bluuebunny/crossref_metadata_2025 huggingface dataset:
The PDE4 Inhibitor Tanimilast Restrains the Tissue-Damaging Properties of Human Neutrophils
Authors: Schioppa Tiziana , Nguyen Hoang Oanh , Salvi Valentina , Maugeri Norma , Facchinetti Fabrizio , Villetti Gino , Civelli Maurizio , Gaudenzi Carolina , Passari Mauro , Sozio Francesca , Barbazza Ilaria , Tamassia Nicola , Cassatella Marco A. , Del Prete Annalisa , Bosisio Daniela , Tiberio Laura
Published: April 2022

Neutrophils, the most abundant subset of leukocytes in the blood, play a pivotal role in host response against invading pathogens. However, in respiratory diseases, excessive infiltration and activation of neutrophils can lead to tissue damage. Tanimilast-international non-proprietary name of CHF6001—is a novel inhaled phosphodiesterase 4 (PDE4) inhibitor in advanced clinical development for the treatment of chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease where neutrophilic inflammation plays a key pathological role. Human neutrophils from healthy donors were exposed to pro-inflammatory stimuli in the presence or absence of tanimilast and budesonide—a typical inhaled corticosteroid drug-to investigate the modulation of effector functions including adherence to endothelial cells, granule protein exocytosis, release of extracellular DNA traps, cytokine secretion, and cell survival. Tanimilast significantly decreased neutrophil-endothelium adhesion, degranulation, extracellular DNA traps casting, and cytokine secretion. In contrast, it promoted neutrophil survival by decreasing both spontaneous apoptosis and cell death in the presence of pro-survival factors. The present work suggests that tanimilast can alleviate the severe tissue damage caused by massive recruitment and activation of neutrophils in inflammatory diseases such as COPD.
RNAi-Mediated Knockdown of Calreticulin3a Impairs Pollen Tube Growth in Petunia
Authors: Wasąg Piotr , Suwińska Anna , Lenartowska Marta , Lenartowski Robert
Published: April 2022

Pollen tube growth depends on several complex processes, including exo/endocytosis, cell wall biogenesis, intracellular transport, and cell signaling. Our previous results provided evidence that calreticulin (CRT)—a prominent calcium (Ca2+)-buffering molecular chaperone in the endoplasmic reticulum (ER) lumen—is involved in pollen tube formation and function. We previously cloned and characterized the CRT gene belonging to the CRT1/2 subgroup from Petunia hybrida (PhCRT1/2), and found that post-transcriptional silencing of PhCRT1/2 expression strongly impaired pollen tube growth in vitro. Here, we report cloning of a new PhCRT3a homolog; we identified the full-length cDNA sequence and described its molecular characteristics and phylogenetic relationships to other plant CRT3 genes. Using an RNA interference (RNAi) strategy, we found that knockdown of PhCRT3a gene expression caused numerous defects in the morphology and ultrastructure of cultivated pollen tubes, including disorganization of the actin cytoskeleton and loss of cytoplasmic zonation. Elongation of siPhCRT3a pollen tubes was disrupted, and some of them ruptured. Our present data provide the first evidence that PhCRT3a expression is required for normal pollen tube growth. Thus, we discuss relationships between diverse CRT isoforms in several interdependent processes driving the apical growth of the pollen tube, including actomyosin-dependent cytoplasmic streaming, organelle positioning, vesicle trafficking, and cell wall biogenesis.
α-Arrestins and Their Functions: From Yeast to Human Health
Authors: Zbieralski Kacper , Wawrzycka Donata
Published: April 2022

α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary precedence over their extensively studied relatives of the β-arrestin family, α-arrestins have been discovered relatively recently, and thus their properties are mostly unexplored. The predominant function of α-arrestins is the selective identification of membrane proteins for ubiquitination and degradation, which is an important element in maintaining membrane protein homeostasis as well as global cellular metabolisms. Among members of the arrestin clan, only α-arrestins possess PY motifs that allow canonical binding to WW domains of Rsp5/NEDD4 ubiquitin ligases and the subsequent ubiquitination of membrane proteins leading to their vacuolar/lysosomal degradation. The molecular mechanisms of the selective substrate’s targeting, function, and regulation of α-arrestins in response to different stimuli remain incompletely understood. Several functions of α-arrestins in animal models have been recently characterized, including redox homeostasis regulation, innate immune response regulation, and tumor suppression. However, the molecular mechanisms of α-arrestin regulation and substrate interactions are mainly based on observations from the yeast Saccharomyces cerevisiae model. Nonetheless, α-arrestins have been implicated in health disorders such as diabetes, cardiovascular diseases, neurodegenerative disorders, and tumor progression, placing them in the group of potential therapeutic targets.
Low Concentration of the Neutrophil Proteases Cathepsin G, Cathepsin B, Proteinase-3 and Metalloproteinase-9 Induce Biofilm Formation in Non-Biofilm-Forming Staphylococcus epidermidis Isolates
Authors: Gómez-Alonso Itzia S. , Martínez-García Sergio , Betanzos-Cabrera Gabriel , Juárez Esmeralda , Sarabia-León María C. , Herrera María Teresa , Gómez-Chávez Fernando , Sanchez-Torres Luvia , Rodríguez-Martínez Sandra , Cancino-Diaz Mario E. , Cancino Jorge , Cancino-Diaz Juan C.
Published: April 2022

