bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficacy of corticosteroids therapy in patients with moderate to severe SARS-CoV-2 infection: a multicenter, randomized, open-label trial
Authors: Ghanei Mostafa , Solaymani-Dodaran Masoud , Qazvini Ali , Ghazale Amir Hosein , Setarehdan Seyed Amin , Saadat Seyed Hassan , Ghobadi Hassan , Hoseininia Saeed , Elahikhah Maryam , Samadi Ali Hossein , Imani Yousef , Vahedi Ensieh , Babamahmoodi Farhang , Rostami Fatemeh Tajik , Ardebili Mohammad Hossein Azimzadeh , Ansarifar Akram , Golmaei Fatemeh Fallahpoor , Asadollah Atieh 
Published: September 2021

Abstract
Background
We performed a multicenter, randomized open-label trial in patients with moderate to severe Covid-19 treated with a range of possible treatment regimens. Methods: Patients were randomly assigned to one of three regimen groups at a ratio of 1:1:1. The primary outcome of this study was admission to the intensive care unit. Secondary outcomes were intubation, in-hospital mortality, time to clinical recovery, and length of hospital stay (LOS). Between April 13 and August 9, 2020, a total of 336 patients were randomly assigned to receive one of the 3 treatment regimens including group I (hydroxychloroquine stat, prednisolone, azithromycin and naproxen; 120 patients), group II (hydroxychloroquine stat, azithromycin and naproxen; 116 patients), and group III (hydroxychloroquine and lopinavir/ritonavir (116 patients). The mean LOS in patients receiving prednisolone was 5.5 in the modified intention-to-treat (mITT) population and 4.4 days in the per-protocol (PP) population compared with 6.4 days (mITT population) and 5.8 days (PP population) in patients treated with Lopinavir/Ritonavir.

Results
The mean LOS was significantly lower in the mITT and PP populations who received prednisolone compared with populations treated with Lopinavir/Ritonavir (p = 0.028; p = 0.0007). We observed no significant differences in the number of deaths, ICU admission, and need for mechanical ventilation between the Modified ITT and per-protocol populations treated with prednisolone and Lopinavir/Ritonavir, although these outcomes were better in the arm treated with prednisolone. The time to clinical recovery was similar in the modified ITT and per-protocol populations treated with prednisolone, lopinavir/ritonavir, and azithromycin (P = 0.335; P = 0.055; p = 0.291; p = 0.098).

Conclusion
The results of the present study show that therapeutic regimen (regimen I) with low dose prednisolone was superior to other regimens in shortening the length of hospital stay in patients with moderate to severe COVID-19. The steroid sparing effect may be utilized to increase the effectiveness of corticosteroids in the management of diabetic patients by decreasing the dosage.
The effect of additional antimicrobial therapy on the outcomes of patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis
Authors: Chen Ching-Yi , Chen Chao-Hsien , Wang Cheng-Yi , Lai Chih-Cheng , Chao Chien-Ming , Wei Yu-Feng 
Published: September 2021

Abstract
Background
The effect of additional antimicrobial agents on the clinical outcomes of patients with idiopathic pulmonary fibrosis (IPF) is unclear.

Methods
We performed comprehensive searches of randomized control trials (RCTs) that compared the clinical efficacy of additional antimicrobial agents to those of placebo or usual care in the treatment of IPF patients. The primary outcome was all-cause mortality, and the secondary outcomes were changes in forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and the risk of adverse events (AEs).

Results
Four RCTs including a total of 1055 patients (528 receiving additional antibiotics and 527 receiving placebo or usual care) were included in this meta-analysis. Among the study group, 402 and 126 patients received co-trimoxazole and doxycycline, respectively. The all-cause mortality rates were 15.0% (79/528) and 14.0% (74/527) in the patients who did and did not receive additional antibiotics, respectively (odds ratio [OR] 1.07; 95% confidence interval [CI] 0.76 to 1.51; p = 0.71). No significant difference was observed in the changes in FVC (mean difference [MD], 0.01; 95% CI − 0.03 to 0.05; p = 0.56) and DLCO (MD, 0.05; 95% CI − 0.17 to 0.28; p = 0.65). Additional use of antimicrobial agents was also associated with an increased risk of AEs (OR 1.65; 95% CI 1.19 to 2.27; p = 0.002), especially gastrointestinal disorders (OR 1.54; 95% CI 1.10 to 2.15; p = 0.001).

