Th17/Treg differentiation balance. Thus, our data suggest that AhR may be a potential therapeutic target for CD.
Heterogeneity of the tumor immune microenvironment and its clinical relevance
Authors: Jia Qingzhu , Wang Aoyun , Yuan Yixiao , Zhu Bo , Long Haixia 
Published: April 2022

AbstractDuring the course of tumorigenesis and subsequent metastasis, malignant cells gradually diversify and become more heterogeneous. Consequently, the tumor mass might be infiltrated by diverse immune-related components, including the cytokine/chemokine environment, cytotoxic activity, or immunosuppressive elements. This immunological heterogeneity is universally presented spatially or varies temporally along with tumor evolution or therapeutic intervention across almost all solid tumors. The heterogeneity of anti-tumor immunity shows a profound association with the progression of disease and responsiveness to treatment, particularly in the realm of immunotherapy. Therefore, an accurate understanding of tumor immunological heterogeneity is essential for the development of effective therapies. Facilitated by multi-regional and -omics sequencing, single cell sequencing, and longitudinal liquid biopsy approaches, recent studies have demonstrated the potential to investigate the complexity of immunological heterogeneity of the tumors and its clinical relevance in immunotherapy. Here, we aimed to review the mechanism underlying the heterogeneity of the immune microenvironment. We also explored how clinical assessments of tumor heterogeneity might facilitate the development of more effective personalized therapies.
Metagenomic sequencing reveals time, host, and body compartment-specific viral dynamics after lung transplantation
Authors: Widder Stefanie , Görzer Irene , Friedel Benjamin , Rahimi Nina , Schwarz Stefan , Jaksch Peter , Knapp Sylvia , Puchhammer-Stöckl Elisabeth 
Published: April 2022

AbstractBackgroundThe virome of lung transplant recipients (LTRs) under immunosuppressive therapy is dominated by non-pathogenicAnelloviridaeand further includes several pathogenic viruses such as Herpesviruses or respiratory viruses. It is unclear whether the donor-derived virome in the transplanted lung influences recipient virome dynamics in other body compartments and if so, to which degree. Likewise, it is unknown whether dependencies exist among virus populations that mutually shape viral loads and kinetics.ResultsTo address these questions, we characterized viral communities in airways and plasma of 49 LTRs and analyzed their abundance patterns in a data modeling approach. We found distinct viral clusters that were specific for body compartments and displayed independent dynamics. These clusters robustly gathered specific viral species across the patient cohort. In the lung, viral cluster abundance associated with time after transplantation and we detected mutual exclusion of viral species within the same human host. In plasma, viral cluster dynamics were associated with the indication for transplantation lacking significant short-time changes. Interestingly, pathogenic viruses in the plasma co-occurred specifically withAlpha torque virusgenogroup 4 andGamma torque virusstrains suggesting shared functional or ecological requirements.ConclusionsIn summary, the detailed analysis of virome dynamics after lung transplantation revealed host, body compartment, and time-specific dependency patterns among viruses. Furthermore, our results suggested genetic adaptation to the host microenvironment at the level of the virome and support the hypothesis of functional complementarity betweenAnellovirusgroups and other persistent viruses.