Neutrophils play a crucial role in eliminating bacteria that invade the human body; however, cathepsin G can induce biofilm formation in a non-biofilm-forming Staphylococcus epidermidis 1457 strain, suggesting that neutrophil proteases may be involved in biofilm formation. Cathepsin G, cathepsin B, proteinase-3, and metalloproteinase-9 (MMP-9) from neutrophils were tested on the biofilm induction in commensal (skin isolated) and clinical non-biofilm-forming S. epidermidis isolates. From 81 isolates, 53 (74%) were aap+, icaA−, icaD− genotype, and without the capacity of biofilm formation under conditions of 1% glucose, 4% ethanol or 4% NaCl, but these 53 non-biofilm-forming isolates induced biofilm by the use of different neutrophil proteases. Of these, 62.3% induced biofilm with proteinase-3, 15% with cathepsin G, 10% with cathepsin B and 5% with MMP -9, where most of the protease-induced biofilm isolates were commensal strains (skin). In the biofilm formation kinetics analysis, the addition of phenylmethylsulfonyl fluoride (PMSF; a proteinase-3 inhibitor) showed that proteinase-3 participates in the cell aggregation stage of biofilm formation. A biofilm induced with proteinase-3 and DNAse-treated significantly reduced biofilm formation at an early time (initial adhesion stage of biofilm formation) compared to untreated proteinase-3-induced biofilm (p < 0.05). A catheter inoculated with a commensal (skin) non-biofilm-forming S. epidermidis isolate treated with proteinase-3 and another one without the enzyme were inserted into the back of a mouse. After 7 days of incubation period, the catheters were recovered and the number of grown bacteria was quantified, finding a higher amount of adhered proteinase-3-treated bacteria in the catheter than non-proteinase-3-treated bacteria (p < 0.05). Commensal non-biofilm-forming S. epidermidis in the presence of neutrophil cells significantly induced the biofilm formation when multiplicity of infection (MOI) 1:0.01 (neutrophil:bacteria) was used, but the addition of a cocktail of protease inhibitors impeded biofilm formation. A neutrophil:bacteria assay did not induce neutrophil extracellular traps (NETs). Our results suggest that neutrophils, in the presence of commensal non-biofilm-forming S. epidermidis, do not generate NETs formation. The effect of neutrophils is the production of proteases, and proteinase-3 releases bacterial DNA at the initial adhesion, favoring cell aggregation and subsequently leading to biofilm formation.
The Predictive Role of Plasma Biomarkers in the Evolution of Aortopathies Associated with Congenital Heart Malformations
Authors: Făgărășan Amalia , Săsăran Maria Oana
Published: April 2022

Dilatation of the aorta is a constantly evolving condition that can lead to the ultimate life-threatening event, acute aortic dissection. Recent research has tried to identify quantifiable biomarkers, with both diagnostic and prognostic roles in different aortopathies. Most studies have focused on the bicuspid aortic valve, the most frequent congenital heart disease (CHD), and majorly evolved around matrix metalloproteinases (MMPs). Other candidate biomarkers, such as asymmetric dimethylarginine, soluble receptor for advanced glycation end-products or transforming growth factor beta have also gained a lot of attention recently. Most of the aortic anomalies and dilatation-related studies have reported expression variation of tissular biomarkers. The ultimate goal remains, though, the identification of biomarkers among the serum plasma, with the upregulation of circulating MMP-1, MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), asymmetric dimethylarginine (ADMA), soluble receptor for advanced glycation end-products (sRAGE) and transforming growth factor beta (TGF-β) being reported in association to several aortopathies and related complications in recent research. These molecules are apparently quantifiable from the early ages and have been linked to several CHDs and hereditary aortopathies. Pediatric data on the matter is still limited, and further studies are warranted to elucidate the role of plasmatic biomarkers in the long term follow-up of potentially evolving congenital aortopathies.
Multi-Omics Techniques for Soybean Molecular Breeding
Authors: Cao Pan , Zhao Ying , Wu Fengjiao , Xin Dawei , Liu Chunyan , Wu Xiaoxia , Lv Jian , Chen Qingshan , Qi Zhaoming
Published: April 2022

Soybean is a major crop that provides essential protein and oil for food and feed. Since its origin in China over 5000 years ago, soybean has spread throughout the world, becoming the second most important vegetable oil crop and the primary source of plant protein for global consumption. From early domestication and artificial selection through hybridization and ultimately molecular breeding, the history of soybean breeding parallels major advances in plant science throughout the centuries. Now, rapid progress in plant omics is ushering in a new era of precision design breeding, exemplified by the engineering of elite soybean varieties with specific oil compositions to meet various end-use targets. The assembly of soybean reference genomes, made possible by the development of genome sequencing technology and bioinformatics over the past 20 years, was a great step forward in soybean research. It facilitated advances in soybean transcriptomics, proteomics, metabolomics, and phenomics, all of which paved the way for an integrated approach to molecular breeding in soybean. In this review, we summarize the latest progress in omics research, highlight novel findings made possible by omics techniques, note current drawbacks and areas for further research, and suggest that an efficient multi-omics approach may accelerate soybean breeding in the future. This review will be of interest not only to soybean breeders but also to researchers interested in the use of cutting-edge omics technologies for crop research and improvement.
A Multi-Granular Aggregation-Enhanced Knowledge Graph Representation for Recommendation
Authors: Liu Xi , Song Rui , Wang Yuhang , Xu Hao
Published: April 2022