Conclusions
In patients with IPF, adding antimicrobial therapy to usual care did not improve mortality or lung function decline but increased gastrointestinal toxicity.
Association between circulating alpha-1 antitrypsin polymers and lung and liver disease
Authors: Núñez Alexa , Belmonte Irene , Miranda Elena , Barrecheguren Miriam , Farago Georgina , Loeb Eduardo , Pons Mònica , Rodríguez-Frías Francisco , Gabriel-Medina Pablo , Rodríguez Esther , Genescà Joan , Miravitlles Marc , Esquinas Cristina 
Published: September 2021

Abstract
Background
Alpha-1 antitrypsin deficiency (AATD) is considered one of the most common genetic diseases and is characterised by the misfolding and polymerisation of the alpha-1 antitrypsin (AAT) protein within hepatocytes. The relevance of circulating polymers (CP) of AAT in the pathogenesis of lung and liver disease is not completely understood. Therefore, the main objective of our study was to determine whether there is an association between the levels of CP of AAT and the severity of lung and liver disease.

Method
This was a cross-sectional study in patients with different phenotypes of AATD and controls. To quantify CP, a sandwich ELISA was performed using the 2C1 monoclonal antibody against AAT polymers. Sociodemographic data, clinical characteristics, and liver and lung parameters were collected.

Results
A cohort of 70 patients was recruited: 32 Pi*ZZ (11 on augmentation therapy); 29 Z-heterozygous; 9 with other genotypes. CP were compared with a control group of 47 individuals (35 Pi*MM and 12 Pi*MS). ZZ patients had the highest concentrations of CP (p < 0.001) followed by Z heterozygous. The control group and patients with Pi*SS and Pi*SI had the lowest CP concentrations. Pi*ZZ also had higher levels of liver stiffness measurements (LSM) than the remaining AATD patients. Among patients with one or two Z alleles, two patients with lung and liver impairment showed the highest concentrations of CP (47.5 µg/mL), followed by those with only liver abnormality (n = 6, CP = 34 µg/mL), only lung (n = 18, CP = 26.5 µg/mL) and no abnormalities (n = 23, CP = 14.3 µg/mL). Differences were highly significant (p = 0.004).

Conclusions
Non-augmented Pi*ZZ and Z-patients with impaired lung function and increased liver stiffness presented higher levels of CP than other clinical phenotypes. Therefore, CP may help to identify patients more at risk of developing lung and liver disease and may provide some insight into the mechanisms of disease.
Patterns of nodal spread in stage III NSCLC: importance of EBUS-TBNA and 18F-FDG PET/CT for radiotherapy target volume definition
Authors: Guberina Maja , Darwiche Kaid , Hautzel Hubertus , Pöttgen Christoph , Guberina Nika , Gauler Thomas , Ploenes Till , Umutlu Lale , Theegarten Dirk , Aigner Clemens , Eberhardt Wilfried E. E. , Metzenmacher Martin , Wiesweg Marcel , Karpf-Wissel Rüdiger , Schuler Martin , Herrmann Ken , Stuschke Martin 
Published: September 2021

Abstract
Purpose
The aim of this study was to compare the pattern of intra-patient spread of lymph-node (LN)-metastases within the mediastinum as assessed by 18F-FDG PET/CT and systematic endobronchial ultrasound-guided transbronchial-needle aspiration (EBUS-TBNA) for precise target volume definition in stage III NSCLC.

Methods
This is a single-center study based on our preceding investigation, including all consecutive patients with initial diagnosis of stage IIIA-C NSCLC, receiving concurrent radiochemotherapy (12/2011–06/2018). Inclusion criteria were curative treatment intent, 18F-FDG PET/CT and EBUS-TBNA prior to start of treatment. The lymphatic drainage was classified into echelon-1 (ipsilateral hilum), echelon-2 (ipsilateral LN-stations 4 and 7) and echelon-3 (rest of the mediastinum, contralateral hilum). The pattern of spread was classified according to all permutations of echelon-1, echelon-2, and echelon-3 EBUS-TBNA findings.