Knowledge graph (KG) helps to improve the accuracy, diversity, and interpretability of a recommender systems. KG has been applied in recommendation systems, exploiting graph neural networks (GNNs), but most existing recommendation models based on GNNs ignore the influence of node types and the loss of information during aggregation. In this paper, we propose a new model, named AMulti-Granular Aggregation-Enhanced Knowledge Graph Representation for Recommendation (MAKR), that relieves the sparsity of the network and overcomes the limitation of information loss of the traditional GNN recommendation model. Specifically, we propose a new graph, named the Improved Collaborative Knowledge Graph (ICKG), that integrates user–item interaction and a knowledge graph into a huge heterogeneous network, divides the nodes in the heterogeneous network into three categories—users, items, and entities, and connects the edges according to the similarity between the users and items so as to enhance the high-order connectivity of the graph. In addition, we used attention mechanisms, the factorization machine (FM), and transformer (Trm) algorithms to aggregate messages from multi-granularity and different types to improve the representation ability of the model. The empirical results of three public benchmarks showed that MAKR outperformed state-of-the-art methods such as Neural FM, RippleNet, and KGAT.
Dynamics of Embankment Slope Stability under Combination of Operating Water Levels and Drawdown Conditions
Authors: Utepov Yelbek Bakhitovich , Aldungarova Aliya Kairatovna , Mkilima Timoth , Pidal Ignacio Menéndez , Tulebekova Assel Serikovna , Zharassov Shyngys Zharassovich , Abisheva Assem Kairatovna
Published: April 2022

This study investigated the potential influence of operating water levels and loading conditions on the slope stability of an embankment dam. Four different operating reservoir levels (normal, reduced, embankment height, and overflow) were considered in the study. Numerical modeling was used to investigate the problem in the case of the Chardara dam within the Syrdarya catchment in Kazakhstan. Based on the drawdown rates and operating conditions, minimum factor of safety values ranging from 0.56 (total failure) to 2.5 were retrieved. Furthermore, a very high correlation was observed between drawdown days, the minimum factor of safety values, the maximum factor of safety values, and pore-water pressures, with correlation coefficients ranging from 0.561 to 0.997 (strong to very strong correlation). On the other hand, the highest negative correlation of 0.997 was observed between the minimum factor of safety values and pore-water pressures. Additionally, based on the results from the analysis of variance, three reservoir operating levels (normal, embankment height, and overflow) resulted in p-values less than 0.05, indicating that the variations in the factor of safety values from the drawdown rates were statistically significant. The findings of this study demonstrated that, not only may the drawdown rate be detrimental to the embankments, but that different operating levels can also affect slope stability in different ways.
Surface Properties and Architectures of Male Moth Trichoid Sensilla Investigated Using Atomic Force Microscopy
Authors: Baker Thomas Charles , Zhou Qiong , Linn Charles E. , Baker James Y. , Tighe Timothy B.
Published: April 2022

The surfaces of trichoid sensilla on male moth antennae have been sculpted over evolutionary time to capture pheromone odorant molecules emitted by the females of their species and transport the molecules in milliseconds into the binding protein milieu of the sensillum lumen. The capture of pheromone molecules likely has been optimized by the topographies and spacings of the numerous ridges and pores on these sensilla. A monolayer of free lipids in the outer epicuticle covers the sensillar surfaces and must also be involved in optimal pheromone odorant capture and transport. Using electro-conductive atomic force microscopy probes, we found that electrical surface potentials of the pores, ridges and flat planar areas between ridges varied in consistent ways, suggesting that there is a heterogeneity in the distribution of surface lipid mixtures amongst these structures that could help facilitate the capture and transport of pheromone molecules down through the pores. We also performed experiments using peak force atomic force microscopy in which we heated the sensilla to determine whether there is a temperature-related change of state of some of the surface lipid exudates such as the prominent domes covering many of the pores. We found that these exudates were unaffected by heating and did not melt or change shape significantly under high heat. Additionally, we measured and compared the topographies of the trichoid sensilla of five species of moths, including the distributions, spacings, heights and diameters of ridges, pores and pore exudates.
Serial T2-Weighted Thoracic and Abdominal Lymphatic Imaging in Fontan Patients—New Insights into Dynamics of Lymphatic Abnormalities after Total Cavopulmonary Connection
Authors: Moosmann Julia , Schroeder Christian , Rompel Oliver , Purbojo Ariawan , Dittrich Sven
Published: April 2022

Lymphatic congestion in single-ventricle patients has been associated with increased morbidity and poor outcomes. Little is known about the dynamics of lymphatic abnormalities over time, on their association with clinical presentation or response to catheter interventions. This retrospective, single-center study describes Fontan patients who underwent at least two magnetic resonance imaging (MRI) studies. T2-weighted lymphatic imaging was used to classify thoracic and abdominal (para-aortic and portal-venous) lymphatic abnormalities. The relationship between lymphatic congestion and hemodynamic changes after cardiac catheter interventions, clinical presentation and MRI data was analyzed. A total of 33 Fontan patients underwent at least two cardiac MRI studies. Twenty-two patients had two, eight had three and three had four lymphatic imaging studies (total of 80 MRIs studies). No significant changes in lymphatic classification between MRI 1 and 2 were observed for thoracic (p = 0.400), para-aortic (0.670) and portal-venous (p = 0.822) abnormalities. No significant correlation between lymphatic classification and hemodynamic changes after intervention or MRI parameters was found. This study illustrates thoracic and abdominal lymphatic abnormalities in serial T2-weighted imaging after Fontan. Fontan patients did not demonstrate significant changes in their lymphatic perfusion, despite clinical or hemodynamic changes. We assume that lymphatic congestion might develop after total cavopulmonary connection (TCPC) and remain relatively stable, despite further intervention targeting hemodynamic parameters.
Alveolar Bone Remodeling with or without Collagen Filling of the Extraction Socket: A High-Resolution X-ray Tomography Animal Study
Authors: Covani Ugo , Giammarinaro Enrica , Panetta Daniele , Salvadori Piero A. , Cosola Saverio , Marconcini Simone
Published: April 2022