Results
In total, 180 patients were enrolled. Various patterns of LN-spread could be identified. Skip lesions with an involved echelon distal from an uninvolved one were detected in less than 10% of patients by both EBUS-TBNA and PET. The pattern with largest asymmetry was detected in cases with EBUS-TBNA- or PET-positivity at all three echelons (p < 0.0001, exact symmetry test). In a multivariable logistic model for EBUS-positivity at echelon-3, prognostic factors were PET-positivity at echelon-3 (Hazard ratio (HR) = 12.1; 95%-CI: 3.2–46.5), EBUS-TBNA positivity at echelon-2 (HR = 6.7; 95%-CI: 1.31–31.2) and left-sided tumor location (HR = 4.0; 95%-CI: 1.24–13.2). There were significantly less combined ipsilateral upper (LN-stations 2 and 4) and lower (LN-station 7) mediastinal involvements (16.8% of patients) with EBUS-TBNA than with PET (38.9%, p < 0.0001, exact symmetry test). EBUS-TBNA detected a lobe specific heterogeneity between the odds ratios of LN-positivity in the upper versus lower mediastinum (p = 0.0021, Breslow-Day test), while PET did not (p = 0.19).

Conclusion
Frequent patterns of LN-metastatic spread could be defined by EBUS-TBNA and PET and discrepancies in the pattern were seen between both methods. EBUS-TBNA showed more lobe and tumor laterality specific patterns of LN-metastases than PET and skipped lymph node stations were rare. These systematic relations offer the opportunity to further refine multi-parameter risk of LN-involvement models for target volume delineation based on pattern of spread by EBUS-TBNA and PET.
Norm-based comparison of the quality-of-life impact of ravulizumab and eculizumab in paroxysmal nocturnal hemoglobinuria
Authors: Schwartz Carolyn E. , Stark Roland B. , Borowiec Katrina , Nolte Sandra , Myren Karl-Johan 
Published: September 2021

Abstract
Aims
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening intravascular hematologic disorder with significant morbidity and premature mortality. Clinical trials (NCT02946463 and NCT03056040) comparing ravulizumab with eculizumab for PNH have supported the non-inferiority of the former and similar safety and tolerability. This secondary analysis compared PNH trial participants after 26 weeks on either treatment (n = 438) to a general-population sample (GenPop) (n = 15,386) and investigated response-shift effects.

Methods
Multivariate analysis of covariance (MANCOVA) investigated function and symptom scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 of people with PNH as compared to GenPop, after covariate adjustment. Risk-factor groups were created based on clinical indicators known to be associated with worse PNH outcomes, and separate MANCOVAs were computed for lower- and higher-risk-factor groups. Differential item functioning (DIF) analyses examined whether item response varied systematically (1) by treatment, (2) compared to GenPop, and (3) over time, the latter two suggesting and reflecting response-shift effects, respectively. DIF analyses examined 24 items from scales with at least two items. Recalibration response shift was operationalized as uniform DIF over time, reflecting the idea that, for a given group, the difficulty of endorsing an item changes over time, after adjusting for the total subscale score. Reprioritization response shift was operationalized as non-uniform DIF over time, i.e., the relative difficulty of endorsing an item over time changes across the total domain score.

Results
Across PNH risk-factor levels, people who had been on either treatment for 26 weeks reported better-than-expected functioning and lower symptom burden compared to GenPop. Ravulizumab generally showed larger effect sizes. Results were similar for lower and higher PNH risk factors, with slightly stronger effects in the former. DIF analyses revealed no treatment DIF, but did uncover group DIF (9 items with uniform DIF, and 11 with non-uniform) and DIF over time (7 items with uniform DIF, and 3 with non-uniform).

Conclusions
This study revealed that people with PNH on ravulizumab or eculizumab for 26 weeks reported QOL levels better than those of the general population. Significant effects of DIF by group and DIF over time support recalibration and reprioritization response-shift effects. These findings suggest that the treatments enabled adaptive changes.
Mapping the evolving landscape of super-enhancers during cell differentiation
Authors: Kai Yan , Li Bin E. , Zhu Ming , Li Grace Y. , Chen Fei , Han Yingli , Cha Hye Ji , Orkin Stuart H. , Cai Wenqing , Huang Jialiang , Yuan Guo-Cheng 
Published: September 2021

AbstractBackgroundSuper-enhancers are clusters of enhancer elements that play critical roles in the maintenance of cell identity. Current investigations on super-enhancers are centered on the established ones in static cell types. How super-enhancers are established during cell differentiation remains obscure.ResultsHere, by developing an unbiased approach to systematically analyze the evolving landscape of super-enhancers during cell differentiation in multiple lineages, we discover a general trend where super-enhancers emerge through three distinct temporal patterns: conserved, temporally hierarchical, and de novo. The three types of super-enhancers differ further in association patterns in target gene expression, functional enrichment, and 3D chromatin organization, suggesting they may represent distinct structural and functional subtypes. Furthermore, we dissect the enhancer repertoire within temporally hierarchical super-enhancers, and find enhancers that emerge at early and late stages are enriched with distinct transcription factors, suggesting that the temporal order of establishment of elements within super-enhancers may be directed by underlying DNA sequence. CRISPR-mediated deletion of individual enhancers in differentiated cells shows that both the early- and late-emerged enhancers are indispensable for target gene expression, while in undifferentiated cells early enhancers are involved in the regulation of target genes.ConclusionsIn summary, our analysis highlights the heterogeneity of the super-enhancer population and provides new insights to enhancer functions within super-enhancers.
Inter-laboratory comparison of water solubility methods applied to difficult-to-test substances
Authors: Letinski Daniel J. , Redman Aaron D. , Birch Heidi , Mayer Philipp 
Published: September 2021

AbstractWater solubility is perhaps the single most important physical–chemical property determining the environmental fate and effects of organic compounds. Its determination is particularly challenging for compounds with extremely low solubility, frequently referred to as “difficult-to-test” substances and having solubility’s generally less than 0.1 mg/L. The existing regulatory water solubility test for these compounds is the column elution method. Its applicability, however, is limited, to non-volatile solid or crystalline hydrophobic organic compounds. There currently exists no test guideline for measuring the water solubility of very hydrophobic liquid, and potentially volatile, difficult-to-test compounds. This paper describes a “slow-stir” water solubility methodology along with results of a ring trial across five laboratories evaluating the method’s performance. The slow-stir method was applied to n-hexylcyclohexane, a volatile, liquid hydrophobic hydrocarbon. In order to benchmark the inter-laboratory variability associated with the proposed slow-stir method, the five laboratories separately determined the solubility of dodecahydrotriphenylene, a hydrophobic solid compound using the existing column elution guideline. Results across the participating laboratories indicated comparable reproducibility with relative standard deviations (RSD) of 20% or less reported for each test compound – solubility method pair. The inter-laboratory RSD was 16% for n-hexylcyclohexane (mean 14 µg/L, n = 5) using the slow-stir method. For dodecahydrotriphenylene, the inter-laboratory RSD was 20% (mean 2.6 µg/L, n = 4) using the existing column elution method. This study outlines approaches that should be followed and the experimental parameters that have been deemed important for an expanded ring trial of the slow-stir water solubility method.
Accurate numerical scheme for singularly perturbed parabolic delay differential equation
Authors: Woldaregay Mesfin Mekuria , Duressa Gemechis File 
Published: September 2021

AbstractObjectivesNumerical treatment of singularly perturbed parabolic delay differential equation is considered. Solution of the equation exhibits a boundary layer, which makes it difficult for numerical computation. Accurate numerical scheme is proposed using$$\theta$$θ-method in time discretization and non-standard finite difference method in space discretization.ResultStability and uniform convergence of the proposed scheme is investigated. The scheme is uniformly convergent with linear order of convergence before Richardson extrapolation and second order convergent after Richardson extrapolation. Numerical examples are considered to validate the theoretical findings.
Authentication of a novel antibody to zebrafish collagen type XI alpha 1 chain (Col11a1a)
Authors: Reeck Jonathon C. , Hardy Makenna J. , Pu Xinzhu , Keller-Peck Cynthia , Oxford Julia Thom 
Published: September 2021

AbstractObjectiveExtracellular matrix proteins play important roles in embryonic development and antibodies that specifically detect these proteins are essential to understanding their function. The zebrafish embryo is a popular model for vertebrate development but suffers from a dearth of authenticated antibody reagents for research. Here, we describe a novel antibody designed to detect the minor fibrillar collagen chain Col11a1a in zebrafish (AB strain).ResultsThe Col11a1a antibody was raised in rabbit against a peptide comprising a unique sequence within the zebrafish Col11a1a gene product. The antibody was affinity-purified and characterized by ELISA. The antibody is effective for immunoblot and immunohistochemistry applications. Protein bands identified by immunoblot were confirmed by mass spectrometry and sensitivity to collagenase. Col11a1a knockout zebrafish were used to confirm specificity of the antibody. The Col11a1a antibody labeled cartilaginous structures within the developing jaw, consistent with previously characterized Col11a1 antibodies in other species. Col11a1a within formalin-fixed paraffin-embedded zebrafish were recognized by the antibody. The antibodies and the approaches described here will help to address the lack of well-defined antibody reagents in zebrafish research.
Risk factors for invasive aspergillosis in ICU patients with COVID-19: current insights and new key elements
Authors: Montrucchio G. , Lupia T. , Lombardo D. , Stroffolini G. , Corcione S. , De Rosa F. G. , Brazzi L. 
Published: September 2021