The healing process of the tooth extraction socket often leads to significant resorption of the alveolar bone, eventually causing clinical difficulties for future implant-supported rehabilitations. The aim of the present animal study was to evaluate alveolar bone remodeling after tooth extraction in a rabbit model, either with or without the use of a plain collagen plug inside the socket, by means of micro-computed tomography. The study included the micro-tomography analysis of 36 rabbits’ incisor extraction sockets, either left empty or filled with a collagen plug. All animals were euthanized in a staggered manner, in order to address molecular, histologic, and radiographic analyses at different time-points, up to 90 days after surgery. The three-dimensional evaluation was carried out using micro-computed tomography technology on excised bone blocks including the alveolus and the contralateral bone. Both linear and volumetric measures were recorded: the percentage of bone volume change (ΔBV) within the region of interest was considered the primary endpoint of the study. The micro-CT analysis revealed mean volumetric changes of −58.1% ± from baseline to 3 months for the control group, and almost no bone loss for the test group, −4.6%. The sockets treated with the collagen plug showed significantly less dimensional resorption, while the natural-healing group showed an evident collapse of the alveolar bone three months after extraction surgery.
Atrial Function Impairments after Pediatric Cardiac Surgery Evaluated by STE Analysis
Authors: Cantinotti Massimiliano , Marchese Pietro , Scalese Marco , Franchi Eliana , Assanta Nadia , Koestenberger Martin , Pizzuto Alessandra , Pak Vitali , Santoro Giuseppe , Jani Vivek , Kutty Shelby , Giordano Raffaele
Published: April 2022

Background: Applications of atrial speckle tracking echocardiography (STE) strain (ε) analysis in pediatric cardiac surgery have been limited. This study aims to evaluate the feasibility of atrial STE ε analysis and the progression of atrial ε values as a function of post-operative time in children after pediatric cardiac surgery. Methods: 131 children (mean 1.69 ± 2.98; range 0.01–15.16 years) undergoing cardiac surgery were prospectively enrolled. Echocardiographic examinations were performed pre-operatively and at 3 different post-operative intervals: Time 1 (24–36 h), Time 2 (3–5 days), Time 3 (>5 days, before discharging). The right and left atrium longitudinal systolic contractile (Ct), Conduit (Cd), and Reservoir (R) ε were evaluated with a novel atrial specific software with both P- and R-Gating methods. One hundred and thirty-one age-matched normal subjects (mean 1.7 ± 3.2 years) were included as controls. Results: In all, 309 examinations were performed over the post-operative times. For each post-operative interval, all STE atrial ε parameters assessed were significantly lower compared to controls (all p < 0.0001). The lowest atrial ε values were found at Time 1, with only partial recovery thereafter (p from 0.02 to 0.04). All atrial ε values at discharge were decreased compared to the controls (all p < 0.0001). Significant correlations of the atrial ε values with cardio-pulmonary-bypass time, left and right ventricular ε values (p < 0.05), and ejection fraction (p < 0.05) were demonstrated. Conclusions: Atrial ε is highly reduced after surgery with only partial post-operative recovery in the near term. Our study additionally demonstrates that post-surgical atrial and ventricular ε responses correlated with each other.
Analysis of the Classification Systems for Thoracolumbar Fractures in Adults and Their Evolution and Impact on Clinical Management
Authors: Costachescu Bogdan , Popescu Cezar Eugen , Iliescu Bogdan Florin
Published: April 2022

Although they represent a significant chapter of traumatic pathology with a deep medical and social impact, thoracolumbar fractures have proven to be elusive in terms of a definitive classification. The ever-changing concept of the stability of a thoracolumbar injury (from Holdsworth’s two-column concept to Denis’ three-column theory), the meaningful integration of neurological deficit, and a reliable clinical usability have made reaching a universally accepted and reproductible classification almost impossible. The advent of sophisticated imaging techniques and an improved understanding of spine biomechanics led to the development of several classification systems. Each successive system has contributed significantly to the understanding of physiopathological mechanisms and better treatment management. Magerl et al. developed a comprehensive classification system based on progressive morphological damage determined by the following three fundamental forces: compression, distraction, and axial torque. Vaccaro et al. devised the thoracolumbar injury severity score based on the following three independent variables: the morphology of the injury, posterior ligamentous complex (PLC) integrity, and neurological status at the time of injury. However, there are limitations to the classification system, especially when magnetic resonance imaging yields an uncertain status of PLC. The authors review the various classification systems insisting on their practical relevance and caveats and illustrate the advantages and disadvantages of the most widely used systems with relevant cases from their practice.
Inhaled Sedation for Invasively Ventilated COVID-19 Patients: A Systematic Review
Authors: Landoni Giovanni , Belloni Olivia , Russo Giada , Bonaccorso Alessandra , Carà Gianmarco , Jabaudon Matthieu
Published: April 2022