AbstractInvasive pulmonary aspergillosis (IPA) has always been a challenging diagnosis and risk factors an important guide to investigate specific population, especially in Intensive Care Unit. Traditionally recognized risk factors for IPA have been haematological diseases or condition associated with severe immunosuppression, lately completed by chronic conditions (such as obstructive pulmonary disease, liver cirrhosis, chronic kidney disease and diabetes), influenza infection and Intensive Care Unit (ICU) admission. Recently, a new association with SARS-CoV2 infection, named COVID-19-associated pulmonary aspergillosis (CAPA), has been reported worldwide, even if its basic epidemiological characteristics have not been completely established yet. In this narrative review, we aimed to explore the potential risk factors for the development of CAPA and to evaluate whether previous host factors or therapeutic approaches used in the treatment of COVID-19 critically ill patients (such as mechanical ventilation, intensive care management, corticosteroids, broad-spectrum antibiotics, immunomodulatory agents) may impact this new diagnostic category. Reviewing all English-language articles published from December 2019 to December 2020, we identified 21 papers describing risk factors, concerning host comorbidities, ICU management, and COVID-19 therapies. Although limited by the quality of the available literature, data seem to confirm the role of previous host risk factors, especially respiratory diseases. However, the attention is shifting from patients’ related risk factors to factors characterizing the hospital and intensive care course, deeply influenced by specific features of COVID treatment itself. Prolonged invasive or non-invasive respiratory support, as well as the impact of corticosteroids and/or immunobiological therapies seem to play a pivotal role. ICU setting related factors, such as environmental factors, isolation conditions, ventilation systems, building renovation works, and temporal spread with respect to pandemic waves, need to be considered. Large, prospective studies based on new risk factors specific for CAPA are warranted to guide surveillance and decision of when and how to treat this particular population.
Accumulation of compatible solutes in rice (Oryza sativa L.) cultivars by inoculation of endophytic plant growth promoting bacteria to alleviate salt stress
Authors: Ahmed Shamim , Heo Tae-Young , Roy Choudhury Aritra , Walitang Denver I. , Choi Jeongyun , Sa Tongmin 
Published: September 2021

AbstractSalinization of agricultural lands, particularly rice paddies, results in the drastic decline of crop yields. Soil salinization impacts the plant physiology by inducing salt stress which may leads to osmotic stress, ionic stress and water-related nutrient imbalance. These imbalances necessitate the need for plants to produce osmolytes including proline and glycine betaine. This study aimed to elucidate the dynamic changes in proline and glycine betaine accumulation modulated by the inoculation of Brevibacterium linens RS16 in salt-sensitive and moderately salt-tolerant rice plants under salt stress conditions. This study showed the interaction of four major factors including rice genotypes with differing tolerance to salt stress, length of exposure to salt stress, level of salt stress and effects of inoculation. Salt stress resulted in significant reduction in plant growth parameters with the salt-sensitive rice genotype (IR29) having a more significant growth reduction. Both the salt-sensitive and salt-tolerant rice genotypes increased in total proline and glycine betaine accumulation at 3 days and 10 days after subjecting under 50 mM and 150 mM salt stress conditions. A significant increase in proline and glycine betaine was observed in the salt-sensitive genotype after 10 days under 50 mM and 150 mM salt stress conditions. Inoculation of the rice genotypes with B. linens RS16 resulted in the improvement of plant growth parameters in both rice genotypes, and total proline and glycine betaine accumulation, especially in IR29. This study showed that proline and glycine betaine are compatible osmolytes of rice under salt stress, and that inoculation of rice genotypes with B. linens RS16 mediated salt tolerance through improvement of plant growth parameters and proline and glycine betaine accumulation in rice plants.