Background: Volatile anesthetics were used as sedative agents in COVID-19 (Coronavirus Disease 2019) invasively ventilated patients for their potentially beneficial pharmacological effects and due to the temporary shortages of intravenous agents during the pandemic crisis. Methods: Online databases (PubMed, EMBASE, The Cochrane Central Register of Controlled Trial) and the “clinicaltrials.gov” website were searched for studies reporting the use of isoflurane, sevoflurane or desflurane. Results: We identified three manuscripts describing the beneficial effects of isoflurane on 41 COVID-19 patients with acute respiratory distress syndrome (ARDS) in Germany (n = 2) and in the USA (n = 1), in terms of reduction in the use of opioids and other sedatives. We also found a case report of two patients with transient nephrogenic diabetes insipidus, which started after 6 and 8 days of sevoflurane sedation. We identified two randomized controlled trials (RCTs; 92 patients overall), two observational studies (238 patients) on the use of volatile anesthetics in COVID-19 patients that were completed but not yet published, and one RCT interrupted for a low recruitment ratio (19 patients) and thus not published. We also identified five ongoing RCTs on the use of inhaled sedation in ARDS, which are also likely to be recruiting COVID-19 patients and which have currently enrolled a total of >1643 patients. Conclusion: Isoflurane was the most frequently used volatile agent in COVID-19 patients and allowed a reduction in the use of other sedative and analgesic drugs. Randomized evidence is building up and will be useful to confirm or challenge these findings.
Assessment of Rib Fracture in Acute Trauma Using Automatic Rib Segmentation and a Curved, Unfolded View of the Ribs: Is There a Saving of Time?
Authors: Pregler Benedikt , Beyer Lukas Philipp , Platz Batista da Silva Natascha , Steer Sebastian , Zeman Florian , Popp Daniel , Stroszczynski Christian , Müller-Wille René
Published: April 2022

Introduction: The fast and accurate diagnosis of rib fractures in polytrauma patients is important to reduce the mortality rate and relieve long-term pain and complications. Aim: To evaluate the diagnostic accuracy and potential time savings using automatic rib segmentation and a curved, unfolded view for the detection of rib fractures in trauma patients. Methods: The multidetector computed tomography raw data of 101 consecutive polytrauma patients (72 men; mean age 45 years, age range 17 to 84 years) admitted to a university hospital were retrospectively post-processed to generate a curved, unfolded view of the rib cage. No manual corrections were performed. Patients with reconstruction errors and movement artifacts were excluded from further analysis. All fractures were identified and classified by the study coordinator using the original data set. Two readers (reader 1 and reader 2) evaluated the original axial sections and the unfolded view, separately. The fracture locations, fracture type, and reading times were recorded. Sensitivity and specificity were calculated on a per-rib basis using a ratio estimator. Cohen’s Kappa was calculated as an index of inter-rater agreement. Results: 26 of 101 patients (25.7%) were excluded from further analysis owing to breathing artifacts (6.9%) or incorrect centerline computation in the unfolded view (18.8%). In total, 107 (5.9%) of 1800 ribs were fractured in 25 (33%) of 75 patients. The unfolded view had a sensitivity/specificity of 81%/100% (reader 1) and 71%/100% (reader 2) compared to 94%/100% (reader 1; p = 0.002/p = 0.754) and 63%/99% (reader 2; p < 0.001/p = 0.002). The sensitivity (reader 1; reader 2) was poor for buckled fractures (31%; 38%), moderate for undislocated fractures (78%; 62%), and good for dislocated fractures (94%; 90%). The assessment of the unfolded view was performed significantly faster than that of the original layers (19.5 ± 9.4 s vs. 68.6 ± 32.4 s by reader 1 (p < 0.001); 24.1 ± 9.5 s vs. 40.2 ± 12.7 s by reader 2 (p < 0.001)). Both readers demonstrated a very high interobserver agreement for the unfolded view (κ = 0.839) but only a moderate agreement for the original view (κ = 0.529). Conclusion: Apart from a relatively high number of incorrect centerline reconstructions, the unfolded view of the rib cage allows a faster diagnosis of dislocated rib fractures.
Acceptability of Human Papilloma Virus Self-Sampling for Cervical Cancer Screening in a Cohort of Patients from Romania (Stage 2)
Authors: Grigore Mihaela , Vasilache Ingrid-Andrada , Cianga Petru , Constantinescu Daniela , Duma Odetta , Matasariu Roxana Daniela , Scripcariu Ioana-Sadiye
Published: April 2022

(1) Background: Low patient’s adherence to conventional cervical cancer screening methods determined the need to take into consideration alternative approaches, and vaginal HPV self-sampling is one of them. We aimed to evaluate, using an online survey, the Romanian women’s acceptability of vaginal HPV self-sampling. (2) Methods: A 13-questions online survey was distributed on three Facebook groups, and the results were summarized. (3) Results: Despite of good educational background, 10.8% (n = 60) of the respondents did not know what a Pap smear is, and 33% (n = 183) were not informed about the free national cervical cancer screening program. Multivariate analysis revealed an increased likelihood of vaginal self-sampling acceptance among respondents who did not know about Pap test (OR: 7.80; 95%CI: 1.062–57.431; p = 0.021), national cervical cancer screening program (OR: 1.96; 95%CI: 1.010–3.806; p = 0.02), HPV infection (OR: 7.35; 95%CI: 3.099–17.449; p< 0.001) or HPV test (OR: 1.67; 95%CI: 0.950–2.948; p = 0.03). Moreover, women who did not previously undergo a cervical cancer screening program were more likely to accept the new screening method (OR: 1.62; 95%CI: 0.878–3.015; p = 0.04). (4) Conclusions: Our results showed high acceptability rates of vaginal HPV self-sampling among participants.
Non-Invasive Ventilation as a Therapy Option for Acute Exacerbations of Chronic Obstructive Pulmonary Disease and Acute Cardiopulmonary Oedema in Emergency Medical Services
Authors: Schmitt Felix C. F. , Gruneberg Daniel , Schneider Niko R. E. , Fögeling Jan-Ole , Leucht Moritz , Herth Felix , Preusch Michael R. , Schmidt Werner , Bopp Christian , Bruckner Thomas , Weigand Markus A. , Hofer Stefan , Popp Erik
Published: April 2022

In this observational prospective multicenter study conducted between October 2016 and October 2018, we tested the hypothesis that the use of prehospital non-invasive ventilation (phNIV) to treat patients with acute respiratory insufficiency (ARI) caused by severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and acute cardiopulmonary oedema (ACPE) is effective, time-efficient and safe. The data were collected at four different physician response units and three admitting hospitals in a German EMS system. Patients with respiratory failure due to acute exacerbation of chronic obstructive pulmonary disease and acute cardiopulmonary oedema were enrolled. A total of 545 patients were eligible for the final analysis. Patients were treated with oxygen supplementation, non-invasive ventilation or invasive mechanical ventilation. The primary outcomes were defined as changes in the clinical parameters and the in-hospital course. The secondary outcomes included time efficiency, peri-interventional complications, treatment failure rate, and side-effects. Oxygenation under phNIV improved equally to endotracheal intubation (ETI), and more effectively in comparison to standard oxygen therapy (SOT) (paO2 SOT vs. non-invasive ventilation (NIV) vs. ETI: 82 mmHg vs. 125 mmHg vs. 135 mmHg, p-value SOT vs. NIV < 0.0001). In a matched subgroup analysis phNIV was accompanied by a reduced time of mechanical ventilation (phNIV: 1.8 d vs. ETI: 4.2 d) and a shortened length of stay at the intensive care unit (3.4 d vs. 5.8 d). The data support the hypothesis that the treatment of severe AECOPD/ACPE-induced ARI using prehospital NIV is effective, time efficient and safe. Compared to ETI, a matched comparison supports the hypothesis that prehospital implementation of NIV may provide benefits for an in-hospital course.
Texture Analysis in Diagnosing Skin Pigmented Lesions in Normal and Polarized Light—A Preliminary Report
Authors: Popecki Paweł , Jurczyszyn Kamil , Ziętek Marcin , Kozakiewicz Marcin
Published: April 2022

The differential diagnosis of benign nevi (BN), dysplastic nevi (DN), and melanomas (MM) represents a considerable clinical problem. These lesions are similar in clinical examination but have different prognoses and therapeutic management techniques. A texture analysis (TA) is a mathematical and statistical analysis of pixel patterns of a digital image. This study aims to demonstrate the relationship between the TA of digital images of pigmented lesions under polarized and non-polarized light and their histopathological diagnosis. Ninety pigmented lesions of 76 patients were included in this study. We obtained 166 regions of interest (ROI) images for MM, 166 for DN, and 166 for BN. The pictures were taken under polarized and non-polarized light. Selected image texture features (entropy and difference entropy and long-run emphasis) of ROIs were calculated. Those three equations were used to construct the texture index (TI) and bone index (BI). All of the presented features distinguish melanomas, benign and dysplastic lesions under polarized light very well. In non-polarized images, only the long-run emphasis moment and both indices effectively differentiated nevi from melanomas. TA is an objective method of assessing pigmented lesions and can be used in automatic diagnostic systems.
Self-Reported Practices and Emotions in Prescribing Opioids for Chronic Noncancer Pain: A Cross-Sectional Study of German Physicians
Authors: Schulte Erika , Petzke Frank , Spies Claudia , Denke Claudia , Schäfer Michael , Donner-Banzhoff Norbert , Hertwig Ralph , Wegwarth Odette
Published: April 2022

Background: The pressure on physicians when a patient seeks pain relief and their own desire to be self-effective may lead to the prescription of strong opioids for chronic noncancer pain (CNCP). This study, via physician self-reporting, aims to identify and measure (i) physician adherence to national opioid prescribing guidelines and (ii) physician emotions when a patient seeks a dosage increase of the opioid. Methods: Within a cross-sectional survey—conducted as part of a randomized controlled online intervention trial (ERONA)—600 German physicians were queried on their opioid prescribing behavior (choice and formulation of opioid, indications) for CNCP patients and their emotions to a case vignette describing a patient seeking an opioid dosage increase without signs of objective deterioration. Results: The prescription of strong opioids in this study was not always in accordance with current guidelines. When presented with a scenario in which a patient sought to have their opioid dose increased, some physicians reported negative feelings, such as either pressure (25%), helplessness (25%), anger (23%) or a combination. The risk of non-guideline-compliant prescribing behavior using the example of ultrafast-acting fentanyl for CNCP was increased when negative emotions were present (OR: 1.7; 95%-CI: 1.2–2.6; p = 0.007) or when sublingual buprenorphine was prescribed (OR: 15.4; 95%-CI: 10.1–23.3; p < 0.001). Conclusions: Physicians’ emotional self-awareness represents the first step to identify such direct reactions to patient requests and to ensure a responsible, guideline-based opioid prescription approach for the long-term well-being of the patient.
Special Issue “Managing Dry Eye Disease over Time: An Italian Consensus Conference”
Authors: Aragona Pasquale , Giannaccare Giuseppe , Rolando Maurizio
Published: April 2022

Dry eye disease (DED) is a chronic, progressive, highly prevalent condition affecting 5 to 33% of the global adult population [...]
Comparative Study of S2-Alar-Iliac Screw Trajectories between Males and Females Using Three-Dimensional Computed Tomography Analysis: The True Lateral Angulation of the S2-Alar-Iliac Screw in the Axial Plane
Authors: Funao Haruki , Yamanouchi Kento , Fujita Naruhito , Kado Yukihiro , Kato Shuzo , Otomo Nao , Isogai Norihiro , Sasao Yutaka , Ebata Shigeto , Kitagawa Yuko , Watanabe Kota , Obara Hideaki , Ishii Ken
Published: April 2022

The S2 alar-iliac screw (S2AIS) is commonly used for long spinal fusion as a rigid distal foundation in spinal deformity surgeries, and it is also used in percutaneous sacropelvic fixation for providing an in-line connection to the proximal spinal constructs without using offset connectors. Although the pelvic shape is different between males and females, reports on S2AIS trajectories according to gender have been scarce in the literature. In this paper, S2AIS trajectories are compared between males and females using pelvic three-dimensional computed tomography (3D-CT) in a normal Japanese population. After resetting the caudal angulation in CT-imaging plane manipulation, the angulation of S2AIS was more lateral in the axial plane and more horizontal in the coronal plane in females. Mean distances from the midline to starting points of S2AIS tended to be shorter in females, whereas mean distances from the midline to the posterior superior iliac spine was significantly longer in females. We also found that there were positive correlations between the patients’ height and the maximal lengths of S2AISs, and the patients’ height and minimal areas of S2AIS pathways. Our results are useful not only for conventional open spinal surgery, but also for minimally invasive spine surgery.
The Leading Role of the Immune Microenvironment in Multiple Myeloma: A New Target with a Great Prognostic and Clinical Value
Authors: Desantis Vanessa , Savino Francesco Domenico , Scaringella Antonietta , Potenza Maria Assunta , Nacci Carmela , Frassanito Maria Antonia , Vacca Angelo , Montagnani Monica
Published: April 2022

Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components’ immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune effector cells are silenced and become progressively anergic, thus contributing to explaining the mechanisms of drug resistance in unresponsive and relapsed MM patients. Besides traditional treatments, several new strategies seek to re-establish the immunological balance in the BMME, especially in already-treated MM patients, by targeting key components of the immunoediting process. Immune checkpoints, such as CXCR4, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), PD-1, and CTLA-4, have been identified as common immunotolerance steps for immunotherapy. B-cell maturation antigen (BCMA), expressed on MMPCs, is a target for CAR-T cell therapy, antibody-(Ab) drug conjugates (ADCs), and bispecific mAbs. Approved anti-CD38 (daratumumab, isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) mAbs interfere with immunoediting pathways. New experimental drugs currently being evaluated (CD137 blockers, MSC-derived microvesicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R blockers) or already approved (denosumab and bisphosphonates) may help slow down immune escape and disease progression. Thus, the identification of deregulated mechanisms may identify novel immunotherapeutic approaches to improve MM patients’ outcomes.
Determinants of Higher Mortality at Six Months in Patients with Hip Fracture: A Retrospective Study
Authors: González-Marcos Enrique , González-García Enrique , Rodríguez-Fernández Paula , Sánchez-González Esteban , González-Bernal Jerónimo J. , González-Santos Josefa
Published: April 2022

(1) Background: Hip fracture is a pathology with high mortality, but the lack of a universal adaptation of the factors associated with death makes it difficult to predict risk and implement prevention in this group. This study aimed to identify the factors that determine a higher mortality at six months following hip fracture. (2) Methods: A retrospective longitudinal study, whose study population consisted of patients over 65 years of age. The main variable was mortality at 6 months of fracture. Relevant data related to sociodemographic and clinical variables for subsequent bivariate (χ2) and multivariate analysis were obtained. (3) Results: In all, 665 people participated in the study, 128 of whom died within 6 months of the fracture. The multivariate adjusted analysis demonstrated significant relationships between the main variable and aspects such as institutionalization at discharge (Odds Ratio (OR) = 2.501), a worse overall functional capacity (OR = 2.453) and cognitive capacity (OR = 3.040) at admission, and complications such as heart failure (OR = 5.767) or respiratory infection (OR = 5.308), in addition to the taking of certain drugs and the presence of a greater number of comorbidities. (4) Conclusions: There are certain factors related to higher mortality at six months in patients with hip fracture who are aged 65 years or older.
Methylene Blue Reduces Fluid Loading and Norepinephrine Requirements for Post-Resuscitation Syndrome in a Pig Model of Refractory Cardiac Arrest Resuscitated with Veno-Arterial ECMO
Authors: Pequignot Benjamin , Lescroart Mickael , Orlowski Sophie , Reynette Nathan , Martini Bana , Albuisson Eliane , Pina Héloise , Tran N’Guyen , Grandmougin Daniel , Levy Bruno
Published: April 2022

Background: Refractory cardiac arrest management relies on extracorporeal cardiopulmonary resuscitation (ECPR), requiring the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Circulatory flow recovery can be associated with an ischemia–reperfusion injury, leading to vasoplegia and vasopressor requirement. The aim of this work was to evaluate the impact on hemodynamics of a methylene blue bolus infusion in a porcine model of ischemic refractory cardiac arrest. Methods: Ischemic refractory cardiac arrest was induced in 20 pigs. After a low flow period of 30 min, VA-ECMO was initiated and the pigs were randomly assigned to the standard care group (norepinephrine + crystalloids) or methylene blue group (IV 2 mg·kg−1 bolus of methylene blue over 30 min + norepinephrine and crystalloids). Macrocirculatory parameters and lactate clearance were measured. Sublingual microcirculation was evaluated with sidestream dark field (SDF) imaging. The severity of the ischemic digestive lesions was assessed according to the histologic Chiu/Park scale. Results: Eighteen pigs were included. The total crystalloid load (5000 (6000–8000) mL vs. 17,000 (10,000–19,000) mL, p = 0.007, methylene blue vs. standard care group) and catecholamine requirements (0.31 (0.14–0.44) μg·kg−1·min−1 vs. 2.32 (1.17–5.55) μg·kg−1·min−1, methylene blue vs. standard care group, p = 0.004) were significantly reduced in the methylene blue group. There were no significant between-group differences in lactate clearance, sublingual capillary microvascular parameters assessed by SDF or histologic Chiu/Park scale. Conclusions: In our refractory cardiac arrest porcine model treated with ECPR, methylene blue markedly reduced fluid loading and norepinephrine requirements in comparison to standard care during the first 6 h of VA-ECMO.
Is Poor Lithium Response in Individuals with Bipolar Disorder Associated with Increased Degradation of Tryptophan along the Kynurenine Pathway? Results of an Exploratory Study
Authors: Fellendorf Frederike T. , Manchia Mirko , Squassina Alessio , Pisanu Claudia , Dall’Acqua Stefano , Sut Stefania , Nasini Sofia , Congiu Donatella , Reininghaus Eva Z. , Garzilli Mario , Guiso Beatrice , Suprani Federico , Paribello Pasquale , Pulcinelli Vittoria , Iaselli Maria Novella , Pinna Ilaria , Somaini Giulia , Arru Laura , Corrias Carolina , Pinna Federica , Carpiniello Bernardo , Comai Stefano
Published: April 2022

Bipolar disorder is associated with an inflammation-triggered elevated catabolism of tryptophan to the kynurenine pathway, which impacts psychiatric symptoms and outcomes. The data indicate that lithium exerts anti-inflammatory effects by inhibiting indoleamine-2,3-dioxygenase (IDO)-1 activity. This exploratory study aimed to investigate the tryptophan catabolism in individuals with bipolar disorder (n = 48) compared to healthy controls (n = 48), and the associations with the response to mood stabilizers such as lithium, valproate, or lamotrigine rated with the Retrospective Assessment of the Lithium Response Phenotype Scale (or the Alda scale). The results demonstrate an association of a poorer response to lithium with higher levels of kynurenine, kynurenine/tryptophan ratio as a proxy for IDO-1 activity, as well as quinolinic acid, which, overall, indicates a pro-inflammatory state with a higher degradation of tryptophan towards the neurotoxic branch. The treatment response to valproate and lamotrigine was not associated with the levels of the tryptophan metabolites. These findings support the anti-inflammatory properties of lithium. Furthermore, since quinolinic acid has neurotoxic features via the glutamatergic pathway, they also strengthen the assumption that the clinical drug response might be associated with biochemical processes. The relationship between the lithium response and the measurements of the tryptophan to the kynurenine pathway is of clinical relevance and may potentially bring advantages towards a personalized medicine approach to bipolar disorder that allows for the selection of the most effective mood-stabilizing drug.
Clinical Evaluation of the Efficacy and Tolerability of Rigenase® and Polyhexanide (Fitostimoline® Plus) vs. Hyaluronic Acid and Silver Sulfadiazine (Connettivina® Bio Plus) for the Treatment of Acute Skin Wounds: A Randomized Trial
Authors: Russo Raffaele , Carrizzo Albino , Barbato Alfonso , Rasile Barbara Rosa , Pentangelo Paola , Ceccaroni Alessandra , Marra Caterina , Alfano Carmine , Losco Luigi
Published: April 2022

Objectives: Compare the efficacy and tolerability of Connettivina® Bio Plus (Group A) gauze and cream, and Fitostimoline® Plus (Group B) gauze and cream for the treatment of acute superficial skin lesions. Design: Single-center, parallel, randomized trial. A block randomization method was used. Setting: University of Salerno—AOU San Giovanni di Dio e Ruggi d’Aragona. Participants: Sixty patients were enrolled. All patients fulfilled the study requirements. Intervention: One application of the study drugs every 24 h, and a six-week observation period. Main outcome measures: Efficacy and tolerability of the study drugs. Results: In total, 60 patients (Group A, n = 30; Group B, n = 30) were randomized; mean age was 58.5 ± 15.8 years. All patients were included in the outcome analysis. Total wound healing was achieved in 17 patients undergoing treatment with Connettivina® Bio Plus and 28 patients undergoing treatment with Fitostimoline® Plus. The greater effectiveness of the latter was significant (p = 0.00104). In Group B, a significantly greater degree of effectiveness was observed in reducing the fibrin in the wound bed (p = 0.04746). Complications or unexpected events were not observed. Conclusions: Both Connettivina® Bio Plus and Fitostimoline® Plus are secure and effective for treating acute superficial skin lesions. Fitostimoline® Plus was more effective than Connettivina® Bio Plus in wound healing of acute superficial skin lesions, especially if fibrin had been observed in the wound bed.